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CAS No. : | 769-39-1 | MDL No. : | MFCD00002157 |
Formula : | C6H2F4O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PBYIIRLNRCVTMQ-UHFFFAOYSA-N |
M.W : | 166.07 | Pubchem ID : | 69858 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 28.3 |
TPSA : | 20.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.84 cm/s |
Log Po/w (iLOGP) : | 1.47 |
Log Po/w (XLOGP3) : | 2.07 |
Log Po/w (WLOGP) : | 3.63 |
Log Po/w (MLOGP) : | 3.21 |
Log Po/w (SILICOS-IT) : | 3.08 |
Consensus Log Po/w : | 2.69 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.58 |
Solubility : | 0.439 mg/ml ; 0.00265 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.12 |
Solubility : | 1.25 mg/ml ; 0.00752 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.93 |
Solubility : | 0.195 mg/ml ; 0.00117 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.26 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
16% | With sodium hydride In N,N-dimethyl-formamide at 50℃; for 1.5 h; | Chalcone 1d, 1.0 g (3.4 mmol), was added to a solution of 0.64 g (6.7 mmol) of guanidine hydrochloride and 0.32 g (13.4 mmol) of sodium hydride in 10 mL of DMF. The mixture was stirred for 1.5 h at 50°C, cooled, poured onto ice, and treated with ethyl acetate. The undissolved material at the phase boundary was filtered off. We thus isolated 0.1 g (16percent) of 2-amino-6-phenyl-5,6-dihydropyrimidin-4(1H)-one (7a) which was identical to a sample described in [19] in 1H NMR data and melting point (mp 255–257°C; 257.3°C [19]). The extract was washed with water and dried over CaCl2, the solvent was removed under reduced pressure ona rotary evaporator, and the residue, 0.29 g, was analyzed by NMR and GC/MS. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | 10111] 10.1 g of2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (61.4 mmol) was taken up in 22 mE fuming sulphuric acid (30% S03) and stirred at ambient temperature for 18 h before pouring the mixture into 200 mE iced brine. The product was precipitated by adding 6 g of NaC1 and stirred until no thrther precipitate was formed. This mixture was filtered through a sintered glass disc and the collected solids were taken up in 330 mE boiling acetonitril, filtered while hot, and allowed to cool slowly to ambient temperature. The colourless crystalline product was collected by filtration and dried in vacuum yielding 5.42 g (20.2 mmol, 33% yield) of 4-sulfo-tetrafluoro phenol sodium salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | boron trifluoride diethyl etherate;Heating / reflux; | Using a known procedure [Nucleic Acids Res 1993, 21, 145], a mixture of 2,3, 5,6- TETRAFLUOROPHENOL (55.2 g, 0.33 MOL), trifluoroacetic anhydride (60 ML, 0.42 mol) and boron TRIFLUORIDE etherate (0.5 ML) was REFLUXED for 16 hr. TRIILUOROACETIC anhydride and trifluoroacetic acid were removed by distillation at atmospheric pressure. The trifluoroacetic anhydride fiaction (bp 40C) was returned to the reaction mixture along with 0. 5 ML of boron trifluoride etherate, and the MIXTURE WAS REFLUXED for 24 hr. This process was repeated two times to ensure complete reaction. After distillation at atmospheric pressure, the desired product was collected at 62C/45 mm (45C/18 mm) as a colorless liquid : yield: 81.3 (93%); d = 1.52 g/mL; IR (CHCI3) 3010,1815, 1525,1485, 1235, TL80, and 955 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2 % Chromat. | With 2-iodoxybenzoic acid amide resin; tetraethylammonium bromide In dichloromethane at 20℃; for 0.5h; | |
With bromine; trifluoroacetic acid at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | Part E: (3S,4RS)-3-[(N-Benzyloxycarbonyl)Alaninyl]Amino-5-(2?,3?,5?,6?-Tetrafluorophenoxy)-4-Oxopentanoic Acid tert-Butyl Ester (0161) To a solution of (3S)-3-[(N-benzyloxycarbonyl)alaninyl]amino-5-bromo-4-oxopentanoic acid tert-butyl ester (0.167 g, 0.355 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.071 g, 0.426 mmol) in N,N-dimethylformamide (2 mL) at room temperature under nitrogen was added potassium fluoride (0.082 g, 1.42 mmol). After stirring at room temperature for 4 hrs, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride solutions, dried over anhydrous sodium sulfate and evaporated to dryness. The crude material (0.144 g) was taken on to the next step without purification. | |
With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere; | To a solution of (3 S)-3 -[(N-benzyloxycarbonyl)alaninyl]amino-5-bromo-4-oxopentanoic acid tert-butyl ester (0.167 g, 0.355 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.071 g,0.426 mmol) in N,N-dimethylformamide (2 mL) at room temperature under nitrogen was addedpotassium fluoride (0.082 g, 1.42 mmol). After stirring at room temperature for 4 hrs, the mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride solutions, dried over anhydrous sodium sulfate and evaporated to dryness. The crude material (0.144 g) was taken on to the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 2h; | To a stirring quantity of 150 mL of DMF at room temperature, added 25 g (150 mmol, 1 eq) of the <strong>[769-39-1]tetrafluorophenol</strong>. Subsequently added 35 mL (250 mmol, 1.7 eq) of the bromohexane and followed it by the addition of 28 g (250 mmol, 1.7 eq) of the base. Put in 80 C. bath. After 2 hours of reaction, TLC (1Hex: 1DCM, Rf=0.9) indicated completion of reaction. Poured reaction over 1 L of water. Extracted with 700 mL of ether. Collected organic layer and rotovaped. Performed column chromatography using 9Hex: 1DCM to elute the product. 34.83 g of a transparent liquid was obtained. Yield was 92%. 1H-NMR (TCE): delta 0.88 (3H, t), 1.30 (4H, m), 1.43 (2H, m), 1.74 (2H, m), 4.19 (2H, t), 6.79 (1H, m). |
With tetrabutylammomium bromide; potassium carbonate; In butanone; for 4h;Heating / reflux; | First StepTo 20.0 g of 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (1) dissolved in 100 mL of MEK there were added 18.3 g of potassium carbonate, 4.26 g of TBAB and 21.9 g of bromohexane dissolved in 50 mL of MEK, with heating under reflux for 4 hours. After cooling and addition of water, the organic layer was separated and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. The solvent was evaporated to yield 27.5 g (110 mmol) of 4-hexyloxy-2,3,5,6-tetrafluorobenzene (4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: NaNO2; aq. HCl / 0 °C 1.2: 50 percent / aq. NaOH / 1 h / 20 °C 2.1: 73 percent / sodium dithionite / aq. ethanol / 1 h / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | potassium fluoride; In DMF (N,N-dimethyl-formamide); at 20℃; for 18h; | Potassium fluoride (2.8 g), was added portionwise to a stirred solution of (S)-3- benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert- butyl ester (18.6 g) and 2,3, 5,6-<strong>[769-39-1]tetrafluorophenol</strong> (9.3 g) in anhydrous DMF (250 mL) under nitrogen at room temperature. The mixture was then stirred for 18 hours before being quenched with ethyl acetate and water. The organic layer was removed and washed with sodium bicarbonate solution, dried (magnesium sulfate) and concentrated to give the sub-title product as an off- white solid (21. 1 g, 96%) ; 1H NMR (400 MHz, CDC13) 8 1.43 (9H, S), 2.76 (1H, dd), 3.06 (1H, dd), 4.67-4. 71 (1H, m), 5.12 (1H, d), 5.22 (1H, d), 5.86 (1H, d), 7.35-7. 38 (5H, m) ; 19F NMR (376 MHz, CDC13) (proton decoupled) 8-139. 98, - 140. 00, -140.04,-140. 06, -157. 05,-157. 07,-157. 11, - 157. 13; MS ES (+) 486. 23 (M+H). |
96% | Potassium fluoride (2.8 g) was added portionwise to a stirred solution of (S)-3- benzyloxycarbonylamino-5-bromo-4-oxo-pentanoic acid tert- butyl ester (18.6 g) and 2,3, 5,6-<strong>[769-39-1]tetrafluorophenol</strong> (9.3 g) in anhydrous DMF (250 mL) under nitrogen at room temperature. The mixture was then stirred for 18 hours before being quenched with ethyl acetate and water. The organic layer was removed and washed with sodium bicarbonate solution, dried (magnesium sulfate) and concentrated to give the sub-title product as an off- white solid (21.1 g, [96%). 1H NMR] (400 MHz, [CDC13)] 6 1.43 (9H, [S),] 2.76 [(1H,] [DD),] 3.06 [(1H,] dd), 4.67-4. 71 [(1H,] m), 5.12 [(1H,] d), 5. 22 [(1H,] d), 5.86 [(1H,] d), 7.35-7. 38 (5H, m) ppm; [19F] NMR (376 MHz, [CDC13)] (proton decoupled) [8-] 139.98,-140. 00, -140.04,-140. 06, -157.05,-157. 07, - 157.11,-157. 13; MS ES (+) 486.23 (M+H). | |
82% | With sodium hydrogencarbonate; potassium iodide; In N,N-dimethyl-formamide; at 0℃; for 17h;Inert atmosphere; | To a sulution of (S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-5-bromo-4-oxopentanoate (27.00 g, 67.46 mmol, 1.00eq) in DMF (200.00 mL) were added 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (13.44 g, 80.95 mmol, 1.20eq), NaHCO3(11.33 g, 134.91 mmol, 5.25 mL, 2.00eq) and KI (1.12 g, 6.75 mmol, 0.10eq) under N2. The mixture was stirred at 0 C for 17 h. Water (600 mL) was added to the reaction mixture. The resulting solution was extracted with EtOAc (600 mL * 3). The combined organic phase was washed with brine (600 mL), water (600 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (Eluent Petroleum ether : EtOAc = 1 : 0 ~ 1: 1). Compound(S)-tert-butyl 3-(((benzyloxy)carbonyl)amino)-4-oxo-5-(2,3,5,6-tetrafluoro phenoxy)pentanoate (11)(26.70 g, 55.00 mmol, 82% yield) was obtained as a white solid.LCMS (ESI)m/z: Calcd. for C23H23F4NO6[M]: 485.2, found:508.2[M + Na]+. The product was analyzed by SFC(Chiralpak AD-3, 3 um, 150×4.6 mm I.D.Mobile phase: A for SFC CO2and B forethanol (0.05% DEA);Gradient: B in A from 5% to 40% in 5 minutesand hold 40% for 2.5minutes, then 5% of B for 2.5 minutes;Flow rate: 2.5 mL/min;Wavelength: 220 nm), ee % = 94 %, RT (retention time) = 3.08 min (major), 2.74 min (minor). |
56% | With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 15h;Inert atmosphere; | Compounds 1-j (25.00 g, 62.46 mmol, 1.00 eq) and 1-k (12.45 g, 74.95 mmol, 1.20 eq) were dissolved in DMF (350.00 mL), and KF (14.52 g, 249.84 mmol, 5.85 mL, 4.00 eq) was added thereto under the protection of nitrogen gas. The reaction was stirred at 20C for 15 hours. After the reaction was completed, it was added with 500 mL of ethyl acetate, and washed successively with saturated sodium hydrogen carbonate solution (350 mL), water (350 mL) and saturated brine (350 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give a crude product. The crude product was purified by column chromatography (petroleum ether : ethyl acetate = 1:0?3:1) to give compound 1-l (18.00 g, yield: 56%). |
56% | With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 15h;Inert atmosphere; | Compound A-3 (25.00 g, 62.46 mmol, 1.00 eq)And A-4 (12.45 g, 74.95 mmol, 1.20 eq) was dissolved in DMF (350.00 mL).KF (14.52 g, 249.84 mmol, 5.85 mL, 4.00 eq) was added under nitrogen.The reaction was stirred at 20 C for 15 hours.After the reaction was completed, 500 mL of ethyl acetate was added and washed with saturated sodium hydrogen carbonate (350 mL), water (350 mL) and brine (350 mL).The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude crystals.Purification afforded Compound A-5 (18.00 g, yield: 56%). |
56% | With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 15h;Inert atmosphere; | Compound A-3 (25.00 g, 62.46 mmol, 1.00 eq) and A-4 (12.45 g, 74.95 mmol, 1.20 eq) were dissolved in DMF(350.00 mL). KF (14.52 g, 249.84 mmol, 5.85 mL, 4.00 eq) was added thereto under the protection of nitrogen, and thenthe reaction was stirred at 20C for 15 hours. After the reaction was completed, 500 mL of ethyl acetate was addedthereto, and it was washed with saturated sodium bicarbonate solution (350 mL), water (350 mL) and saturated saline(350 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated to give crude product, whichwas purified by column chromatography (petroleum ether: ethyl acetate = 1:0-3:1) to give compound A-5 (18.00 g, yield:56%). |
42% | With potassium fluoride; In DMF (N,N-dimethyl-formamide); for 12h; | 2,3, 5, 6-<strong>[769-39-1]tetrafluorophenol</strong> (150 mg, 0.90 mmol, 1.05 eq. ) and KF (100 mg, 1.78 mmol, 2 eq. ) in DMF (3 mL) were added to a dry round bottom flask equipped with a magnetic stir bar. Composition 11 (353 mg, 0.88 mmol) was added to the solution and the reaction was stirred overnight (12 h). Saturated [NAHCO3] solution (-50 mL) was added to the completed reaction and the aqueous layer extracted with EtOAc (2 x 50 mL). The organic layers were combined and washed with saturated brine solution (50 mL), dried over [NA2S04] and concentrated in vacuo to give a clear oil. Purification via column chromatography (silica gel, 2: 1 hexanes/EtOAc) yeilded 12 as a sticky off-white solid (186 mg, 0.36 mmol, 42% yield) ESMS: 486.4 (M + [H+),] 509.6 (M + [NA+).] |
