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CAS No. : | 74427-22-8 | MDL No. : | MFCD02093342 |
Formula : | C3H3F5O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NKULBUOBGILEAR-UHFFFAOYSA-N |
M.W : | 214.11 | Pubchem ID : | 2774089 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 8.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 26.88 |
TPSA : | 51.75 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.39 cm/s |
Log Po/w (iLOGP) : | 1.17 |
Log Po/w (XLOGP3) : | 1.71 |
Log Po/w (WLOGP) : | 4.3 |
Log Po/w (MLOGP) : | 0.91 |
Log Po/w (SILICOS-IT) : | 1.56 |
Consensus Log Po/w : | 1.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.98 |
Solubility : | 2.24 mg/ml ; 0.0105 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.41 |
Solubility : | 0.828 mg/ml ; 0.00387 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.45 |
Solubility : | 7.58 mg/ml ; 0.0354 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.57 |
Signal Word: | Danger | Class: | 8,3 |
Precautionary Statements: | P501-P240-P210-P233-P234-P243-P241-P242-P264-P280-P370+P378-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P403+P235-P406-P405 | UN#: | 2920 |
Hazard Statements: | H314-H226-H290 | Packing Group: | Ⅱ |
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 |
---|---|---|
94% | With triethylamine; In dichloromethane; at -60 - 20℃; | Triflic anhydride (120 g, 0.427 mol) was dissolved in anhydrous dichloromethane (70 mL) and cooled to -60% C. A solution of triethylamine (59.5 mL, 0.427 mol) and difluoroethanol (35 g, 0.427 mol) in dichloromethane (70 mL) was added slowly, so that the internal temperature did not exceed -50% C. After complete addition the resulting yellow solution was allowed to reach room temperature. Dichloromethane was distilled off under atmospheric pressure, and the remaining liquid fractionally distilled under reduced pressure (70-80 mbar), using a 20 cm Vigreux column to give the title sulfonate (86.2 q, 94%) (b.p.: 58-60 C.). 1H-NMR (CDCl3) delta 4.58 (dt, J=3.6, 12.8 Hz, 2H), 6.05 (tt, J=3.6, 54 Hz, 1H); 19F-NMR (CDCl3) delta -74.6 (s), -127 (s). |
67.9% | With 2,6-dimethylpyridine; In dichloromethane; at -10℃; for 1h;Inert atmosphere; | Trifluoromethanesulfonic anhydride (3.97 ml, 23.5 mmol) was added dropwise to a solution of 2,2-difluoroethan-1-ol (1.75 g, 21.3 mmol) in DCM (40 mL at) at -10 C. (salt/ice bath). Lutidine (2.98 ml, 25.6 mmol) was then added, and the reaction was stirred for 1 hour at -10 C. The reaction was then quenched with water, and the layers were separated. The organic layer was washed with water and then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2,2-difluoroethyl trifluoromethanesulfonate (3.10 g, 67.9%) as a colorless liquid. 1H NMR (500 MHz, CDCl3, 27 C.) 4.57 (2H, td), 6.03 (1H, tt). |
67.9% | With 2,6-dimethylpyridine; In dichloromethane; at -10℃; for 1h; | Trifluoromethanesulfonic anhydride (3.97 ml, 23.5 mmol) was added dropwise to a solution of2,2-difluoroethan-1-ol (1.75 g, 21.3 mmol) in DCM (40 mL at) at -10C (salt/ice bath).Lutidine (2.98 ml, 25.6 mmol) was then added, and the reaction was stirred for 1 hour at -10C. The reaction was then quenched with water, and the layers were separated. The organiclayer was washed with water and then dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford 2,2-difluoroethyl trifluoromethanesulfonate (3.10 g, 67.9%) as a colorless liquid. ?H NMR (500 MHz, CDC13, 27 C) 4.57 (2H, td), 6.03 (1H, if). |
67.9% | With 2,6-dimethylpyridine; In dichloromethane; at -10℃; for 1h; | Trifluoromethanesulfonic anhydride (3.97 ml, 23.5 mmol) was added dropwise to a solution of 2,2-difluoroethan-l-ol (1.75 g, 21.3 mmol) in DCM (40 mL at ) at -10 C (salt/ice bath). Lutidine (2.98 ml, 25.6 mmol) was then added, and the reaction was stirred for 1 hour at -10 C. The reaction was then quenched with water, and the layers were separated. The organic layer was washed with water and then dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2,2-difluoroethyl (0393) trifluoromethanesulfonate (3.10 g, 67.9%) as a colorless liquid. Eta NMR (500 MHz, CDCls, 27 C) 4.57 (2H, td), 6.03 (1H, tt). |
64% | at 84℃;Cooling with ice; | Triflic anhydride (27.9g, 99.1 mmol) was placed in a flask and cooled with an ice bath. 2,2-Difluoroethanol (8.1g, 99.1 mmol) was added and the reaction was heated to 84SC for 1 hour. The reaction was cooled in an ice bath and poured into 100ml cold 5%NaHCO3 solution. The mixture was extracted with diethyl ether, dried over MgSO4, and concentrated under reduced pressure to remove the ether. The residue was vaccuum distilled to give 2,2-difluoroethyl trifluoromethanesulfonate as a clear liquid (13.6g, 64%, bp~55sC). 1H NMR (400 MHz, CDCl3) delta ppm 6.17-5.88 (1 H)1 4.61-4.13 (2H) |
61% | at 0℃; for 1.5h;Schlenk technique; Reflux; | Trifluoromethanesulfonicanhydride (84.6 g, 300mmol) was added dropwise into 2,2-difluoroethanol (24.6 g, 300mmol) in a 250 mL Schlenk flask (equipped with a condenser) at 0 oC.The mixture was heated at reflux for 1.5 h, cooled to room temperature, and washedby saturated aqueous NaHCO3 solution and water. The organic layerwas dried over anhydrous Na2SO4 and distilled to give 39.1g of TfOCH2CF2H as a colorless liquid (61% yield). 1HNMR: delta 6.05 (tt, J = 53.6 Hz, J = 3.8 Hz, 1H), 4.60 (td, J= 12.6 Hz, J = 3.7 Hz, 2H). 19F NMR: delta -74.4 (s, 3F), -126.9(dt, J = 53.9 Hz, J = 13.1 Hz, 2F). |
61% | With triethylamine; In dichloromethane; at 0 - 20℃; for 5.2h; | The round bottom flask was added 2,2-difluoro alcohol 10 (^, 2058 triethylamine and anhydrous dichloromethane 900mL. Between 0 C, a solution of trifluoromethanesulfonic anhydride 200g was slowly added dropwise to the above solution, after naturally to room temperature, the reaction 5.2 hours. the reaction mixture was poured into ice water, the organic phase was separated, washed with water, brine, and dried, to give the crude spin dry, to give the compound (IV) (120.lg, pale yellow liquid) in a yield of 61% 1H-NMR (400MuEtaz, CDCl3) delta: 4. 58 (dt, J = 3. 6, 12. 8Hz, 2H),6. 05 (tt, J = 3. 6, 54Hz, 1H). |
61% | at -20℃; for 1.5h;Inert atmosphere; Schlenk technique; Reflux; | Trifluoromethanesulfonic anhydride (42.3 g,150.0 mmol) was added dropwise to 2,2-difluoroethanol (12.3 g, 150.0 mmol) in a 250 mL Schlenk flask (equipped with a condenser) at -20C. The mixture was then heated at reflux for 1.5 h, cooled to room temperature, washed with aqueous NaHCO3 solution (30 mL) and brine (3×50 ml), dried over anhydrous MgSO4, and distilled to give 2,2-difluoroethyl trifluoromethanesulfonate (2b) as a colorless liquid (19.6 g, 91.6 mmol, 61%). 1H NMR (400 MHz, CDCl3) delta 6.04 (tt, J = 53.8 Hz, J = 3.4 Hz, 1H), 4.58 (td, J = 12.4 Hz, J = 2.4 Hz, 2H). 19F NMR (376 MHz, CDCl3) delta -74.1 (s, 3F), -126.5 (td, J = 54.8 Hz, J = 12.8 Hz, 2F). 13C NMR (100 MHz, CDCl3) delta 118.5 (q, J = 315.8 Hz), 110.7 (t, J = 246.8 Hz), 71.0 (t, J = 31.3 Hz). |
