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CAS No. : | 14533-84-7 | MDL No. : | MFCD00134438 |
Formula : | C8F8O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VCQURUZYYSOUHP-UHFFFAOYSA-N |
M.W : | 280.07 | Pubchem ID : | 4327891 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 10.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 37.92 |
TPSA : | 26.3 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.67 cm/s |
Log Po/w (iLOGP) : | 1.9 |
Log Po/w (XLOGP3) : | 3.29 |
Log Po/w (WLOGP) : | 6.21 |
Log Po/w (MLOGP) : | 4.47 |
Log Po/w (SILICOS-IT) : | 4.57 |
Consensus Log Po/w : | 4.09 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.7 |
Solubility : | 0.0562 mg/ml ; 0.000201 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.52 |
Solubility : | 0.0851 mg/ml ; 0.000304 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.37 |
Solubility : | 0.012 mg/ml ; 0.000043 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 3.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 1.91 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | 3272 |
Hazard Statements: | H225-H315-H319-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
99% | at 40℃; for 18 h; | A mixture of pentafluorophenol (50.0 g, 271 mmol) and trifluoroacetic anhydride (85.0 g, 404 mmol) was stirred at 4O0C for 18 h. The resulting mixture was fractionally distilled to afford pentafluorophenol trifluoroacetate as a colourless liquid (75.2 g, 99percent); bp 122-125°C.A solution of oleic acid (30.0 g, 106 mmol) in anhydrous DMF (100 mL) was added to a solution of pentfluorophenol trifluoroacetate (32.7 g, 116 mmol) in anhydrous DMF (100 mL), followed slowly by pyridine (9.16 g, 116 mmol). The resulting mixture was stirred at room temperature for 18 h, then diluted with ethyl acetate (200 mL) and washed successively with 0.1 N hydrochloric acid (1 x 100 mL), saturated aq. sodium bicarbonate solution (1 x 100 mL), and brine (1 x 50 mL). The organic solution was dried (MgSO4) and concentrated in vacuo to leave oleic acid pentafluoroacetate as a colourless viscous liquid (45.0 g, 95percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: With pyridine In N,N-dimethyl-formamide for 0.0833333 h; |
Biotin (5 g; 23.1 mmol; 1.0 eq) is suspended in anhydrous DMF (50 ml) and pyridine (2.07 ml; 25.4 mmol; 1.1 eq). After stirring for 5 minutes, pentafluorophenyl trifluoroacetate (PFP-TFA: 4.621 ml, i.e. 7.50 g; 25.4 mmol; 1.1 eq) is added. After stirring for one night, the reaction is finished, and the solvents are evaporated on the rotary evaporator. The evaporation residue is taken up in 100 ml of ethyl ether to suspend it, then filtered off on a fritted filter, and the cake is rinsed with a minimum of ether. Note: in the TLC a small trace of biotin is observed, but that will have no impact on what follows. m=7.106 g. Yield: 81percent. TLC eluent: DCM/MeOH: 90/10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine In N,N-dimethyl-formamide for 0.75h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 70℃; for 1h; | D-Biotin (1.00 g, 4.09 mmol) was dissolved in 20 mL DMF at 70 C and allowed to cool to rt. TEA (0.83g, 1.14 mL, 8.19 mmol) was added, followed by pentafluorophenyl trifluoroacetate (1.60 g, 0.98 mL, 5.73 mmol). The reaction was allowed to stir for 1 h at 0 C and became pink. Solvent was reduced to 1 mL in vacuo and the crude material was triturated with cold diethyl ether. The pFp ester product was recovered as a white solid (1.54 g, 96%). Biotin-pFp ester (1.00 g, 2.44 mmol) was dissolved in 10 mL DMF and cooled to 0 C. A flask containing a suspension of NaBH4 (3.4 mmol) in dry DMF (5 mL) was also cooled to 0 C. The pFp-ester was transferred dropwise via a cannula over 15 min and the mixture was stirred at 0 C. The reaction was followed by TLC and upon completion the cold mixture was acidified with 1 N HC1 and reduced to 1 mL in vacuo. The residue was triturated with cold diethyl ether and the product alcohol was recovered as a white solid (0.528 g, 94%). The alcohol (0.528 g, 2.29 mmol) and TEA (0.39 ml, 1.2 eq) were dissolved in DMF (10 mL) and added dropwise to a stirred solution of 4-nitrophenyl chloroformate (4-NCF, 1.38 g, 6.87 mmol, 3.0 eq) in DMF (10 mL) over a period of 1 h at -10C. The reaction mixture was allowed to warm to rt, stirred overnight, and subsequently and reduced to 1 mL in vacuo. The residue was triturated with cold diethyl ether. The nitrophenol carbonate product was recovered as a white solid (0.96 g, 95%). Fmoc-L-Lys-OH (1.03 g, 2.83 mmol, 1.3 eq.) was suspended under argon in anhydrous DMF (10 ml) containing DiPEA (0.50 ml, 1.3 eq.). To this white suspension, a clear solution of the nitrophenol-carbonate (2.18 mmol, 1.0 eq.) in anhydrous DMF (10 mL) was added drop wise under argon at rt over a period of 2 h. The reaction mixture was stirred for additional 4 h at rt, before the solution as acidified to pH 2 with 1 N HC1. All volatiles were evaporated under reduced pressure and the residue was triturated with cold diethyl ether. The crude product was purified by column chromatography (DCM : MeOH 95 : 5 v/v) to give the Fmoc-protected ncAA as a white solid. The Fmoc- protected ncAA was dissolved in 20% piperidine in DMF (5 ml) and stirred for 1 h at r.t.. All volatiles were removed under reduced pressure and the residue was triturated with cold diethyl ether. Drying of the residue in vaccuum yield the pure ncAA as a white powder (0.622 g, 71 %). 1H-NMR (D6-DMSO, 400 MHz): delta = 1.30-1.45 (m, 6H), 1.50-1.65 (m, 4H), 1.85 (m, 2H), 2.65 (d, J = 12.2 Hz, 1H), 2.84 (dd, J= 5.0 Hz, J= 12.2 Hz, 1H), 2.95 (m, 2H), 3.13 (m, 1H), 3.42 (m, 1H), 3.66 (m, 1H), 3.85 (dd, J= 13.8 Hz, J = 1.0 Hz 1H), 3.93 (t, J= 7.5 Hz, 2H), 4.17 (dd, J= 8.2 Hz, J= 7.3 Hz, 1H), 4.35 (dd, J= 8.1 Hz, J= 7.2 Hz, 1H), 7.11 (t, J= 5.4 Hz, 1H), 8.50 (br, 3H), 8.53 (br, 1H), 8.68 (br, 1H).13C-NMR (D6-DMSO, 100 MHz): 13C-NMR (CDCI3, 100 MHz): delta = 171.44, 163.29, 156.82, 64.00, 61.61, 60.35, 59.79, 55.95, 52.28, 39.10, 30.05, 29.35, 29.02, 28.78, 28,73, 25.91, 22.05. HR-MS (C17H31N4O5S): calculated: 403.20097, found: 403.20159. |
81% | Biotin (5 g; 23.1 mmol; 1.0 eq) is suspended in anhydrous DMF (50 ml) and pyridine (2.07 ml; 25.4 mmol; 1.1 eq). After stirring for 5 minutes, pentafluorophenyl trifluoroacetate (PFP-TFA: 4.621 ml, i.e. 7.50 g; 25.4 mmol; 1.1 eq) is added. After stirring for one night, the reaction is finished, and the solvents are evaporated on the rotary evaporator. The evaporation residue is taken up in 100 ml of ethyl ether to suspend it, then filtered off on a fritted filter, and the cake is rinsed with a minimum of ether. Note: in the TLC a small trace of biotin is observed, but that will have no impact on what follows. m=7.106 g. Yield: 81%. TLC eluent: DCM/MeOH: 90/10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine In dichloromethane at 20℃; for 1h; | |
99% | With pyridine at 20℃; for 1h; | |
87% | With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of indole carboxylic acid (0.5 g, 3.10 mmol) in DMF (3.00 ml) was added pentafluorophenyl trifluoroacetate (6.2 mmol, 1.068 ml) followed by pyridine (0.281 ml). The reaction mixture (a suspension was obtained at this stage) was stirred at r.t. under inert atmosphere for approximately 30 minutes. The reaction mixture was poured into ether (40 ml) and diluted with ethyl acetate (2 x 50 ml). The organics were washed with water, dried (NajSO-t) and concentrated to obtain an off white solid (70% yield, 720 mg, t.l.c. Rf- 0.71 EtOAc : Hexane, 1:1). No purification was necessary: 1H NMR (DMSO-cfe, 400 MHz) delta 11.7 (S5IH, NH), 8.49 (s, IH), 7.87-7.84 (dd, J = 8 Hz , 4Hz, IH), 7.59-7.55 (m, 2H), 6.67-6.66 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h; | [0275] To a solution of the product of Example 2, Step A, 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid (10.0 g, 24.4 mmol), and pyridine (2.16 mL, 26.8 mmol) in anhydrous dimethylformamide (49 mL) was added <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (5.35 mL, 30.5 mmol). The resultant solution was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (600 mL) and washed with 0.1 M aqueous hydrochloric acid (2×240 mL), 25% saturated aqueous sodium bicarbonate (2×240 mL), and saturated brine (240 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford an oil that was purified on silica gel. Elution with hexanes-ethyl acetate (19:1) afforded 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid pentafluorophenyl ester (12.8 g, 91%) as a pale-yellow powder: m.p. 108.5-110.0 C.; 1H-NMR (400 MHz, CDCl3) delta 8.77 (br s, 1H), 8.07 (br s, 1H), 7.69 (br s, 1H), 7.48 (br d, J=7.0 Hz, 1H), 6.91 (br d, J=7.2 Hz, 1H), 6.67 (br s., 1H); 19F-NMR (376 MHz, CDCl3) delta -123.74 (s, 1F), -139.17 (d, J=16.8 Hz, 1F), -152.35 (d, J=21.4 Hz, 2F), -156.96 (t, J=21.4 Hz, 1F), -161.81 (t, J=21.4 Hz, 2F). Anal. Calcd/found for C19H6NO2F7ClI: C, 39.65/39.32; H, 1.05/0.91; N, 2.43/2.35; F, 23.10/22.85; Cl, 6.16/6.92; I, 22.05/22.50. |
91% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Step B Preparation of 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic Acid Pentafluorophenyl Ester To a solution of the product of Example 6, Step A, 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid (10.0 g, 24.4 mmol), and pyridine (2.16 mL, 26.8 mmol) in anhydrous dimethylformamide (49 mL) was added <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (5.35 mL, 30.5 mmol). The resultant solution was stirred at ambient temperature for 2 h. The reaction mixture was diluted with ethyl acetate (600 mL) and washed with 0.1 M aqueous hydrochloric acid (2*240 mL), 25% saturated aqueous sodium bicarbonate (2*240 mL), and saturated brine (240 mL). The organics were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford an oil that was purified on silica gel. Elution with hexanes-ethyl acetate (19:1) afforded 2-(2-chloro-4-iodophenylamino)-3,4-difluorobenzoic acid pentafluorophenyl ester (12.8 g, 91%) as a pale-yellow powder: mp. 108.5-110.0 C.; 1H-NMR (400 MHz, CDCl3) delta 8.77 (br s, 1H), 8.07 (br s, 1H), 7.69 (br s, 1H), 7.48 (br d, J=7.0 Hz, 1H), 6.91 (br d, J=7.2 Hz, 1H), 6.67 (br s., 1H); 19F-NMR (376 MHz, CDCl3) delta -123.74 (s, IF), -139.17 (d, J=16.8 Hz, IF), -152.35 (d, J=21.4 Hz, 2F), -156.96 (t, J=21.4 Hz, 1F), -161.81 (t, J=21.4 Hz, 2F). Anal. Calcd/found for C19H6NO2F7ClI: C, 39.65/39.32; H, 1.05/0.91; N, 2.43/2.35; F, 23.10/22.85; Cl, 6.16/6.92; I, 22.05/22.50. aa0-5aa |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.3% | With pyridine; In DMF (N,N-dimethyl-formamide); at 20℃; for 20.5h; | In an oven-dried three-neck, 2 L flask was taken 3, 4-DUFLUORO-2- [ (2- fluoro-4-iodophenyl) amino] benzoic acid (196.7g, 0.5 moles) and DMF (900 mL). To this stirred solution was added pyridine (44.4 mL, 43.5g, 0.55 moles) at RT, and then pentafluorophenyl trifluoroacetate (95 mL, 154g, 0.55 moles) was added dropwise within 30 minutes. The mixture was stirred at RT for 20 hours. The mixture was diluted with hexanes-diethyl ether (1 : 1, v/v, 3L) and washed successively with water (2x2L), 1M HC1 (2x2L), saturated NAHCO3 solution (2x2L) and finally with water (2x2L). The organic layer was dried and concentrated under reduced pressure to afford 2,3, 4,5, 6-pentafluorophenyl-3,4- difluoro-2- [ (2-fluoro-4-iodophenyl) amino] benzoate as a red oil (92.3%, 258.5g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With pyridine; In N,N-dimethyl acetamide; at 20℃; for 2h; | 4-(2-FLUORO-4-IODOANILINO)-1-METHYL-6-OXO-1, 6-DIHYDRO-3-PYRIDINECARBOXYLIC acid (894 mg, 2.30 MMOL) and pyridine (909 mg, 11.5 MMOL) were dissolved in DMA (15 mL). To this mixture was added pentafluorophenyl TRIFLUOROACETATE (3.22 g, 11.5 MMOL) then the solution was allowed to stir at R. T. for 2 h. The DMA solution was diluted with EtOAc (150 mL), which was washed sequentially with 1 M HCI (2X100 ML), water (100 mL), sat. NaHCO3 (2X100 mL), and brine (100 mL). The EtOAc fraction was then dried (Na2SO4) and the solvent removed under reduced pressure to yield a viscous oil which was purified by column chromatography on silica gel (50% EtOAc/PE as ELUANT). This afforded 2,3, 4,5, 6-PENTAFLUOROPHENYL-4- (2-FLUORO-4- iodoanilino)-1-methyl-6-oxo-1, 6-dihydro-3-pyridinecarboxylate as a cream foam (1.22 g, 96%) which was used directly in subsequent STEPS. H NMR [(CD3)2SO, 400 MHz] 8 9.03 (s, 1 H), 8.70 (s, 1 H), 7.79 (DD, J = 10. 1,1. 9 Hz, 1 H), 7.62 (BR DD, J = 8. 4,1. 0 Hz, 1 H), 7.29 (t, J = 8. 4 Hz, 1 H), 5.36 (d, J = 1.6 Hz, 1 H), 3.45 (s, 3 H). LCMS (APCI+) calcd for C19HGF6N203 555 (MH+), found 555. |
With pyridine; In DMF (N,N-dimethyl-formamide); at 20℃; for 24h; | To a stirred solution of 4-(2-FLUORO-4-IODO-PHENYLAMINO)-1-METHYL-6-OXO-1, 6-dihydro- PYRIDINE-3-CARBOXYLIC acid (5.62 g, 14.5 mmol) in DMF (50 mL) was added pyridine (3.5 mL, 43.4 MMOL) then followed by dropwise addition of <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (4.5 mL, 43.4 MMOL). The mixture was stirred at room temperature for 24 hours. To this mixture was added hydrazine monohydrate (2.8 mL, 58 MMOL). The reaction mixture was stirred at room temperature for another 24 hours. The precipitated white solid was collected by filtration and washed with water (5 mL) and hexanes. After drying, the 4-(2-Fluoro-4-iodo-phenylamino)-1- METHYL-6-OXO-1, 6-DIHYDRO-PYRIDINE-3-CARBOXYLIC acid hydrazide was obtained as a white solid (6.55 g, 81%). 1H NMR [(CD3) 2SO, 400 MHz] 0 9.90 (s, 1 H), 9.63 (s, 1H), 8. 15 (s, 1 H), 7.73 (d, 1 H), 7.58 (d, 1 H), 7.26 (t, 1 H), 5.58 (s, 1 H), 4.42 (br s, 1 H), 2.50 (T, 3 H). Anal. Calcd for CR5H14FIN203 : C, 43.3 ; H, 3.4 ; N, 6.7. Found: C, 43.7 ; H, 3.1 ; N, 7.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 13; General Method for the Preparation of Active Esters of N-Substituted Piperazine Acetic Acid from Trifluoroacetate Esters; A solution of the trifluoroacetate in THF (0.58 M, 1.2 equiv) was added to a solid sample of N-methyl piperazine acetic acid and mixed in a vortex or shaker until a homogeneous solution was obtained. The reaction of the carboxylic acid with the trifluoroacetate ester was generally complete within 30 min for all cases except N-hydroypyrrolidinone (NHP, 18 h). The progress of conversion to the active ester was monitored by ES-MS. The amount of product and any starting material (N-MPA) could be determined by direct infusion of a sample of the reaction (in ethanol) into the ES-MS. In some cases the active ester product was precipitated as dihydrochloride salt by the addition of a solution by addition of HCl solution in dioxane (4 M, 50% volume of the reaction) followed by washing with THF, ethyl acetate and hexanes. In other cases the product was isolated from the reaction as the mono TFA salt. Addition of TFA could be performed if the bis-TFA salt was desired. Dhbt ester, Calculated MH+ = 304.14 Found = 304.20 NHP ester, Calculated MH+ = 242.15 Found = 242.20 4-NP ester, Calculated MH+ = 280.13 Found = 280.20 1H NMR (400 MHz, CDCl3) d 8.20 (d, 2H, J=9.2 Hz, aromatic protons), 7.25 (d, 2H, J=9.2 Hz, aromatic protons), 3.69-3.40 (broad, 2H, ring protons), 3.57 (s, 2H, -CH2-CO-), 3.15-2.90 (broad, 6H, ring protons), 2.78 (s, 3H, -CH3). Pfp ester, Calculated MH+ = 325.10 Found = 325.10 Pcp ester, Calculated MH+ = 404.95 Found = 405.90 3-NP ester, Calculated MH+ = 280.13 Found = 280.20 NHS ester, Calculated MH+ = 256.13 Found = 256.10 | ||