With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 2h; | Preparation 2-1); [ 163] (S)-3-Benzyloxycarbonylamino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-penta noic acid tert-butyl ester; [164] To N-benzyloxycarbonyl-beta-t-butylaspartic acid (17.93g, 55.46 mmol) and NMM EPO <DP n="18"/>(6.70 mNo. , 1.10 eq) was added anhydrous tetrahydrofuran (150 mNo. ) under nitrogen gas, which was maintained at -150C. Isobutylchloroformate (7.56 mNo. , 1.05 eq) was added thereto, and reaction mixture was stirred for about 20 min. The mixture was maintained at O0C, during which diazalphanethane-ether solution (synthesized from 2.0 eq l-methyl-3-nitro-l-nitroso-guanidine, 60 mi ) was added, and stirred at O0C for 30 min to give a diazoketone derivative. 30% HBr/ AcCH (22.6 mNo. , 2.0 eq) was added thereto at O0C, and stirred for 30 min. The reaction mixture was extracted with ethyl acetate, washed with water, saturated sodium hydrogen carbonate solution (twice) and aqueous sodium chloride solution, dried (anhydrous Na SO ), and concentrated under reduced2 4 pressure to give a bralphanalphanethylketone derivative (22.2g) in a stoichiometric yield. [165] The brcmcmethylketone derivative (22.2g, 55.45mmol) and2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (11.05g, 1.2eq) were dissolved in dimethylformamide (130 mi ), KF (8.05g, 2.5 eq) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water, saturated sodium hydrogen ca rbonate solution (twice) and aqueous sodium chloride solution, dried (anhydrous Na2SO ), and concentrated under reduced pressure to give42,3,5,6-tetrafluorophenoxymethylketone derivative. This compound was dissolved in methanol (150 mH ), NaBH (4.19g, 2.0 eq) was slowly added thereto at O0C, and the4 mixture was stirred for 1 h. Saturated ammonium acetate solution was added to stop the reaction, and the reaction mixture was distilled under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (200 nil x 2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na SO ), and con-2 4 centrated under reduced pressure. The residue was purified-separated by column chromatography (10-20% ethyl acetate/hexane) to give the title compound (19.6g, Yield 73%). | |
With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 2h; | The bromomethylketone derivative (22.2 g, 55.45 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (11.05 g, 1.2 eq) were dissolved in dimethylformamide (130 ml), KF (8.05 g, 2.5 eq) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water, saturated sodium hydrogen carbonate solution (twice) and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure to give 2,3,5,6-tetrafluorophenoxymethylketone derivative. This compound was dissolved in methanol (150 ml), NaBH4 (4.19 g, 2.0 eq) was slowly added thereto at 0 C., and the mixture was stirred for 1 h. Saturated ammonium acetate solution was added to stop the reaction, and the reaction mixture was distilled under reduced pressure to remove methanol. The residue was extracted with ethyl acetate (200 ml×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure. The residue was purified-separated by column chromatography (10-20% ethyl acetate/hexane) to give the title compound (19.6 g, Yield 73%). | |
With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 2h; | [299] The bromomethylketone derivative (23g, 55.7mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong>(10.2g, l.leq) were dissolved in dimethylformamide (150 D ), KF (8.14g, 2.5eq) was added thereto, and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution (x2) and aqueous sodium chloride solution, dried (anhydrous Na SO ), and concentrated again under reduced pressure to2 4 give 2,3,5,6-tetrafluorophenoxymethylketone derivative. This compound was dissolved in methanol (150 D ) and reacted by slowly adding NaBH 4 (4.24g) (0C-r.t., 2 hours).The reaction was stopped by acetic acid, and distillation under reduced pressure was carried out to remove methanol. The residue was extracted with ethyl acetate (200 D x 2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na 2 SO 4), and concentrated under reduced pressure. The residue was separated-purified by column chromatography (15% ethyl acetate/hexane) to give the title compound (20.2g,74%) in a diastereomeric form. [300] Mass : M+H 488 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With diamide; triphenylphosphine; In tetrahydrofuran; at 20℃; | <strong>[769-39-1]2,3,5,6-Tetrafluorophenol</strong> (556 mg, 3.35 mmol), 2- [3- (4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (1.01 g, 3.10 mmol) and triphenylphosphine (813 mg, 3. 10 mmol) were dissolved in THF (10 mL) and TMAD (533 mg, 3.10 mmol) was added in three portions over 50 min. The reaction mixture was stirred at room temperature overnight. A small amount of a white precipitate was filtered off. The filtrate was evaporated, redissolved in ether and filtered again. The filtrate was washed with 5% NaHCO3 and brine, concentrated in vacuo, and the residue purified by flash chromatography using EtOAc/toluene (3: 7 followed by 1: 4) as eluent. This gave 584 mg (40%) of the title compound as its N-t-BOC derivative. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium fluoride; In N-methyl-acetamide; | Part B (3S,4RS)-3-(N-Benzoxycarbonyl)Amino-5-(2',3',5',6'-Tetrafluorophenoxy)-4-Hydroxypentanoic Acid tert-Butyl Ester To a solution of (3S)-3-(N-benzyloxycarbonyl)amino-5-bromo-4-oxopentanoic acid tert-butyl ester (0.857 g, 2.14 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.410 g, 2.45 mmol) in dimethylformamide (5.0 mL) at room temperature under nitrogen was added potassium fluoride (0.40 g, 6.9 mmol). After stirring at room temperature for 16 hrs, the mixture was diluted with EtOAc, washed with saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a to give the crude tetrafluorophenoxymethyl ketone (1.08 g, 98%) as a yellow, viscous oil. TLC(EtOAc-hexane; 1:1) Rf=0.57. |
98% | With potassium fluoride; In N-methyl-acetamide; | Part B (3S,4RS)-3-(N-Benzyloxycarbonyl)Amino-5-(2',3',5',6'-Tetrafluorophenoxy)-4-Hydroxypentanoic Acid tert-Butyl Ester To a solution of (3S)-3-(N-benzyloxycarbonyl)amino-5-bromo-4-oxopentanoic acid tert-butyl ester (0.857 g, 2.14 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.410 g, 2.45 mmol) in dimethylformamide (5.0 mL) at room temperature under nitrogen was added potassium fluoride (0.40 g, 6.9 mmol). After stirring at room temperature for 16 hrs, the mixture was diluted with EtOAc, washed with saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a to give the crude tetrafluorophenoxymethyl ketone (1.08 g, 98%) as a yellow, viscous oil. TLC(EtOAc-hexane; 1:1) Rf=0.57. |
98% | With potassium fluoride; In N-methyl-acetamide; | Part B (3S,4RS)-3-(N-Benzyloxy carbonyl)Amino-5-(2',3',5',6'-Tetrafluorophenoxy)-4-Hydroxypentanoic Acid tert-Butyl Ester To a solution of (3S)-3-(N-benzyloxycarbonyl)amino-5-bromo-4-oxopentanoic acid tert-butyl ester (0.857 g, 2.14 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.410 g, 2.45 mmol) in dimethylformamide (5.0 mL) at room temperature under nitrogen was added potassium fluoride (0.40 g, 6.9 mmol). After stirring at room temperature for 16 hrs, the mixture was diluted with EtOAc, washed with saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a to give the crude tetrafluorophenoxymethyl ketone (1.08 g, 98%) as a yellow, viscous oil. TLC(EtOAc-hexane; 1:1)Rf=0.57. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium fluoride; In tetrahydrofuran; | Part C (3S)-3-[(N-Benzyloxycarbonyl)Valinyl]Amino-5-(2',3',5',6'-Tetrafluorophenoxy)-4-Oxopentanoic Acid tert-Butyl Ester To a solution of (3S)-3-[(N-benzyloxycarbonyl)valinyl]amino-5-bromo-4-oxopentanoic acid tert-butyl ester (9.71 g, 19.4 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3.65 g, 22 mmol) in tetrahydrofuran (20 mL) at room temperature under nitrogen was added potassium fluoride (2.91 g, 50 mmol). After stirring at room temperature for 4 hrs, the mixture was diluted with EtOAc (approx.100 mL), washed with saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a dryness. The residue was purified by flash chromatography on silica gel eluding with EtOAc-hexane (1:3) to give the title compound (9.19 g, 79%) as a white solid after trituration with Et2O-hexane. TLC(EtOAc-hexane; 1:1) Rf=0.70. |
79% | With potassium fluoride; In tetrahydrofuran; | Part C (3S)-3-[(N-Benzyloxycarbonyl)Valinyl]Amino-5-(2',3',5',6'-Tetrafluorophenoxy)-4-Oxopentanoic Acid tert-Butyl Ester To a solution of (3S)-3-[(N-benzyloxycarbonyl)valinyl]amino-5-bromo-4-oxopentanoic acid tert-butyl ester (9.71 g, 19.4 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3.65 g, 22 mmol) in tetrahydrofuran (20 niL) at room temperature under nitrogen was added potassium fluoride (2.91 g, 50 mmol). After stirring at room temperature for 4 hrs, the mixture was diluted with EtOAc (approx.100 mL), washed with saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to a dryness. The residue was purified by flash chromatography on silica gel eluding with EtOAc-hexane (1:3) to give the title compound (9.19 g, 79%) as a white solid after trituration with Et2O-hexane. TLC(EtOAc-hexane; 1:1) Rf=0.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroborane diethyl ether; trifluoroacetic anhydride; | 2,3,5,6-Tetrafluorophenyl trifluoroacetate A mixture of 2,3,5,6-tetrafluorophenol (55.2 g, 0.33 mol), trifluoroacetic anhydride (60 mL, 0.42 mol) and boron trifluoride etherate (0.5 mL) was refluxed for 16 hr. Trifluoroacetic anhydride and trifluoroacetic acid were removed by distillation at atmospheric pressure. The trifluoroacetic anhydride fraction (bp 40 C.) was returned to the reaction mixture along with 0.5 mL of boron trifluoride etherate, and the mixture was refluxed for 24 hr. This process was repeated two times to ensure complete reaction. After distillation at atmospheric pressure, the desired product was collected at 62 C./45 mm (45 C./18 mm) as a colorless liquid: yield=81.3 g (93%); d=1.52 g/mL; nD21=1.3747; IR (CHCl3) 3010, 1815, 1525, 1485, 1235, 1180, 1110, and 955 cm-1. Anal. Calcd for C8HF7O2: C, 36.66; H, 0.38; F, 50.74. Found: C, 36.31; H, 0.43; 30 F, 50.95. | |
With trifluoroborane diethyl ether; trifluoroacetic anhydride; | 2,3 5,6-Tetrafluorophenyl trifluoroacetate. A mixture of 2,3,5,6-tetrafluorophenol (55.2 g, 0.33 mol), trifluoroacetic anhydride (60 mL, 0.42 mol) and boron trifluoride etherate (0.5 mL) was refluxed for 16 hr. Trifluoroacetic anhydride and trifluoroacetic acid were removed by distillation at atmospheric pressure. The trifluoroacetic anhydride fraction (bp 40 C.) was returned to the reaction mixture along with 0.5 mL of boron trifluoride etherate, and the mixture was refluxed for 24 hr. This process was repeated two times to ensure complete reaction. After distillation at atmospheric pressure, the desired product was collected at 62 C./45 mm (45 C./18 mm) as a colorless liquid: yield=81.3 g (93%); d=1.52 g/mL; nD21 =1.3747; IR (CHCl3) 3010, 1815, 1525, 1485, 1235, 1180, 1110, and 955 cm-1. Anal. Calcd for C8 HF7 O2: C, 36.66; H, 0.38; F, 50.74. Found: C, 36.31; H, 0.43; F, 50.95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; acetonitrile; at 20℃; for 1h; | The biotin-4,7,10-trioxa-1,13-tridecanediamine-diglycolic carboxylate (1.0 g, 1.78 mmol) thus prepared, then was placed in a dry flask and dissolved in anhydrous CH3CN/DMF (75/25 mL). Tetrafluorophenol (2.13 mmol, 0.353 g) was added to the solution followed by 0.41 g (2.13 mmol) of EDC. The reaction mixture was stirred at room temperature for 1 hour (followed by HPLC), and the solvents were removed under vacuum. The residue was extracted with 200 mL chloroform, washed with (2×25 mL) saturated sodium bicarbonate solution, then with (2×50 mL) water. The chloroform solution was dried over anhydrous sodium sulfate and the chloroform removed under vacuum. The product was tritrated in 100 mL ether and was filtered. The filtrate was dried under vacuum to yield 0.8 g (63%) of desired product as a solid. 1HNMR (CDCl3, delta) 1.3-1.8 (m, 10H), 2.1 (t, 2H), 2.7 (d, 1H), 2.8 (dd, 1H), 3.1 (m, 1H), 3.2-3.6 (m, 15H), 3.8 (t, 2H), 4.08 (s, 1H), 4.27 (m, 3H), 4.4 (m, 2H), 5.7 (s, 1H), 6.4 (s, 1H), 6.5 (m, 1H), 7.0 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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73% | In nitrogen; water; acetonitrile; | EXAMPLE 18 2-(2,3,5,6-Tetrafluorophenoxy)-5-nitrobenzonitrile In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.050 moles) of <strong>[16588-02-6]2-chloro-5-nitrobenzonitrile</strong>, 8.55 (0.0515 moles) of 2,3,5,6-tetrafluorophenol, 7.10 g (0.0515 moles) of anhydrous K2 CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of deionized water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from 300 ml of absolute ethanol to give 11.36 g (73% yield) of purified 2-(2,3,5,6-tetrafluorophenoxy)-5-nitrobenzonitrile, mp 152.5-154.5 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Aryloxymethyl ketone azide 61.