51% | With triethylamine; In dichloromethane; at -78℃; for 0.25h; | [1361] At -78 C., a solution of 1.00 g (12.2 mmol) of2,2-difluoroethanol and 1.87 ml (13.4 mmol) of triethylaminein 5 ml of dichloromethane was added dropwise to 2.26 ml(13.4 mmol) oftrifluoromethanesulphonic anhydride in 5 mlof dichloromethane such that the internal temperature did notexceed -50 C. The mixture was stirred at -78 C. for another15 min and spontaneously warmed to RT. The reaction mixturewas diluted with 50 ml of methyl tert-butyl ether andwashed three times with 25 ml of a mixture of saturatedaqueous sodium chloride solution/IN hydrochloric acid(3: 1 ), dried over magnesium sulphate, filtered and concentratedat 25 C. and a pressure of ;;,:1 00 mbar. Yield: 1.48 g(51% of theory)[1362] 1H-NMR (400 MHz, CDCI3 ): o [ppm]=6.05 (tt,lH), 4.59 (dt, 2H). |
With triethylamine; In chloroform; at 0℃; for 0.5h;Cooling; | 1) Production of 2,2-difluoroethyl trifluoromethanesulfonate: With cooling with ice, 2.7 ml of trifluoromethanesulfonic acid anhydride was added to a chloroform (100 mL) solution of 1 mL of 2,2-difluoroethanol and 2.2 mL of triethylamine, and stirred for 30 minutes. The reaction liquid was diluted with chloroform, and washed with aqueous saturated sodium bicarbonate solution and saturated saline water in that order. The organic layer was dried with anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure to obtain the entitled compound. | |
9.04 g | With triethylamine; In dichloromethane; at -78℃; for 0.75h;Inert atmosphere; | 1st Step A CH2Cl2 (10 ml) solution containing 2,2-difluoroethanol (5.0 g) and triethylamine (8.44 ml) was slowly added to a CH2Cl2 (10 ml) solution containing trifluoromethanesulfonic anhydride (10.2 ml) at -78 C. in a nitrogen atmosphere, followed by stirring for 45 minutes. The solvent was distilled away under reduced pressure. Colorless oily matter of 2,2-difluoroethyl trifluoromethane sulfonate (9.04 g) was thus obtained. |
With triethylamine; In dichloromethane; at -78 - 20℃; | To a solution of trifluoromethanesulfonic anhydride (34.39 g, 0.12 mol) in DCM (20 mL) was cooled to -78Cthen added 2,2-difluoroethanol 1a (10 g, 0.12 mol) and TEA (12 g, 0.12 mol) in DCM (10 mL) slowly. The mixture waswarmed to rt then concentrated to afford crude 2,2-difluoroethyl trifluoromethanesulfonate 1b (53.00 g) as a yellow oil.It was used in the next step without further purification | |
1.48 g | With triethylamine; In dichloromethane; at -78 - 20℃; for 0.25h; | At -78 C, a solution of 1.00 g (12.2 mmol) of2,2-difluoroethanol and 1.87 ml (13.4 mmol) of triethylamine in 5 ml ofdichloromethane was added dropwise to 2.26 ml (13.4 mmol) oftrifluoromethanesulphonic anhydride in 5 ml of dichloromethane such that theinternal temperature did not exceed -50 C. The mixture was stirred at -78 C foranother 15 min and spontaneously warmed to RT. The reaction mixture was dilutedwith 50 ml of methyl tert-butyl ether and washed three times with 25 ml of amixture of saturated aqueous sodium chloride solution/1N hydrochloric acid(3:1), dried over magnesium sulphate, filtered and concentrated at 25 C and a pressure of >100 mbar. Yield: 1.48 g (51% of theory) |
With 2,6-dimethylpyridine; In dichloromethane; at 0℃; for 1h;Inert atmosphere; | Trifluoromethanesulfonic anhydride (17.66 mL, 105.0 mmol) was added to a cooled solutionof 2,2-difluoroethan-1-ol (6.33 mL, 100 mmol) in DCM (194 mL) at 0 C. 2,6-Dimethylpyridine (12.81 mL, 110.0 mmol) was added dropwise in DCM (20 mL) and the reaction was stirred at 0 C for 1 hour. The reaction mixture was washed with 2N HC1 (200 mL) and saturated aqueous sodium chloride (100 mL). The organic phase was dried over Na2SO4 and filtered, then used directly in solution (approx 0.4M in DCM). | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 10℃; for 3h;Inert atmosphere; | To a solution of 2,2-difluoroethanol (50.0 mg, 6.09 mmol, 1.0 eq) and DIPEA(945.08 mg, 7.31 mmol, 1.28 mL, 1.20 eq) in DCM (5.0 mL) was added Tf20 (1.89 g, 6.70mmol, 1.11 mL, 1.10 eq) at 0 C under N2, and the mixtture was stirred at 10 C for 3 h. Thestarting material have lower boiling point and the reaction was not detected. The mixture wasdiluted with DCM (10 mL) and washed with water (20 mL*2) and brine (20 mL*1). The organicphase was dried over anhydrous Na2SO4 and filtered. DMF(1 mL) was added. The resultingmixture was concentrated in vacuo to get a DMF solution of (2,2,2-trifluoroethyltrifluoromethanesulfonate (5.68 mmol, 1 mL), which directly used in the next step. | |
9.04 g | With triethylamine; In dichloromethane; at -78℃; for 0.75h;Inert atmosphere; | 1st step A dichloromethane (10 ml) solution containing 2,2-difluoroethanol (5.0 g) and triethylamine (8.44 ml) was slowly added to a dichloromethane (10 ml) solution containing trifluoromethanesulfonic anhydride (10.2 ml) at -78C in a nitrogen atmosphere, followed by stirring for 45 minutes. The solvent was distilled away under reduced pressure, and colorless oily matter of 2,2-difluoroethyl trifluoromethane sulfonate (9.04 g) was thus obtained. |
With 2,6-dimethylpyridine; In dichloromethane; at 0℃; for 1h; | Intermediate 6b: (R)-N-(2,2-Difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine Trifluoromethanesulfonic anhydride (9.4 mL, 55.87 mmol) was added to a cooled solution of 2,2-difluoroethane-1-ol (3.37 mL, 53.21 mmol) in DCM (110 mL). 2,6-Dimethylpyridine (6.82 mL, 58.54 mmol) in DCM (11 mL) was then added dropwise and the reaction was stirred at 0 C. for 1 hour. 2N HCl (200 mL) was added and the layers were separated. The organic phase was dried over Na2SO4 to afford a 0.4 M solution of 2,2-difluoroethyl trifluoromethanesulfonate in DCM (133 mL, 53 mmol) which was added in portions (over 20 minutes) to a stirred suspension of (R)-1-(1H-indol-3-yl)propan-2-amine (7.70 g, 44.17 mmol) and DIPEA (10.68 mL, 61.83 mmol) in 1,4-dioxane (68.8 mL). The reaction was stirred at RT for 2 hours. The mixture was washed with sat. NH4Cl solution, dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography, elution gradient 20 to 60% EtOAc in heptane to afford the title compound (9.45 g, 90%) as a pale yellow oil; 1H NMR (400 MHz, DMSO-d6) 0.97 (3H, d), 1.76 (1H, s), 2.59 (1H, dd), 2.84 (1H, dd), 2.88-3.02 (3H, m), 5.96 (1H, m), 6.97 (1H, m), 7.06 (1H, m), 7.14 (1H, d), 7.33 (1H, m), 7.52 (1H, d), 10.79 (1H, s); m/z: ES+ [M+H]+ 239.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 20 - 100℃; | 2,2-Difluoroethyl trifluoromethanesulfonate (1.40 g, 6.5 mmol) was added to 3,5- diamino-6-(2,3-dichlorophenyl) -1,2,4-triazine (0.50 g, 2.0 mmol) and dimethylformamide (3.5 ml). The warm mixture was stirred and heated at 100 0C for 2h and then allowed to stand at room temperature overnight. Ether (35 ml) was added, and the mixture stirred for 0.5h. After the mixture settled, the solvent was decanted from the oily precipitate and the residue stirred with water (10 ml) and aqueous ammonia solution (5 ml , d = 0.88) for 6h. A tan solid was removed by filtration, washed with water (3 ml) and air-dried. Recrystallisation from propan-2-ol gave the title compound as a light tan solid (0.25 g), mp 179-181 0C (decomp., rapid heating) deltaH (500 MHz, dmso-d6) 4.30 (2H, brt, J = 13.8 Hz, NCH2), 5.6-7.0 (2H, vbrpeak, NH2, exchang.), 6.39 (IH, brt, J = 56 Hz, CHF2), 7.3-7.7 (IH, vbrpeak, NH, exchang.), 7.41 (IH, d, J= 7.7 Hz, aromatic H), 7.45 (IH, t, J= 7.7 Hz, aromatic H), 7.74 (IH, d, J= 7.7 Hz, aromatic H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.8% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 25℃; for 72h; | Compound 57a (0.41 g; 