In tetrahydrofuran; for 0.5h; | Example 13; General Method For The Preparation Of Active Esters Of N-Substituted Piperazine Acetic Acid From Trifluoroacetate Esters; A solution of the trifluoroacetate in THF (0.58 M, 1.2 equiv) was added to a solid sample of N-methyl piperazine acetic acid and mixed in a vortex or shaker until a homogeneous solution was obtained. The reaction of the carboxylic acid with the trifluoroacetate ester was generally complete within 30 min for all cases except N-hydroypyrrolidinone (NHP, 18 h). The progress of conversion to the active ester was monitored by ES-MS. The amount of product and any starting material (N-MPA) could be determined by direct infusion of a sample of the reaction (in ethanol) into the ES-MS. In some cases the active ester product was precipitated as dihydrochloride salt by the addition of a solution by addition of HCl solution in dioxane (4 M, 50% volume of the reaction) followed by washing with THF, ethyl acetate and hexanes. In other cases the product was isolated from the reaction as the mono TFA salt. Addition of TFA could be performed if the bis-TFA salt was desired. Dhbt ester, Calculated MH+ = 304.14 Found = 304.20 NHP ester, Calculated MH+ = 242.15 Found = 242.20 4-NP ester, Calculated MH+ = 280.13 Found = 280.20 1H NMR (400 MHz, CDCl3) d 8.20 (d, 2H, J=9.2 Hz, aromatic protons), 7.25 (d, 2H, J=9.2 Hz, aromatic protons), 3.69-3.40 (broad, 2H, ring protons), 3.57 (s, 2H, -CH-CO-), 3.15-2.90 (broad, 6H, ring protons), 2.78 (s, 3H, -CH3). Pfp ester, Calculated MH+ = 325.10 Found = 325.10 Pcp ester, Calculated MH+ = 404.95 Found = 405.90 3-NP ester, Calculated MH+ = 280.13 Found = 280.20 NHS ester, Calculated MH+ = 256.13 Found = 256.10 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In N,N-dimethyl-formamide; at 15 - 20℃; for 1 - 2.16667h;Product distribution / selectivity; | Example 1 i) Pentafluorophenyl trifluoroacetate (48.9ml, 284mmol) was added dropwise, over 40 minutes maintaining the internal temperature below 15C, to a solution of (3 -amino- IH- pyrazol-5-yl)acetic acid (20.Og, 142mmol) and pyridine (25.3ml, 313mmol) in dimethylformamide (200ml). The mixture was then allowed to warm to room temperature and stirred for 1.5 hours. 3-Fluoroaniline (31.6g, 284mmol) was added in a single portion and the mixture was then stirred at room temperature for 1.5 hours. The mixture was poured into a dilute solution of hydrochloric acid and the resultant solid was filtered, washed with water and then diethyl ether to leave 2,2,2-trifluoro-N-(5-{2-[(3-fluorophenyl)amino]-2-oxoethyl}- lH-pyrazol-3-yl)acetamide (33.3g, 71% yield). MS (+ve ESI): 331 (M+Eta)+; Example 5 i) Pentafluorophenyl trifluoroacetate (24.4ml, 142mmol) was added dropwise, over 30 minutes maintaining the internal temperature below 15C, to a solution of (3 -amino- IH- pyrazol-5-yl)acetic acid (10. Og, 71mmol) and pyridine (12.6ml, 156mmol) in15 dimethylformamide (100ml). The mixture was then allowed to warm to room temperature and stirred for 30 minutes. 2,3-Difluoroaniline (18.3g, 142mmol) was added in a single portion and the mixture was then stirred at room temperature for 3 hours. The mixture was heated at 90C for 2 hours. The mixture was poured into a dilute solution of hydrochloric acid and the resultant solid was filtered, washed with water and then toluene and iso-hexane to20 leave N-(5-{2-[(2,3-difluorophenyl)amino]-2-oxoethyl}-lH-pyrazol-3-yl)-2,2,2- trifiuoroacetamide (18.0g, 74% yield). MS (-ve ESI): 347 (M-H)" |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;Product distribution / selectivity; | To a solution of compound 3 (1.8 g, 7.72 mmol) in DMF (50 ml) in the presence of triethylamine (1.18 ml, 8.49 mmol) was added pentafluorophenyl trifluoroacetate (1.46 ml, 8.49 mmol) dropwise in 5 min at 0 C. The reaction mixture was then stirred at room temperature overnight. After evaporation of solvent, the residue was dissolved in EtOAc and the organic phase was washed with water (50 ml X 3) and dried over Na2SO4. The compound was purified by chromatography using toluene-EtOAc (35:1) as eluent to give a powder (1.68 g, 55%). MS: 422.04 (M+Na+). 1H NMR (DMSO-d6) 8.66 (s, 1H), 8.00 (d, 1H), 7.64 (d, 1H), 7.40 (s, 1H), 4.36 (q, 2H), 1.34 (t, 3H) |
In N,N-dimethyl-formamide; at 20℃; for 0.75h;Product distribution / selectivity; | To a solution of 1 (7.02 g, 30.0 mmol, see Scheme 1) in EtOAc (60 mL) was added 10% Pd over activated carbon (2.0 g). The mixture was hydrogenated at 3540 psi for 30 min. The crude product was filtered through a bed of Celite, the Celite washed with EtOAc (100 ml) and the solvents removed in vacuo to give a 2 as a yellow solid, which was used without further purification in the coupling reaction. The activated acid 4 was prepared by slowly adding pentafluorophenyl trifluoroacetate (3.78 mL, 22.0 mmol) to a stirring solution of 3 (4.66 g, 20.0 mmol) in DMF (45 mL). The mixture was stirred at rt for 45 min. The crude product 4 was used without additional purification. The product of the reduction, 2, dissolved in DMF (25 mL) and diisopropylethylamine (3.84 mL, 22.0 mmol) were then added to the solution containing 4. The reaction mixture was heated at 55 C. for 6 h. The reaction mixture was then concentrated in vacuo, taken up in EtOAc (200 mL) and washed with water (100 mL), 0.1 N HCl (100 mL), and water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give 8.86 g of the crude product 5 as dense brown oil. The product was used without additional purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | To a solution of compound 32 (0.154 g, 0.44 [mol) in DMF (5 mL) in the presence of DIEA (93 ml, 0.53 mmol) was added dropwise <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (92 mul, 0.53 mmol) at 0 C. The resulting reaction mixture was stirred at room temperature overnight. HPLC showed that the reaction was completed. The solvent was then evaporated to dryness, and the residue was carefully washed with ether to give compound 33 in quantitative yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 18h; | A mixture of pentafluorophenol (50.0 g, 271 mmol) and trifluoroacetic anhydride (85.0 g, 404 mmol) was stirred at 4O0C for 18 h. The resulting mixture was fractionally distilled to afford pentafluorophenol trifluoroacetate as a colourless liquid (75.2 g, 99%); bp 122-125C.A solution of oleic acid (30.0 g, 106 mmol) in anhydrous DMF (100 mL) was added to a solution of pentfluorophenol trifluoroacetate (32.7 g, 116 mmol) in anhydrous DMF (100 mL), followed slowly by pyridine (9.16 g, 116 mmol). The resulting mixture was stirred at room temperature for 18 h, then diluted with ethyl acetate (200 mL) and washed successively with 0.1 N hydrochloric acid (1 x 100 mL), saturated aq. sodium bicarbonate solution (1 x 100 mL), and brine (1 x 50 mL). The organic solution was dried (MgSO4) and concentrated in vacuo to leave oleic acid pentafluoroacetate as a colourless viscous liquid (45.0 g, 95%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 0℃; for 1h; | [00178] To a solution of 1.2 (20 g, 93 mmol) in DCM were added pentafluorophenyltrifluoroacetate (20 mL, 112 mmol) and triethylamine (17 mL, 112 mmol) at 0 0C. The reaction mixture was stirred for 1 h. The solution was concentrated and the mixture <n="53"/>purified by flash column chromatography (100% DCM) to give 1.3 (35 g, quant.) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 1.5h; | DIMAC-fluorescein (S11) 6,7-dimethoxyazacyclooct-4-yne (DIMAC) (Sletten, E. M.; Bertozzi, C. R. Org. Lett. 2008, 10, 3097-3099; S9, 8.0 mg, 0.030 mmol, 1.0 equiv.) was dissolved in CH3CN (1 mL, anhydrous) and cooled to 0 C. DIPEA (10 muL, 0.057 mmol, 1.9 equiv.) was added and the mixture was stirred for 10 min, at which point pentafluorophenyltrifluoroacetate (15 muL, 0.087 mmol, 2.9 equiv.) was added. The reaction was warmed to room temperature and stirred for 1.5 h. It was then evaporated to dryness and purified by silica gel chromatography eluting with toluene/ether (7:1, 5:1, 3:1, anhydrous solvents used for chromatography). This procedure resulted in DIMAC-pentafluorophenyl ester (13 mg, 0.030 mmol, quant.). Half of the DIMAC-pentafluorophenyl ester (6.5 mg, 0.015 mmol, 1.0 equiv.) was dissolved in dimethylformamide (0.5 mL, anhydrous). In a separate flask, fluorescein-piperazine (Hangauer, M. J.; Bertozzi, C. R. Angew. Chem. Int. Ed. 2008, 47, 2394-2397; 11 mg, 0.028 mmol, 1.8 equiv.) was dissolved in dimethylformamide (0.5 mL, anhydrous) and DIPEA (?10 muL, 0.06 mmol, 4 equiv.). The DIMAC solution was added to the fluorescein-piperazine solution at 0 C. The reaction was warmed to room temperature over 5 h, at which point it was evaporated to dryness and purified first by silica gel chromatography (5:3:1 EtOAc/MeOH/H2O) then by HPLC (C18 column, with methanol/water, 40-100% methanol over 25 min, elutes at 15 min). This procedure resulted in pure DIMAC-fluorescein (3 mg, 0.005 mmol, 31% yield). Rf=0.7 in 5:3:1 ethyl acetate/methanol/water. HRMS (ESI): calcd. for C37H37O8N3Na [M+Na]+, 674.2473; found, 674.2478. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | 21.4 2-(4-Chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester To a solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (4.5 g, 12.1 mmol; example 5.1) in DMF (45 ml) was added pyridine (1.07 ml, 13.3 mmol) and <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (4.16 ml, 24.1 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 12 h, poured onto ice water/0.1 N HCl 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/sat. aqueous NaHCO3 solution 1/1, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give 2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester as a yellow oil (9 g, 16.7 mmol; quant.) which was directly used in the next reaction step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Pentafluorophenyltrifluoroacetate (0.49 mL, 2.82 mmol) was added to the stirred solution of freshly prepared MFCO-acid (1) (0.40 g, 2.35 mmol) in dichloromethane (10 mL) at 0 C. Diisopropylethylamine (0.47 mL, 2.82 mmol) was then added and the reaction was stirred at 0 C for 30 min, then allowed to warm to rt and maintained an additional 2 h. The reaction mixture was then filtered through a short silica gel column eluted with 2-5% ethyl acetate in hexanes. Column fractions containing product were combined and concentrated in vacuo to yield the desired PFP ester (2) as a yellow oil (0.58 g, 73%). |
0.85 g | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere; | <strong>[14533-84-7]Pentafluorophenyl trifluoroacetate</strong> (0.70 g, 2.52 mmol, 433 muL) was added to a solution of 1-fluorocyclooct-2-ynecarboxylic acid 5 (0.36 g, 2.12 mmol) and N,N-diisopropylethylamine (0.32 g, 2.52 mmol, 438 muL) in dry DCM (21 mL) brought to 0 C. The mixture was stirred at room temperature for 3 h and filtered over silica. The activated acid (0.85 g, 2.55 mmol), N-(2-aminoethyl)maleimide 6 (0.34 g, 3.19 mmol) and N,N-diisopropylethylamine (0.39 g, 3.06 mmol, 533 muL) were agitated in dry DMF (41 mL) for 16 h at room temperature. Distilled water (20 mL) was added. The organic phase was extracted with DCM (3 30 mL), washed with brine (80 mL) and dried over MgSO4. After filtration the mixture was concentrated in vacuum. Purification over silica gel (EtOAc/hexane, 20:80-30:70) afforded 1 (0.38 g, 61%). Rf = 0.45 (EtOAc/hexane, 1:1). 1H NMR (CDCl3, 300 MHz): delta 6.72 (s, 2H), 3.71 (m, 2H), 3.54 (m, 2H), 2.29 (m, 4H), 1.93 (m, 4H), 1.62 (m, 1H), 1.44 (m, 1H); 13C NMR (CDCl3, 75 MHz) delta (ppm): 171.4, 169.2 (d), 134.7, 109.7 (d), 96.0, 93.5, 87.2 (d), 46.3 (d), 39.2, 37.5, 34.2, 29.3, 26.0, 21.1; MS (ES+ for C15H17FN2O3): m/z = 293 [M+H+], 315 [M+Na+], calcd 292. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine In N,N-dimethyl-formamide at 20℃; for 5.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.5% | [00182] 20.5 g (0.093 mol) of <strong>[213598-11-9]methyl 3-cyano-4-isopropoxybenzoate</strong> was dissolved in 200 mL of a 6:4 mixture of methanol and water. To this was added 5.61 g (0.14 mol) of NaOH, and the mixture was stirred for 2 hours at room temperature. The solution was then filtered through a silica gel plug and the solvents removed under vacuum. The resulting solid was re-dissolved in 200 mL of CH2Cl2 and treated with 19.3 mL (0.11 mol) of perfluorophenyl 2,2,2-trifluoroacetate and 19.5 mL (0.14 mol) of triethylamine. After stirring overnight, the solution was filtered and any solids rinsed with CH2Cl2. The combined organic mixtures were run through a short silica gel column and then evaporated to dryness to give 29 g (83.5% yield) of 2 which was characterized by LCMS and HNMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 102[0257] To the 97 (700mg, 4.96mMol) in 7mL of DMF at 0 C was added pyridine (883muL, 863mg, 10.9ImMoI) followed by careful, dropwise addition of pentafluorophenyl trifluoroacetate (1.68mL, 2.78g, 9.92mMol). Reaction mixture was stirred at 0 C for 10 minutes and 90 minutes at room temperature. 4-fluorobenzylamine (1.13mL, 1.12g, 9.92mMol) was added and reaction mixture was stirred overnight at room temperature. Reaction was poured into 5OmL of IN HCl, organic layer was separated. Aqueous layer was extracted with EtOAc. Organic fractions were combined, washed with brine, dried over Na2SO4, filtered and solvent was evaporated to give 1.7Ig (quant.) of crude product 102 that was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 98 [0253] To compound 97 (700mg, 4.96mMol) in 7mL of DMF at 0 C was added pyridine (883muL, 863mg, 10.9ImMoI) followed by careful, dropwise addition of pentafluorophenyl trifluoroacetate (1.68mL, 2.78g, 9.92mMol). Reaction mixture was stirred at 0 C for 10 minutes and 90 minutes at room temperature. 3-fluoroaniline (954muL, l.lg, 9.92mMol) was added and reaction mixture was stirred overnight at room temperature. Reaction was poured into 5OmL of IN HCl, organic layer was separated. Aqueous layer was extracted with EtOAc. Organic fractions were combined, washed with brine, dried over Na2SO4, filtered and solvent was evaporated to give 1.6g (quant.) of crude product 98 that was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 100[0255] To compound 97 (700mg, 4.96mMol) in 7mL of DMF at O0C was added pyridine (883 muL, 863mg, 10.9ImMoI) followed by careful, dropwise addition of pentafluorophenyl trifluoroacetate (1.68mL, 2.78g, 9.92mMol). Reaction mixture was stirred at 0 C for 10 minutes and 90 minutes at room temperature. 2-chloro-6-methylaniline (1.22mL, 1.4g, 9.92mMol) was added and reaction mixture was stirred overnight at room temperature. Reaction was poured into 5OmL of IN HCl, organic layer was separated. Aqueous layer was extracted with EtOAc. Organic fractions were combined, washed with brine, dried over Na2SO4, filtered and solvent was evaporated to give 1.79g (quant.) of crude product 100 that was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | 4.2 [2-(4-Chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester To a solution of [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid (300 mg, 836 umol) in DMF (3 ml) was added pyridine (70 ul, 920 umol) and <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (290 ul, 1.7 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 12 h, poured onto ice water/0.1 N HCl 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/sat. aqueous NaHCO3 solution 1/1, ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester as an orange oil (762 mg; quant.) which was directly used in the next reaction step without further purification. |
100% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere; | 4.2 [2-(4-Chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester; To a solution of [2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]- cyclohexyl-acetic acid (300 mg, 836 umol) in DMF (3 ml) was added pyridine (70 ul, 920 umol) and pentafluorophenyl trifluoro acetate (290 ul, 1.7 mmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 12 h, poured onto ice water / 0.1 N HC1 1 / 1 and extracted two times with iPrOAc. The combined extracts were washed with ice water / sat. aqueous NaHC03 solution 1 / 1, ice water / brine 1 / 1 and dried over Na2S04. After filtration the solvent was removed under reduced pressure to give [2-(4-chloro- phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-cyclohexyl-acetic acid pentafluorophenyl ester as an orange oil (762 mg; quant.) which was directly used in the next reaction step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; In tetrahydrofuran; at 20℃; for 2h; | 1-Oxo-1,3-dihydroisobenzofuran-5-carboxylic acid 65 (370 mg, 2.08 mmol) was dissolved in THF (15 mL). To this solution was added pyridine (1.64 g, 20.8 mmol), followed by pentafluorophenyltrifluoroacetate (2.91 g, 10.4 mmol) and the resulting mixture stirred at rt for 2 h. All solvent was removed under reduced pressure to give an oil which was dissolved in EtOAc (100 mL) and washed with 1 M HCl (2 × 50 mL), water (50 mL), satd NaHCO3 (2 × 50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered, and the solvent removed under reduced pressure to give a crude product which was purified by flash column chromatography on silica gel (20% EtOAc/hexanes as eluant) to give the intermediate pentafluorophenyl ester (666 mg, 93%) which was used immediately in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In dichloromethane; at 20℃; for 1h; | Procedure for the preparation of compound 34, shown below. Triethylamine (0.616 g, 6.09 mmol) was added to a solution of <strong>[19694-02-1]1-pyrenecarboxylic acid</strong> (1.0 g, 4.06 mmol) in dry DCM (20 ml) followed by pentafluorophenyl trifluoroacetate (1.251 g, 4.47 mmol). The reaction was kept at room temperature for 1 h, concentrated in vacuo and then diluted with MeOH. The resultant solid material was isolated by filtration, washed with MeOH and dried in vacuo to give the PFP 1-pyrenecarboxylate (1.50 g, 3.64 mmol, yield=90%) as yellow fluffy solid. A portion of the PFP 1-pyrenecarboxylate (1.38 g, 3.35 mmol) was added to a mixture of compound 25 (2.79 mmol) and triethylamine (0.847 g, 8.37 mmol) in dry DCM (20 ml). The suspension was stirred under argon at room temperature overnight, then diluted with 10% citric acid and extracted with DCM. The organic solution was separated, washed with saturated aqueous NaHCO3, saturated aqueous NaCl, dried over MgSO4, filtered from drying agent, and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 0-20% acetone in EtOAc) to give product 34 (1.78 g, 2.09 mmol, 75%) as white solid. 1H NMR (DMSO-d6): delta 12.43 (s, 1H), 8.94 (t, J=5.7 Hz, 1H), 8.56 (d. J=9.0 Hz, 1H). 8.36-8.08 (m, 9H), 7.31-7.13 (m, 9H), 6.78-6.73 (m, 4H), 6.54 (dd, J=7.0; 4.0 Hz, 1H), 5.36 (d, J=-4.8 Hz, 1H). 4.52 (qn, J=5.3 Hz, 1H), 3.93 (dd, J=9.5: 5.5 Hz, 1H), 3.70-3.60 (m, 8H), 3.12-2.99 (m, 2H), 2.92 (t, J=7.0 Hz, 2H), 2.81-2.74 (m, 1H), 2.36-2.27 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; In dichloromethane; at 20℃; for 12h; | Pentafluorophenyl 3,3,3-trifluoropropanoate (2.44 mL, 13.4 mmol, 2.0 eq.) was added to a solution of 128 (4.18 g, 6.70 mmol, 1.0 eq.) in 50 mL of dichloromethane followed by pyridine (1.61 mL, 20.1 mmol, 3.0 eq.). Reaction was allowed to stir at room temperature for ~12 hours. Reaction was concentrated in vacuo and the residue was purified by silica chromatography (Gradient: 0%-70% acetone in heptanes) producing 135 (5.2 g, 98%) as a white foam. LC-MS (Protocol Ql): m/z 812.1 [M+Na+] retention time =1.24 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; In dichloromethane; at 20℃; for 2h; | Pentafluorophenyl 3,3,3-trifluoropropanoate (1.3 mL, 7.1 mmol, 2.0 eq.) was added to a solution of 136 (2.8 g, 3.5 mmol, 1.0 eq.) in 30 mL of dichloromethane followed by the addition of pyridine (0.85 mL, 10.6 mM). The reaction was allowed to stir at room temperature for 2 hours. The reaction was concentrated in vacuo, and the residue was purified by silica chromatography (Gradient: 0%-70% acetone in heptane) producing 137 ( 3.1 g, 92%) as a white powder. LC-MS (Protocol Ql): m/z 959.2 [M+H+] retention time =1.28 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With pyridine; In dichloromethane; at 20℃; for 1h; | To a solution of 5 (19.43 g, 37.03 mmol, 1 eq.) in dichloromethane (100 mL) and pyridine (5.86 g, 74.1 mmol, 2 eq.) was added <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (20.7 g, 74.1 mmol, 2 eq.) and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 to 52% ethyl acetate in heptane) to afford 174 (23.58 g, 92%) as a yellow oil. LC-MS (Protocol Ql): m/z 691.2 [M+H+], retention time = 1.23 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine; In dichloromethane; at 20℃; for 2.5h; | To a solution of 198 (0.28 g, 0.47 mmol, 1 eq.) in dichloromethane (2 mL) was added pyridine (75 mg, 0.94 mmol, 2 eq.) followed by a solution of <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (268 mg, 0.94 mmol, 2 eq.) in dichloromethane (1.5 mL). The mixture was stirred at room temperature for 2.5 hours, and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 1 to 10% methanol in dichloromethane) to afford compound 206 (348 mg, 97%) as white solid. LC- MS (protocol Ql): m/z 763.5 [M+H+], retention time = 0.9 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Triacid 20 (4 g, 14.43 mmol) was dissolved in DMF (120 mL) and diisopropylethylamine (12.35 mL, 72 mmoles). Pentaflourotriflouroacetate (PFPTFA, 8.9 mL, 52 mmoles) was added dropwise, under argon, and the reaction was allowed to stir at room temperature for 30 minutes. The reaction mixture was poured onto water, extracted with ethyl acetate, and the organic layer was washed successively with water and brine. The organic layer was dried over sodium sulfate, and evaporated to provide Compound 21 as a white solid. The yield was 94% and the NMR and LCMS data were consistent with structure. |
82% | With triethylamine; In dichloromethane; at 20℃; for 0.333333h; | A solution of 4-(2-carboxyethyl)-4-nitroheptanedioic acid (3.00 g, 10.8 mmol) in DCM (54 mL) was charged in an additional funnel and added dropwise to a solution of perfluorophenyl 2,2,2-trifluoroacetate (6.15 mL, 35.7 mmol) and TEA (9.0 mL, 65 mmol) in DCM (54 mL). Upon completion of addition, the solution was stirred an additional 20 min at room temperature, during which time a white precipitate formed. The precipitate was filtered and washed with 3 : 7 DCM : hexanes and then washed with hexanes to give the title compound (6.87 g, 82%) as a white solid. 1H- MR (400 MHz, CDC13) delta 2.88-2.71 (m, 6H), 2.59-2.41 (m, 6H). 19F- MR (376 MHz, CDC13) delta -152.71 (d, J= 17.1 Hz), -157.08 (t, J= 21.7 Hz), -161.86 (dt, J= 21.4, 10.7 Hz). |
82% | With triethylamine; In dichloromethane; at 20℃; for 0.333333h; | bis(perfluorophenyl) 4-nitro-4-(3-oxo-3- (perfluorophenoxy)propyl)heptanedioate: A solution of 4-(2-carboxyethyl)-4- nitroheptanedioic acid (3.00 g, 10.8 mmol) in DCM (54 mL) was charged in an additional funnel and added dropwise to a solution of perfluorophenyl 2,2,2-trifluoroacetate (6.15 mL, 35.7 mmol) and TEA (9.0 mL, 65 mmol) in DCM (54 mL). Upon completion of addition, the solution was stirred an additional 20 min at room temperature, during which time a white precipitate formed. The precipitate was filtered and washed with 3 : 7 DCM : hexanes and then washed with hexanes to give the title compound (6.87 g, 82%) as a white solid. |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h; | Compound 222 is commercially available. 44.48 ml (0.33 mol) of compound 222 was treated with tosyl chloride (25.39 g, 0.13 mol) in pyridine (500mL) for 16 hours. The reaction was then evaporated to an oil, dissolved in EtOAc and washed with water, sat. NaHC03, brine, and dried over Na2S04. The ethyl acetate was concentrated to dryness and purified by column chromatography, eluted with EtOAc/hexanes (1 : 1) followed by 10% methanol in CH2CI2 to give compound 223 as a colorless oil. LCMS and NMR were consistent with the structure. 10 g (32.86 mmol) of 1 -Tosyltriethylene glycol (compound 223) was treated with sodium azide (10.68 g, 164.28 mmol) in DMSO (l OOmL) at room temperature for 17 hours. The reaction mixture was then poured onto water, and extracted with EtOAc. The organic layer was washed with water three times and dried over Na2S04. The organic layer was concentrated to dryness to give 5.3g of compound 224 (92%). LCMS and NMR were consistent with the structure. 1 -Azidotriethylene glycol (compound 224, 5.53 g, 23.69 mmol) and compound 4 (6 g, 18.22 mmol) were treated with 4A molecular sieves (5g), and TMSOTf (1.65 ml, 9.1 1 mmol) in dichloromethane (l OOmL) under an inert atmosphere. After 14 hours, the reaction was filtered to remove the sieves, and the organic layer was washed with sat. NaHC03, water, brine, and dried over Na2S04. The organic layer was concentrated to dryness and purified by column chromatography, eluted with a gradient of 2 to 4%> methanol in dichloromethane to give compound 225. LCMS and NMR were consistent with the structure. Compound 225 (1 1.9 g, 23.59 mmol) was hydrogenated in EtOAc/Methanol (4: 1 , 250mL) over Pearlman's catalyst. After 8 hours, the catalyst wasremoved by filtration and the solvents removed to dryness to give compound 226. LCMS and NMR were consistent with the structure. In order to generate compound 227, a solution of nitromethanetrispropionic acid (4.17 g, 15.04 mmol) and Hunig's base (10.3 ml, 60.17 mmol) in DMF (lOOmL) were treated dropwise with pentaflourotrifluoro acetate (9.05 ml, 52.65 mmol). After 30 minutes, the reaction was poured onto ice water and extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na2S04. The organic layer was concentrated to dryness and then recrystallized from heptane to give compound 227 as a white solid. LCMS and NMR were consistent with the structure. Compound 227 (1.5 g, 1.93 mmol) and compound 226 (3.7 g, 7.74 mmol) were stirred at room temperature in acetonitrile (15 mL) for 2 hours. The reaction was then evaporated to dryness and purified by column chromatography, eluting with a gradient of 2 tol0% methanol in dichloromethane to give compound 228. LCMS and NMR were consistent with the structure. Compound 228 (1.7 g, 1.02 mmol) was treated with Raney Nickel (about 2g wet) in ethanol (lOOmL) in an atmosphere of hydrogen. After 12 hours, the catalyst was removed by filtration and the organic layer was evaporated to a solid that was used directly in the next step. LCMS and NMR were consistent with the structure. This solid (0.87 g, 0.53 mmol) was treated with benzylglutaric acid (0.18 g, 0.8 mmol), HBTU (0.3 g, 0.8 mmol) and DIEA (273.7 mu, 1.6 mmol) in DMF (5mL). After 16 hours, the DMF was removed under reduced pressure at 65C to an oil, and the oil was dissolved in dichloromethane. The organic layer was washed with sat. NaHC03, brine, and dried over Na2S04. After evaporation of the organic layer, the compound was purified by column chromatography and eluted with a gradient of 2 to 20% methanol in dichloromethane to give the coupled product. LCMS and NMR were consistent with the structure. The benzyl ester was deprotected with Pearlman's catalyst under a hydrogen atmosphere for 1 hour. The catalyst was them removed by filtration and the solvents removed to dryness to give the acid. LCMS and NMR were consistent with the structure. The acid (486 mg, 0.27 mmol) was dissolved in dry DMF (3 mL). Pyridine (53.61 mu, 0.66 mmol) was added and the reaction was purged with argon. Pentaflourotriflouro acetate (46.39 mu, 0.4 mmol) was slowly added to the reaction mixture. The color of the reaction changed from pale yellow to burgundy, and gave off a light smoke which was blown away with a stream of argon. The reaction was allowed to stir at room temperature for one hour (completion of reaction was confirmed by LCMS). The solvent was removed under reduced pressure (rotovap) at 70 C. The residue was diluted with DCM and washed with IN NaHSC^, brine, saturated sodium bicarbonate and brine again. The organics were dried over Na2S04, filtered, and were concentrated to dryness to give 225 mg of compound 229 as a brittle yellow foam. LCMS and NMR were consistent with the structure. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h; | In order to generate compound 227, a solution of nitromethanetrispropionic acid (4.17 g, 15.04mmol) and Hunig's base (10.3 ml, 60.17 mmol) in DMF (lOOmL) were treated dropwise with pentaflourotrifluoro acetate (9.05 ml, 52.65 mmol). After 30 minutes, the reaction was poured onto ice waterand extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na2S04. Theorganic layer was concentrated to dryness and then recrystallized from heptane to give compound 227 as awhite solid. LCMS and NMR were consistent with the structure. Compound 227 (1.5 g, 1.93 mmol) and5 compound 226 (3.7 g, 7.74 mmol) were stirred at room temperature in acetonitrile (15 mL) for 2 hours. Thereaction was then evaporated to dryness and purified by column chromatography, eluting with a gradient of 2tolO% methanol in dichloromethane to give compound 228. LCMS and NMR were consistent with thestructure. Compound 228 (1.7 g, 1.02 mmol) was treated with Raney Nickel (about 2g wet) in ethanol(lOOmL) in an atmosphere of hydrogen. After 12 hours, the catalyst was removed by filtration and the10 organic layer was evaporated to a solid that was used directly in the next step. LCMS and NMR wereconsistent with the structure. This solid (0.87 g, 0.53 mmol) was treated with benzylglutaric acid (0.18 g, 0.8mmol), HBTU (0.3 g, 0.8 mmol) and DIEA (273.7 Jll, 1.6 mmol) in DMF (5mL). After 16 hours, the DMFwas removed under reduced pressure at 65C to an oil, and the oil was dissolved in dichloromethane. Theorganic layer was washed with sat. NaHC03, brine, and dried over Na2S04. After evaporation of the organic15 layer, the compound was purified by column chromatography and eluted with a gradient of 2 to 20%methanol in dichloromethane to give the coupled product. LCMS and NMR were consistent with thestructure. The benzyl ester was deprotected with Pearlman's catalyst under a hydrogen atmosphere for 1hour. The catalyst was them removed by filtration and the solvents removed to dryness to give the acid.LCMS and NMR were consistent with the structure. The acid ( 486 mg, 0.27 mmol) was dissolved in dry20 DMF (3 mL). Pyridine (53.61 Jll, 0.66 mmol) was added and the reaction was purged with argon.Pentaflourotriflouro acetate ( 46.39 Jll, 0.4 mmol) was slowly added to the reaction mixture. The color of thereaction changed from pale yellow to burgundy, and gave off a light smoke which was blown away with astream of argon. The reaction was allowed to stir at room temperature for one hour (completion of reactionwas confirmed by LCMS). The solvent was removed under reduced pressure (rotovap) at 70 C. The25 residue was diluted with DCM and washed with IN NaHS04, brine, saturated sodium bicarbonate and brineagain. The organics were dried over Na2S04, filtered, and were concentrated to dryness to give 225 mg ofcompound 229 as a brittle yellow foam. LCMS and NMR were consistent with the structure. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h; | In order to generate compound 227, a solution of nitromethanetrispropionic acid (4.17 g, 15.04 mmol) and Hunig?s base (10.3 ml, 60.17 mmol) in DMF (100mL) were treated dropwise with pentaflourotrifluoro acetate (9.05 ml, 52.65 mmol). After 30 minutes, the reaction was poured onto ice water and extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na2SO4. The organic layer was concentrated to dryness and then recrystallized from heptane to give compound 227 as a white solid. LCMS and NMR were consistent with the structure | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h; | In order to generate compound 227, a solution of nitromethanetrispropionic acid (4.17 g, 15.04 mmol) and Hunig?s base (10.3 ml, 60.17 mmol) in DMF (100mL) were treated dropwise with pentaflourotrifluoro acetate (9.05 ml, 52.65 mmol). After 30 minutes, the reaction was poured onto ice water and extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na2SO4. The organic layer was concentrated to dryness and then recrystallized from heptane to give compound 227 as a white solid. LCMS and NMR were consistent with the structure | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h; | In order to generate compound 227, a solution of nitromethanetrispropionic acid (4.17 g, 15.04 mmol) and Hunig?s base (10.3 ml, 60.17 mmol) in DMF (lOOmL) were treated dropwise withpentaflourotrifluoro acetate (9.05 ml, 52.65 mmol). After 30 minutes, the reaction was poured onto ice water and extracted with EtOAc. The organic layer was washed with water, brine, and dried over Na2SO4. The organic layer was concentrated to dryness and then recrystallized from heptane to give compound 227 as a white solid. LCMS and NMR were consistent with the structure. Compound 227 (1.5 g, 1.93 mmol) and compound 226 (3.7 g, 7.74 mmol) were stirred at room temperature in acetonitrile (15 mL) for 2 hours. Thereaction was then evaporated to dryness and purified by column chromatography, eluting with a gradient of 2 tolO% methanol in dichloromethane to give compound 228. LCMS and NMR were consistent with the structure. Compound 228 (1.7 g, 1.02 mmol) was treated with Raney Nickel (about 2g wet) in ethanolOOmL) in an atmosphere of hydrogen. After 12 hours, the catalyst was removed by filtration and the organic layer was evaporated to a solid that was used directly in the next step. LCMS and NMR wereconsistent with the structure. This solid (0.87 g, 0.53 mmol) was treated with benzylglutaric acid (0.18 g, 0.8 mmol), HBTU (0.3 g, 0.8 mmol) and DIEA (273.7 jil, 1.6 mmol) in DMF (5mL). After 16 hours, the DMF was removed under reduced pressure at 65C to an oil, and the oil was dissolved in dichloromethane. The organic layer was washed with sat. NaHCO3, brine, and dried over Na2SO4. After evaporation of the organic layer, the compound was purified by column chromatography and eluted with a gradient of 2 to 20%methanol in dichloromethane to give the coupled product. LCMS and NMR were consistent with the structure. The benzyl ester was deprotected with Pearlman?s catalyst under a hydrogen atmosphere for 1 hour. The catalyst was them removed by filtration and the solvents removed to dryness to give the acid. LCMS and NMR were consistent with the structure. The acid (486 mg, 0.27 mmol) was dissolved in dry DMF (3 mL). Pyridine (53.61 jil, 0.66 mmol) was added and the reaction was purged with argon.Pentaflourotriflouro acetate (46.39 jil, 0.4 mmol) was slowly added to the reaction mixture. The color of the reaction changed from pale yellow to burgundy, and gave off a light smoke which was blown away with a stream of argon. The reaction was allowed to stir at room temperature for one hour (completion of reaction was confirmed by LCMS). The solvent was removed under reduced pressure (rotovap) at 70 C. The residue was diluted with DCM and washed with iN NaHSO4, brine, saturated sodium bicarbonate and brineagain. The organics were dried over Na2SO4, filtered, and were concentrated to dryness to give 225 mg of compound 229 as a brittle yellow foam. LCMS and NMR were consistent with the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.6% | With phosphorus pentoxide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 1h;Inert atmosphere; | Compound 4 (5.0 g, 10.8 mmol) was added to a 200 ml round bottom flask and dried overnight under vacuum over P2O5. Compound 4 was then dissolved in DCM (32 mL) under Ar gas. To this solution were added DIEA (2.3 mL, 13 mmol) followed by PFPTFA (2.2 mL, 13 mmol). The reaction was stirred at room temperature for 1 h and then poured into DCM (270 ml). The organic layer was washed with 1 M NaHSO4 (3 x 100 mL), sat. NaHCO3 (3 x 100 mL) and brine (2x100 mL). The organic layer was dried with Na2SO4, filtered and concentrated to a powdery solid (6.79 g). This material was purified by silica gel column chromatography (25 - 0% hexans/ethyl acetate) to obtain 5.89 g (86.6%) of desired product. MWcal: 627.17; MWfd: 628.2 [M+H+]. 1H NMR (300 MHz, DMSO-d6) delta (ppm) 1.32-1.58 (m, 4H), 1.62-1.80 (m, 5H), 1.86-2.02 (m, 6H), 2.11 (s, 3H), 2.77 (t, J=7.36 Hz, 2H), 3.39-3.50 (m, 1H), 3.72 (dt, J=9.92, 5.98 Hz, 1H), 3.88 (dt, J=11.14, 8.83 Hz, 1H), 3.98-4.08 (m, 3H), 4.50 (d, J=8.45 Hz, 1H), 4.97 (dd, J=11.20, 3.39 Hz, 1H), 5.22 (d, J=3.46 Hz, 1H), 7.82 (d, J=9.22 Hz, 1H). 13C NMR (75 MHz, DMSO-d6) d (ppm) 20.4, 20.4, 22.7, 23.9, 24.5, 28.4, 32.4, 49.3, 61.4, 66.7, 68.4, 69.8, 70.5, 100.9, 169.2, 169.5, 169.6, 169.8, 169.9. 19F NMR (282 MHz, DMSO-d6) delta (ppm) -153.55 - -153.71 (m, 2F), -158.15 (t, J=23.2 Hz, 1F), -162.67 (dd, J=19.1, 23.2 Hz, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 80% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | Compounds 101a-d (0.15 mmoles), individually, were dissolved in DMF (15 mL) and pyridine(0.016 mL, 0.2 mmoles). <strong>[14533-84-7]Pentafluorophenyl trifluoroacetate</strong> (0.034 mL, 0.2 mmoles) was added dropwise, under argon, and the reaction was allowed to stir at room temperature for 30 minutes. At that time, the DMFwas reduced by >75% under reduced pressure, and then the mixture was dissolved in dichloromethane. Theorganic layer was washed with sodium bicarbonate, water and brine. The organic layer was then separatedand dried over sodium sulfate, filtered and reduced to an oil under reduced pressure. The resultant oil was5 purified by silica gel chromatography (2%-->5% methanoVdichloromethane) to give compounds 102a-d in anapproximate 80% yield. LCMS and proton NMR were consistent with the structure. |
Ca. 80% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | Compounds lOla-d (0.15 mmoles), individually, were dissolved in DMF (15 mL) and pyridine (0.016 mL, 0.2 mmoles). <strong>[14533-84-7]Pentafluorophenyl trifluoroacetate</strong> (0.034 mL, 0.2 mmoles) was added dropwise, under argon, and the reaction was allowed to stir at room temperature for 30 minutes. At that time, the DMF was reduced by >75% under reduced pressure, and then the mixture was dissolved in dichloromethane. The organic layer was washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced to an oil under reduced pressure. The resultant oil waspurified by silica gel chromatography (2%-->5% methanolldichloromethane) to give compounds 102a-d in an approximate 80% yield. LCMS and proton NMR were consistent with the structure. |
With pyridine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | Compounds lOla-d (0.15 mmoles), individually, were dissolved in DMF (15 mL) and pyridine (0.016 mL, 0.2 mmoles). <strong>[14533-84-7]Pentafluorophenyl trifluoroacetate</strong> (0.034 mL, 0.2 mmoles) was added dropwise, under argon, and the reaction was allowed to stir at room temperature for 30 minutes. At that time, the DMF was reduced by >75% under reduced pressure, and then the mixture was dissolved in dichloromethane. The organic layer was washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced to an oil under reduced pressure. The resultant oil was purified by silica gel chromatography (2%- >5% methanol/dichloromethane) to give compounds 102a-d in an approximate 80% yield. LCMS and proton NMR were consistent with the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In N,N-dimethyl-formamide; for 1h; | Compound 13b (5.2 g) and TEA (1.14 mL, 3 eq.) were dissolved in DMF (25 mL) and PFP- TFA (0.937 mL, 2 eq.) was added. After one hour, LC MS analysis showed that the reaction was completed. The DMF was removed under reduced pressure at 50 C. The residue was diluted with dichloromethane and the solution thus obtained was washed with IN NaHS04 (80 mL), brine, saturated aqueous sodium bicarbonate and brine, dried over Na2S04, filtered and concentrated to dryness to yield compound 13c (5.75 g, quantitative) as a light pink foam. The structure of Compound 13c was confirmed by LCMS, NMR and 19F NMR. |
100% | With TEA; In N,N-dimethyl-formamide; for 1h; | Compound 13b (5.2 g) and TEA (1.14 mL, 3 eq.) were dissolved in DMF (25 mL) and PFP-TFA (0.937 mL, 2 eq.) was added. After one hour, LC MS analysis showed that the reaction was completed. The DMF was removed under reduced pressure at 50 C. The residue was diluted with dichloromethane and the solution thus obtained was washed with 1N NaHSO4 (80 mL), brine, saturated aqueous sodium bicarbonate and brine, dried over Na2SO4, filtered and concentrated to dryness to yield compound 13c (5.75 g, quantitative) as a light pink foam. The structure of Compound 13c was confirmed by LCMS, 1H NMR and 19F NMR. |
79% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Compound 112 was synthesized following the procedure described in the literature (J. Med. Chem. 2004, 47, 5798-5808).Compound 112 (5 g, 8.6 mmol) was dissolved in 1 :1 methanol/ethyl acetate (22 mL/22 mL). Palladium hydroxide on carbon (0.5 g) was added. The reaction mixture was stirred at room temperature under hydrogen for 12 h. The reaction mixture was filtered through a pad of celite and washed the pad with 1 : 1 methanol/ethyl acetate. The filtrate and the washings were combined and concentrated to dryness to yield Compound 105a (quantitative). The structure was confirmed by LCMS.Compound 113 (1.25 g, 2.7 mmol), HBTU (3.2 g, 8.4 mmol) and DIEA (2.8 mL, 16.2 mmol) were dissolved in anhydrous DMF (17 mL) and the reaction mixture was stirred at room temperature for 5 min. To this a solution of Compound 105a (3.77 g, 8.4 mmol) in anhydrous DMF (20 mL) was added. The reaction was stirred at room temperature for 6 h. Solvent was removed under reduced pressure to get an oil. The residue was dissolved in CH2CI2(100 mL) and washed with aqueous saturated NaHCOs solution (100 mL) and brine (100 mL). The organic phase was separated, dried (Na2S04), filtered and evaporated. The residue was purified by silica gel column chromatography and eluted with 10 to 20 % MeOH in dichloromethane to yield Compound 114 (1.45 g, 30%). The structure was confirmed by LCMS andlH NMR analysis.Compound 114 (1.43 g, 0.8 mmol) was dissolved in 1 :1 methanol/ethyl acetate (4 mL/4 mL). Palladium on carbon (wet, 0.14 g) was added. The reaction mixture was flushed with hydrogen and stirred at room temperature under hydrogen for 12 h. The reaction mixture was filtered through a pad of celite. The celite pad was washed with methanol/ethyl acetate (1 :1). The filtrate and the washings were combined together and evaporated under reduced pressure to yield Compound 115 (quantitative). The structure was confirmed by LCMS andlH NMR analysis.Compound 83a (0.17 g, 0.75 mmol), HBTU (0.31 g, 0.83 mmol) and DIEA (0.26 mL, 1.5 mmol) were dissolved in anhydrous DMF (5 mL) and the reaction mixture was stirred at room temperature for 5 min. To this a solution of Compound 115 (1.22 g, 0.75 mmol) in anhydrous DMF was added and the reaction was stirred at room temperature for 6 h. The solvent was removed under reduced pressure and the residue was dissolved in CH2CI2. The organic layer was washed aqueous saturated NaHC03solution and brine and dried over anhydrous Na2S04and filtered. The organic layer was concentrated to dryness and the residue obtained was purified by silica gel column chromatography and eluted with 3 to 15 % MeOH in dichloromethane to yield Compound 116 (0.84 g, 61%). The structure was confirmed by LC MS andlH NMR analysis.Compound 116 (0.74 g, 0.4 mmol) was dissolved in 1 :1 methanol/ethyl acetate (5 mL/5 mL). Palladium on carbon (wet, 0.074 g) was added. The reaction mixture was flushed with hydrogen and stirred at room temperature under hydrogen for 12 h. The reaction mixture was filtered through a pad of celite. The celite pad was washed with methanol/ethyl acetate (1 :1). The filtrate and the washings were combined together and evaporated under reduced pressure to yield compound 117 (0.73 g, 98%). The structure was confirmed by LCMS andlH NMR analysis.Compound 117 (0.63 g, 0.36 mmol) was dissolved in anhydrous DMF (3 mL). To this solution N,N- Diisopropylethylamine (70 L, 0.4 mmol) and <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (72 L, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 12 h and poured into a aqueous saturated NaHCOs solution. The mixture was extracted with dichloromethane, washed with brine and dried over anhydrous Na2S04. The dichloromethane solution was concentrated to dryness and purified with silica gel column chromatography and eluted with 5 to 10 % MeOH in dichloromethane to yield compound 118 (0.51 g, 79%). The structure was confirmed by LCMS andlH andlH and19F NMR. |