[0173] Procedure G was followed using bromomethyl ketone 59 (0.48 g, 2.33 mmol), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (1.16 g, 6.99 mmol), and potassium fluoride (0.406 g, 6.99 mmol) in DMF (7.0 mL). The reaction mixture was stirred for 3 h. The crude reaction mixture was purified by silica gel chromatography (Hexanes/Ethyl Acetate = 20/80) to afford 0.38O g (56%) of 61 as a clear oil. General synthesis of 2,3,5,6-tetrafluorophenoxymethyl ketone azides 47c and 61-62 (Procedure G).[0171] To a 0.6 M solution of 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3.0-3.1 equiv) in DMF at 0 0C was added potassium fluoride (3.0 equiv), and the reaction mixture was stirred for 10 min. The appropriate bromomethyl ketone 48, 59, or 60 (1.0 equiv) was then added in a small amount of DMF. The reaction mixture was stirred at 0 0C for 3-7 h. The reaction mixture was <n="69"/>diluted with CH2Cl2 and washed with water (Ix), saturated NaHCO3 (Ix), water (2x), and brine (Ix). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Column chromatography afforded the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 4-(dimethylamino)pyridinium tosylate; diisopropyl-carbodiimide; In dichloromethane; acetonitrile; at 20℃; for 14h; | Example 26 Synthesis ofBiotinylated-(HA)2 Dimer and BMP-2-(HA)2 Dimer [00155] Biotinylated-(HA)2 dimer and BMP-2-(HA)2 dimer were synthesized as set forth below. [00156] Reagents and conditions: (a) Raney-Ni, H2, EtOH, 55 C, 18 h, 99%; (b) Fluorenylmethyl succinimidyl carbonate, DIPEA, DCM, r.t., 24 h, 99%; (c) HCOOH, r.t., 12 h, 94%; (d) 2, 3, 5, 6- Tetrafluorophenol (<strong>[769-39-1]TFP</strong>), DIC, DPTS, CH3CN: DCM(v:v= 1:1), r.t., 14 h, 92%; (e) 38, DIPEA, CHC13, r.t., 7 h, 96%; (f) Diethylamine, DCM, r.t., 3 h, 91%; (g) Succinic anhydride, NEt3, THF, r.t., 5 h, 75%; (h) 34: Wang Resin-LYLTSIASLETPVS SAKPIK-NH2, HOBt, DIC, DMF, r.t., 3 h; 13: Wang Resin-Lys(Biotin)-NH2, HOBt, DIC, DMF, r.t., 3 h; (i) 28.5: 0.75: 0.75 TFA: TIPS: H20 (v:v:v), r.t., 45 min; ) CuS04, Na Ascorbate, 95: 5 lOxPBS: DMSO (v:v), r.t., 48 h. Compounds 16 and 39 were synthesized following procedures set forth in the relevant literature. See e.g., Newkome, G. R.; Behera, R. K.; Moorefield, C. N.; Baker, G. R. J. Org. Chem. 1991, 56, 7162-7167, the disclosure of which is incorporated herein by reference in its entirety. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dicyclohexyl-carbodiimide; In 1,4-dioxane; at 20℃; | 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (Tfp) active ester of 2-trimethylammonium nicotinic acid was synthesised in three steps starting from 6-chloro nicotinic acid (Sigma-Aldrich). Esterification of 6-chloro nicotinic acid (3 g, 19 mmol) with 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3,25 mg, 19 mmol)) activated by dicyclohexyl carbodiimide (DCC) (3,96, 19 mmol) in 50 m L dioxane following crystallization from hexane gave the 6-chloro nicotine acid Tfp ester in 73 % yield. Generation of the trimethylammonium salt by treating the active 6-chloro nicotinic acid tfp-ester (1 g, 3,27 mmol) in a saturated solution of trimethylamine (continuous bubbling for two hours) in tetrahydrofuran (THF) (15 ml_), gave the trimethylammonium salt with chloride as counterion in 45% yield.Unreacted material could be filtered away since the salt precipitates out of the tetrahydrofuran solution. Generation of the triflate salt can be achieved in two ways; either treatment of the corresponding chloride salt with silver triflate in 1 .2 molar excess in acetonitrile or treatment with trimethylsilyl trifluoromethanesulfonate. The latter is the preferred choice as work-up is simpler and no preparative chromatography is needed. Both methods are almost quantitative. The synthesized precursor (9.2mg) was initially labelled with F by means of K222 (1 Omg) and KF (1 .1 mg) in acetonitrile (0.7ml). The reaction of 19F with the Tfp ester was studied using 1 H- NMR in acetonitrile-d6 at 27O to assay reaction kinetics and impurities formed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 23h; | <strong>[769-39-1]2,3,5,6-Tetrafluorophenol</strong> (90 mg, 0.597 mmol), DMAP (7 mg, 0.054 mmol) and Fmoc-Gly-(OH)3 (3) (95 mg, 0.181 mmol) were dissolved in dry DCM (2 mL). Subsequently, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (114 mg, 0.596 mmol) in DCM (1 mL) was added. After stirring for 23 h at room temperature, the reaction mixture was purified by flash chromatography using a gradient of CHCl3 to CHCl3 containing 6% Et2O. Drying of the product in vacuo resulted in the title compound as a white foam (89 mg, 51%). 1H NMR (CDCl3, 400 MHz): delta 7.66 (d, 2H, J = 7.3 Hz); 7.49 (d, 2H, J = 7.3 Hz); 7.30 (t, 2H, J = 7.3 Hz); 7.22 (d, 2H, J = 7.3 Hz); 6.96-6.87 (m, 3H); 6.20 (br s, 1H); 5.38 (br s, 1H); 4.38 (d, 2H J = 6.2 Hz); 4.13 (t, 1H, J = 7.0 Hz); 3.74 (s, 2H); 2.67 (t, 6H, J = 7.5); 2.20 (t, 6H, J = 7.7 Hz). 13C NMR (CDCl3, 50 MHz): delta 167.7; 147.0; 142.2; 139.9; 136.8; 126.4; 125.7; 123.6; 118.6; 101.9; 66.0; 56.2; 45.7; 44.2; 28.4; 26.3. IR (cm-1): nu 3305, 3080, 2910, 1786, 1685, 1524, 1488, 1265, 1178, 1097, 957, 760. MALDI-TOF-MS: calcd C45H30F12N2O9Na+: m/z 993.16; found m/z 993.17. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 48h;Inert atmosphere; | [00133] Step 2. A mixture of 3-(2-benzyloxycarbonylamino-3-methyl- butyrylamino)-5-bromo-4-oxo-pentanoic acid terf-butyl ester (7.18 g, 14.38 mmol; Step 1 ), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (2.87 g, 17.28 mmol) and potassium fluoride (3.34 g, 57.49 mmol) in 30 ml. of DMF was stirred at roomtemperature under N2 for 48 h then partitioned between EtOAc and water. The organic extract was washed with sat. KH2P04 (2x) and sat. NaCI solutions, dried (MgS04), filtered, concentrated and crystallized from diethyl ether to give 3.20 g (38%) of 3-(2-benzyloxycarbonylamino-3-methyl- butyrylamino)-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid ferf-butyl ester (compound 3) as white solid. The ethereal filtrate was concentrated and chromatographed (silica gel. 20% EtOAc in hexanes) to give another 2.96 g (35%) of the titled compound as white solid. MS (APCI) m/z 585 (M+1 , 9%) and 529 (M-55, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 10℃;Inert atmosphere; | A solution of Phth-dPEG4-tris acid (36.6 g, 51.2 mmol) in 220 mL of anhydrous dichloromethane was placed in a 1 L three-neck round bottom flask equipped with a magnetic stirrer, additional funnel, thermocouple, nitrogen balloon, and a cooling ice bath. In a separate 0.5 L three-neck round bottom flask equipped with a magnetic stirrer, thermocouple, and cooling ice bath a slurry of EDC (51.1 g, 267 mmol) in 200 mL of anhydrous dichloromethane was prepared under a nitrogen blanket. A solution of <strong>[769-39-1]TFP</strong> (43.5 g, 262 mmol) in 60 mL of anhydrous dichloromethane was added to the EDC slurry via syringe at 6[deg.] C. with the rate to maintain temperature at about 5-10[deg.] C. The resulting clear solution stirred for an additional 10 min at 5[deg.] C. and then was added drop wise to the pre-chilled solution of Phth-dPEG4-tris-acid in CH2Cl2 at 0[deg.] C. The reaction mixture stirred at 0[deg.] C. for an additional 30 min. The cooling bath was then removed, and the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was monitored by TLC (Rf=0.4 for product while the Phth-dPEG-4-tris acid stays at origin in 50% CH2Cl2-50% EtOAc) or by HPLC. After the starting tris-acid disappeared, the reaction was quenched with cold saturated NH4Cl (3*200 mL) and extracted with dichloromethane (3*20 mL). The combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 79 g of viscous yellow oil. An excess of <strong>[769-39-1]TFP</strong> was removed by precipitation on 105 g of celite from its solution in EtOAc-hexane=1/5 (160 mL) by dropwise addition of 200 mL of hexane. Resulting suspension was filtered, and the cake was washed with hexane-MTBE=5:1 (250 mL) and the filtrate was discarded. The product was washed from celite with CH2Cl2 (5*120 mL), solvent was removed on rotavap to give 55.7 g of very viscous yellow oil with HPLC purity of 97%. This material was further purified by column chromatography on silica gel. Gradient elution with a mixture of dichloromethane with ethyl acetate from 0% to 60% of EtOAc gives 34.14 g (57% yield) of product. An additional 14.2 g were isolated by chromatography from washes from the <strong>[769-39-1]TFP</strong> removal stage resulting in a total recovery 48.3 g (81% yield) of target compound as clear viscous oil. HPLC (3045FF acid method): RT 40.14 min, purity 100%. H NMR (400 MHz, CDCl3, [delta]): 7.85 (m, 2H, phthalimide), 7.72 (m, 2H, phthalimide), 7.01 (m, 3H, <strong>[769-39-1]TFP</strong>), 6.22 (s, 1H, NH), 3.90 (t, 2H, CH2N), 3.87-3.78 (m, 12H, CH2O), 3.74 (t, 2H, CH2CO), 3.70 (t, 2H, CH2O), 3.62-3.55 (m, 10H, CH2O), 2.92 (t, 6H, CH2CO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | A 2.5 L oven dried RBF fitted with nitrogen blanket, cooling bath, and addition funnel was set up for this reaction. The flask was charged with PhthN-12-tris(acid)3 (120.61 g, 113 mmol) and DCM (565 ml) and cooled to 0[deg.] C. <strong>[769-39-1]TFP</strong> (94 g, 565 mmol) and EDC (108 g, 565 mmol) were dissolved in DCM (565 ml) and placed in the addition funnel. The reaction was cooled and the <strong>[769-39-1]TFP</strong>/EDC mixture was added dropwise and the reaction was warmed to room temp and stirred overnight. HPLC (Acid 60 method) indicated complete consumption of sm (TR=6.385) and formation of tri-<strong>[769-39-1]TFP</strong> (TR=18.7). The reaction mixture was diluted with DCM (1.5 L), washed with sat aq NH4Cl (3*500 mL), washed with sat aq NaHCO3 (5*500 mL), again with NH4Cl (500 mL), brine, dried over Na2SO4, filtered over celite, and concentrated under reduced pressure to give 174.7 g of a yellow viscous oil. TLC (60:40 EtOAc:4/1 DCM/EtOH) indicated a single major product, <strong>[769-39-1]TFP</strong>, and some baseline material. HPLC (Acid60 method) indicated a major product with 99% purity. The residue was preabsorbed on to 200 g SiO2 and was purified on an Isco Torrent using a RediSep Rf 750 g column, EtOAc (A), and 4:1 DCM:EtOH (B). The column was equilibrated with EtOAc and a gradient was run with 4CV of 0% B then ramping up to 60% B over 6CV and holding at 60% for 2 CV. The appropriate fractions were spotted on TLC, fractions 1-26 and the carboy were pooled, and concentrated to give 124.3 g of a pale yellow oil. The oil was dissolved in DCM, dried over Na2SO4, filtered over celite, and concentrated under reduced pressure to give 116.1 g (68%) of a pale yellow viscous oil. TLC (40:60 EtOAc:4/1 DCM/EtOH) indicated a single spot with a trace of residual <strong>[769-39-1]TFP</strong> visible near the solvent front. HPLC (Acids5545FF method): RT 32.14 min, purity 100%. H NMR (400 MHz, CDCl3, [delta]): 7.84 (m, 2H), 7.71 (m, 2H), 7.01 (m, 3H), 6.23 (s, 1H), 3.91 (t, 2H), 3.82-3.72 (m, 12H), 3.79-3.55 (m, 50H), 3.74 (t, 2H), 2.92 (t, 6H), 2.4 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 10℃; for 0.583333h;Inert atmosphere; | A solution of HCO2-Glu-NH-dPEG4-tris-(dPEG11-m)3 acid (7.75 g, 3.54 mmol) in 30 mL of anhydrous dichloromethane was placed in a 200 mL three-neck round bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen balloon, and a cooling ice bath. In a separate 50 mL one-neck round bottom flask equipped with a magnetic stirrer, thermocouple, and cooling ice bath a slurry of EDC (1.28 g, 6.69 mmol) in 15 mL of anhydrous dichloromethane was prepared under a nitrogen blanket. A solution of <strong>[769-39-1]TFP</strong> (1.1 g, 6.62 mmol) in 6 mL of anhydrous dichloromethane was added to the EDC slurry via syringe at 6[deg.] C. with the rate to maintain temperature at about 5-10[deg.] C. The resulting clear solution stirred for an additional 5 min at 5[deg.] C. and then was added dropwise via syringe to the solution of the above acid in CH2Cl2 at 0[deg.] C. The reaction mixture stirred at this temperature for an additional 30 min. The cooling bath was then removed, and the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was monitored by TLC (Rf=0.25 for HOCO2-Glu-NH-dPEG4-tris(dPEG11-m)3, and Rf=0.38 for product in 90% CH2Cl2-10% MeOH) or by HPLC. After the starting tris-acid disappeared, the reaction was quenched with cold with 1:1 diluted NaHCO3 (80 mL) containing 10 mL of brine, and extracted with dichloromethane (3*30 mL). The organic phase was washed with cold water (80 mL) containing 10 mL of brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 10.2 g of clear viscous oil with HPLC purity of ~100%. An excess of <strong>[769-39-1]TFP</strong> was removed by precipitation 12 g celite from its solution in EtOAc-MTBE=1:1 (50 mL) by dropwise addition of hexane-MTBE=4:1 mixture (100 mL). Resulting suspension was filtered, and the cake was washed with hexane-MTBE=5:1 (60 mL) and the filtrate was discarded. The product was washed from celite cake with dichloromethane (4*30 mL), and this filtrate was concentrated under reduced pressure until constant weigh to give 7.7 g (93% yield) of viscous clear oil which slowly solidifies into a paraffin-like white solid. HPLC (3045FF acid method): RT 30.32 min, 99%. H NMR (400 MHz, CDCl3, [delta]): 7.01 (m, 1H, <strong>[769-39-1]TFP</strong>), 6.78 (t, 3H, NH), 6.56 (s, 1H, NH), 6.46 (broad t, 1H, NH), 3.86-3.48 (m, 182H, CH2O), 3.49-3.39 (m, 9H, CH2O), 3.37 (s, 9H, CH3O), 2.77 (t, 2H, CH2CO), 2.47-2.38 (m, 8H, CH2CO), 2.34 (t, 2H, CH2CO), 2.10 (quintet, 2H, CH2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 5℃; for 0.416667h;Inert atmosphere; | A solution of Phth-dPEG12-tris-(dPEG12-CO2H)3 acid (2.14 g, 0.747 mmol) in 12 mL of anhydrous dichloromethane was placed in a 50 mL three-neck round bottom flask equipped with a magnetic stirrer, thermocouple, nitrogen balloon, and a cooling ice bath. In a separate 25 mL one-neck round bottom flask equipped with a magnetic stirrer, thermocouple, and cooling ice bath a slurry of EDC (0.805 g, 4.2 mmol) in 15 mL of anhydrous dichloromethane was prepared under a nitrogen atmosphere. A solution of <strong>[769-39-1]TFP</strong> (0.812 g, 4.89 mmol) in 6 mL of anhydrous dichloromethane was added to the EDC slurry via syringe at 5[deg.] C. The resulting clear solution stirred for an additional 5 min at 5[deg.] C. and then was added dropwise via syringe to the solution of the above acid in CH2Cl2 at 0[deg.] C. The reaction mixture stirred at this temperature for an additional 20 min. The cooling bath was then removed, and the reaction was allowed to warm to ambient temperature and stirred overnight. The reaction was monitored by TLC (Rf=0.07, tailing from the origin for Phth-dPEG12-tris(dPEG12-CO2)3, and Rf=0.43 for product, in 90% CH2Cl2-10% MeOH) or by HPLC. After the starting tris-acid disappeared, the reaction was quenched with cold with 1:1 diluted NaHCO3 (50 mL) containing 10 mL of brine, and extracted with dichloromethane (3*50 mL). The organic phase was washed with cold water (80 mL) containing 10 mL of brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3.04 g of clear yellowish oil. This crude material was purified by column chromatography on silica gel. Gradient elution with a mixture of dichloromethane-isopropyl alcohol from 0 to 30% IPA gives 1.85 g of product as yellowish oil. It further was re-dissolved in 15 mL of EtOAc, slowly diluted with MTBE-hexane=2:1 (30 mL) and precipitated from this solution on 4 g of celite with 50 mL of hexane. Resulting slurry stirred for 20 min, filtered, celite cake washed with MTBE-hexane-1:1 (3*25 mL) and filtrates were discarded. The product was washed from celite with dichloromethane (3*80 mL), and this filtrate was concentrated under reduced pressure to constant weight to give 1.76 g (71% yield) of target <strong>[769-39-1]TFP</strong>-ester. This material slowly crystallizes to off-white solid. HPLC (3045FF acid method): RT 38.72 min, purity 96.3%. H NMR (400 MHz, CDCl3, [delta]): 7.84 (m, 2H, phthimide), and 7.72 (m, 2H, phthalimide), 7.0 (m, 3H, <strong>[769-39-1]TFP</strong>), 6.78 (t, 3H, NH), 6.56 (s, 1H, NH), 3.91-3.85 (m, 8H, CH2O), 3.81-3.52 (m, 206H, CH2O), 3.45-3.39 (m, 7H, CH2O), 2.95 (t, 6H, CH2CO), 2.48-2.38 (m, 8H, CH2CO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 30℃; for 4h; | In the glove box under a dry nitrogen atmosphere (rel hum=18%), a 250 mL, 4-necked, RB flask fitted with PTFE stoppers, egg-shaped magnetic stir bar, and immersion well, was charged with EDC (5.7 g, 29.7 mmol), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (4.3 g, 25.9 mmol), and dry (over sieves) Dichloromethane (20.00 ml). Separately, also in the glove box, was dissolved bis-MAL-dPEG2-Lysine-dPEG4-acid (22.2 g, 21.89 mmol) in dry (over sieves) Dichloromethane (20.00 ml). After the EDC/<strong>[769-39-1]TFP</strong> solution in the reaction vessel had cooled to 0[deg.] C., dripped in the acid solution, keeping the temperature at or below 5[deg.] C. After all of the acid solution had dripped in, allowed the reaction to continue on ice for 1 hour, then heated to 30[deg.] C. for 2 hours. Reaction was complete by RP-HPLC after 1 hour of heating. Continued stirring overnight at ambient. Transferred the reaction mixture to a 250 mL filter flask. Diluted reaction mixture to 150 mL with dry dichloromethane. Placed the filter flask in an ice bath and connected filter flask to a bleed of dry nitrogen. Washed the reaction mixture 4*25 mL with ice cold 0.363 M aq. HCl (made from concentrated aq. HOD. (NOTE: Stir SLOWLY, just enough to agitate the layers without mixing. Rapid stirring leads to emulsions that are very difficult to break.) Washed the reaction mixture 1*25 mL with 10% brine. Washed the reaction mixture 1*50 mL with saturated brine. Dried the reaction mixture over 40.2 grams of Na2SO4 for 120 minutes. Filtered away the sodium sulfate through 4 layers of glass fiber in a Buechner funnel under a nitrogen shower. Washed the filter cake with dry DCM. Filtered the reaction mixture through a bed of AW Standard Super-Cel NF in a fritted glass funnel under a nitrogen shower. Removed the solvent by rotary evaporation at 35[deg.] C. under high vacuum. The residue (15 g) was taken up in DCM and preabsorbed onto 30 g of bulk silica and purified on a 120 g RediSep using DCM (A) and EtOH (B). The column was primed with 20% B for 1CV and then 0% B for 2CV. The SLSC was inserted and a gradient was run at 5% B for 5CV then ramping to 17% over 8CV and bumping up to 30% to finish eluting product. A small amount of pink UV active material eluted, followed by <strong>[769-39-1]TFP</strong>, and finally product. Fractions 30-56 were pooled and concentrated to give a viscous pale yellow semi-solid. Trituration with Et2O gave an off-white solid. This solid was crushed under hexanes, the hexanes decanted, and the off-white powdery solid was dried under high vac overnight to give 10.968 g (43%) of a white powdery solid. TLC (85:15 DCM:EtOH) indicated a single spot. HPLC (Acids4020 method): RT 13.64 min, purity 98.1%. H NMR (400 MHz, CDCl3, [delta]): 7.21-6.96 (overlapping m, 4H), 6.83 (br t, 1H), 6.71 (s, 4H), 6.55 (br t, 1H), 4.43 (m, 1H), 3.93-3.29 (m, 42H), 3.21 (br q, 2H), 2.96 (t, 2H), 2.59-2.38 (overlapping t, 8H), 1.77 (m, 1H), 1.64 (m, 1H), 1.48 (m, 2H), 1.31 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.16667h; | General procedure: The general procedure for synthesis of dye-<strong>[769-39-1]TFP</strong> ester was as follows: 1 2 3 Fifty muiotaetaomicronIota dye, free acid 1 was dissolved in 4 ml DMF and cooled to 0C. To this solution 0.3 mmol dicyclohexylcarbodiimide 2, 60 muiotaetaomicronIota <strong>[769-39-1]2,3,5,6-tetrafluoro-4-hydroxybenzene</strong> 3 and then 60 muiotaetaomicronIota diisopropylethylamin were added. After ten minutes at 0C the reaction mixture was warmed to room temperature and stirred for two hours. The solvents were distilled off in high vacuum. The residue was purified by column chromatography (RP-18 silica gel; acetonitrile/water).The following compound according to general formula la is synthesized according to general procedure for compound I and general procedure for dye-<strong>[769-39-1]TFP</strong> ester, PEG4-682-<strong>[769-39-1]TFP</strong>-ester: yield : 30 mg (50%) UV-vis (ethanol): abs = 690 nm em = 708 nm MS (ESI-) [M/z] : 572.2 [M]2_ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide In acetonitrile at 60℃; for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With triethylamine; In diethyl ether; for 0.166667h; | Et3N (0.54 mL, 0.39 g, 3.87 mmol) was added dropwise to a vigorously stirred solution of 4-fluorobenzoyl chloride 25 (0.46 mL, 0.61 g, 3.87 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.64 g, 3.87 mmol) in Et20 (30 mL) and the stirring was continued for a further 10 min. The reaction mixture was filtered, washed with H20 (15 mL) and brine (2 10 mL), dried and concentrated under reduced pressure. The residue was recr^stallized from hexane to give 24 (0.41 g) as a colorless solid. The mothe liquor was concentrated under reduced pressure and the residue was recrystallized from hexane to give a second crop of 24 (0.45 g, total 77%). (0334) Rf = 0.62, EtOAcrhexane = 1 :10. (0335) ^-NMRiCDCla, 300 MHz): 5= 7.07 (tt, J = 9.9, 7.1 Hz, 1 H), 7.21-7.30 (m, 2 H), 8.21- 8.37 (m, 2 H); (0336) I9F-NMR |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 4-(dimethylamino)pyridinium tosylate; diisopropyl-carbodiimide; In acetonitrile; at 20℃; for 16h; | Example 1 General Procedures for Preparation ofN02-(COO<strong>[769-39-1]TFP</strong>)n [00118] To the mixture of the dendron N02-(COOH)n (1 equiv.), <strong>[769-39-1]tetrafluorophenol</strong> (<strong>[769-39-1]TFP</strong>) (1.2 xn equiv.) and 4-(dimethylamino)pyridinium 4- toluenesulfonate (DPTS) (0.1 xn equiv.) in anhydrous CH3CN (~0. 5 g/ 10 mL for compound N02-(COOH)n), diisopropylcarbodiimide (DIC) (1.2xn equiv.) were added dropwise. The reaction mixture was stirred at r.t. for 16h. Then it was concentrated in roto vapor and dissolved in CHC13. The insoluble white solid was filtered. The filtrate was concentrated to obtain the crude product and purified by flash chromatography. Example 2 Preparation ofN02-(COO<strong>[769-39-1]TFP</strong>)2 (18). [00119] N02-(COO<strong>[769-39-1]TFP</strong>)2 (18) was synthesized as shown in the scheme below and described in Example 1 above: [00120] The crude product was purified by flash chromatography using 1:1 CHC13: hexane (v:v). The product was obtained as white solid (1.1695g, 90%). NMR (CDCI3, 300 MHz): delta ppm 1.70 (s, 3 H), 2.24 - 2.43 (m, 2 H), 2.50 - 2.67 (m, 2 H), 2.77 (m, J=6.15, 2.93 Hz, 4 H), 7.03 (s, 2 H). 13C NMR (CDC13, 500 MHz): ppm 168.0, 147.0, 145.1, 141.6, 139.6, 103.7, 103.5, 103.3, 89.1, 33.8, 28.2, 21.7. 19F NMR ( CDCI3, 500 MHz): delta ppm -138.8, -153.0. IR (cm 1): v 3086, 2926, 1786, 1644, 1524, 1488, 1384, 1179, 1107, 953, 841, 714. ESI-MS: Calc. for C20H13F8NO5Na+: m/z 538.1; Found: m/z 537.6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 1h; | General procedure: To a solution of 2,4-dichloropyrimidine 1 (1 g, 6.71 mmol) inDMF (2 mL) was added the required polyfluorophenol 2 (1 equiv, 6.71 mmol), followed by DIPEA (1.04 g, 1.4 mL, 8.05 mmol) and the mixture heated to 80 C for 1 h. The reaction mixture was cooled to ambient temperature and partitioned between a mixture of water(50 mL) and diethyl ether (70 mL). The organic layer was washed with water (30 mL2), aqueous 0.1MNaOH (30 mL) and brine. Theorganic layer was then dried (MgSO4), filtered and concentrated invacuo to yield 3a-c as colourless oils, which slowly solidified towaxy solids upon standing. |
84% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 1h; | To a solution of 2,4-dichloropyrimidine (1 g, 6.71 mmol) in DMF (2 mL) was added <strong>[769-39-1]tetrafluorophenol</strong> (1 eq, 6.71 mmol), followed by DIPEA (1.04 g, 1.4 mL, 8.05 mmol). The mixture was heated to 80 C for 1 h, then cooled to ambient temperature and partitioned between a mixture of water (20 mL) and diethyl ether (20 mL). The organic layer was washed with water (20 mL x2), aqueous 0.1M NaOH (20 mL) and brine (20 mL). The organic layer was then dried (MgSO4), filtered and concentrated in vacuo to yield 1 as a colourless oil, which slowly solidified to a waxy solid upon standing, (1.57 g, 84%); 1H NMR (500MHz, DMSO-d6) delta8.84 (d, J 5.7 Hz, 1H), 8.03 (m, 1H), 7.61 (d, J 5.7 Hz, 1H); 13C NMR (125 MHz, CDCl3) delta168.0, 160.9, 160.5, 146.1 (1JC-F 253 Hz), 140.9 (1JC-F 252 Hz), 130.4, 106.6, 103.7 (2JC-F23 Hz); MS m/z: 279.0 (M+H)+; HRMS (ESI): calcd. for C10H3ClF4N2O (MH+) 278.9948; found278.9960. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 5 - 20℃; for 15h; | A 250ml_ 4-neck round bottom flask was charged with magnetic stir bar, thermo probe, t-boc-NH-dPEG4-CO-Tyr(-OTBA)-OH (10g, 15.56mmol) dissolved in CH2CI2 (40mL) and cooled to 5C in an ice/water bath. The <strong>[769-39-1]tetrafluorophenol</strong> (<strong>[769-39-1]TFP</strong>, 3.36g, 20.23mmol) and EDC (4.47g, 23.34mmol) were weighed in the dry box and the <strong>[769-39-1]TFP</strong> was added to the flask followed by EDC in one portion as a solid. The ice bath was removed and the reaction warmed to room temperature and stirred for 15 hours. By TLC (CH2Cl2/MeOH=9/1 ) the starting material was completely consumed and the reaction was washed with cold water (2x1 OmL) and saturated brine (10ml_). After drying over magnesium sulfate for one hour, the solution was filtered and concentration under reduced pressure the product (1 1 .5g, 89.5% yield) was obtained as yellow, viscous oil. 1H NMR (400 MHz, CDCI3, delta): 7.1 1 (d, 2H, tyrosine), 7.1 1 (s, 1 H, NH) 7.03 (m, 1 H, <strong>[769-39-1]TFP</strong>) 6.86 (d, 2H, tyrosine), 5.20 (s, 1 H, NH), 4.80 (m, 1 H, CHN), 4.47 (s, 2H, OCH2CO), 3.58 (m, 16H, CH20), 3.29 (m, 2H, CH2N), 3.18 and 3.05 (m, 2H, CH2), 2.48 (m, 2H, CH2CO), 1.48 (s, 9H, CH3), 1 .44 (s, 9H, CH3) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;Inert atmosphere; | A mixture of Mal-dPEG4-(Tyr-OAA)-NH-mdPEG12 (3.04g, 2.58mmol) and <strong>[769-39-1]tetrafluorophenol</strong> (<strong>[769-39-1]TFP</strong>, 0.889g, 5.83mmol) was placed into a 250ml_ 4-neckround bottom flask equipped with a thermocouple, magnetic stirrer, N2-filled balloon and cooling ice-water bath. Anhydrous dichloromethane (25ml_) was added, obtained solution was cooled to ~0C, and solid EDC (0.863g, 4.5mmol) was added to the reaction in one portion. Reaction was allowed to warm up to ambient temperature under stirring overnight. The reaction was monitored by TLC (in CH2CI2-MeOH=9/1 ) and after completion was diluted with DCM (80mL) and quenched with cold water (1 x50mL). Organic phase was separated, aqueous layer extracted with CH2CI2 (2x30mL) and combined organic phases were washed with brine (1x50mL) and died over anhydrous Na2S04. Drying agent was removed by filtration over celite, and clear filtrate was concentrated under reduced pressure to give 4.48g of viscous "tan" oil. This crude was purified by chromatography on silica gel (80g biotage column) using gradient elution with CH2CI2-EtOAc from 100% to 50% CH2CI2 to remove an excess of <strong>[769-39-1]TFP</strong>; after that the gradient was switched to CH2CI2-IPA from 100% to 75% CH2CI2. Pure fractions were combined and concentrated under reduced pressure at ambient temperature and kept under high vacuum for 2days in order to remove residual isopropanol. Obtained 1 .77g (52% yield) of product as viscous oil. 1H NMR (400 MHz, CDCI3, delta): 7.20 and 6.90 (2d, 4H, aromatic, tyrosine), 7.08 (m, 1 H, in <strong>[769-39-1]TFP</strong>), 7.03(d, 1 H, HNCO), 6.70 (s, 2H, CH=CH), 6.53 (m, 2H, HNCO), 5.00 (s, 2H, OCH2CO), 4.60 (m, 1 H, NCHCO), 3.83 (t, 2H, CH2N), 3.80-3.40 (m, 64H, CH20), 3.38 (s, 3H, CH30), 3.05 (m, 2H, CH2 in tyrosine), 2.52 (t, 2H, CH2CO), 2.47 (m, 2H, CH2CO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;Inert atmosphere; | A mixture of Mal-dPEG4-(Tyr-OAA)-NH-mdPEG24 (3.60g, 2.108mmol) and <strong>[769-39-1]tetrafluorophenol</strong> (<strong>[769-39-1]TFP</strong>, 0.85g, 5.12mmol) was placed into a 250ml_ 4- neckround bottom flask equipped with a thermocouple, magnetic stirrer, N2-filled balloon and cooling ice-water bath. Anhydrous dichloromethane (25ml_) was added, obtained solution was cooled to ~0C, and solid EDC (0.747g, 3.90mmol) was added to the reaction in one portion. Reaction was allowed to warm up to ambient temperature under stirring overnight. The reaction was monitored by TLC (in CH2CI2-MeOH=9/1 ) and after completion was diluted with DCM (100ml_) and quenched with cold water (60ml_). Organic phase was separated, aqueous layer extracted with CH2CI2 (2x30ml_) and combined organic phases were washed with brine (60ml_) and died over anhydrous Na2S04. Drying agent was removed by filtration over celite, and clear filtrate was concentrated under reduced pressure to give 5.32 of viscous oil. This crude was purified by chromatography on silica gel (80g biotage column) using gradient elution with CH2CI2-EtOAc from 100% to 50% CH2CI2 to remove an excess of <strong>[769-39-1]TFP</strong>; after that the gradient was switched to CH2CI2-IPA from 100% to 75% CH2CI2. Pure fractions were combined and concentrated under reduced pressure at ambient temperature and kept under high vacuum for 2days in order to remove residual isopropanol. Obtained 3.32g (85% yield) of product as viscous oil which slowly solidifies into white solid. 1H NMR (400 MHz, CDCI3, delta): 7.20 and 6.90 (2d, 4H, aromatic, tyrosine), 7.07 (m, 1 H, in <strong>[769-39-1]TFP</strong>), 7.03(m, 1 H, HNCO), 6.71 (s, 2H, CH=CH), 6.55 (broad m, 2H, HNCO), 5.01 (s, 2H, OCH2CO), 4.61 (dd, 1 H, NCHCO), 3.85 (t, 2H, CH2N), 3.80- 3.40 (m, 1 12H, CH20), 3.39 (s, 3H, CH30), 3.05 (m, 2H, CH2 in tyrosine), 2.57 (t, 2H, CH2CO), 2.48 (m, 2H, CH2CO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35%; 15% | With diisopropyl-carbodiimide; In N,N-dimethyl-formamide; for 120h; | General procedure: The iron protected mono and bis-<strong>[769-39-1]TFP</strong> ester of HBED-CC were synthesized according to previously published methods [19,24] (Scheme 1) with the following steps: (a) formation of HBED-CC iron complex: 1 (30mg, 56.9mumol), FeCl3 (1.2 equiv., 11.1mg), DIPEA 2 - 5% (v/v) in MeOH/H2O (2.0mL, 1:1, v/v); (b) <strong>[769-39-1]TFP</strong> ester activation: The two propionic acid functions of [Fe(HBED-CC)]- (0.056mmol) reacted with an excess of <strong>[769-39-1]TFP</strong> (2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong>) (10 equiv, 95.0mg) and DIPC (4 equiv, 0.08mmol, 118muL) for 5days in DMF (0.5mL, RT). The mono-<strong>[769-39-1]TFP</strong> ester (yield 35%, HPLC tR=2.9min) and bis-<strong>[769-39-1]TFP</strong> ester (25%, tR=4.8min) were isolated with semi-preparative HPLC and identified with mass spectrometry: C32H28F4FeN2O10 (-), MW: 732.1; m/z [M+H]+: 733.2; C38H28F8FeN2O10 (-), MW: 880.5, [M+H]+ m/z: 881.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.2% | With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 3h; | Tert-butyl-N-[(5S)-5-(cyclopentanecarbonylamino)-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptyl]carbamate (43a) To a solution of tert-butyl-N-[(5S)-7-bromo-5-(cyclopentanecarbonylamino)-6-oxo-heptyl]carbamate (1.10 g, 2.62 mmol, 1.00 eq) in DMF (20 mL) was added 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (523 mg, 3.15 mmol, 1.20 eq) and KF (457 mg, 7.87 mmol, 3.00 eq). The reaction mixture was stirred at 20 C. for 3 h. The mixture was diluted with H2O (50 mL) and extracted with EA (40 mL*3). The organic layers were combined, washed with brine (50 mL*5), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE/EA=4/1) to give tert-butyl-N-[(5S)-5-(cyclopentanecarbonylamino)-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptyl]carbamate (1.10 g, 2.18 mmol, 83.2% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.7% | With potassium fluoride; In N,N-dimethyl-formamide; at 20℃; for 12h; | Tert-butyl-N-[(5S)-5-[(3-azidobenzoyl)amino]-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptyl]carbamate (45a) To a solution of tert-butyl-N-[(5S)-5-[(3-azidobenzoyl)-amino]-7-bromo-6-oxo-heptyl]carbamate (2.90 g, 6.19 mmol, 1.00 eq) in DMF (20 mL) were added 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (1.54 g, 9.29 mmol, 1.50 eq) and KF (1.80 g, 30.95 mmol, 5.00 eq). The mixture was stirred at 20 C. for 12 h. The mixture was diluted with H2O (100 mL), extracted with EA (100 mL). The organic layer was washed with brine (100 mL*5), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with PE:EA=4:1 to give tert-butyl-N-[(5S)-5-[(3-azidobenzoyl)amino]-6-oxo-7-(2,3,5,6-tetrafluorophenoxy)heptyl]carbamate (2.80 g, 5.06 mmol, 81.7% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 0 - 20℃; for 24h; | A mixture of 3 (500 mg, 4.27 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong>(780 mg, 4.7 mmol) in anhydrous DMF (10 mL) was cooled to 0 C. DCCin DMF (3 mL) was added dropwise over a period of 10 min. The reactionmixture was stirred in an ice bath for 10 min, followed by stirringat room temperature for 24 h. Dicycyclohexyl was removed by filtration,and the filtrate was concentrated under vacuum and purified bysilica gel chromatography (ethyl acetate:hexane, 3:2, v/v) to obtaincompound 6 as a white solid (680 mg, 60%). 1H NMR (300 MHz,CDCl3): delta 8.17 (s, 1H) 6.25 (bs, 1H), 7.04 (m, 1H), 3.68 (q, 2H), 2.95 (t,2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | The reaction system are summarized in Figure 4. Silver oxide (3.57 g, 15.4 mmol)Add toBromo-5H- dibenzo [b, d] thiophene -5-ium (5.00 g, 14.7 mmol) in methanol(50 ml) of the solution, and stirred overnight. The reaction mixture was filtered through celite TM, methanol (50 ml), and the organic layer was such Merger. Then add 2,3,5,6-tetrafluoro-phenol (2.42 g, 14.7 mmol), and stirred at room temperature for 4 hours. The solution was concentrated to an oil, the oil-based precipitate into MTBE (250 ml). The solid was filtered and to MuTauBetaEpsilon (2 chi 200 mL) to give a white solid of5-phenyl -5H- dibenzo [b, d] thiophene -5-ium2,3,5,6-tetrafluoro-phenol salt (3.00 g, 48%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.5% | With potassium carbonate; In acetone; at 50℃; for 14h; | 4-Chloro-6-(1-fluoroethyl)-1,3,5-triazin-2-amine (5.00 g, 28.32 mmol, 1.00 eq.) is added to a mixture of 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (4.70 g, 28.32 mmol, 1.00 eq.) and K2003 (7.83 g, 56.63 mmol, 2.00 eq.) in aceton. The reaction mixture is heated to 50 00 stirred for 14 hours before cooled to ambient temperature. Water and EtOAc are added, the phases separated and theorganic phase is dried over Na2504. After filtration of the solids and removal of the volatiles under reduced pressure the crude product is purified via colum chromatography (ISCOCombiFlash Rf cyclohexane/ethyl acetate) yielding the desired compound as a colorless solid(6.20 g, 71.5%).MS (ESI) m/z 307.1 [M+Hj1H NMR (400 MHz, 0D013): 6 = 7.08 - 7.00 (m, 1 H), 6.36 (brs, 1 H), 5.58 (brs, 1 H), 5.39 (dq, J =48.4 Hz, J = 6.7 Hz, 1H), 1.66 (dd, J = 24.1 Hz, J = 6.7 Hz, 3 H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 20h; | General procedure: A mixture of 3 (1.87 g, 8 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3.32 g, 20 mmol) in dichloromethane (40 mL) was added N,N?-dicyclohexylcarbodiimide (3.30 g, 16 mmol). The resulting solution was stirred at room temperature for 20 h, and filtered. The filtrate was washed with aqueous NaOH solution (1 N, 100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography with 15:85 diethyl ether/hexane to yield 5 as white solid (2.42 g, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 20h; | A mixture of 3 (1.87 g, 8 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3.32 g, 20 mmol) in dichloromethane (40 mL) was added N,N?-dicyclohexylcarbodiimide (3.30 g, 16 mmol). The resulting solution was stirred at room temperature for 20 h, and filtered. The filtrate was washed with aqueous NaOH solution (1 N, 100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography with 15:85 diethyl ether/hexane to yield 5 as white solid (2.42 g, 57%). Melting point = 125 C. 1H NMR (300 MHz, CDCl3) delta 7.17 - 6.91 (m, 2H), 4.56 (s, 2H), 4.43 (s, 2H), 1.50 (s, 9H). MS (ESI) calculated for C21H15F8NO6 529.1, found [M + Na]+ 552.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 20h; | General procedure: A mixture of 3 (1.87 g, 8 mmol) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (3.32 g, 20 mmol) in dichloromethane (40 mL) was added N,N?-dicyclohexylcarbodiimide (3.30 g, 16 mmol). The resulting solution was stirred at room temperature for 20 h, and filtered. The filtrate was washed with aqueous NaOH solution (1 N, 100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography with 15:85 diethyl ether/hexane to yield 5 as white solid (2.42 g, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With N-ethyl-N,N-diisopropylamine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 27h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | Intermediate 5: <strong>[769-39-1]2,3,5,6-tetrafluorophenyl</strong> 3-(2-(2-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)ethoxy)ethoxy)ethoxy)propanoate (MT-<strong>[769-39-1]TFP</strong>) (0703) (0704) [00426] To a stirred solution of MT-OH (0.520 g, 1.73 mmol, 1 eq) in dichloromethane (10 mL) was added 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.301 g, 1.81 mmol, 1.05 eq), followed by N-(3- dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (0.348 g, 1.81 mmol, 1.05 eq). The reaction was stirred at room temperature. After 18hr, the reaction solvent was evaporated under reduced pressure and the resulting residue was purified by flash chromatography to yield the title compound (0.323 g, 42% yield). NMR (400 MHz, Chloroform- ) delta 7.02 (tt, J = 9.9, 7.1 Hz, 1H), 6.71 (s, 2H), 3.90 (t, J= 6.3 Hz, 2H), 3.75 (td, J = 5.6, 0.9 Hz, 2H), 3.70 - 3.64 (m, 6H), 3.63 (s, 4H), 2.98 (t, J = 6.3 Hz, 2H). m/z calc'd for G9H19F4NO7 449.11. Found [M+H]+ = 450.48, [M+Na]+ = 472.48 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 6h;Inert atmosphere; | General procedure: Adipic acid (1.00 g, 6.84mmol) and EDC (3.15g, 16.8 mmol) was dissolved in 50 mL dryCH2Cl2. The solution was allowed cool to 0 oC in ice bath, after which <strong>[769-39-1]tetrafluorophenol</strong> (<strong>[769-39-1]TFP</strong>-OH, 2.50 g,15.1 mmol) was added. The solution was allowed to warm to rt and stirred for 6 h. After removal of thesolvent under reduced pressure, the crude product was purified by flash column chromatography (PE/DCM1:1) on silica gel to give <strong>[769-39-1]TFP</strong> linker 5 (2.54 g, 84%) as white solid. 1H NMR (600 MHz, Chloroform-d) delta7.01 (t, J = 8.8 Hz, 2H), 2.77 (s, 4H), 1.94 (d, J = 4.8 Hz, 4H). 19F NMR (376 MHz, Chloroform-d) delta-138.40 - -140.13 (m), -152.79 - -153.62 (m). 