0.9 mmol) is dissolved in dichloromethane (4 ml) and DIEA (0.233 ml) is added. To this mixture trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (0.338 mg; 1.6 mmol), dissolved in 1 ml dichloromethane, is added in one portion. The mixture is stirred at 25 C for 72 h. The organic phase is then washed with aqueous ammonium acetate and NaCl solution, dried over Na2SO4 and evaporated to dryness. The crude product is purified by flash chromatography over SiO2. Yield : 0.299 g (63.8 %). ESI-MS: m/z = 519 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | To a -78C solution of diethyl-(N-benzylideneaminomethyl)phosphonate (200 mg, 0.784 mmol) in 1 mL of THF was added LDA (480 (iL,0.863 mmol). The mixture was stirred from -78 C to rt for 10 min and cooledback -78C. To the mixture was added triflate (251 mg, 1.176 mmol) in 0.5 mLof THF. The solution was stirred for 20 min from -78 C to rt, quenched byEtOH and purified by silica gel chromatography using SiCh (pretreated by 2%TEA / hexane) (eluted with 20% to 60% EtOAc / hexane) to give alkylatedproduct as a pale yellow liquid (150 mg, 60%). XH-NMR (300 MHz, CDCls): 88.38 (dd, 1H), 7.83-7.70 (m, 2H), 7.50-7.35 (m, 3H), 6.20-5.58 (m, 1H), 4.30-4.07(m, 4H), 4.00-3.60 (m, 1H), 2.75-2.40 (m, 2H), 1.45-1.30 (m, 6H). LC/MS: 320(M+ + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
~ 86% | Example 5 Cyclic Anhydride ApproachStep 1: Cylcoaddition25 g of difluoroethyl triflate (117 mmol, 1 equiv.) were added dropwise at 20-250C to a solution of 16 ml trimethylsilylmethyl-amine (1 equiv.) and 20 ml ethyldiisopropylamine (1 equiv.) in 225 ml THF. After 2 h, the reaction mixture was treated with 11.46 ml 37% aqueous formaldehyde (1.3 equiv.). After 10 min. at room temperature, a solution consisting of 34.61 g dibenzyl maleate (1 equiv.), 12.5 ml THF and 913 ul trifluoroacetic acid (0.1 equiv.) was added. After 17 h reaction, the reaction mixture was concentrated to ca 80 ml. 125 ml MTBE and 104 ml IM HClaq (2.5 equiv.) were added. The aqueous phase was separated and re-extracted with 62.5 ml MTBE. The organic phases were washed with 125 ml water and 167 ml half saturated aqueous NaHCtheta3 solution, combined, dried over MgSO/t, filtered and concentrated to dryness under reduced pressure to give 45.5 g of crude cycloadduct (ca 86% yield, contains ca 11% m/m dibenzyl maleate).The crude product can be purified for instance by chromatography but is more conveniently introduced in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Example 2 <n="19"/>Preparation of crystalline form A of the compound of formula (I); 53.2 g of 3-(5-Chloro-pyridin-2-ylcarbamoyl)-4-[2-fluoro-4-(2-oxo-2H-pyridin-l-yl)- henylcarbamoyl] -pyrrolidine- 1-carboxylic acid tert-butyl ester (95.7 mmol, 1 equiv.) were added at room temperature, in portions to a solution consisting of 160 ml water and 160 ml 37% HClaq (20 equiv.). After completion of the reaction (ca 30 min., HPLC in process control), the resulting solution was added over Ih to a hot (50 0C) solution consisting of 197 g sodium bicarbonate (24.5 equiv.), 320 ml water, 530 ml ethyl acetate and 23 g, <strong>[74427-22-8]2,2-difluoroethyl triflate</strong> (1.1 equiv.). The addition funnel was washed with 15 ml water. After completion of the reaction (ca 30 min., HPLC in process control), the reaction mixture was cooled to RT. The aqueous phase was separated and re-extracted with 530 ml ethyl acetate. The organic phases were washed sequentially with 265 ml half saturated NaCl solution. The combined ethyl acetate phases were dried over Na2SC>4 and filtered. The Na2SC>4 filter cake was washed with 230 ml ethyl acetate. The filtrate was concentrated to 1 1 and a solvent exchange to ethanol was performed (constant volume, 60 0C jacket temperature, ca 2 1, ethanol used). The hot solution was cooled to RT and seeded with form A upon which the crystallization started. After stirring overnight at room temperature, the white suspension was cooled to -20 0C. After Ih at -20 0C, the suspension was filtered and washed in portions with in total 100 ml cold (-20 0C) ethanol. The crystals were dried to constant weight (50 0C / reduced pressure) to give 40 g of a white powder (78% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | 4-Bromo-pyridine-2,6-diamine (2.2 g) was dissolved under an argon atmosphere in THF (15 mL) and cooled to 0 C. At this temperature LiHMDS (12.9 mL 1 M solution in THF) was added slowly to the solution. The reaction mixture was stirred at 0 C. for 1 h. After that difluorethyltriflate (2.76 g) was added and the reaction mixture was stirred at 25 C. for 18 h. Complete conversion was observed by LC-MS analysis. The reaction mixture was evaporated to dryness, dissolved in ethyl acetate and extracted with water and brine. The organic layer was dried over Na2SO4, filtrated and evaporated to dryness. The crude product was purified by flash chromatography over silica gel (70 g SiO2, gradient ethyl acetate/n-heptane 1:4?1:0) to yield 4-bromo-N-(2,2-difluoroethyl)-pyridine-2,6-diamine (0.943 g; 32%) as a dark red oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | A -40deltaC solution of 2M (in Ethylbenzene/THF/Heptane) LDA (36ml, 72mmol) in THF (80ml) was placed in flask with THF (80ml) was treated with a solution of methyl (1 R,4S)-4-(2,5-dimethyl-1 H-pyrrol-1 -yl)cyclopent-2-ene-1 -carboxylate (7.9g, 36.3mmol) in THF (17ml) while keeping the temperature less than -328C. The reaction was stirred for 30min and then 2,2-difluoroethyl trifluoromethanesulfonate was added slowly, keeping the temperature <-28sC. The reaction was stirred with cold bath in place and allow to slowly warm. After 4 hours the reaction was poured into NH4CI solution and extracted twice with ethyl acetate. The combined organics were washed with brine, dried over MgSO4 and concentrated to give a brown oil. The oil was passed through a column of silica gel with 10% ethyl acetate/hexanes to give methyl (1 S,4S)-1 -(2,2-difluoroethyI)- 4-(2,5-dimethy.-1 H-pyrrol-1 -yl)cyclopent-2-ene-1 -carboxylate as a brown oil. (7.5g, 73%). 1H NMR (400 MHz, CDCI3) delta ppm 6.07-6.04 (1 H), 6.02-6.00 (0.25H) 5.98-5.96 (1 H), 5.88-5.86 (0.5H), 5.75-5.72 (2.25H), 5.36-5.30 (1 H), 3.74 (3H), 2.53-2.41 (2H), 2.39-2.22 (2H), 2.19 (6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; | Example 108 trans-8-Chloro-5-(2,2-difluoro-ethyl)-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene A mixture of trans-8-chloro-1-[4-(6-methyl-pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (0.10 g, 0.24 mmol) and N,N-diisopropylethylamine (0.080 ml, 0.49 mmol) in dichloromethan (1 ml) was treated with trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (63 mg, 0.29 mmol) at 0 C. The cooling bath was removed after 30 min. and the reaction mixture was stirred at room temperature over night. The mixture was partitioned between aqueous saturated ammonium chloride solution (50 ml) and ethyl acetate (50 ml). The aqueous layer was extracted with one 50-ml portion of ethyl acetate. The combined organic layers were washed with two 50-ml portions of a 1 M aqueous solution of sodium carbonate. The aqueous layers were each extracted with one 50-ml portion of ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and concenrated in vacuo. Purification