79% | In N,N-dimethyl-formamide; at 20℃; for 12h; | Compound 117 (0.63 g, 0.36 mmol) was dissolved in anhydrous DMF (3 mL). To this solution N,NDiisopropylethylamine(70 JlL, 0.4 mmol) and <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (72 JlL, 0.42 mmol) wereadded. The reaction mixture was stirred at room temperature for 12 h and poured into a aqueous saturated10 NaHC03 solution. The mixture was extracted with dichloromethane, washed with brine and dried overanhydrous Na2S04. The dichloromethane solution was concentrated to dryness and purified with silica gelcolumn chromatography and eluted with 5 to 10% MeOH in dichloromethane to yield compound 118 (0.51g, 79%). The structure was confirmed by LCMS and 1H and 1H and 19F NMR. |
79% | With pyridine; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 12h; | Compound 117 (0.63 g, 0.36 mmol) was dissolved in anhydrous DMF (3 mL). To this solution N,NDiisopropylethylamine (70 jiL, 0.4 mmol) and <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (72 jiL, 0.42 mmol) were added. The reaction mixture was stirred at room temperature for 12 h and poured into a aqueous saturatedNaHCO3 solution. The mixture was extracted with dichloromethane, washed with brine and dried over anhydrous Na2SO4. The dichloromethane solution was concentrated to dryness and purified with silica gel column chromatography and eluted with 5 to 10 % MeOH in dichloromethane to yield compound 118 (0.51 g, 79%). The structure was confirmed by LCMS and ?H and ?H and ?9F NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h;pH 9 - 10;Inert atmosphere; | Compound 153 (0.33 g, 0.18 mmol) was dissolved in anhydrous DMF (5 mL) with stirring under nitrogen. To this N,N-Diisopropylethylamine (65 L, 0.37 mmol) and PFP-TFA (35 L, 0.28 mmol) were added. The reaction mixture was stirred under nitrogen for ~ 30 min. The reaction mixture turned magenta upon contact, and gradually turned orange. The pH of the reaction mixture was maintained at pH = 9-10 by adding more N,-Diisopropylethylamine. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the majority of the solvent was removed under reduced pressure. The residue was diluted with CH2CI2(50 mL), and washed with saturated aqueous NaHCOs, followed by brine. The organic layer was dried over MgSO i, filtered, and concentrated to an orange syrup. The residue was purified by column chromatography and eluted with 2-10 % MeOH in CH2Cl2to yield Compound 154 (0.29 g, 79 %). LCMS andlH NMR were consistent with the desired product. |
79% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h;Inert atmosphere; | Compound 153 (0.33 g, 0.18 mmol) was dissolved in anhydrous DMF (5 mL) with stirring undernitrogen. To this N,N-Diisopropylethylamine (65 JlL, 0.37 mmol) and PFP-TFA (35 JlL, 0.28 mmol) wereadded. The reaction mixture was stirred under nitrogen for~ 30 min. The reaction mixture turned magentaupon contact, and gradually turned orange. The pH of the reaction mixture was maintained at pH = 9-1 0 by15 adding more N,-Diisopropylethylamine. The progress of the reaction was monitored by TLC and LCMS.Upon completion, the majority of the solvent was removed under reduced pressure. The residue was dilutedwith CH2Cb (50 mL), and washed with saturated aqueous NaHC03, followed by brine. The organic layerwas dried over MgS04, filtered, and concentrated to an orange syrup. The residue was purified by columnchromatography and eluted with 2-10% MeOH in CH2Cbto yield Compound 154 (0.29 g, 79 %). LCMS20 and 1H NMR were consistent with the desired product. |
79% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h;Inert atmosphere; | Compound 153 (0.33 g, 0.18 mmol) was dissolved in anhydrous DMF (5 mL) with stirring under nitrogen. To this N,N-Diisopropylethylamine (65 muL, 0.37 mmol) and PFP-TFA (35 muL, 0.28 mmol) were added. The reaction mixture was stirred under nitrogen for ~ 30 min. The reaction mixture turned magenta upon contact, and gradually turned orange. The pH of the reaction mixture was maintained at pH = 9-10 by adding more N,-Diisopropylethylamine. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the majority of the solvent was removed under reduced pressure. The residue was diluted with CH2Cl2 (50 mL), and washed with saturated aqueous NaHCO3, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated to an orange syrup. The residue was purified by column chromatography and eluted with 2-10 % MeOH in CH2Cl2 to yield Compound 154 (0.29 g, 79 %). LCMS and 1H NMR were consistent with the desired product. |
79% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h;Inert atmosphere; | Compound 153 (0.33 g, 0.18 mmol) was dissolved in anhydrous DMF (5 mL) with stirring under nitrogen. To this N,N-Diisopropylethylamine (65 muL, 0.37 mmol) and PFP-TFA (35 muL, 0.28 mmol) were added. The reaction mixture was stirred under nitrogen for ~ 30 min. The reaction mixture turned magenta upon contact, and gradually turned orange. The pH of the reaction mixture was maintained at pH = 9-10 by adding more N,-Diisopropylethylamine. The progress of the reaction was monitored by TLC and LCMS. Upon completion, the majority of the solvent was removed under reduced pressure. The residue was diluted with CH2Cl2 (50 mL), and washed with saturated aqueous NaHCO3, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated to an orange syrup. The residue was purified by column chromatography and eluted with 2-10 % MeOH in CH2Cl2 to yield Compound 154 (0.29 g, 79 %). LCMS and 1H NMR were consistent with the desired product. |
79% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.5h;pH 9 - 10;Inert atmosphere; | Compound 153 (0.33 g, 0.18 mmol) was dissolved in anhydrous DMF (5 mL) with stirring under nitrogen. To this N,N-Diisopropylethylamine (65 jiL, 0.37 mmol) and PFP-TFA (35 jiL, 0.28 mmol) were added. The reaction mixture was stirred under nitrogen for 30 mm. The reaction mixture turned magenta upon contact, and gradually turned orange. The pH of the reaction mixture was maintained at pH = 9-10 by adding more N,-Diisopropylethylamine. The progress of the reaction was monitored by TLC and LCMS.Upon completion, the majority of the solvent was removed under reduced pressure. The residue was diluted with CH2C12 (50 mL), and washed with saturated aqueous NaHCO3, followed by brine. The organic layer was dried over MgSO4, filtered, and concentrated to an orange syrup. The residue was purified by column chromatography and eluted with 2-10 % MeOH in CH2C12 to yield Compound 154 (0.29 g, 79 %). LCMS and ?H NMR were consistent with the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.7% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.333333h;Inert atmosphere; | To a 25 ml round bottom flask were added compound 14 (1.318, 1.15 mmol), a magnetic stir bar, DMF (3.2 mL), DIEA (300 mL, 1.725 mmol) and PFPTFA (300 mL, 1.725 mmol). The reaction was allowed to stir under Ar gas at room temperature. After 20 min, the reaction was determined to be complete by LCMS. The reaction mixture was poured into H2O (40 ml) and extracted with ethyl acetate (2x50 mL). The combined organic layer was washed with sat NaHCO3 (2 x 50 ml), 1 M NaHSO4 (2 x 50 ml), and brine (2 x 50 ml). The organic layer was dried with Na2SO4, filtered and concentrated to 1.4597 g (96.7%). MWcal: 1311.53; MWfd:1312.5 (M+H+). 1H NMR (300 MHz, DMSO-d6) delta (ppm) 1H NMR (300 MHz, DMSO-d6) delta (ppm) 1.18-1.57 (m, 23H), 1.61-1.70 (m, 2H), 1.77 (d, J=1.02 Hz, 6H), 1.88-2.13 (m, 22H), 2.72-2.82 (m, 2H), 2.89-3.12 (m, 4H), 3.35-3.46 (m, 2H), 3.69 (dt, J=9.89, 6.19 Hz, 2H), 3.87 (dt, J=11.07, 8.86 Hz, 2H), 3.98-4.19 (m, 7H), 4.48 (dd, J=8.45, 1.79 Hz, 2H), 4.96 (dd, J=11.20, 3.26 Hz, 2H), 5.21 (d, J=3.46 Hz, 2H), 7.68-7.89 (m, 5H); 19F NMR (282 MHz, DMSO-d6) delta (ppm) -153.51 - -153.64 (m, 2F), -158.14 (t, J=23.2 Hz, 1F), -162.56 - -162.74 (m, 2F); 13C NMR (75 MHz, DMSO-d6) delta (ppm) 20.4, 20.4, 20.4, 22.7, 22.8, 23.9, 25.0, 25.4, 28.5, 28.7, 28.7, 28.9, 31.8, 32.4, 35.1, 35.4, 38.1, 38.2, 49.4, 52.4, 61.4, 66.7, 68.7, 69.8, 70.5, 100.9, 169.2, 169.2, 169.4, 169.6, 169.8, 169.9, 171.6, 171.7, 172.0. |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Compound 120 is commercially available, and the synthesis of compound 126 is described in Example 49. Compound 120 (1 g, 2.89 mmol), HBTU (0.39 g, 2.89 mmol), and HOBt (1.64 g, 4.33 mmol) were dissolved in DMF (10 mL. and N,N-diisopropylethylamine (1.75 mL, 10.1 mmol) were added. After about 5 min, aminohexanoic acid benzyl ester (1.36 g, 3.46 mmol) was added to the reaction. After 3h, the reaction mixture was poured into 100 mL of 1 M NaHS04 and extracted with 2 x 50 mL ethyl acetate. Organic layers were combined and washed with 3 x 40 mL sat NaHCOs and 2 x brine, dried with Na2SO i, filtered and concentrated. The product was purified by silica gel column chromatography (DCM:EA:Hex , 1 :1 :1) to yield compound 231. LCMS and NMR were consistent with the structure. Compounds 231 (1.34 g, 2.438 mmol) was dissolved in dichloromethane (10 mL) and trifluoracetic acid (10 mL) was added. After stirring at room temperature for 2h, the reaction mixture was concentrated under reduced pressure and co- evaporated with toluene ( 3 x 10 mL). The residue was dried under reduced pressure to yield compound 232 as the trifuloracetate salt. The synthesis of compound 166 is described in Example 54. Compound 166 (3.39 g, 5.40 mmol) was dissolved in DMF (3 mL). A solution of compound 232 (1.3 g, 2.25 mmol) was dissolved in DMF (3 mL) and N,N-diisopropylethylamine (1.55 mL) was added. The reaction was stirred at room temperature for 30 minutes, then poured into water (80 mL) and the aqueous layer was extracted with EtOAc (2x100 mL). The organic phase was separated and washed with sat. aqueous NaHC03(3 x 80 mL), 1 M NaHS04(3 x 80 mL) and brine (2 x 80 mL), then dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel column chromatography to yield compound 233. LCMS and NMR were consistent with the structure. Compound 233 (0.59 g, 0.48 mmol) was dissolved in methanol (2.2 mL) and ethyl acetate (2.2 mL). Palladium on carbon (10 wt% Pd/C, wet , 0.07 g) was added, and the reaction mixture was stirred under hydrogen atmosphere for 3 h. The reaction mixture was filtered through a pad of Celite and concentrated to yield the carboxylic acid. The carboxylic acid (1.32 g, 1.15 mmol, cluster free acid) was dissolved in DMF (3.2 mL). To this N,N-diisopropylehtylamine (0.3 mL, 1.73 mmol) and PFPTFA (0.30 mL, 1.73 mmol) were added. After 30 min stirring at room temperature the reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 x 50 mL). A standard work-up was completed as described above to yield compound 234. LCMS and NMR were consistent with the structure. Oligonucleotide 235 was prepared using the general procedure described in Example 46. The GalNAc2cluster portion (GalNAc2-24a) of the conjugate group GalNAc2-24 can be combined with any cleavable moiety present on the oligonucleotide to provide a variety of conjugate groups. The structure of GalNAc2-24 (GalNAc2-24a-CM) is shown below: | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Compound 120 is commercially available, and the synthesis of compound 126 is described in10 Example 35. Compound 120 (1 g, 2.89 mmol), HBTU (0.39 g, 2.89 mmol), and HOBt (1.64 g, 4.33 mmol)were dissolved in DMF (1 0 mL) and N,N-diisopropylethylamine (1. 