13C NMR (101 MHz, Chloroform-d) delta 168.90 , 145.97 (dtd, J= 248.5, 11.9, 4.2 Hz), 140.53 (dddd, J = 250.4, 15.3, 4.8, 2.3 Hz), 129.80 - 129.23 (m), 103.19 (t, J = 22.8Hz), 32.87 , 23.84. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 1.5h; | To a solution of 8-(trans-4-(4-(2-(ethyl(m-tolyl)amino)-2-oxoethyl)-4H-thieno[3,2- b]pyrrole-5-carboxamido)cyclohexane-l-carboxamido)octanoic acid (54 mg, 0.089 mmol) in DCM (5 mL), N,N'-dicyclohexylcarbodiimide (27 mg, 0.13 mmol), DMAP (2 mg, cat.), and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (29 mg, 0.18 mmol) was added. The solution stirred at RT for 1.5 h. The mixture was diluted with DCM and washed with HC1 (1 M). The organic layers were combined, dried with sodium sulfate, filtered, concentrated, and purified with silica gel chromatography to afford the desired product (52 mg, 77%) as a white solid. ESI MS m/z 757 [M + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In acetone;Reflux; | Compound 9 was prepared by the modification of the literature method. 7 (2.05 mg, 12.4 mmol), 8(5.53 mg, 12.9 mmol) and K2CO3 (5.14 g, 37.2 mmol) were mixed in acetone (50 mL) and refluxedovernight. Water was added after the mixture had been cooled, and the mixture was extracted with CH2Cl2 three times. The combined organic layer was dried over MgSO4, filtered and evaporatedunder reduced pressure. The crude product was purified by flash column chromatography (SiO2,EtOAc/hexane, 3:97-5:95) to yield analytically pure 9 (3.86 g, 9.36 mmol, 76%) as a colorless oil.1H NMR (392 MHz, CDCl3, delta): 0.06 (s, 6H), 0.89 (s, 9H), 3.55 (t, J = 5.5 Hz, 2H), 3.63-3.71 (m,4H), 3.77 (t, J = 5.5 Hz, 2H), 3.84 (t, J = 4.7 Hz, 2H), 4.38 (t, J = 4.5 Hz, 2H), 6.73-6.82 (m, 1H).13C NMR (99 MHz, CDCl3, ): -5.40 (CH3), 18.28 (C) 25.82 (CH3), 62.45 (CH2), 70.18 (CH2) 70.72(CH2) 70.85 (CH2), 72.65 (CH2), 74.10 (CH2), 99.38 (t, JC-F = 22.6 Hz, CH), 138.05-138.45 (m, C),141.06 (ddt, JC-F = 3.9, 14.6, 246.6 Hz), 146.21 (ddt, JC-F = 4.1, 12.6, 246.8 Hz, C). MS-ESI (m/z):[M+H]+ calcd for C18H29F4O4Si, 413.17658; found, 413.17702. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.5% | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 24h; | To a solution of Intermediate 2-A (40 mg, 0.03 mmol), <strong>[769-39-1]TFP</strong> (90 mg, 0.54 mmol) and EDC (40 mg, 0.27 mmol) in ACN (1.0 mL) was added pyridine (0.05 mL, 50 mg, 0.62 mmol) at room temperature. The solution was stirred at room temperature for 24 hours. The reaction was purified directly by Prep-HPLC using method 7 to provide Intermediate 2-B (33 mg, 82.5%) as a wax after concentration using a Biotage V10 Rapid Evaporator |
82.5% | With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 24h; | A bifunctional chelate, 4-[1 1 -oxo-1 1 -(2,3,5,6- tetrafluorophenoxy)undecyl]carbamoyl}-2-[4,7,10-tris(carboxymethyl)-1 ,4,7,10- tetraazacyclododecan-1 -yl]butanoic acid (Compound B), was synthesized according to the scheme provided in Figure 2. To a solution of 5-(tert-butoxy)-5-oxo-4-(4,7,10- tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10-tetraazacyclododecan-1 -yl)pentanoic acid (DOTA-GA-(tBu)4, 50 mg, 0.07 mmol) in ACN (2.0 mL) was added DSC (50 mg , 0.21 mmol) followed by pyridine, (0.20 mL, 2.48 mmol). The reaction was stirred at room temperature for 1 h. To the reaction mixture was added 1 1 -aminoundecanoic acid, (70 mg, 0.36 mmol) followed by PBS solution (1 .0 mL) at room temperature. The reaction was stirred for 72 h at room temperature. The reaction mixture was filtered with syringe filter and purified directly by Prep-HPLC using method 6 to yield Intermediate 2-A (71 mg, 74.8 %). To a solution of Intermediate 2-A (40 mg , 0.03 mmol), <strong>[769-39-1]TFP</strong> (90 mg , 0.54 mmol) and EDC (40 mg, 0.27 mmol) in ACN (1 .0 mL) was added pyridine (0.05 mL , 50 mg , 0.62 mmol) at room temperature. The solution was stirred at room temperature for 24 h. The reaction was purified directly by Prep-HPLC using method 7 to provide Intermediate 2-B (33 mg, 82.5 %) as a wax after concentration using a Biotage V1 0 Rapid Evaporator. (0439) Intermediate 2-B (33 mg, 0.022 mmol) was dissolved DCM / TFA (1 .0 mL / 2.0 mL) and allowed to stir at room temperature for 24 h. The reaction was concentrated by air stream and purified directly by Prep-HPLC using method 8 to yield Compound B (14 mg, 50.0 %) as a clear wax after concentration. An aliquot was analyzed by HPLC-MS elution method 3; retention time: 4.15 min; MS (positive ESI): found m/z 808.1 [M+H]+; C36H54F4N5Oi i (calc. 808.8). (0440) 1 H NMR (600 MHz, DMSO-d6) delta 7.99 - 7.88 (m, 1 H), 7.82 (t, J = 5.5 Hz, 1 H), 3.78 (broad s, 4H), 3.43 (broad s, 12H), 3.08 (broad s, 4H), 3.00 (m, 3H), 2.93 (broad s, 3H), 2.77 (t, J = 7.2 Hz, 2H), 2.30 (broad s, 2H), 1 .88 (broad s, 2H), 1 .66 (p, J = 7.3 Hz, 2H), 1 .36 (m, 4H), 1 .32 - 1 .20 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 3h; | To vial containing Intermediate 1-A (82 mg, 60 mumol) was added ACN (2 mL), 28 NEt3 (50 muL, 360 mumol, 6 equiv.), 29 HBTU (23 mg, 60 mumol, 1 equiv) and a <strong>[769-39-1]TFP</strong> solution (50 mg, 300 mumol, 5 equiv., dissolved in 250 muL of ACN). The resulting clear solution was stirred at ambient temperature for 3 hours. The reaction was worked up by concentrating the solution to dryness under an air stream and was then diluted with ACN/H2O (1:1, 3 mL total) and purified on preparative HPLC using elution method 4. The fractions containing product were pooled and concentrated under vacuum and then co-evaporated with ACN (3×2 mL). Intermediate 1-B was obtained as a clear residue (67 mg, 74% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 80% | With dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; | c: 1 mmol of compound 2 and 1 mmol of <strong>[769-39-1]tetrafluorophenol</strong> were placed in a dry reaction flask, and 1 mL of N,N-dimethylformamide (DMF) was added under argon atmosphere.After dissolving 1 mmol of dicyclohexylcarbodiimide (DCC) in 1 mL of N,N-dimethylformamide (DMF), it was added to a reaction flask and stirred at room temperature for 24 hours.After cooling to 0 C, the reaction was carried out for 1 hour, and after filtration, the solvent was spin-dried through a column and purified by chromatography to give compound 3 in a yield of about 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 3h; | A bifunctional chelate, 4-[2-(2-{2-[3-oxo-3-(2,3,5,6- tetrafluorophenoxy)propoxy]ethoxy}ethoxy)ethyl]carbamoyl}-2-[4,7, 10- tris(carboxymethyl)-1 ,4,7,10-tetraazacyclododecan-1 -yl]butanoic acid (Compound C), was synthesized according to the scheme provided in Figure 3. To a solution of 5-(tert-butoxy)-5-oxo-4-(4,7,1 0-tris(2-(tert-butoxy)-2-oxoethyl)-1 ,4,7,10- tetraazacyclododecan-1 -yl)pentanoic acid (DOTA-GA(tBu)4, 100 mg, 0.143 mmol) in ACN (8.0 mL) was added DSC (73 mg, 0.285 mmol) and pyridine (0.80 mL, 9.89 mmol). The reaction mixture was stirred for 90 min at ambient temperature. This solution was added to a semi-solution of amino-PEG3-acid (63 mg, 0.285 mmol in 1 .2 mL of DMF) in a 100 mL round bottom flask. After 4 hours at ambient (0444) temperature, the reaction was worked up by concentrating to dryness under a stream of air. The crude material was purified by HPLC elution method 2 (dissolved the crude in 6 mL of 20% ACN/H20). The fractions containing product were pooled and concentrated under vacuum and then co-evaporated with ACN (3 x 2 mL). (0445) Intermediate 1 -A was obtained in 82% yield. (0446) To vial containing Intermediatel -A (82 mg, 60 muiotaetaomicronIota) was added ACN (2 mL), (0447) NEt3 (50 muIota_, 360 muiotaetaomicronIota, 6 equiv.), HBTU (23 mg, 60 muiotaetaomicronIota, 1 equiv) and a <strong>[769-39-1]TFP</strong> solution (50 mg, 300 muiotaetaomicronIota, 5 equiv., dissolved in 250 [i of ACN). The resulting clear solution was stirred at ambient temperature for 3 h. The reaction was worked up by concentrating the solution to dryness under an air stream and was then diluted with (0448) ACN/H20 (1 :1 , 3 mL total) and purified on preparative HPLC using elution method 4. (0449) The fractions containing product were pooled and concentrated under vacuum and then co-evaporated with ACN (3 x 2 mL). Intermediate 1 -B was obtained as a clear residue (67 mg, 74% yield). (0450) To a vial containing Intermediate 1 -B (67 mg, 64 muiotaetaomicronIota) was added DCM (2 mL) and TFA (2 mL) and the resulting solution was stirred at ambient temperature for (0451) 16 h. Additional TFA (2 mL) was added and the reaction was stirred at ambient temperature for 6 h. The reaction was concentrated to dryness under an air stream with the crude product being finally dissolved in ACN/H20 (1 mL of 10% ACN/H20). (0452) The crude reaction solution was then purified by preparative HPLC using elution method 5. The fractions containing product were pooled, frozen and lyophilized. (0453) Compound C was obtained as a white solid (36 mg, 63% yield). An aliquot was analyzed by HPLC-MS elution method 3; retention time: 3.1 1 min; MS (positive ESI): found m/z 828.4 [M+H]+; C34H5oF4N5Oi4 (calc. 828.3). (0454) 1 H NMR (DMSO-d6, 600 MHz) delta 7.97-7.91 (m, 2H), 3.77 (t, 2H, J = 6.0 Hz), (0455) 3.58-3.55 (m, 2H), 3.53-3.48 (m, 8H), 3.44-3.38 (m, 10H), 3.23-3.08 (m, 1 1 H), 3.02 (0456) (t, 2H, J = 6.0 Hz), 2.93 (broad s, 4H), 2.30 (broad s, 2H), 1 .87 (broad s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 12h; | To a solution of compound 60.2 (40 mg, 77.8 iimol, 1 eq) in DMF (2 mL) was added DIEA (30.17 mg, 233.5 imol, 40.7 iL, 3 eq) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (19.4 mg,116.73 imol, 1.5 eq). The mixture was stirred at 25 C for 12 hours. The reaction mixture was quenched by addition H20 (10) mL at 25C and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=1 :1) togive compound 60.1 (20 mg, 31.07 imol, 40% yield) as a white solid. LCMS (ESI) m/z: [M+ H]+ calcd for C30H37N3O8F4: 644; found 544; RT=1.402 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | To a 50 mL round bottom flask equipped with magnetic stir bar is added 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (2 g, 12.04 mmol), K2C03 (3.33 g, 24.09 mmol), and DMF (15 mL). To this stirring mixture isadded 4-methoxy-benzoyl chloride (1.89 g, 12.04 mmol, 1.63 mL) dropwise and the reaction mixture is stirred overnight at room temperature under nitrogen. The solvent is removed under reduced pressure to give a solid residue that is then partitioned between layers of EtOAc and water. The aqueous layer is separated and extracted with EtOAc (3x). The combined organic layer is washed with brine and dried with MgSO4, and the drying agent isremoved by vacuum filtration. The filtrate is concentrated to dryness to afford crude material as yellow oil. For purification, the cmde material is loaded onto the SNAP Ultra 50g silica gel column and the product is eluted with 0-20% EtOAc in hexanes gradient. Removal of solvent under reduced pressure provided 4-methoxybenzyl ether product (128) (2.76 g, 80%) as crystalline white solid. ?H NMR (400 MHz, Chloroform-d3) 7.39 - 7.30 (m, 2H), 6.93 -6.85 (m, 2H), 6.74 (tt, J= 10.0, 7.0 Hz, 1H), 5.19 (s, 2H), 3.81 (s, 3H); ?9F NMR (376 MHz,Chloroform-d) -140.13 to -140.27 (m, 2F), -155.87 to -155.98 (m, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.64% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl acetamide; at 25℃; for 4h; | To a solution of compound 5 (0.08 g, 115.12 umol), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (57.36 mg, 345.37 umol) in DMA (3 mL) and DCM (1 mL) was added EDCI (66.21 mg, 345.37 umol). The mixture was stirred at 25 C for 4 hr. LC-MS showed compound 5 was consumed completely and a peak with desired mass (m/z: 843.1([M+H+])) was detected. The reaction mixture was directly purified by prep-HPLC (A: H20, B: ACN) to give Compound PLI-16 (0.06 g, 64.06 umol, 55.64% yield) as a yellow solid. (Calculated MW: 842.9 observed m/z: 843.1([M+H+])) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl acetamide; at 20℃; for 2h; | To a solution of compound 1.6 (150.0 mg, 314.8 mumomicronl, 1 eq) and 2,3,5,6- <strong>[769-39-1]tetrafluorophenol</strong> (156.8 mg, 944.3 mumomicronl, 3 eq) in DMA (4.5 mL) and DCM (1.5 mL) was added EDCI (181.0 mg, 944.3 mumomicronl, 3 eq). The mixture was stirred at 20C for 2 hr. LC-MS showed the desired compound was detected. The mixture was purified by prep-HPLC (ACN/H2O condition). Compound 1.7 (140.0 mg, 224.1 mumomicronl, 71.2% yield) was obtained as a white solid. MS (ESI) m/z: calcd. for [M+H]+, 625.17; found, 625.1 (M/1+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.9% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; N,N-dimethyl acetamide; at 25℃; for 16h; | To a solution of compound 2.5 (0.04 g, 72.64 mumomicronl, 1 eq), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (36.2 mg, 217.91 mumomicronl, 3 eq) in DMA (3 mL) and DCM (l mL) was added EDCI (41.8 mg, 217.91 mumomicronl, 3 eq). The mixture was stirred at 25 C for 16 hr. LC-MS showed compound 5 was consumed completely and one main peak with desired MS was detected. The reaction was directly purified by prep-HPLC (ACN/H2O condition). Compound 2.6 (0.035 g, 50.09 mumomicronl, 68.9% yield) was obtained as a white solid. MS (ESI) m/z: calcd. for [M+H]+, 698.19; found, 699.0 (M/l+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.74% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 25℃; for 2h; | To a solution of compound 2 (0.040 g, 93.35 umol, 1 eq) in DMA (5 mL) was added EDCI (53.69 mg, 280.06 umol, 3 eq), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (46.51 mg, 280.06 umol, 3 eq) and DMAP (1.14 mg, 9.34 umol, 0.1 eq). The mixture was stirred at 25 C for 2 hr. LC-MS showed compound 2 was consumed completely and a peak with desired mass (m/z:577. 