by flash column chromatography gave the title compound (98 mg, 85%) as white solid. MS m/e: 474 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | A mixture of methyl 5-bromo-3-[ (trifluoroacetyl) amino] thiophene-2-carboxylate (500 mg, 1.51 mmol) , 2,2-difluoroethyl trifluoromethanesulfonate (441 mg, 2.06 mmol), cesium carbonate (1.23 g, 3.78 mmol) and DMF (10 mL) was microwave-irradiated at 900C for 1 h. Then, water was added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SCU and filtered. After removal of the solvent at reduced pressure, the residue was dissolved in MeOH (3 mL) . To the solution were added potassium carbonate (100 mg) and water (1.5 mL) . The mixture was stirred at room temperature for 0.5 h. After removal of the solvent at reduced pressure, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SOs and filtered. After removal of the solvent at reduced pressure, the residue was pmurified by column chromatography (Purif, silica gel, hexane to 85:15 hexane/EtOAc) to give the title compound (290 mg, 64%) as a yellow solid:1H NMR (300 MHz, CDCl3) delta 3.51-3.67 (2H, m) , 3.80 (3H, s) , 5. 60-6. 09 ( IH, m) , 6. 69 ( IH, s) , 7 . 05 ( IH, br s ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium hydride; In N,N-dimethyl-formamide; | Step A 1-(2,2-difluoroethyl)-7-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-6-carboxylic acid ethyl ester The compound (4.57 g, 19.6 mmol) of Reference Example 114, step B was dissolved in N,N-dimethylformamide (70 ml), 60% sodium hydride (970 mg, 24.3 mmol) was added under ice-cooling with stirring, and thereafter the mixture was stirred at room temperature for 30 min. The reaction mixture was ice-cooled again, 2,2-difluoroethyl trifluoromethanesulfonate (5.98 g, 27.9 mmol) was added with stirring, and the mixture was stirred at 0 C. for 100 min. To the reaction mixture was added 10% <strong>[5949-29-1]citric acid</strong> water, and the mixture was extracted with an ethyl acetate:hexane=1:1 mixed solvent. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (4.73 g, yield 81%) as a colorless solid. 1H-NMR (400 MHz, CDCl3); delta(ppm) 1.39 (t, J=7.2, 3H), 2.62 (s, 3H), 2.68-2.72 (m, 2H), 2.92-2.96 (m, 2H), 4.27 (dt, J=4.6, 13, 2H), 4.35 (q, J=7.2, 2H), 6.10 (tt, J=4.6, 56, 1H), 6.96 (s, 1H), 7.78 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 6h; | Production Example 159 To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60C for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as "active compound 162"). [Show Image] [Show Image] 1H-NMR (CDCl3) delta: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J=54.8, 4.0 Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h; | Production Example 159To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate(2,2-difluoroethyl)ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60 C. for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as ?active compound 162?).Active Compound 1621H-NMR (CDCl3) delta: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J=54.8, 4.0 Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h; | Production Example 159To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2- yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difiuoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60C for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl- oxazolo[5,4-b]pyridine (hereinafter, referred to as "active compound 162").Active compound 1621H-NMR (CDCI3) delta: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J=54.8, 4.0 Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H) |
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 6h; | To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2- yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60C for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl- oxazolo[5,4-b]pyridine (hereinafter, referred to as "active compound 162").Active compound 1621H-NMR (CDC13) delta: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J=54.8, 4.0 Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 6h; | To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2- yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60C for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl- oxazolo[5,4-b]pyridine (hereinafter, referred to as "active compound 162"). Active compound 162-NMR (CDC13) delta: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J-54.8, 4.0 Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 6h; | Production Example 159To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2- yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60C for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl- oxazolo[5,4-b]pyridine (hereinafter, referred to as "active compound 162").Active compound 1621H-NMR (CDCI3) delta: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J-54.8, 4.0 Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; | Production Example 159To a mixture of 0.31 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2- yl)pyridin-3-ol, 0.23 g of potassium carbonate and 3 ml of DMF, a mixture of 0.50 g of trifluoromethanesulfonate (2,2-difluoroethyl) ester and 7 ml of DMF was added at room temperature, and then stirred while heating at 60C for six hours. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.10 g of 2-[3-(2,2-difluoroethoxy)pyridin-4-yl]-6-trifluoromethyl- oxazolo[5,4-b]pyridine (hereinafter, referred to as "active compound 162"). Active compound 162-NMR (CDC13) delta: 8.76-8.74 (m, 1H), 8.62 (s, 1H), 8.57 (d, J=5.1 Hz, 1H), 8.41-8.40 (m, 1H), 8.09 (d, J=5.1 Hz, 1H), 6.30 (tt, J=54.8, 4.0 Hz, 1H), 4.53 (td, J=12.7, 4.1 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage 4: Preparation of 3-(trifluoromethyl)-1-{2,4-dimethyl-5-[(2,2-difluoroethyl)sulphanyl]phenyl}-1H-1,2,4-triazole (I-A-1) Under nitrogen, 1 g of 1,1'-[disulphanediylbis(4,6-dimethylbenzene-3,1-diyl)]bis[3-(trifluoromethyl)-1H-1,2,4-triazole] is dissolved in 20 ml of dimethylformamide, admixed with 0.96 g of sodium dithionite, 2.04 g of Na2HPO4 in 20 ml of water, and stirred at 60 C. for 2 hours, after which 0.76 g of 2,2-difluoroethoxytrifluoromethylsulphonate is added and the mixture is stirred until reaction is complete. The major amount of the dimethylformamide is distilled off under reduced pressure and the residue is stirred with water and methylene chloride. Concentration of the organic phase on a rotary evaporator and chromatographic purification gives 0.45 g of white solid. This corresponds to a yield of 73% of theory.logP (HCOOH): 3.74M+: 3371H NMR (D6-DMSO): 9.10 (s, 1H), 7.63 (s, 1H), 7.36 (s, 1H), 6.13-6.32 (m, 1H), 3.52-3.59 (m, 2H), 2.38 (s, 3H), 2.12 (s, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 65℃; for 7h; | Step 3 : 9-Benzenesulfonyl-3-bromo-5-ri-(2,2-difluoroethyl)-piperidin-4-yloxyl-9H- dipyridor2,3-b;4' '-d1pyrrole-6-carbonitrileTo a suspension of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3- b;4',3'-d]pyrrole-6-carbonitrile (450 mg, 0.88 mmol) in THF (8 mL) was added 2,2- difluoroethyl trifluoromethanesulfonate (282 mg, 1.32 mmol) in THF (1 mL), followed by DIPEA (250 The resultant reaction mixture was heated at 65 C for 7 hours, then concentrated in-vacuo. The residue was triturated with ethyl acetate to afford the title compound as a pale yellow solid (485 mg, 96%). NMR (300 MHz, DMSO-d6): 9.46 (s, 1H), 8.90 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.24-8.23 (m, 2H), 7.78 (t, J = 7.5 Hz, 1H), 7.64 (t, J = 7.8 Hz, 2H), 6.13 (tt, J = 55.8, 4.3 Hz, 1H), 4.85-4.85 (m, 1H), 3.17-3.12 (m, 2H), 2.75 (td, J = 15.7, 4.3 Hz, 2H), 2.37 (t, J = 10.9 Hz, 2H), 2.08- 2.07 (m, 2H), 1.96-1.95 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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37% | With caesium carbonate; In acetonitrile; at 20℃; for 20h; | Example 34trans-8-Chloro-5-(2,2-difluoro-ethyl)-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azuleneA mixture of trans-8-chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (81.9 mg, 0.251 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (53.8 mg, 0.251 mmol) in acetonitrile (0.6 ml) was stirred at room temperature for 20 h. The reaction mixture was partitioned between a water-brine mixture (1:1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (24 mg, 37%) as off-white solid. MS m/e: 462 ([M+H]+) |