75 mL, 10.1 mmol) were added. After about 5 min, aminohexanoic acid benzyl ester (1.36 g, 3.46 mmol) was added to the reaction. After 3h, thereaction mixture was poured into 100 mL of 1 M NaHS04 and extracted with 2 x 50 mL ethyl acetate.Organic layers were combined and washed with 3 x 40 mL sat NaHC03 and 2 x brine, dried with Na2S04,filtered and concentrated. The product was purified by silica gel column chromatography (DCM:EA:Hex ,5 1:1:1) to yield compound 231. LCMS and NMR were consistent with the structure. Compounds 231 (1.34 g,2.438 mmol) was dissolved in dichloromethane (10 mL) and trifluoracetic acid (10 mL) was added. Afterstirring at room temperature for 2h, the reaction mixture was concentrated under reduced pressure and coevaporatedwith toluene (3 x 10 mL). The residue was dried under reduced pressure to yield compound 232as the trifuloracetate salt. The synthesis of compound 166 is described in Example 40. Compound 166 (3.3910 g, 5.40 mmol) was dissolved in DMF (3 mL). A solution of compound 232 (1.3 g, 2.25 mmol) was dissolvedin DMF (3 mL) and N,N-diisopropylethylamine (1.55 mL) was added. The reaction was stirred at roomtemperature for 30 minutes, then poured into water (80 mL) and the aqueous layer was extracted with EtOAc(2x100 mL). The organic phase was separated and washed with sat. aqueous NaHC03 (3 x 80 mL), 1 MNaHS04 (3 x 80 mL) and brine (2 x 80 mL), then dried (Na2S04), filtered, and concentrated. The residue was15 purified by silica gel column chromatography to yield compound 233. LCMS and NMR were consistent withthe structure. Compound 233 (0.59 g, 0.48 mmol) was dissolved in methanol (2.2 mL) and ethyl acetate (2.2mL). Palladium on carbon (10 wt% Pd/C, wet, 0.07 g) was added, and the reaction mixture was stirred underhydrogen atmosphere for 3 h. The reaction mixture was filtered through a pad of Celite and concentrated toyield the carboxylic acid. The carboxylic acid (1.32 g, 1.15 mmol, cluster free acid) was dissolved in DMF20 (3.2 mL). To this N,N-diisopropylehtylamine (0.3 mL, 1.73 mmol) and PFPTFA (0.30 mL, 1.73 mmol) wereadded. After 30 min stirring at room temperature the reaction mixture was poured into water (40 mL) andextracted with EtOAc (2 x 50 mL). A standard work-up was completed as described above to yieldcompound 234. LCMS and NMR were consistent with the structure. Compound 235 is prepared using thegeneral procedure described in Example 32. The GalNAc2 cluster portion (GalNAc2-24a) of the conjugate25 group GalNAc2-24 can be combined with any cleavable moiety present on the therapeutic agent to provide avariety of conjugate groups. The structure of GalNAc2-24 (GalNAc2-24a-CM) is shown below: |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Compound 60 (0.59 g, 0.48 mmol) was dissolved in methanol (2.2 mL) and ethyl acetate (2.2 mL). Palladium on carbon (10 wt% Pd/C, wet , 0.07 g) was added, and the reaction mixture was stirred under hydrogen atmosphere for 3 h. The reaction mixture was filtered through a pad of Celite and concentrated to yield the carboxylic acid. The carboxylic acid (1.32 g, 1.15 mmol, cluster free acid) was dissolved in DMF (3.2 mL). To this N,N-diisopropylehtylamine (0.3 mL, 1.73 mmol) and PFPTFA (0.30 mL, 1.73 mmol) were added. After 30 min stirring at room temperature the reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 x 50 mL). A standard work-up was completed as described above to yield compound 61. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | The carboxylic acid (1.32 g, 1.15 mmol, cluster free acid) was dissolved in DMF (3.2 mL). To this N,N-diisopropylehtylamine (0.3 mL, 1.73 mmol) and PFPTFA (0.30 mL, 1.73 mmol) were added. After 30 min stirring at room temperature the reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 x 50 mL). A standard work-up was completed as described above to yield compound 234. LCMS and NMR were consistent with the structure | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | The carboxylic acid (1.32 g, 1.15 mmol, cluster free acid) was dissolved in DMF (3.2 mL). To this N,N-diisopropylehtylamine (0.3 mL, 1.73 mmol) and PFPTFA (0.30 mL, 1.73 mmol) were added. After 30 min stirring at room temperature the reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 x 50 mL). A standard work-up was completed as described above to yield compound 234. LCMS and NMR were consistent with the structure | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Compound 120 is commercially available, and the synthesis of compound 126 is described inExample 49. Compound 120 (1 g, 2.89 mmol), HBTU (0.39 g, 2.89 mmol), and HOBt (1.64 g, 4.33 mmol)were dissolved in DMF (10 mL. and N,N-diisopropylethylamine (1.75 mL, 10.1 mmol) were added. Afterabout 5 mm, aminohexanoic acid benzyl ester (1.36 g, 3.46 mmol) was added to the reaction. After 3h, thereaction mixture was poured into 100 mL of 1 M NaHSO4 and extracted with 2 x 50 mL ethyl acetate.Organic layers were combined and washed with 3 x 40 mL sat NaHCO3 and 2 x brine, dried with Na2SO4,filtered and concentrated. The product was purified by silica gel column chromatography (DCM:EA:Hex1:1:1) to yield compound 231. LCMS and NMR were consistent with the structure. Compounds 231 (1.34 g,2.438 mmol) was dissolved in dichloromethane (10 mL) and trifluoracetic acid (10 mL) was added. Afterstirring at room temperature for 2h, the reaction mixture was concentrated under reduced pressure and co15 evaporated with toluene ( 3 x 10 mL). The residue was dried under reduced pressure to yield compound 232as the trifuloracetate salt. The synthesis of compound 166 is described in Example 54. Compound 166 (3.39g, 5.40 mmol) was dissolved in DMF (3 mL). A solution of compound 232 (1.3 g, 2.25 mmol) was dissolved in DMF (3 mL) and N,N-diisopropylethylamine (1.55 mL) was added. The reaction was stirred at room temperature for 30 minutes, then poured into water (80 mL) and the aqueous layer was extracted with EtOAc (2x100 mL). The organic phase was separated and washed with sat. aqueous NaHCO3 (3 x 80 mL), 1 M NaHSO4 (3 x 80 mL) and brine (2 x 80 mL), then dried (Na2SO4), filtered, and concentrated. The residuewas purified by silica gel column chromatography to yield compound 233. LCMS and NMR were consistent with the structure. Compound 233 (0.59 g, 0.48 mmol) was dissolved in methanol (2.2 mL) and ethyl acetate (2.2 mL). Palladium on carbon (10 wt% Pd/C, wet, 0.07 g) was added, and the reaction mixture was stirred under hydrogen atmosphere for 3 h. The reaction mixture was filtered through a pad of Celite and concentrated to yield the carboxylic acid. The carboxylic acid (1.32 g, 1.15 mmol, cluster free acid) wasdissolved in DMF (3.2 mL). To this N,N-diisopropylehtylamine (0.3 mL, 1.73 mmol) and PFPTFA (0.30 mL,1.73 mmol) were added. After 30 mm stirring at room temperature the reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 x 50 mL). A standard work-up was completed as described above to yield compound 234. LCMS and NMR were consistent with the structure. Oligonucleotide 235 was prepared using the general procedure described in Example 46. The Ga1NAc2 cluster portion (Ga1NAc2-24a)of the conjugate group Ga1NAc2-24 can be combined with any cleavable moiety present on the oligonucleotide to provide a variety of conjugate groups. The structure of Ga1NAc2-24 (Ga1NAc2-24a-CM) is shown below: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
HOOC-PEG0.6K-ECT (Compound 6). To a 100 mL one-neck round-bottom flask was added ECT (473 mg, 2.0 mmol, Omm Scientific) followed by anhydrous tetrahydrofuran (20 mL) and triethylamine (0.307 mL, 2.2 mmol). This mixture was stirred at 0C for 5 min before trifluoroacetic acid pentafluorophenyl ester (0.368 mL, 2.14 mmol) was added drop wise to the stirred reaction. The mixture was stirred at 0C for 5 min then warmed to room temperature. [000220] After allowing to react for 20 min at room temperature, the reaction was diluted into EtOAc (100 mL) and extracted with saturated aqueous solution of NaHC03 (3x40 mL). The EtOAc layer was separated, dried over Na2S04, filtered and then evaporated providing the crude PFP-ester 4 as yellow oil. | ||
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.5h; | HOOC-PEG0.6K-ECT (Compound 6). To a 100 mL one-neck round-bottom flask was added ECT (473 mg, 2.0 mmol, Omm Scientific) followed by anhydrous tetrahydrofuran (20 mL) and triethylamine (0.307 mL, 2.2 mmol). This mixture was stirred at 0 C for 5 min before trifluoro acetic acid pentafluorophenyl ester (0.368 mL, 2.14 mmol) was added drop wise to the stirred reaction. The mixture was stirred at 0 C for 5 min then warmed to room temperature. (0589) [268] After allowing to react for 20 min at room temperature, the reaction was diluted into EtOAc (100 mL) and extracted with saturated aqueous solution of NaHC03 (3x40 mL). The EtOAc layer was separated, dried over Na2S04, filtered and then evaporated providing the crude PFP-ester 4 as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.0833333h;Inert atmosphere; | To a 250 mL one-neck round bottom flask was added TL-02- 19 (3.3 g, 7.0 mmol, thoroughly dried overnight on high vacuum) followed by anhydrous THF (60 mL, lot B 0313244). This mixture was stirred under a flow of argon gas and then cooled to 0 C for 5 min. Then trifluoroacetic acid pentafluorophenyl ester (4.0 mL, 23.2 mmol, lot 69096MJ) was added drop wise followed by triethylamine (3.24 mL, 23.2 mmol, lot B0518226). The reaction was then warmed to room temperature under a flow of argon gas. [000371] The reaction progress can be followed by TLC (Si02, 100% CH2C12) by looking for the disappearance of the starting material TL-02-19 (Rf=0.0) and the appearance of the PFP activated product MD-03-20 (Rf=0.49). After stirring for 2.0 h at room temperature the starting material was completely consumed by TLC. [000372] Once the starting material was consumed by TLC the crude reaction was evaporated using a rotary evaporator to remove all the THF. Once the crude reaction was condensed to a viscous oil the mixture was dissolved with CH2CI2 (150 mL) and extracted using saturated aqueous NaHCC>3 (3x50mL). The organic layer was separated, dried over Na2S04, filtered and evaporated providing 6.0 g (89%) of the final product as a white solid. All solvents and volatile reagents were thoroughly removed using high vacuum (0.5 mmHg) overnight before the crude product was used in the next synthetic step. No characterization of the final product was preformed other than TLC analysis (TLC conditions described above). The TLC analysis of the final product showed the material was only one compound (Rf=0.49). Ninhydrin TLC based (300 mg ninhydrin dissolved in 100 mL EtOH and 3 mL AcOH) analysis showed that there was no Fmoc deprotected product produced via this process. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | Compounds lOla-d (0.15 mmoles), individually, were dissolved in DMF (15 mL) and pyridine (0.016 mL, 0.2 mmoles). Pentafluorophenyl trifluoro acetate (0.034 mL, 0.2 mmoles) was added dropwise, under argon, and the reaction was allowed to stir at room temperature for 30 minutes. At that time, the DMF was reduced by >75%> under reduced pressure, and then the mixture was dissolved in dichloromethane. The organic layer was washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced to an oil under reduced pressure. The resultant oil was purified by silica gel chromatography (2%~>5% methanol/dichloromethane) to give compounds 102a-d in an approximate 80% yield. LCMS and proton NMR were consistent with the structure. |
80% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 0.5h;Inert atmosphere; | Compounds 101a-d (0.15 mmoles), individually, were dissolved in DMF (15 mL) and pyridine (0.016 mL, 0.2 mmoles). <strong>[14533-84-7]Pentafluorophenyl trifluoroacetate</strong> (0.034 mL, 0.2 mmoles) was added dropwise, under argon, and the reaction was allowed to stir at room temperature for 30 minutes. At that time, the DMF was reduced by >75% under reduced pressure, and then the mixture was dissolved in dichloromethane. The organic layer was washed with sodium bicarbonate, water and brine. The organic layer was then separated and dried over sodium sulfate, filtered and reduced to an oil under reduced pressure. The resultant oil was purified by silica gel chromatography (2%-->5% methanol/dichloromethane) to give compounds 102a-d in an approximate 80% yield. LCMS and proton NMR were consistent with the structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With phosphorus pentoxide; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 21h; | To a 100 mL round bottom flask were added Compound 22 (458 mg, 0.267 mmol, 1 eq.) and a magnetic stirring bar. The flask was dried over P2O5 under vacuum for 3 h. Compound 22 was dissolved in anhydrous DMF (2.1 mL) and TEA (335 ml, 2.4 mmol, 9 eq.) followed by PFPTFA (275 ml, 1.6 mmol, 6 eq.). The reaction was stirred at room temperature for 19 h and concentrated by rotary evaporation under reduced pressure. The residue was dissolve in DCM (20 ml) and washed with 3 x 1 M NaHSO4, 3 x sat NaHCO3 and 2 x brine (10 ml each). The organic layer was dried with anhydrous Na2SO4, then filtered, and concentrated to 0.4725 g (94% yield). M.W.cal: 1882.81; M.W.fd:1883.7 [M+H+]. 1H NMR (300 MHz, DMSO-d6) d ppm 1.13 - 1.72 (m, 39 H) 1.77 (s, 9 H) 1.89 (s, 10 H) 1.96 - 2.18 (m, 25 H) 2.71 - 2.82 (m, 3 H) 2.98 (m, 6 H) 3.34 - 3.47 (m, 4 H) 3.69 (dt, J=9.82, 6.10 Hz, 3 H) 3.78 - 3.94 (m, 3 H) 3.97 - 4.23 (m, 11 H) 4.48 (d, J=8.45 Hz, 3 H) 4.96 (dd, J=11.33, 3.26 Hz, 3 H) 5.21 (d, J=3.33 Hz, 3 H) 7.65 - 7.98 (m, 8H). 13C NMR (75 MHz, DMSO-d6) delta (ppm) 20.4, 20.4, 22.7, 22.8, 23.8, 25.0, 25.1, 25.4, 28.4, 28.7, 28.8, 31.4, 31.7, 32.4, 35.1, 35.4, 38.1, 38.3, 49.3, 52.4, 52.4, 52.6, 61.4, 66.7, 68.7, 69.8, 70.4, 100.9, 169.2, 169.4, 169.6, 169.8, 169.9, 171.2, 171.6, 171.8, 172.4; 19F NMR (282MHz, DMSO-d6) delta (ppm) -153.48 - -153.66 (m, 2F), -158.11 (t, J=23.2 Hz, 1F), -162.46 - -162.77 (m, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Cooling with ice; | Purified Compound 6 (50 g, 91 mmol) was suspended in dry DCM (425 mL). The reaction mixture was cooled in an ice bath and diisopropylethylamine (DIEA) was added (120 mL, 730 mmol, 8 eq.), and the reaction was purged with nitrogen. PFP-TFA (53.5 mL, 311 mmol, 3.4 eq.) was added slowly to the reaction mixture via addition funnel (~ 3.5 mL/min). The color of the reaction changed from colorless to light pink and gave off a light smoke which was blown away with a stream of nitrogen. After the addition was complete, the reaction was stirred on ice for 15 minutes, then at room temperature for 1 hour. Over the course of the reaction the color changed to burgundy and then to dark orange. The reaction was monitored by TLC (7:3 hexanes / EtOAc) and LCMS. At completion ice water (400 mL) and saturated aqueous NaHC03 (100 mL) was added. The reaction mixture was stirred vigorously, and was transferred to a separately funnel. The organic layer was recovered and washed with water (2 x 500 mL), then with brine (1 x 500 mL). The organics were dried over MgS04, filtered, and concentrated under reduced pressure to a dark orange oil to provide the crude product (72.0 g). The crude product was diluted with DCM (~ 100 mL), and was passed through a pad of silica gel (600 mL fritted funnel, 4" wide, 2.5" thick). The product was eluted with DCM (~ 500 mL). The majority of the orange color was trapped by the silica gel. The filtrate was concentrated under reduced pressure to give Compound 7 (89 g, 93%) as a dark orange syrup. The structure of Compound 7 was confirmed by LCMS, NMR and 19F NMR. |
93% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Cooling with ice; | Purified Compound 6 (50 g, 91 mmol) was suspended in dry DCM (425 mL). The reaction mixture was cooled in an ice bath and diisopropylethylamine (DIEA) was added (120 mL, 730 mmol, 8 eq.), and the reaction was purged with nitrogen. PFP-TFA (53.5 mL, 311 mmol, 3.4 eq.) was added slowly to the reaction mixture via addition funnel (3.5 mL/min). The color of the reaction changed from colorless to light pink and gave off a light smoke which was blown away with a stream of nitrogen. After the addition was complete, the reaction was stirred on ice for 15 minutes, then at room temperature for 1 hour. Over the course of the reaction the color changed to burgundy and then to dark orange. The reaction was monitored by TLC (7:3 hexanes/EtOAc) and LCMS. At completion ice water (400 mL) and saturated aqueous NaHCO3 (100 mL) was added. The reaction mixture was stirred vigorously, and was transferred to a separatory funnel. The organic layer was recovered and washed with water (2×500 mL), then with brine (1×500 mL). The organics were dried over MgSO4, filtered, and concentrated under reduced pressure to a dark orange oil to provide the crude product (72.0 g). The crude product was diluted with DCM (100 mL), and was passed through a pad of silica gel (600 mL fritted funnel, 4? wide, 2.5? thick). The product was eluted with DCM (500 mL). The majority of the orange color was trapped by the silica gel. The filtrate was concentrated under reduced pressure to give Compound 7 (89 g, 93%) as a dark orange syrup. The structure of Compound 7 was confirmed by LCMS, 1H NMR and 19F NMR. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | General procedure: A mixture of 5 (260 mg, 0.40 mmol), <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (0.14 mL, 0.8 mmol) andtriethylamine (0.22 mL, 1.60 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The mixturewas diluted with AcOEt (80 mL), which was washed with H2O (50 mL), aqueous NaHCO3 (saturated, 50 mL)and brine (50 mL), then dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (2.0 × 12 cm, 30% AcOEt in hexane containing 0.3% pyridine) to give 6 (300 mg,89%) as a white form: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | General procedure: A mixture of 5 (260 mg, 0.40 mmol), <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (0.14 mL, 0.8 mmol) andtriethylamine (0.22 mL, 1.60 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The mixturewas diluted with AcOEt (80 mL), which was washed with H2O (50 mL), aqueous NaHCO3 (saturated, 50 mL)and brine (50 mL), then dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (2.0 × 12 cm, 30% AcOEt in hexane containing 0.3% pyridine) to give 6 (300 mg,89%) as a white form: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 1h; | A mixture of 5 (260 mg, 0.40 mmol), <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (0.14 mL, 0.8 mmol) andtriethylamine (0.22 mL, 1.60 mmol) in DMF (10 mL) was stirred at room temperature for 1 h. The mixturewas diluted with AcOEt (80 mL), which was washed with H2O (50 mL), aqueous NaHCO3 (saturated, 50 mL)and brine (50 mL), then dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gelcolumn chromatography (2.0 × 12 cm, 30% AcOEt in hexane containing 0.3% pyridine) to give 6 (300 mg,89%) as a white form: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.3% | Synthesis of OCT-Fluorophore Conjugates (FIG. 4) Synthesis of OCT-PEG (3). To a solution of OCT acid 15 (32 mg, 123 mumol) in dry dichloromethane (DCM, 750 muL) was added triethylamine (TEA, 34 muL, 246 mumol). The mixture was stirred for 5 minutes at ambient temperature. <strong>[14533-84-7]Pentafluorophenyl trifluoroacetate</strong> (PFP-TFA, 42 muL, 246 mumol) was added slowly to the reaction mixture over 3 minutes and the reaction was allowed to proceed for 3 hours. The reaction mixture was concentrated in vacuo, then purified by silica chromatography (10% ethyl acetate in hexane) to afford OCT-PFP 2 as a colorless solid (45.6 mg, 107 mumol, 87.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; In N,N-dimethyl-formamide; at 10 - 20℃; for 5h; | Method B: Compound (IX) (150 g, 0.6 mole) (IX was purchased from Shanghai Haoyuan Chemexpress Co., Ltd.) was dissolved in 1.0 L N,N-dimethyl formamide (DMF). Pyridine (69.3 g, 1.0 mole) was added to the solution. The solution was cooled in ice water until the system internal temperature was below 10C. <strong>[14533-84-7]Pentafluorophenyl trifluoroacetate</strong> (184.5 g, 0.66 mole) was slowly added dropwise to the solution. After <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> was added completely, the solution was allowed to warm naturally to room temperature, and was stirred for 5 h. The reaction was monitored by HPLC. Afier the conversion of the raw material was complete, 2.0 L tap water was added to the reaction solution. The reaction solution was extracted twice with 1 .0 L methyl tertiary-butyl ether. The organic phase was washed with 0.5 L saturated salt water, then dried for not less than 3 h, filtered and concentrated to get 186.2 g compound (VIII) in 93% yield. The resulting product was directly used in the nextstep. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; In N,N-dimethyl-formamide; at 20℃;Sealed tube; | To a 100 ml round bottom flask was addedl6-(tert-butoxy)-16- oxohexadecanoic acid (5900 mg, 17.23 mmol), N,N-dimethylformamide (30 mL), pyridine (3.48 mL, 43.1 mmol), and perfluorophenyl 2,2,2-trifluoroacetate (9649 mg, 34.5 mmol). The flask was sealed with a septum and kept under a blanket of nitrogenand stirred overnight at rt. The next day the reaction was poured into a saturated citric acid solution and extracted with CH2C12 3x. The organic layers were combined and washed with brine, dried over Na2SO4 and evaporated in vacuo. The crude product 1-tert-butyl 16-(perfluorophenyl) hexadecanedioate (8.7 g, 17.11 mmol, 99 % yield) was used as is without purification. ?H NMR (400MHz, CHLOROFORM-d) oe 2.68 (t, J7.4 Hz, 2H), 2.23 (t, J7.5 Hz, 2H), 1.89 - 1.71 (m, 2H), 1.65 - 1.54 (m, 2H), 1.47 (s, 9H), 1.28 (m, 20H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 24h;Inert atmosphere; | To a 20 ml scint vial was added(S)-5-(tert-butoxy)-4-(18-(tert-butoxy)-18- oxooctadecanamido)-5-oxopentanoic acid (518 mg, 0.932 mmol),N,Ndimethylformamide (3 mL), pyridine (162 mg, 2.050 mmol), and perfluorophenyl2,2,2-trifluoroacetate (522 mg, 1.864 mmol). The reaction was allowed to stir for 24 hr at rt. After 24 hr the reaction mixture was poured into a saturated citric acid solution, and extracted with CH2C12 3x. The organic fractions were combined, washed with brine, dried over Na2SO4 and evaporated in vacuo. The crude oil (S)-1- tert-butyl 5 -(perfluorophenyl) 2-( 1 8-(tert-butoxy)- 18-oxooctadecanamido)pentanedioate (670 mg, 0.928 mmol, 100 % yield) was used as is in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine; In N,N-dimethyl-formamide; | To a solution of <strong>[843666-40-0]18-(tert-butoxy)-18-oxooctadecanoic acid</strong> (5.00 g, 13.49mmol) in DMF (54.0 ml) was added pyridine (3.82 ml, 47.2 mmol), followed bypentafluorophenyl trifluoroacetate (5.81 ml, 33.7 mmol). A gel formed, and an additional stir bar was added to the reaction mixture. The mixture was stirred vigorously overnight. The reaction mixture was filtered (Buchner funnel/paper) to afford a white solid, which was washed with a small amount of DMF. A nitrogen-rich atmosphere was sucked through the filter cake for a few hours to provide 1 -tertbutyl 1 8-(perfluorophenyl) octadecanedioate (6.50 g, 11.63 mmol, 90 % yield). Analysis condition D: Retention time = 4.12 mm; ESI-MS(+) m/z 559.1 (M + Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With pyridine; In dichloromethane; at 0℃; for 3.5h;Heating; Inert atmosphere; | To a vial containing 1 ,2-dimethyl-D-prolyl-/V-[(1 R,3R)-1 -(acetyloxy)-1 -(4-carboxy-1 ,3-thiazol-2- yl)-4-methylpentan-3-yl]-/V-methyl-L-isoleucinamide (A5, 256 mg, 0.475 mmol) was added DCM (10 mL) and pyridine (130 mu, 0.950 mmol). The reaction was cooled to 0 C under N2 and <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (167 L, 0.950 mmol) was added. After ~5 minutes, the ice bath was removed and the reaction was stirred under N2 for 3.5 h, concentrated, re- dissolved in DCM (3 mL), and purified by flash silica gel chromatography (0% to 60% MeOH in DCM) to provide the title compound A31 (283 mg, 85% yield) as a white solid. LC-MS (Protocol B): m/z 705.5 [M+H]+; Retention time = 1 .64 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.7% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.0833333h;Inert atmosphere; | To a 100 ml round bottom flask were added compound 8 (1.288 g, 1.73 mmol) and a magnetic stir bar. The acid was dissolved in DCM (6 ml) under Ar gas while stirred. To this solution were added DIEA (0.37 mL, 2.08 mmol) followed by PFPTFA (0.36 mL, 2.08 mmol). The reaction mixture was allowed to stir at room temperature overnight and then poured into DCM (50 ml). This solution was washed with 1M NaHSO4 (3 x 40 mL), sat. NaHCO3 (3 x 40 mL) and brine (2 x 40 mL). The organic layer was dried with anhydrous Na2SO4, filtered and concentrated to 1.492 g (94.7%) of an off-white solid. This compound was used without further purification. MWcal: 910.36; MWfd: 911.4 1H NMR (300 MHz, DMSO-d6) d (ppm) 1.12 - 1.73 (m, 19H) 1.74 - 1.94 (m, 9H) 1.96 - 2.07 (m, 6H) 2.10 (s, 3H) 2.77 (t, J=7.30 Hz, 2H) 2.91 - 3.13 (m, 4H) 3.36 - 3.48 (m, 1H) 3.69 (dt, J=9.79, 6.11 Hz, 1H) 3.79 - 3.94 (m, 1H) 3.97 - 4.09 (m, 3H) 4.09 - 4.19 (m, 1H) 4.48 (d, J=8.45 Hz, 1H) 4.96 (dd, J=11.26, 3.46 Hz, 1H) 5.21 (d, J=3.33 Hz, 1H) 7.66 - 7.96 (m, 4H); 13C NMR (75 MHz, CDCl3) delta (ppm) 20.7, 22.5, 23.1, 23.3, 24.3, 25.1, 25.6, 26.1, 28.7, 29.0, 29.0, 31.7, 33.1, 36.3, 38.5, 39.2, 51.2, 53.1, 61.5, 66.8, 69.6, 70.2, 70.6, 101.3, 169.3, 170.3, 170.5, 170.5, 170.7, 170.7, 171.8, 173.6; 19F NMR (282 MHz, DMSO-d6) delta(ppm) -153.51 - -153.63 (m, 2F), -158.13 (t, J=23.2 Hz, 1F), -162.53 - -162.74 (m, 2F) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | To a stirred solution of 7 (174.5 mg, 0.67 mmol) in MeOH (0.67 mL) and THF (0.67 mL) at room temperaturewas added 2N aq. NaOH (0.67 mL). After being stirred for 3 h at 60 C, the reaction mixture was quenchedwith 1N aq. HCl, and extracted twice with EtOAc. The combined organic layers were washed with brine, driedover Na2SO4, filtered, and concentrated in vacuo. The obtained residue was used for the next reaction withoutpurification. To a stirred solution of the obtained product in pyridine (0.16 mL) and DMF (1.2 mL) at roomtemperature was added C6F5O2CCF3 (0.125 mL, 0.73 mmol) and the resulting mixture was stirred for 15 minat room temperature. The reaction was quenched by the addition of 1N aq. HCl and the resulting mixture wasextracted twice with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO3 andbrine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gelcolumn chromatography (SiO2, n-hexane/ EtOAc = 4/1) to give the desired product 16 (265 mg, 96% yield) aswhite solid. | |
265 mg | A solution of the compound 3-1 (174.5 mg, 0.67 mmol) in MeOH (0.67 mL) and THF (0.67 mL) was stirred at room temperature, to which a 2 N NaOH aqueous solution (0.67 mL) was added. After stirring at 60 C. for 3 hours, a 1 N HCl aqueous solution was added to the reaction mixture to terminate the reaction, and the reaction mixture was extracted with ethyl acetate twice. The mixed organic phase was washed with a brine, dried over Na2S2O3, filtered, and concentrated under reduced pressure. The resulting residue was used for the subsequent reaction without purification. A solution of the resulting product in pyridine (0.16 mL) and DMF (1.2 mL) was stirred at room temperature, to which C6F5O2CCF3 (0.125 mL, 0.73 mmol) was added, and the resulting mixture was stirred at room temperature for 15 minutes. A 1 N HCl aqueous solution was added to the reaction mixture to terminate the reaction, and the reaction mixture was extracted with ethyl acetate twice. The mixed organic phase was washed with a NaHCO3 aqueous solution and a brine, dried over Na2S2O3, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2, n-hexane/EtOAc=4/1), so as to provide the target compound 2a-1-1 (265 mg, 96% yield) as a white solid substance (melting point Mp.: 149-152 C., Rf=0.38 (n-hexane/EtOAc=2/1)). Data of Compound 2a-1-1; 1H NMR (400 MHz, CDCl3) delta 3.92 (s, 3H), 3.98 (s, 3H), 6.11-6.14 (m, 1H), 6.66-6.67 (m, 1H), 6.78 (br-s, 1H), 7.05-7.07 (m, 1H), 7.60-7.62 (m, 2H); 13C NMR (100 MHz, CDCl3) delta 36.7 (2C), 107.6, 111.0, 112.0, 116.6, 122.9, 123.9, 125.3, 128.7, 136.7-136.9 (m), 139.1-139.3 (m), 140.5-140.7 (m), 142.9-143.1 (m), 156.2, 159.4; IR (ATR) nu 1742, 1644, 1522, 1412, 1316, 1231, 1192, 1109, 1038, 738 cm-1; HRMS (ESI-TOF) m/z; [M+Na]+ Calcd. for C18H12F5N3NaO3+ 436.0691; Found 436.0687. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; In N,N-dimethyl-formamide; at 20℃; for 3h;Inert atmosphere; | Anhydrous pyridine(2.23 mmol, 4.5 equiv) was added to a stirring solution of1 (400 mg, 0.496 mmol, 1 equiv) in anhydrous DMF (5.7 mL)under N2. To this solution was added dropwise pentafluorophenyltrifluoroacetate (1.48 mmol, 3 equiv) under N2. Thereaction mixture was allowed to stir at room temperatureovernight. Reaction progress was monitored by TLC (35%EtOAc/hexane). Once the reaction was complete, the mixturewas concentrated in vacuo and azeotroped with toluenemultiple times to remove the TFA generated in situ. Theresidue was purified by flash chromatography (40:60 acetone/hexane) and concentrated in vacuo to afford an off-white solid(440 mg, 91%): 1H NMR (500 MHz, chloroform-d) delta 7.78 (d,J = 7.5 Hz, 2H), 7.63 (dd, J = 13.8, 7.5 Hz, 2H), 7.41 (t, J = 7.5Hz, 2H), 7.36-7.31 (m, 2H), 6.21 (d, J = 7.7 Hz, 1H), 5.35 (d,J = 9.3 Hz, 1H), 5.22 (t, J = 9.9 Hz, 1H), 5.07 (t, J = 9.7 Hz,1H), 4.89 (td, J = 7.8, 3.7 Hz, 1H), 4.78 (d, J = 11.9 Hz, 1H),4.69 (d, J = 10.3 Hz, 1H), 4.61-4.50 (m, 2H), 4.43 (t, J = 8.9Hz, 1H), 4.28 (t, J = 6.9 Hz, 1H), 4.16-4.05 (m, 2H), 3.83 (q,J = 10.0 Hz, 1H), 3.72-3.67 (m, 1H), 3.50 (dd, J = 14.7, 4.0Hz, 1H), 3.08 (dd, J = 14.8, 8.3 Hz, 1H), 2.06 (s, 3H), 2.04 (s,3H), 2.00 (s, 3H); 13C NMR (126 MHz, chloroform-d) delta170.67, 169.29, 166.95, 156.02, 154.30, 143.74, 143.49, 141.32,127.80, 127.14, 125.08, 124.94, 120.07, 83.71, 76.29, 74.49,73.02, 68.27, 67.31, 62.10, 54.88, 53.70, 47.11, 31.58, 20.59,20.50; HRMS calcd for (M + H)+ m/z 971.0846, found m/z971.0833; IR (KBr pellet) 3339.8, 3068.4, 2955.5, 2670.0,2461.8, 1753.4, 1519.4, 1450.9, 1374.5, 1223.3, 994.8, 916.0,878.0, 817.5 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With pyridine; In dichloromethane; at 20℃; for 1h; | To a vial containing 2-{(1 f?,3f?)-1 -(acetyloxy)-4-methyl-3-[methyl(/V-[(2f?)-1 -methylpiperidin-2- yl]carbonyl}-L-isoleucyl)amino]pentyl}-1 ,3-thiazole-4-carboxylic acid (A3, 150 mg, 0.153 mmol) was added DCM (1 .0 mL) and pyridine (25 mu, 0.306 mmol) followed by <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (53 mu, 0.306 mmol) and the reaction was stirred for 1 h at rt. The reaction was concentrated to a thick oil and was purified by silica gel chromatography (0% to 100% EtOAc in heptanes). The purified product was azeotroped with heptane/DCM (1/1) to provide the title compound A30 (106 mg, 98% yield) as a white solid. LC-MS (Protocol C): /z 705.1 [M+H]+; Retention time = 0.89 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 25℃; for 3h; | [0294] To a solution of G-11 (6.3 g, 3.18 mmol, 1.00 equiv.) in N,N-dimethylformamide (63 mL) was added N,N-diisopropylethylamine (1.0 g, 7.95 mmol, 2.50 equiv.). This was followed by the addition of pentafluorophenyl 2,2,2-trifluoroacetate (1.33 g, 4.77 mmol, 1.50 equiv.) dropwise with stirring at 0oC. The resulting solution was stirred for 3 h at 25oC. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash with the following conditions: C18 gel column, eluent A water, eluent B acetonitrile; gradient: 20% up to 80% within 15 min, 100% maintained 3 min; Detector, UV 210 nm. This resulted in 5 g (73%) of GalNAc-6 as a white solid. MS m/z [M/2+H]+ (ESI): 1073; H-NMR (DMSO, 300MHz, ppm): 7.71-7.80 (m, 9H), 6.98 (s, 1H), 5.22 (d, J = 3.3 Hz, 3H), 4.99 (dd, J = 11.1 Hz, 3.3 Hz, 3H), 4.50 (d, J = 8.4 Hz, 3H), 4.02 (s, 9H), 3.82-3.92 (m, 3H), 3.69-3.74 (m, 3H), 3.52-3.56 (m, 12H), 3.39-3.44 (m, 3H), 3.03 (s, 12H), 2.75-2.79 (m, 2H), 2.28 (t, J = 6.3 Hz, 6H), 2.00-2.10 (m, 26H), 1.89 (s, 9H), 1.77 (s, 9H), 1.64-1.68 (m, 2H), 1.25-1.53 (m, 28H); F-NMR (DMSO, 162MHz, ppm): -153.60, -153.67, -153.68, -153.69, -158.05, -158.14, -158.22, -162.53, -162.60, -162.62, -162.69, -162.70. |
73% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 25℃; for 3h; | To a solution of G-11 (6.3 g, 3.18 mmol, 1.00 equiv.) in N,N-dimethylformamide (63 mL) was added N,N-diisopropylethylamine (1.0 g, 7.95 mmol, 2.50 equiv.). This was followed by the addition of pentafluorophenyl 2,2,2-trifluoroacetate (1.33 g, 4.77 mmol, 1.50 equiv.) dropwise with stirring at 0C. The resulting solution was stirred for 3 h at 25C. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash with the following conditions: CI 8 gel column, eluent A water, eluent B acetonitrile; gradient: 20% up to 80% within 15 min, 100% maintained 3 min; Detector, UV 210 nm. This resulted in 5 g (73%) of GalNAc-6 as a white solid. MS m/z [M/2+H]+ (ESI): 1073; H-NMR (DMSO, 300MRz, ppm): 7.71-7.80 (m, 9H), 6.98 (s, 1H), 5.22 (d, J= 3.3 Hz, 3H), 4.99 (dd, J= 11.1 Hz, 3.3 Hz, 3H), 4.50 (d, J= 8.4 Hz, 3H), 4.02 (s, 9H), 3.82-3.92 (m, 3H), 3.69-3.74 (m, 3H), 3.52-3.56 (m, 12H), 3.39-3.44 (m, 3H), 3.03 (s, 12H), 2.75-2.79 (m, 2H), 2.28 (t, J= 6.3 Hz, 6H), 2.00-2.10 (m, 26H), 1.89 (s, 9H), 1.77 (s, 9H), 1.64-1.68 (m, 2H), 1.25-1.53 (m, 28H); F-NMR (DMSO, 162MHz, ppm): -153.60, -153.67, -153.68, -153.69, -158.05, -158.14, -158.22, -162.53, -162.60, -162.62, -162.69, -162.70. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 16h;Inert atmosphere; | Perfluorophenyl-2,2,2-trifluoroacetate (1.89 mL, 11.02 mmol) followed by DIPEA (3.17 mL, 18.36 mmol) was added to a stirred solution of N-Boc-N-Me-L-Isoleucine (14) (1.8 g, 7.34 mmol) in dichloromethane (20 mL) at 0 C. The reaction mixture was stirred at ambient temperature under nitrogen atmosphere for 16 h. Solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using 0-3% ethyl acetate in pet-ether to afford tert-butyl(1S,2S)-1-((perfluorophenoxy)carbonyl)-2-methylbutylmethyl carbamate (15) (2.29 g, 76% yield) as a light-yellow liquid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of 321 P14 (9.6 g, 26 mmol) in 11 DMF (100 mL) was added 12 DIPEA (14 mL, 79 mmol), and 324 perfluorophenyl 2,2,2-trifluoroacetate (15 g, 53 mmol). This mixture was stirred at room temperature overnight, which was monitored by LCMS. The reaction mixture was then diluted with ether (200 mL) and washed with water (300 mL) and brine (200 mL). The organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0-10% 91 ethyl acetate in 92 petroleum ether) to give 325 compound P15 (12 g, 88% yield) as a white solid. ESI m/z: 531 (M+H)+. 1H NMR (500 MHz, DMSOd6) delta 7.43 (d, J=7.1 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.2 Hz, 1H), 6.93 (dd, J=10.2, 5.5 Hz, 2H), 6.76 (dd, J=8.4, 2.5 Hz, 1H), 5.05 (s, 2H), 2.81 (dd, J=16.3, 4.5 Hz, 1H), 2.77-2.68 (m, 1H), 2.28-2.19 (m, 2H), 2.18 (dd, J=13.4, 5.6 Hz, 1H), 2.00-1.83 (m, 2H), 1.74 (d, J=11.8 Hz, 1H), 1.65 (d, J=14.1 Hz, 1H), 1.47 (s, 3H), 1.38-1.27 (m, 2H), 1.08 (s, 3H) ppm. |
88% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Pentafluorophenyl (1S,4aS,10aR)-6-(benzyloxy)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydrophenanthrene-1-carboxylate (P1-10) To a solution of P1-9 (9.6 g, 26 mmol) in DMF (100 mL) was added DIPEA (14 mL, 79 mmol), and perfluorophenyl 2,2,2-trifluoroacetate (15 g, 53 mmol). This mixture was stirred at room temperature overnight, and monitored by LCMS. The reaction mixture was then diluted with ether (200 mL) and washed with water (300 mL) and brine (200 mL). The organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0-10% ethyl acetate in petroleum ether) to give compound P1-10 (12 g, 88% yield) as a white solid. ESI m/z: 531 (M+H)+. 1H NMR (500 MHz, DMSOd6) delta 7.43 (d, J=7.1 Hz, 2H), 7.38 (t, J=7.4 Hz, 2H), 7.31 (t, J=7.2 Hz, 1H), 6.93 (dd, J=10.2, 5.5 Hz, 2H), 6.76 (dd, J=8.4, 2.5 Hz, 1H), 5.05 (s, 2H), 2.81 (dd, J=16.3, 4.5 Hz, 1H), 2.77-2.68 (m, 1H), 2.28-2.19 (m, 2H), 2.18 (dd, J=13.4, 5.6 Hz, 1H), 2.00-1.83 (m, 2H), 1.74 (d, J=11.8 Hz, 1H), 1.65 (d, J=14.1 Hz, 1H), 1.47 (s, 3H), 1.38-1.27 (m, 2H), 1.08 (s, 3H) ppm. |
88% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | To a solution of P1-9a (9.6 g, 26 mmol) in DMF (100 mL) was added DIPEA (14 mL, 79 mmol), and perfluorophenyl 2,2,2-trifluoroacetate (15 g, 53 mmol). This mixture was stirred at room temperature overnight and monitored by LCMS. The reaction mixture was then diluted with ether (200 mL) and washed with water (300 mL) and brine (200 mL). The organic solution was dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (0-10% ethyl acetate in petroleum ether) to give compound P1-10a (12 g, 88% yield) as a white solid. ESI m/z: 531 (M + H)+.1H NMR (500 MHz, DMSOd6) t 7.43 (d, J = 7.1 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.2 Hz, 1H), 6.93 (dd, J = 10.2, 5.5 Hz, 2H), 6.76 (dd, J = 8.4, 2.5 Hz, 1H), 5.05 (s, 2H), 2.81 (dd, J = 16.3, 4.5 Hz, 1H), 2.77-2.68 (m, 1H), 2.28- 2.19 (m, 2H), 2.18 (dd, J = 13.4, 5.6 Hz, 1H), 2.00-1.83 (m, 2H), 1.74 (d, J = 11.8 Hz, 1H), 1.65 (d, J = 14.1 Hz, 1H), 1.47 (s, 3H), 1.38-1.27 (m, 2H), 1.08 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 70℃; for 1h; | D-Iminobiotin (1.00 g, 4.10 mmol) was dissolved in 2 mL DMF at 70 C and allowed to cool to rt. TEA (0.83g, 1.14 mL, 8.19 mmol) was added, followed by <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (1.60 g, 0.98 mL, 5.73 mmol). The reaction was allowed to stir for 1 h at 0 C and became pink. Solvent was reduced to 1 mL in vacuo and the crude material was triturated with cold diethyl ether. The pFp ester product was recovered as a white solid (1.50 g, 93%). Iminobiotin-pFp ester (1.00 g, 2.44 mmol) was dissolved in 10 mL DMF and cooled to 0 C. A flask containing a suspension of NaBH4 (3.4 mmol) in dry DMF (5 mL) was also cooled to 0 C. The pFp-ester was transferred dropwise via a cannula over 15 min and the mixture was stirred at 0 C. The reaction was followed by TLC and upon completion the cold mixture was acidified with 1 N HC1 and reduced to 1 mL in vacuo. The residue was triturated with cold diethyl ether and the product alcohol was recovered as a white solid (0.516 g, 92%). The alcohol (0.516 g, 2.25 mmol) and TEA (0.38 ml, 1.2 eq) were dissolved in DMF (10 mL) and added dropwise to a stirred solution of 4- nitrophenyl chloroformate (4-NCF, 1.36 g, 6.75 mmol, 3.0 eq) in DMF (10 mL) over a period of 1 h at -10C. The reaction mixture was allowed to warm to rt, stirred overnight, and subsequently and reduced to 1 mL in vacuo. The residue was triturated with cold diethyl ether. The nitrophenol carbonate product was recovered as a white solid (0.83 g, 93%). Fmoc-L-Lys-OH (0.99 g, 2.72 mmol, 1.3 eq.) was suspended under argon in anhydrous DMF (10 ml) containing DiPEA (0.50 ml, 1.3 eq.). To this white suspension, a clear solution of the nitrophenol-carbonate (2.09 mmol, 1.0 eq.) in anhydrous DMF (10 mL) was added drop wise under argon at rt over a period of 2 h. The reaction mixture was stirred for additional 4 h at rt, before the solution as acidified to pH 2 with 1 N HC1. All volatiles were evaporated under reduced pressure and the residue was triturated with cold diethyl ether. The crude product was purified by column chromatography (DCM : MeOH 95 : 5 v/v) to give the Fmoc -protected ncAA as a white solid. The Fmoc -protected ncAA was dissolved in 20% piperidine in DMF (5 ml) and stirred for 1 h at r.t.. All volatiles were removed under reduced pressure and the residue was triturated with cold diethyl ether. Drying of the residue in vaccuum yield the pure ncAA as a white powder (0.545 g, 65 %). 1H-NMR (D6-DMSO, 400 MHz): delta = 1.30- 1.45 (m, 6H), 1.50 (m, 2H), 1.71 (m, 4H), 2.82 (d, / = 12.2 Hz, 1H), 2.93 - 3.00 (m, 4H), 3.28 (m, 1H), 3.88-3.97 (m, 4H), 4.50 (dd, / = 8.2 Hz, / = 7.3 Hz, 1H), 4.68 (dd, / = 8.1 Hz, / = 7.2 Hz, 1H), 7.06 (t, / = 5.4 Hz, 1H), 7.91 (br, 1H), 8.30 (br, 3H), 8.35 (br, 1H), 8.68 (br, 1H).13C-NMR (D6-DMSO, 100 MHz): 13C-NMR (CDCI3, 100 MHz): delta = 171.55, 160.00, 156.80, 64.89, 63.97, 63.45, 62.88, 55.57, 52.37, 39.03, 30.16, 29.39, 28.99, 28.75, 28.48, 25.81, 22.10. HR-MS (C17H32N5O4S): calculated: 402.21695, found: 402.21654. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 70℃; for 1h; | D-Nordesthiobiotin (0.25 g, 1.25 mmol) was dissolved in 5 mL DMF at 70 C and allowed to cool to rt. TEA (0.25 g, 0.33 mL, 2.20 mmol) was added, followed by <strong>[14533-84-7]pentafluorophenyl trifluoroacetate</strong> (0.49 g, 0.30 mL, 1.75 mmol). The reaction was allowed to stir for 1 h at 0 C and became pink. Solvent was reduced to 0.25 mL in vacuo and the crude material was triturated with cold diethyl ether. The pFp ester product was recovered as a white solid (0.425 g, 93%). Biotin-pFp ester (0.425 g, 1.16 mmol) was dissolved in 4 mL DMF and cooled to 0 C. A flask containing a suspension of NaBH4 (1.6 mmol) in dry DMF (2 mL) was also cooled to 0C. The pFp-ester was transferred dropwise via a cannula over 15 min and the mixture was stirred at 0 C. The reaction was followed by TLC and upon completion the cold mixture was acidified with 1 N HC1 and reduced to 0.3 mL in vacuo. The residue was triturated with cold diethyl ether and the product alcohol was recovered as a white solid (0.199 g, 92%). The alcohol (0.199 g, 1.07 mmol) and TEA (0.16 ml, 1.2 eq) were dissolved in DMF (4 mL) and added dropwise to a stirred solution of 4-nitrophenyl chloroformate (4-NCF, 0.645 g, 3.2 mmol, 3.0 eq) in DMF (4 mL) over a period of 1 h at -10C. The reaction mixture was allowed to warm to rt, stirred overnight, and subsequently and reduced to 0.3 mL in vacuo. The residue was triturated with cold diethyl ether. The nitrophenol carbonate product was recovered as a white solid (0.34 g, 91%). Fmoc-L-Lys-OH (0.465 g, 1.26 mmol, 1.3 eq.) was suspended under argon in anhydrous DMF (3 ml) containing DiPEA (0.25 ml, 1.3 eq.). To this white suspension, a clear solution of the nitrophenol-carbonate (0.97 mmol, 1.0 eq.) in anhydrous DMF (3 mL) was added drop wise under argon at rt over a period of 1 h. The reaction mixture was stirred for additional 4 h at rt, before the solution as acidified to pH 2 with 1 N HC1. All volatiles were evaporated under reduced pressure and the residue was triturated with cold diethyl ether. The crude product was purified by column chromatography (DCM : MeOH 95 : 5 v/v) to give the Fmoc-protected ncAA as a white solid. The Fmoc- protected ncAA was dissolved in 20% piperidine in DMF (2 ml) and stirred for 1 h at r.t.. All volatiles were removed under reduced pressure and the residue was triturated with cold diethyl ether. Drying of the residue in vaccuum yield the pure ncAA as a white powder (0.268 g, 77 %). 1H-NMR (D6-DMSO, 400 MHz): delta = 1.28-1.64 (m, 13H), 1.82 (m, 4H), 2.62 (d, / = 12.2 Hz, 1H), 2.84 (dd, / = 5.0 Hz, / = 12.2 Hz, 1H), 2.98 (m, 2H), 3.19 (m, 2H), 3.94 (t, / = 7.5 Hz, 1H), 4.18 (dd, / = 8.2 Hz, / = 7.3 Hz, 1H), 4.35 (dd, / = 8.1 Hz, / = 7.2 Hz, 1H), 7.13 (t, / = 5.4 Hz, 1H), 8.52 (br, 5H). 13C- NMR (D6-DMSO, 100 MHz): 13C-NMR (CDCI3, 100 MHz): delta = 171.40, 163.23, 156.80, 63.89, 61.58, 59.74, 55.95, 52.27, 30.05, 29.53, 29.35, 29.13, 28.50, 25.61, 22.24, 22.05. HR-MS (C16H33N4O5): calculated: 359.22890, found: 359.22944. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With triethylamine In dichloromethane at 20℃; | C General procedure 2 (GP2): Preparation of bis-pentafluorophenyl) esters General procedure: To a slurry of diacid (1.8-3.9 mmol) and triethylamine (2.1-3.0 equiv.) in DCM (5- 20 mL) was added pentafluorophenyl trifluoroacetate (2.0-2.1 equiv.). The reaction mixture was stirred at ambient temperature for 5-18 hours, then concentrated and purified by silica gel chromatography to afford the desired diester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.5h; | A solution of 22 (0.40 g, 1.6 mmol) in dry N,N-dimethylformamide(4 mL) was added dropwise to a solution of pentafluorophenyltrifluoroacetate (0.59 g, 2.1 mmol) and pyridine (0.14 g,1.8 mmol) in dry N,N-dimethylformamide at 0 C, before stirring atambient temperature for 1.5 h. The mixture was then diluted with ethylacetate (300 mL) and washed with aqueous hydrochloric acid (0.1 M;3×50 mL), aqueous sodium hydrogen carbonate (5%; 3× 50 mL) andbrine (50 mL) before drying the organics with magnesium sulfate, filtrationand solvent removal in vacuo to yield the crude product as acrystalline cream solid was used without purification. deltaH (400 MHz;CDCl3; Me4Si) 5.41 (2H, s) 6.96 (1H, dd, J 1.8, 6.9 Hz) 7.01 (1H, dd, J1.4, 9.2 Hz) 7.35-7.39 (3H, m) 7.42 (1H, dd, J 6.9, 9.2 Hz) 7.52-7.54(2H, m); deltaC (100 MHz) 78.9, 111.4, 124.2 (m), 128.6, 129.4, 130.2,133.1, 135.2, 136.9 (m), 137.0, 138.8 (m), 139.3 (m), 139.9 (m), 141.4(m), 142.4 (m), 155.2, 158.9, 162.9; (+)-ESI-MS: m/z 433.89(M + Na+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: 4-cyano-4-[(dodecylsulfanylthiocarbonyl)-sulfanyl]pentanoic acid With triethylamine In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: pentafluorophenyl trifloroacetate In dichloromethane at 0℃; for 3.75h; Inert atmosphere; |
Tags: 14533-84-7 synthesis path| 14533-84-7 SDS| 14533-84-7 COA| 14533-84-7 purity| 14533-84-7 application| 14533-84-7 NMR| 14533-84-7 COA| 14533-84-7 structure
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