0([M+Hfl) was detected. The reaction fixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (A: H20, B: ACN). Compound PLI-4 (0.030 g, 52.03 umol, 55.74% yield) was obtained as a white solid. Calculated MW: 576.5 observed m/z: 577.0([M+Hf?) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 25℃; for 3h; | To a solution of G10-5 (1 g, 1.57 mmol, 1.00 equiv.) in dichloromethane (10 mL), l -(3- Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (360 mg, 1.88 mmol, 1.20 equiv.), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (310 mg, 1.87 mmol, 1.20 equiv.). The resulting solution was stirred for 3 h at 25C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash. The resulting solution was extracted chloroform and the organic layers were combined. The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. This resulted in 0.5 g (41%) and other batches product were combined to furnish 5.0422 g of G10-6 as light yellow oil. MS m/z [M+H]+ (ESI): 785., 1H NMR (CD3CN, 400Hz, ppm): delta 7.30-7.40 (m, 1H), 6.48-6.60 (m, 2H), 5.30 (s, 1H), 5.04 (dd, J = 1 1.2 Hz, 3.6 Hz, 1H), 4.52-4.59 (m, 3H), 4.08-4.13 (m, 2H), 3.95-3.99 (m, 2H), 3.76-3.78 (m, 3H), 3.60-3.67 (m, 6H), 3.48-3.59 (m, 3H), 3.30-3.48 (m, 2H), 2.14-2.16 (m, 5H), 2.12 (s, 3H), 1.93 (s, 3H), 1.88 (s, 3H), 1.50-1.60 (m, 4H). F NMR (CD3CN, AlphaOmicronzeta, rhorhotaueta): delta -140.76, -140.79, -140.82, -140.84, -154.52, -154.54, -154.57, -154.60. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.7% | 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (25.2 g, 151.8 mmol) was added to the reaction flask.Toluene (120 mL),Potassium carbonate powder (16.89 g, 121 mmol) was added with stirring.Further compound (01) (30.0 g, 151.8 mmol) was added.Stirring for 5 hours,Stop the reaction (sampling test, compound (01) ? 1.0%),Cool down to 50 C,The solvent was evaporated to dryness under reduced pressure. MeOH (150 mL)30% sodium methoxide in methanol (27.4 g, 151.8 mmol) was added dropwise at room temperature.Stirring for 2 hours,Sampling test,Compound (02) ? 1.0%,The reaction was stopped, the temperature was lowered to 40 C, and the solvent was evaporated under reduced pressure. isopropyl acetate (300 mL) was added to the residue, washed three times with water (150 mL), and brine (150 mL) Isopropyl acetate was distilled off under reduced pressure to give 39.1 g of a brown oil as compound (03), yield 95.7%, purity 98.9%, which was directly used for the next reaction.Take the brown oil detected, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 20h; | tert-Butyl 3-(methylsulfonyloxy)azetidin-1-carboxylate (1.00 g, 3.98 mmol), 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (0.65 g, 3.91 mmol) ) and Cs2CO3 (1.55g, 4.78mmol) in DMF (30mL)The mixture was stirred at 110 C for 20 hours.After cooling to room temperature, the mixture was filtered and the solvent of the filtrate was evaporated. The residue was dissolved in EtOAc (75 mL)The solution was washed with water (3×50 mL), dried (Na2SO4) and evaporated. Purified by silica gel chromatography,Where a mixture of isooctane and EtOAc (gradient 0-17% EtOAc) eluted0.60 g (47%) of the title compound was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 60h; | 6.6.26.6.26.1 6.26.1. Synthesis of 2,3,5, 6-tetrafluorophenyl 3-(pyridin-4-yl)propanoate To a solution of 2,3,5, 6-tetrafluorophenol (576 mg, 3.47 mmol, 1.1 eq.) in DCM (25 mL) was added 3-(pyridin-4-yl)propanoic acid (477 mg, 3.16 mmol, 1.0 eq.). The reaction mixture was stirred for 5 min at room temperature and EDC (726 mg, 3.79 mmol, 1.2 eq.) was added at room temperature. The resulting suspension was stirred for 60 h at room temperature. The reaction mixture was diluted with DCM (20 mL) and the mixture was washed with an aqueous 0.1 M HC1 solution (prepared from 22.5 mL water and 2.5 mL 1 M HC1). The organic phase was subsequently washed with sat. NaHCCh solution and brine, dried with Na2S04, and evaporated to dryness to obtain the crude product as a colorless solid (317 mg, 33.6% yield). HPLC (Grace Alltima C18 5 pm column, 25 x 4.6 mm) indicated that the product was 96.5% pure (retention time 10.9 min; gradient: 20 to 100% MeCN/0.1% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 nm). NMR (400 MHz, DMSO-d6): d 8.54-8.39 (m, 2 H), 8.00-7.80 (m, 1 H), 7.39-7.25 (m, 2 H), 3.24-3.15 (m, 2 H), 3.06-2.94 (m, 2 H). | |
Stage #1: 3-pyridin-4-yl-propionic acid; 2,3,5,6-tetraflourophenol In dichloromethane at 20℃; for 0.0833333h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 60h; | 6.26.1 Synthesis of 2,3,5, 6-tetrafluorophenyl 3-(pyridin-4-yl)propanoate To a solution of 2,3,5, 6-tetrafluorophenol (576 mg, 3.47 mmol, 1.1 eq.) in DCM (25 mL) was added 3-(pyridin-4-yl)propanoic acid (477 mg, 3.16 mmol, 1.0 eq.). The reaction mixture was stirred for 5 min at room temperature and EDC (726 mg, 3.79 mmol, 1.2 eq.) was added at room temperature. The resulting suspension was stirred for 60 h at room temperature. The reaction mixture was diluted with DCM (20 mL) and the mixture was washed with an aqueous 0.1 M HC1 solution (prepared from 22.5 mL water and 2.5 mL 1 M HC1). The organic phase was subsequently washed with sat. NaHCCL solution and brine, dried with Na SCL, and evaporated to dryness to obtain the crude product as a colorless solid (317 mg, 33.6% yield). HPLC (Grace Alltima C18 5 pm column, 25 x 4.6 mm) indicated that the product was 96.5% pure (retention time 10.9 min; gradient: 20 to 100% MeCN/0. l% TFA in water/0.1% TFA in 20 min measured at a wavelength of 210 mn). NMR (400 MHz, DMSO-d6): d 8.54-8.39 (m, 2 H), 8.00-7.80 (m, 1 H), 7.39-7.25 (m, 2 H), 3.24-3.15 (m, 2 H), 3.06-2.94 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 4.16667h;Inert atmosphere; | Under argon atmosphere, DIPEA (13.9 mL, 80 mmol, 4.0 eq.) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (10.3 g, 60.4 mmol, 3.0 eq.) were dissolved in dry DCM (100 mL) and were subsequently added dropwise over 2.5 h to a rigorously stirred solution of benzene- 1, 3, 5-tricarbonyl trichloride (3.57 mL, 20.0 mmol, 1.0 eq.) in dry DCM (150 mL) at 0 C. After addition, the mixture was stirred for 40 min and was allowed to warm to 6 C, after which it was gradually heated to the ambient temperature and stirred for another 1 h. Then, the reaction mixture was washed with 1 M HC1 (320 mL) and with 1 M NaOH (320 mL). The alkaline aqueous layer was extracted with DCM (50 mL) and the combined organic layers were washed with brine (100 mL). The organic phase was dried with Na2S04, filtered, and evaporated under reduced pressure. After removal of solvents, a pale brown solid (12.1 g, 93% yield) was obtained. NMR (400 MHz, CDCb): d 9.30 (s, 3 H), 7.17-7.05 (m, 3 H) |
93% | Under argon atmosphere, DIPEA (13.9 mL, 80 mmol, 4.0 eq.) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (10.3 g, 60.4 mmol, 3.0 eq.) were dissolved in dry DCM (100 mL) and were subsequently added dropwise over 2.5 h to a rigorously stirred solution of benzene-l, 3, 5-tricarbonyl trichloride (3.57 mL, 20.0 mmol, 1.0 eq.) in dry DCM (150 mL) at 0 C. After addition, the mixture was stirred for 40 min and was allowed to warm to 6 C, after which it was gradually heated to the ambient temperature and stirred for another 1 h. Then, the reaction mixture was washed with 1 M HC1 (320 mL) and with 1 M NaOH (320 mL). The alkaline aqueous layer was extracted with DCM (50 mL) and the combined organic layers were washed with brine (100 mL). The organic phase was dried with Na2S04, filtered, and evaporated under reduced pressure. After removal of solvents, a pale brown solid (12.1 g, 93% yield) was obtained. NMR (400 MHz, CDCL): d 9.30 (s, 3 H), 7.17-7.05 (m, 3 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 80% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; sodium chloride; In acetonitrile; for 0.5h; | The procedure was adapted from Vugts et al. , Bioconjugate Chern. 2011, 22, 2072-2081. To the reaction mixture containing (Fe)DFO-suc (130 mg, 182 pmol) were added 0.9% NaCl (5 mL), MeCN (1.8 mL) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (290 mg, 1.75 mmol) in MeCN (200 pL). Next, EDC x HC1 (550 mg, 2.87 mmol) was added and the mixture was stirred for 15 min. Subsequently, a second portion of EDC x HC1 (500 mg, 2.61 mmol) was added and the mixture was stirred for another 15 min. The reaction mixture was divided into two equal batches and poured into 0.9% NaCl (30 mL each) and the resulting mixtures were trapped on two activated double Sep-Pak C18 Plus columns. These two double Sep-Pak C18 Plus columns were washed with water (3 x 20 mL each), and the product was eluted with 2 x 1.5 mL MeCN. Thus, two product batches were collected, each containing the product in ~3 mL of solvents. HPLC (Grace Alltima Cl 8 5 pm column, 25 x 4.6 mm) indicated that batch 1 was 94.8% pure and batch 2 was 95.2% pure (retention time 20.4 min; gradient: 5 to 50% MeCN/0. l% TFA in water/0.1% TFA in 20 min measured at a wavelength of 430 nm). It was assumed that the yield was ~ 80% (based on the results obtained by Yugts et al. , Bioconjugate Chem. 2011, 22, 2072- 2081). The two solutions containing product were used in the next step without further workup or purification. |
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; sodium chloride; In acetonitrile; for 0.5h; | The procedure was adapted from Vugts et al, Bioconjugate Chem. 2011, 22, 2072-2081. To the reaction mixture containing (Fe)DFO-suc (130 mg, 182 mhio) were added 0.9% NaCl (5 mL), MeCN (1.8 mL) and 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (290 mg, 1.75 mmol) in MeCN (200 pL). Next, EDC x HC1 (550 mg, 2.87 mmol) was added and the mixture was stirred for 15 min. Subsequently, a second portion of EDC x HC1 (500 mg, 2.61 mmol) was added and the mixture was stirred for another 15 min. The reaction mixture was divided into two equal batches and poured into 0.9% NaCl (30 mL each) and the resulting mixtures were trapped on two activated double Sep-Pak C18 Plus columns. These two double Sep-Pak Cl 8 Plus columns were washed with water (3 x 20 mL each), and the product was eluted with 2 x 1.5 mL MeCN. Thus, two product batches were collected, each containing the product in ~3 mL of solvents. HPLC (Grace Alltima C18 5 pm column, 25 x 4.6 mm) indicated that batch 1 was 94.8% pure and batch 2 was 95.2% pure (retention time 20.4 min; gradient: 5 to 50% MeCN/0. l% TFA in water/0.1% TFA in 20 min measured at a wavelength of 430 nm). It was assumed that the yield was ~ 80% (based on the results obtained by Yugts et ai. Bioconjugate Chem. 2011, 22, 2072- 2081). The two solutions containing product were used in the next step without further workup or purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 20℃; for 2h; | |
With dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 20℃; | ||