37% | With caesium carbonate; In acetonitrile; at 20℃; for 20h; | A mixture of iraw5,-8-chloro-l-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5, 10b- tetraaza-benzo[e]azulene (50.0 mg, 0.126 mmol), cesium carbonate (81.9 mg, 0.251 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (53.8 mg, 0.251 mmol) in acetonitrile (0.6 ml) was stirred at room temperature for 20 h. The reaction mixture was partitioned between a water-brine mixture (1 : 1) (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with two 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid) / methanol as eluent gave the title compound (24 mg, 37%) as off-white solid. MS m/e: 462 ([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
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85% | At RT, 0.35 ml of N,N-diisopropyl-N-ethylamine are added dropwise to a solution of 600 mg (1.85 mmol) of methyl 2-[(2-fluorobenzyl)sulfonyl]amino}nicotinate (compound IIa-2) in 20 ml of acetonitrile. After 5 min of stirring at RT, 10 min 594 mg (2.775 mmol) of 2,2-difluoroethyl trifluoromethanesulfonate are added dropwise at this temperature over a period of 10 min. The reaction mixture is stirred at 60 C. for 8 h, stirred at RT overnight and then stirred at 60 C. for a further 8 h. The reaction mixture is then evaporated to dryness. The residue is taken up in ethyl acetate and purified by column chromatography (SiO2, mobile phase: EtOAc/n-heptane 20:80 to 50:50). This gives 612 mg (85%) of compound II-2.1H-NMR (400 MHz, CDCl3): delta=8.53 (dd, 1H); 8.23 (dd, 1H); 7.49 (td, 1H); 7.35 (dd, 1H); 7.31 (m, 1H); 7.10 (m, 1H); 6.06 (tt, 1H); 4.42 (s, 2H); 4.18 (td, 2H); 3.92 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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68% | In tetrahydrofuran; | Step A N-[2-(2,2-difluoroethyl)-3,5-dimethyl-2H-indazol-6-yl]iminodiacetic acid diethyl ester The compound (664 mg, 1.99 mmol) of Reference Example 137, step E, 2,2-difluoroethyl trifluoromethanesulfonate (654 mg, 3.05 mmol) and N,N-dicyclohexylmethylamine (0.70 ml, 3.30% mmol) were dissolved in tetrahydrofuran (15 ml), and the mixture was heated under reflux for 6 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (541 mg, yield 68%) as a colorless oil. 1H-NMR (400 MHz, CDCl3); delta(ppm) 1.24 (t, J=7.1, 6H), 2.41 (s, 3H), 2.57 (s, 3H), 4.08 (s, 4H), 4.14 (q, J=7.1, 4H), 4.62 (dt, J=4.4, 13, 2H), 6.22 (tt, J=4.4, 57, 1H), 7.31 (s, 1H), 7.33 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With sodium hydrogencarbonate; In ethanol; at 70℃; for 0.666667h;Sealed tube; Inert atmosphere; | [00626] Step 3:[00627] 2,2-difluoroethyl trifluoromethanesulfonate (17 mg, 0.08 mmol) was added to a solution of [ 10-(4-chlorophenyl)-l 1 -oxa-3,8-diazaspiro[5.5]undecan-3-yl]- (4-isopropoxy-3-methyl-phenyl)methanone (22 mg, 0.05 mmol) and NaHC03 (13 mg, 0.15 mmol) in anhydrous ethanol (0.3 mL) at room temperature. The reaction mixture was purged with argon, sealed with a cap and heated at 70 C for 40 minutes. The reaction mixture was cooled to room temperature, diluted with MeOH to 1 mL, microfiltered and purified by Waters mass directed LC/MS : ( 10-99% ACN/ H20 (5mM HC1)) to yield [10-(4-chlorophenyl)-8-(2,2-difluoroethyl)-l l-oxa-3,8- diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (27 mg, 100 %). ESI-MS m/z calc. 506.21478, found 507.2 (M+l)+; Retention time: 2.17 minutes (3 min run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h; | 5.16 Ethyl 3-(2,2-difluoroethoxy)-6-ethyl-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydro-1H-pyrrolo-[3,2-c]pyridine-2-carboxylate (8c) 2,2-Difluoroethyl trifluoromethanesulfonate (336 mg, 1.57 mmol) was added to a mixture of 7a (500 mg, 1.31 mmol) and Cs2CO3 (554 mg, 1.70 mmol) in DMF (5 mL) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water (15 mL) and the precipitate was collected by filtration. The collected material was washed with water, EtOH and Et2O, and dried in vacuo to give the title compound (0.45 g, 77%) as a white solid. 1H NMR (DMSO-d6) delta 1.19 (3H, t, J = 7.4 Hz), 1.30 (3H, t, J = 7.2 Hz), 2.59 (2H, q, J = 7.4 Hz), 3.86 (3H, s), 4.26 (2H, q, J = 7.2 Hz), 4.42 (2H, td, J = 14.9, 3.9 Hz), 5.61 (2H, s), 6.27 (1H, tt, J = 54.9, 3.9 Hz), 6.54 (1H, s), 7.61 (2H, t, J = 7.5 Hz), 7.74 (1H, t, J = 7.5 Hz), 8.10-8.13 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 6h; | A stirred solution of (R)-l-[l-((lS,3R)-3-amino-cyclopentyl)-6-benzenesulfonyl-l,6- dihydro-l,3,5,6-tetraaza-as-indacen-2-yl]-ethanol (607 mg, 1.43 mmol) in DCM/DMF (16 mL, 1 : 1) was treated with triethylamine (794 mu?, 5.71 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (382 mu?^, 2.86 mmol) at room temperature for 6 hours. The mixture was partitioned between DCM and water and the phases were separated. The organic layer was washed with water, dried (sodium sulfate) and concentrated in vacuo. The residue was azeotroped with toluene to provide a colourless gum. Purification by column chromatography on silica gel (gradient: 0 to 20% MeOH in DCM) afforded 584 mg (84%) of (R)-l-{6- benzenesulfonyl- 1 -[(1 S,3R)-3-(2,2-difluoro-ethylamino)-cyclopentyl]- 1 ,6-dihydro- 1 ,3,5,6- tetraaza-as-indacen-2-yl} -ethanol as a white solid. LCMS (Method H, ESI): RT = 2.04 min, m+H = 490.0; 1H NMR (400 MHz, CDC13): delta 8.84 (s, 1 H), 8.22 (m, 2 H), 7.79 (d, 1 H), 7.54 (m, 1 H), 7.50-7.42 (m, 3 H), 6.09-5.75 (tt, 1 H), 5.22-5.05 (m, 2 H), 3.54-3.45 (m, 1 H), 3.06-2.83 (m, 3 H), 2.59-2.46 (m, 1 H), 2.42-2.30 (m, 1 H), 2.21-2.05 (m, 3 H), 1.94-1.84 (m, 1 H), 1.71 (d, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Step 3.1. 7-bromo-1-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-2-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one To a suspension of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [described in Step 1.3.] (1.49 g, 5.64 mmol) in 30 mL of anhydrous DMF is added caesium carbonate (2.0 g, 6.21 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (10 mL, 56.4 mmol) dropwise. The reaction mixture is stirred at room temperature for 16 hours under nitrogen and then poured into water and extracted with a THF/EtOAc mixture (50/50). The organic phase is washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM/MeOH: 100/0 to 98/2) to give 1.45 g of a yellow solid (yield: 61%). Step 4.1. 