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | In a dried 50 mL conical flask, 3-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)propanoic acid (Compound 14, 1.000 g, 4.52 mmol) and maleic anhydride (0.443 g, 4.52 mmol) were dissolved in anhydrous N, A-di ethyl form am i de (5 mL). The reaction was stirred at room temperature for 6hr under N2, at which point it was cooled to 0C and xy-collidine (1.263 mL, 2.1 eq) was added dropwise. In a separate dried 50 mL conical flask, <strong>[769-39-1]tetrafluorophenol</strong> (3.002 g, 4 eq) was dissolved in anhydrous N, L-di m ethyl form am i de (10 mL). The flask was cooled to 0C in an ice bath and trifluoroacetic anhydride (2.548 mL, 4 eq) was added dropwise. This flask was stirred for 15 minutes, at which point ^-collidine (2.407 mL, 4 eq) was added dropwise. The flask was allowed to stir for another 15 minutes, and then the contents were added to the first flask dropwise, via syringe. The reaction was allowed to warm to room temperature and stirring was continued under N2. The reaction was monitored by HPLC-MS for the consumption of starting materials. After 6 days, the reaction was complete with the total consumption of Compound 14, leaving only Compound 15 and a small amount (~5%) of the bis-<strong>[769-39-1]TFP</strong> maleic amide intermediate. The reaction was transferred to a separating funnel, diluted with diethyl ether (75 ml) and washed with 5% Li Cl (1 x 20 mL), 1 M HC1 (2 x 20 mL), sat. NaHCCL (5 x 20 mL) and brine (1 x 20 mL). The organic layer was dried over Na2S04, filtered and evaporated to give brown crude oil with residual DMF. Crude oil was dissolved in 8 mL of 1 : 1 DMF iFLO + 0.1% TFA, loaded onto a 60 g Biotage SNAP Ultra C18 column (Biotage AB, Uppsala, Sweden) and purified under a linear 30-100% gradient of ACN/H2O + 0.1% TFA over 8 column volumes. Pure fractions were pooled and diluted with brine (20 mL), then extracted 3 x 50 mL Et20. Pooled organics were dried over MgSCL, filtered and evaporated to recover a light-yellow oil (1.34 g, 66% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With diisopropyl-carbodiimide; In acetonitrile; at 20℃; for 16h; | To l-(4-(4-amino-2-butyl-liT-imidazo[4,5-c]quinolin-8-yl)piperazin-l-yl)- 3,6,9,l2,l5,l8,2l,24,27,30-decaoxatritriacontan-33-oic acid HCL salt (0.13 mmol, 1 eq) was added a mixture of 2,3,5, 6-<strong>[769-39-1]tetrafluorophenol</strong> (66 mg, 0.4 mmol, 3 eq) and diisopropylcarbodiimide (51 mg, 62 pL, 0.4 mmol, 3 eq) dissolved in acetonitrile (3 mL) and the mixture was stirred at 20 C for 16 h. The mixture was diluted with water (12 mL) and purified by reverse phase chromatography using a gradient eluent of 30-80% acetonitrile/water + 0.1% TFA over 10 min. The pooled fractions were concentrated under reduced pressure and the glassy film was azeotroped with acetonitrile four times (20 mL) to yield 2, 3, 5, 6- tetrafluorophenyl l-(4-(4-amino-2-butyl-liT-imidazo[4,5-c]quinolin-8-yl)piperazin-l-yl)- 3,6,9,l2,l5,l8,2l,24,27,30-decaoxatritriacontan-33-oate in a 54% yield. LC/MS [M+H] 985.49 (calculated); LC/MS [M+H] 985.71 (observed). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In dichloromethane; at 0 - 20℃; for 12h; | Add 200 g of dichloromethane and 175 g of 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (reactant C) to a 500 ml three-necked flask at room temperature, and stir at room temperature for 0.5 h. 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> is completely dissolved, The solution was colorless and transparent. The three-necked bottle was connected to an external gas absorption device, and then 143 g of the reaction intermediate B was slowly added to the 500 ml three-necked bottle via a dropping funnel. The dropping rate was controlled to 1 drop / second, and the reaction temperature was 0 C. Following the dropwise addition of reaction intermediate B, a large amount of heat was released and a large amount of HCl gas was released. After all the solution was dropped, the solution was colorless and transparent. Stirring was continued for 12 hours at room temperature, and then dichloromethane was removed to obtain a pale yellow solid. The yellow solid was crystallized from n-hexane and dried under vacuum for 3 h to obtain 250 g of a white solid with a yield of 92%. This product is compound 14 (2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong>-based vinyl phosphate or 2- (2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong>-based) -2-oxo-1,3,2- Dioxaphosphalane).The HCl gas generated by the reaction is absorbed by water to obtain hydrochloric acid. The hydrochloric acid is sold as a chemical raw material. The organic solvent used in the reaction is distilled and dried to be recovered and reused. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Add to 500ml three-necked bottle at room temperature200g dichloromethane and 175g 2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> (reactant C),Stir at room temperature for 0.5h,2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong> is completely dissolved,The solution is colorless and transparent,The three-necked bottle is connected to an external gas absorption device,Then 127 g of reaction intermediate B was slowly added to a 500 ml three-neck via a dropping funnel., Control the drop acceleration to 1 drop / second,The reaction temperature is 0 C.With the dropwise addition of reaction intermediate B,Emit a lot of heat and a lot of HCl gas,After all dripping, the solution was colorless and transparent.Then warmed to room temperature and continued to stir for 12 hours.The dichloromethane was then removed to give a pale yellow liquid,The pale yellow liquid was distilled under reduced pressure at 200 C to obtain 236 g of a colorless transparent liquid with a yield of 92%.This product is compound 14 (2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong>-based vinyl phosphite or 2- (2,3,5,6-<strong>[769-39-1]tetrafluorophenol</strong>-based) -1,3,2-dioxophosphate Heterocyclopentane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N,N-dimethyl-aniline; at 160℃; for 5h; | Dissolve 210g of <strong>[652-34-6]4-hydroxy-2,3,5,6-tetrafluorobenzoic acid</strong> dry product in 1050g of N,N-dimethylaniline, slowly raise the temperature to reflux with stirring, and reflux for 5 hours at 160C. Sampling and HPLC analysis showed that the raw material <strong>[652-34-6]4-hydroxy-2,3,5,6-tetrafluorobenzoic acid</strong> was completely converted. The temperature was lowered. The reaction solution was poured into 5L cold water, extracted three times with dichloromethane, combined the extracts, and washed three times with water, dried over anhydrous magnesium sulfate, concentrated, distilled, and then rectified to obtain 147 g of 2,3,5,6-tetrafluorophenol with a yield of 88% and an HPLC content of 99.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.7% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 16h; | 8.2.2.1 8.2.2.1. Synthesis and analytical characterization of 2,3,5,6-tetrafluorophenyl 3-(pyridin-4-yl)propanoate 3-(Pyridin-4-yl)propionic acid (500 mg, 3.3 mmol, 1.0 eq.), 2,3,5,6-tetrafluorophenol (604 mg, 3.6 mmol, 1.1 eq.) and EDC x HCI (761 mg, 4.0 mmol, 1.2 eq.) were dissolved in dry DCM (10 mL). The resulting mixture was stirred at room temperature for 16 h. Subsequently, the mixture was extracted with 0.1 M HCI (2x), brine (1x) and dried with Na2SO4 after which the solvent was removed under reduced pressure. The reaction afforded a white solid (530 mg, 47.7% yield). (0222) 1H NMR (400 MHz, CDCI3): d 8.49 (m, 2 H), 7.91 (m, 1 H), 7.35 (d, 2 H), 3.21 (t, 2 H), 3.02 (t, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: Pentafluorobenzoic acid With sodium acetate In N,N-dimethyl-formamide for 6h; Reflux; Stage #2: With sulfuric acid In N,N-dimethyl-formamide at 80℃; for 5h; Reflux; | 1-5 Example 4: Put 404 grams of DMF and 202.3 grams of sodium acetate into a 1L glass reactor. Add 106.0 g of pentafluorobenzoic acid at a temperature of 50-55 °C. The reaction was heated and refluxed for 6 hours. HPLC detected that the raw material content of the reaction solution was lower than 1.0%, and dropped below 80 °C, and 143.8 g of 98% concentrated sulfuric acid was added to the kettle to adjust the pH to less than 1. Then the temperature was raised and refluxed for 5 hours. After the reflux is completed, steam distillation is performed to separate the lower organic matter. The lower organic matter was rectified to obtain 79.0 g of 2,3,5,6-tetrafluorophenol, which turned into white crystals after cooling, with a yield of 95% and a purity of 99.8%. |
91.3% | With water; potassium carbonate at 140 - 145℃; for 20h; Sealed tube; | 9 Example 9 Add 550 grams of water and 222 grams of potassium carbonate to a 1-liter pressure-resistant reactor, and stir at room temperature.Add 110 grams of pentafluorobenzoic acid, seal the reaction kettle, heat up to 140-145°C for 20 hours, and stop the reaction.The reaction system is lowered to room temperature, the reaction solution is taken out, the pH is adjusted to 1-2 with 15% sulfuric acid solution, and the solution is extracted with toluene.The organic phases were combined, dried, concentrated, and rectified to obtain 78.65 g of 2,3,5,6-tetrafluorophenol, with a yield of 91.3% and a purity of 99.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 2,3,5,6-tetrafluorophenol With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 0.5h; Stage #2: 4-Vinylbenzyl chloride In N,N-dimethyl-formamide at 60℃; for 16h; | 3-4.1 Step 1) Preparation of compound 3-4' Potassium carbonate (10.4 g, 75.3 mmol) was placed in a 500 mL round bottom flask, and DMF (200 ml) was added thereto. 2,3,5,6-tetrafluorophenol (10.0 g, 60.22 mmol) was placed in a flask and stirred at 60° C. for 30 minutes. 4-vinylbenzyl chloride (7.66 g, 50.18 mmol) was slowly added to the reaction solution and stirred at 60° C. for 16 hours. Then water (300 mL) and ethyl acetate (200 ml) were added. The organic layer was extracted with ethyl acetate (200 mL×2) and the residue was removed with MgSO4. Compound 3-4' (11.2 g, yield 79%) was prepared by column with ethyl acetate:hexane = 1:9 (v:v). |
79% | Stage #1: 2,3,5,6-tetrafluorophenol With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 0.5h; Stage #2: 4-Vinylbenzyl chloride In N,N-dimethyl-formamide at 60℃; for 16h; | 4.1 Step 1) Preparation of Compound IV′ Potassium carbonate (10.4 g, 75.3 mmol) was placed in a 500 mL round bottom flask, to which DMF (200 ml) was added. To the flask, 2,3,5,6-tetrafluorophenol (10.0 g, 60.22 mmol) was added, and the mixture was stirred at 60° C. for 30 minutes. 4-Vinylbenzyl chloride (7.66 g, 50.18 mmol) was slowly added to the reaction solution and stirred at 60° C. for 16 hours. Then, water (300 mL) and ethyl acetate (200 ml) were added. The organic layer was extracted with ethyl acetate (200 mL×2) and the residual water was removed with MgSO4. The resulting material was subjected to column chromatography from ethyl acetate:hexane=1:9 (v:v) to give Compound IV′ (11.2 g, yield: 79%). |
79% | Stage #1: 2,3,5,6-tetrafluorophenol With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 0.5h; Stage #2: 4-Vinylbenzyl chloride at 60℃; for 16h; | 6.1 Step 1) Preparation of compound 3-4' Potassium carbonate (10.4 g, 75.3 mmol) was added to a 500 mL round bottom flask, and DMF (200 ml) was added thereto.2,3,5,6-tetrafluorophenol (10.0 g, 60.22 mmol) was placed in a flask and stirred at 60° C. for 30 minutes.4-vinylbenzyl chloride (7.66 g, 50.18 mmol) was slowly added to the reaction solution and stirred at 60° C. for 16 hours.Then water (300 mL) and ethyl acetate (200 ml) were added.The organic layer was extracted using ethyl acetate (200 mL × 2), and theresidue was removed with MgSO4 .Compound 3-4' (11.2 g, yield 79%) was prepared by column with ethyl acetate:hexane = 1:9 (v:v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With dicyclohexyl-carbodiimide In 1,4-dioxane at 20℃; for 16h; Cooling with ice; | 14.1 Step 1: Synthesis of 2,3,5,6-Tetrafluorophenyl 3-(2-{2-[3-oxo-3-(2,3,5,6-tetrafluorophenoxy)propoxy]ethoxy}ethoxy)propanoate (Intermediate 13 - A) To a 20 mL scintillation vial containing 3-{2-[2-(2-carboxyethoxy)ethoxy]ethoxy}propanoic acid (Bis-PEG3-acid, 51 mg, 0.20 mmol) and a stir bar was added a solution of 2,3,5,6-tetraflurophenol (76 mg, 0.43 mmol in 1 mL of anhydrous 1,4-dioxanes). The reaction was then placed in an ice bath to stir and after ~5 min noticed was no longer fully soluble. Lastly, added N,N′-Dicyclohexylcarbodiimide (DCC, 90 mg, 0.43 mmol) in anhydrous 1,4-dioxanes (0.5 mL) in one portion and then removed the mixture from the ice bath to stir at room temperature for 16 h. The reaction was then monitored by HPLC-MS and worked up by dilution with MeCN (2 mL) and filtration through a fritted filter. The filtered solid was then washed with an additional MeCN (~5 mL) and the combined filtrate was concentrated under vacuum and purified on a preparative C18 HPLC column to afford Intermediate 13 - A (100 mg, 90%, 96% purity) as a clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.1% | With diisopropyl-carbodiimide In ethyl acetate at 0 - 20℃; for 3h; | 1 [00603] A solution of 3,3'-(ethane-1,2-diylbis(oxy))dipropionic acid (1A) (1.0 eq, 0.200 g, 0.96 mmol) and 2,3,5,6-tetrafluorophenol (2.0 eq, 0.315 g, 1.9 mmol) in ethyl acetate (4 mL) was cooled at 0 °C, N,N'-diisopropylcarbodiimide (3.0 eq, 0.44 mL, 2.8 mmol) was added and reaction mixture was stirred at room temperature for 3 h. Reaction mixture was filtered through Celite bed and Celite bed was washed with ethyl acetate. The filtrate was concentrated to get crude product which was purified by column chromatography using silica gel (100-200 mesh) and 0-10% ethyl acetate in hexane to afford Compound 1B as a colorless viscous liquid. Yield: 0.370 g, 76.1 %; LC-MS m/z 500.96 [M-1]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.6% | With tert.-butylhydroperoxide; 3K(1+)*BO40W12(5-)*14H2O*4C3H3N4O2(1-)*2C3H4N4O2*3Cu(2+) at 60℃; for 2.5h; |
Tags: 769-39-1 synthesis path| 769-39-1 SDS| 769-39-1 COA| 769-39-1 purity| 769-39-1 application| 769-39-1 NMR| 769-39-1 COA| 769-39-1 structure
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P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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