7-(pyrid-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [0834] To a solution of 7-bromo-1-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-2-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [described in Step 3.1] (18.2 g, 46.2 mmol) in 150 mL of DMF placed in a microwave reactor are successively added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (11.4 g, 55.4 mmol), aqueous 2M K3PO4 solution (47 mL, 92.4 mmol) and the catalyst PdCl2(dppf) (1.88 g, 2.31 mmol) under nitrogen. The reactor is sealed and the reaction mixture is stirred for 20 minutes at 150 C. under microwave irradiation. After concentrating the reaction mixture, purification by flash chromatography on silica (DCM/MeOH: 0/100 to 95/5) gives 12.4 g of 7-(pyrid-4-yl)-1-[2-(trimethylsilyl)ethoxy]-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in the form of a white solid (yield: 54%). [0835] LCMS (Method A) MH+=393.2, RT=6.60 and 6.74 min (isomers of pyrazole protected with the SEM group Step 4.2. 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [0836] To a solution of 7-(pyrid-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (0.40 g, 1.0 mmol) in 8 mL of DMF is added caesium carbonate (0.66 g, 2.04 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (0.33 mL, 2.55 mmol). The mixture is stirred for 24 hours at room temperature, and then poured into water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered and concentrated to dryness. After purification on silica by flash chromatography (DCM/EtOH: 100/0 to 95/5), 108 mg of an orange-coloured solid are obtained (yield: 23%). [0837] LCMS (Method A) MH+=457.3, RT=6.94 min Step 4.3. 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one hydrochloride [0838] To a solution of 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg, 0.22 mmol) in 2 mL of DCM is added a 4M solution of anhydrous hydrogen chloride in dioxane (1.10 mL, 4.38 mmol) at room temperature. After stirring at room temperature for 24 hours, the mixture is filtered. The solid obtained is taken up in isopropanol, filtered off and dried under vacuum to give 74 mg of a white powder ( hydrochloride, yield: 94%). [0839] LCMS (Method A): MH+=327.0, RT=4.86 [0840] 1H NMR (400 MHz, DMSO-d6): delta ppm 8.96-9.03 (m, 2H) 8.37-8.56 (m, 4H) 8.19 (s, 1H) 7.98 (d, 1H) 6.43 (tt, 1H) 5.04 (td, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Step 3.1. 7-bromo-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4H-pyrazolo[4,3- c]quinolin-4-one and 7-bromo-2-[2-(trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4H- pyrazolo[4,3-c]quinolin-4-oneTo a suspension of 7-bromo-1 ,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [described in Step 1 .3.] (1 .49 g, 5.64 mmol) in 30 mL of anhydrous DMF is added caesium carbonate (2.0 g, 6.21 mmol) and [2-(chloromethoxy)ethyl](trimethyl)silane (10 mL, 56.4 mmol) dropwise. The reaction mixture is stirred at room temperature for 16 hours under nitrogen and then poured into water and extracted with a THF/EtOAc mixture (50/50). The organic phase is washed with saturated aqueous NaCI solution, dried over Na2S04, filtered and concentrated to dryness. The residue obtained is purified by flash chromatography on silica (DCM/MeOH: 100/0 to 98/2) to give 1 .45 g of a yellow solid (yield: 61 %).LCMS (Method A): MH+ = 396.1 , RT = 8.77 min; Step 4.1. 7-(pyrid-4-yl)-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4H- pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]methyl}- 1 ,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one To a solution of 7-bromo-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4/-/-pyrazolo[4,3- c]quinolin-4-one and 7-bromo-2-[2-(trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4/-/- pyrazolo[4,3-c]quinolin-4-one [described in Step 3.1 .] (18.2 g, 46.2 mmol) in 150 mL of DMF placed in a microwave reactor are successively added 4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)pyridine (1 1.4 g, 55.4 mmol), aqueous 2M K3P04 solution (47 mL, 92.4 mmol) and the catalyst PdCI2(dppf) (1 .88 g, 2.31 mmol) under nitrogen. The reactor is sealed and the reaction mixture is stirred for 20 minutes at 150C under microwave irradiation. After concentrating the reaction mixture, purification by flash chromatography on silica (DCM/MeOH: 0/100 to 95/5) gives 12.4 g of 7-(pyrid-4-yl)-1 -[2- (trimethylsilyl)ethoxy]-1 ,5-dihydro-4/-/-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-4-yl)-2- [2-(trimethylsilyl)ethoxy]-1 ,5-dihydro-4/-/-pyrazolo[4,3-c]quinolin-4-one in the form of a white solid (yield: 54%). LCMS (Method A) MH+ = 393.2, RT = 6.60 and 6.74 min (isomers of pyrazole protected with the SEM group); Step 4.2. 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 ,5- dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-2- [2-(trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one To a solution of 7-(pyrid-4-yl)-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4/-/- pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]methyl}-1 ,5- dihydro-4/-/-pyrazolo[4,3-c]quinolin-4-one (0.40 g, 1 .0 mmol) in 8 mL of DMF is added caesium carbonate (0.66 g, 2.04 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (0.33 mL, 2.55 mmol). The mixture is stirred for 24 hours at room temperature, and then poured into water and extracted with EtOAc. The organic phase is washed with saturated aqueous NaCI solution, dried over Na2S04, filtered and concentrated to dryness. After purification on silica by flash chromatography (DCM/EtOH: 100/0 to 95/5), 108 mg of an orange-coloured solid are obtained (yield: 23%). LCMS (Method A) MH+ = 457.3, RT = 6.94 min; Step 4.3. 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1 ,5-dihydro-4H-pyrazolo[4,3-c]quinolin- 4-one hydrochlorideTo a solution of 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 ,5- dihydro-4/-/-pyrazolo[4,3-c]quinolin-4-one and 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-2-[2- (trimethylsilyl)ethoxy]methyl}-1 ,5-dihydro-4/-/-pyrazolo[4,3-c]quinolin-4-one (100 mg, 0.22 mmol) in 2 mL of DCM is added a 4M solution of anhydrous hydrogen chloride in dioxane (1.10 mL, 4.38 mmol) at room temperature. After stirring at room temperature for 24 hours, the mixture is filtered. The solid obtained is taken up in isopropanol, filtered off and dried under vacuum to give 74 mg of a white powder (hydrochloride, yield: 94%). LCMS (Method A): MH+ = 327.0, RT = 4.861H NMR (400 MHz, DMSO-d6): delta ppm 8.96 - 9.03 (m, 2 H) 8.37 - 8.56 (m, 4 H) 8.19 (s, 1 H) 7.98 (d, 1 H) 6.43 (tt, 1 H) 5.04 (td, 2 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 25℃; for 4h; | In a 5 ml round-bottomed flask, example 34 (100 mg, 138 muiotaetaomicron, Eq: 1.00), 2,2- difluoro ethyl trifluoromethanesulfonate (51.8 mg, 34.3 mu, 242 muiotaetaomicron, Eq: 1.75) and Hunig's base (31.3 mg, 42.3 mu, 242 muiotaetaomicron, Eq: 1.75) were combined with Acetonitrile (1.5 ml) to give a light yellow solution. The reaction mixture was stirred for 4 h at 25 C. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into EtOAc (20 ml) and extracted with aqueous 10% Na2C03 solution (1 x 15 mL).The aqueous layer was back-extracted with EtOAc (2 x 20 mL). The organic layers were combined, washed with saturated aqueous NaCl solution (1 x 15 mL). The organic layers were dried over Na2S04 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 80% EtOAc in heptane) to yield the title compound as a colorless amorphous solid (41 mg; 38%>). m/z = 786.0415 [M-H] |
38% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 25℃; for 4h; | In a 5 ml round-bottomed flask, example 34 (100 mg, 138 mumol, Eq: 1.00), 2,2-difluoroethyl trifluoromethanesulfonate (51.8 mg, 34.3 mul, 242 mumol, Eq: 1.75) and Hunig's base (31.3 mg, 42.3 mul, 242 mumol, Eq: 1.75) were combined with Acetonitrile (1.5 ml) to give a light yellow solution. The reaction mixture was stirred for 4 h at 25 C. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into EtOAc (20 ml) and extracted with aqueous 10% Na2CO3 solution (1×15 mL). The aqueous layer was back-extracted with EtOAc (2×20 mL). The organic layers were combined, washed with saturated aqueous NaCl solution (1×15 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 10% to 80% EtOAc in heptane) to yield the title compound as a colorless amorphous solid (41 mg; 38%). m/z=786.0415 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With triethylamine; In dichloromethane; at 20 - 50℃; for 16h; | Synthesis of final compound 56: To a solution of J-1 (250 mg, 0.72 mmol) in dichloromethane (3.6 mL) was added, at room temperature, 2,2- difluoroethyl triflate (230 mg, 1.08 mmol) followed by triethylamine (0.36 mL, 2.16 mmol, 3 eq).The reaction mixture was then stirred at 50C for 16 hours and treated with water (5 mL). The aqueous crude mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum (300 mg). The crude compound was then purified on silica gel using ethyl acetate (100%) to afford the desired compound 56 as a white solid (200 mg, 67% yield). |
67% | With triethylamine; In dichloromethane; at 50℃; for 16h; | To a solution of J-1 (250 mg, 0.72 mmol) in dichloromethane (3.6 mL) was added, at room temperature, <strong>[74427-22-8]2,2-difluoroethyl triflate</strong> (230 mg, 1.08 mmol) followed by triethylamine (0.36 mL, 2.16 mmol, 3 eq). The reaction mixture was then stirred at 50 C. for 16 hours and treated with water (5 mL). The aqueous crude mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum (300 mg). The crude compound was then purified on silica gel using ethyl acetate (100%) to afford the desired compound 56 as a white solid (200 mg, 67% yield). |
With triethylamine; In dichloromethane; at 50℃; for 16h; | To a solution of J-1 (250 mg, 0.72 mmol) in dichloromethane (3.6 mL) was added, at room temperature, <strong>[74427-22-8]2,2-difluoroethyl triflate</strong> (230 mg, 1.08 mmol) followed by triethylamine (0.36 mL, 2.16 mmol, 3 eq). The reaction mixture was then stirred at 50 C. for 16 hours and treated with water (5 mL). The aqueous crude mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuum (300 mg). The crude compound was then purified on silica gel using ethyl acetate (100%) to afford the desired compound 56 as a white solid (200 mg, 67% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | To a mixture of <strong>[30766-12-2]5-hydroxy-2-pyridinecarboxylic acid methyl ester</strong> (0.253 mL, 2.122 mmol), cesium carbonate (1.11 g, 3.40 mmol) and DMF (4.25 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.682 mL, 3.18 mmol). The reaction was stirred at ambient temperature for 3 hrs. The reaction was partitioned between water and ethyl acetate. The organic portion was concentrated and the residue was treated with 5 mL of THF and LiOH (Aq. 2N) (3.18 mL, 6.37 mmol). The reaction was stirred at ambient temperature for 16 hrs. The reaction was treated with 6N HCl until the pH reached 2 and then diluted with ethyl acetate. The organic portion was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (370 mg, 1.821 mmol, 86%) as a tan solid. MS m/z=204.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a solution of 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 5-(2,2-difluoroethyl)-7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (100 mg, 0.22 mmol) in 2 mL of DCM is added a 4M solution of anhydrous hydrogen chloride in dioxane (1.10 mL, 4.38 mmol) at room temperature. After stirring at room temperature for 24 hours, the mixture is filtered. The solid obtained is taken up in isopropanol, filtered off and dried under vacuum to give 74 mg of a white powder ( hydrochloride, yield: 94%). [0847] LCMS (Method A): MH+=327.0, RT=4.86 [0848] 1H NMR (400 MHz, DMSO-d6): delta ppm 8.96-9.03 (m, 2H) 8.37-8.56 (m, 4H) 8.19 (s, 1H) 7.98 (d, 1H) 6.43 (tt, 1H) 5.04 (td, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.5% | Example 57: (E)-10-((trans-4-((2,2- difluoroethyl)(methyl)amino)cyclohexyl)(ethyl)amino)-3-methyl-5,6,15,16- tetrahydrobenzo[c]pyrido[4,3-j] [l]azac clododecine-l,14(2H,9H)-dione To a microwave tube containing (E)-10-((trans-4-aminocyclohexyl)(ethyl)amino)- 3-methyl-5,6, 15,16-tetrahydrobenzo[c]pyrido[4,3-j][l]azacyclododecine-l, 14(2H,9H)- dione (130 mg, 0.290 mmol) in THF (3 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (124 mg, 0.580 mmol), and TEA (0.162 mL, 1.159 mmol). The reaction vessel was capped and stirred at 70 C for 2 h. The reaction mixture was concentrated to afford an off white solid. To this solid in MeOH (3.00 mL) was added Na(OAc)3BH (184 mg, 0.869 mmol), formaldehyde (37 wt% in water, 0.080 mL, 2.90 mmol) and AcOH (0.050 mL, 0.869 mmol). The reaction mixture was stirred at room temperature for 20 min. The reaction mixture was concentrated and purified by Gilson HPLC (5-40% CH3CN in water, 0.1% TFA in mobile phase). The resulting fractions were concentrated and the residue was passed through a 1 g of Silicycle (carbonate) cartridge eluting with MeOH (30 mL) to afford (E)-10-((trans-4-((2,2- difluoroethyl)(methyl)amino)cyclohexyl)(ethyl)amino)-3-methyl-5,6, 15,16- tetrahydrobenzo[c]pyrido[4,3-j][l]azacyclododecine-l, 14(2H,9H)-dione (103 mg, 0.196 mmol, 67.5 % yield) as a white solid. LC-MS(ES) m/z = 527.4 [M+H]+ (minor), 264.3 (major). 1H MR (400 MHz, DMSO-d6) delta: 11.31 (br. s., 1H), 10.24 (br. s., 1H), 7.96 (br. s., 1H), 7.21 (d, J=4.55 Hz, 2H), 6.88-7.06 (m, 1H), 6.15-6.78 (m, 1H), 5.84 (s, 1H), 5.02- 5.26 (m, 2H), 4.17 (br. s., 2H), 3.54 (br. s., 3H), 3.09-3.30 (m, 1H), 2.99 (br. s., 2H), 2.61- 2.88 (m, 4H), 2.54 (br. s., 1H), 2.22 (br. s., 2H), 2.11 (s, 3H), 1.90-2.01 (m, 2H), 1.86 (br. s., 2H), 1.40 (br. s., 2H), 1.21-1.37 (m, 3H), 0.75 (t, J=6.95 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 70℃; for 1h; | [Example 412] Compound DD-29 3-Chloro-N-[(5-chloro-2-ethylsulfonyphenyl)methyl]-4-[[(3S)-3-(2,2-difluoroethylamino)piperidin-1-yl]methyl]-5-(trifluoromethyl)benzamide [0906] 2,2-Difluoroethyl trifluoromethanesulfonate (25.6 mg, 0.119 mmol) was added to a solution of 4-[[(3S)-3-aminopiperidin-1-yl]methyl]-3-chloro-N-[(5-chloro-2-ethylsulfonylphenyl)methyl]-5-(trifluoromethyl)benzamide (Compound D-18, 55.0 mg, 0.100 mmol) and DIPEA (21.0 mul, 0.119 mmol) in THF (1 ml), and it was stirred at 70C for one hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to yield the title compound (51.0 mg, 83%) as a colorless solid. LCMS: m/z 616 [M+H]+ HPLC retention time: 0.59 min (analysis condition F) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h; | To a solution of (1R,55,6r)-6-(3-iodo- 1H-pyrazol-5-yl)bicyclo[3.1 .0]hexan-3-one (350 mg, 1.22 mmol) and5- (4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (398mg, 1.46mmol) in toluene / ethanol / water (5 mL / 1.5 mL / 0.5 mL) was added tripotassium phosphate tribasic (776 mg, 3.66 mmol) and 1,1?-bis(diphenylphosphino)feffocene-palladium(ll) dichloride (277 mg, 0.378 mmol) under nitrogen. The mixture was stirred at 95 C for 16 h. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. Purification by flash column chromatography(20% - 50% ethyl acetate in petroleum ether) afforded a yellow solid (346 mg, 88% yield). LCMS: [MH]+ = 323.1. |
66% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;Inert atmosphere; | The mixture of (1R,5S,6r)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-one (0.100 g, 0.155 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (66 mg, 0.31 mmol) and cesium carbonate (151 mg, 0.465 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 5 h. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3*15 mL). The combined organic was concentrated to give a crude residue, which was purified by preparative thin layer chromatography (25% ethyl acetate in petroleum ether) to afford product as a white solid (80 mg, 66% yield). LCMS: [MH]+=387.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | To an ice-cooled solution ofN-(( 1 R,55 ,6r)-6-(3-iodo- 1 -isopropyl- 1 H-pyrazol-5-yl)bicyclo [3.1. 0]hexan-3-yl)-2-methylp ropane-2-sulfinamide (230 mg, 0.53 mmol) in tetrahydrofuran (10 mL) was added sodiumhydride (106 mg, 2.65 mmol). After 1 h, 2,2-difluoroethyl trifluoromethanesulfonate (340 mg, 1.6 mmol) was added dropwise, and the resulting mixture was warmed to 20 C for 16 h. Methanol was added to the reaction mixture, and the resulting mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL), and the solution was washed with saturated aqueous sodium chloride solution (2 x 8 mL). The collected organic was dried overanhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (20% ethyl acetate in petroleum ether) provided product as a colorless oil(256 mg, 95%). LCMS (ESI) [MH]+ = 367.1. | |
95% | To an ice-cooled solution of N-((1 R,5 S,6r)-6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-yl)-2-methylpropane-2-sulfinamide (230 mg, 0.53 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (106 mg, 2.65 mmol). After 1 h, 2,2-difluoroethyl trifluoromethanesulfonate (340 mg, 1.6 mmol) was added dropwise, and the resulting mixture was warmed to 20 C. for 16 h. Methanol was added to the reaction mixture, and the resulting mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL), and the solution was washed with saturated aqueous sodium chloride solution (2*8 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (20% ethyl acetate in petroleum ether) provided product as a colorless oil (256 mg, 95%). LCMS (ESI) [MH]+=367.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Cesium carbonate (3.83 g, 11.8 mmol) was added to a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL), followed by 2,2-difluoroethyl trifluoromethanesulfonate (1.38 g, 6.5 mmol) dropwise and the resulting mixture was stirred at rt for 30 min. After this time water (60 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford the subtitled compound as a white solid (1.25 g, 91%). 1H NMR (400 MHz, CDCl3): delta 7.24-7.18 (m, 1H), 7.08 (m, 1H), 7.01 (s, 1H), 6.17-5.85 (m, 1H), 4.14-4.04 (m, 2H). |
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | Cesium carbonate (3.83 g, 11.8 mmol) was added to a solution of 5-chloro-1,3-benzoxazol-2(3H)-one (1 g, 5.89 mmol) in DMF (20 mL), followed by 2,2-difluoroethyl trifluoromethanesulfonate (1.38 g, 6.5 mmol) dropwise and the resulting mixture was stirred at rt for 30 min. After this time water (60 mL) was added and the resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford the subtitled compound as a white solid (1.25 g, 91%). 1H NMR (400 MHz, CDCl3): delta 7.24-7.18 (m, 1H), 7.08 (m, 1H), 7.01 (s, 1H), 6.17-5.85 (m, 1H), 4.14-4.04 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | d: 4-Bromo-1-(2,2,2-trifluoroethyl)-1H-imidazole-2-carbaldehydeA solution of 4-bromo-lH-imidazole-2-carbaldehyde (350mg, 2mmol) in DMF (10 ml) was cooled to 0C. Cs2C03 (1.7 lg, 2mmol) was added slowly at 0C. After stirring for lOmin at 0C, 2, 2-difluoroethyl trifluoromethanesulfonate (928ng, 2mmol) was added drop wise at 0C. The mixture was allowed to 25C and stirred for 2h at same temperature. The reaction mass was diluted with water (50 ml) and extracted with ethyl acetate (3x100 ml). The organic layer was washed with water (2x100ml), brine (50 ml) and dried over sodium sulfate, filtered and evaporated. The crude was purified by combiflash column chromatography eluted with 20% ethyl acetate in hexane to give 4-Bromo-l-(2,2,2-trifluoroethyl)-lH-imidazole-2-carbaldehyde (350mg, 68%) as white solid. MS: M/Z= 257 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With potassium carbonate; potassium iodide; In acetonitrile; at 70℃; for 17h; | N-(Azetidin-3-yl)-5-chloropyrazine-2-carboxamide hydrochloride [Intermediate60] (500 mg, 2.01 mmol, 1 .0 eq), potassium carbonate (832 mg, 6.02 mmol,3.0 eq) and potassium iodide (36 mg, 0.22 mmol, 0.1 eq) were suspended in 22.5mL acetonitrile. Then, 2,2-difluoroethyl trifluoromethanesulfonate [CAS RN:74427-22-8] (644 mg, 3.01 mmol, 1.5 eq) was added and the reaction mixture was heated to 70C for 17 h. On cooling, the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine and the phases were separated by the use of a Whatman filter. The volatile components were removed in vacuo and the crude material was purified via preparative MPLC (Biotage Isolera; 25 g SNAP cartridge: dichloromethane -> dichloromethane/ethanol 95/5) to give 375 mg (64% yield of theory) of the titlecompound.UPLC-MS (Method 2): R = 0.81 mm; MS (Elnep) m/z = 275 [M-H].1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 2.83 (dt, 2H), 3.28 (t, 2H, partially covered by water signal), 3.63 (t, 2H), 4.55 (m, 1H), 5.95 (tt, 1H), 8.87 (d, 1H), 8.96 (d, 1H), 9.31 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | at 120℃; for 6h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78percent).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | at 120℃; for 6.0h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78%).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | at 120℃; for 24h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78%).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | at 120℃; for 24h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78percent).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 120℃; for 6h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78%).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | at 120℃; for 15h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78%).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | at 120℃; for 8h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78%).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | at 20℃; for 72h;Inert atmosphere; Schlenk technique; | General procedure: A. TfOCH2CF2H(0.514 g, 2.4 mmol) and triphenylphosphine (0.525 g, 2 mmol) were placed in aclosed Schlenk flask under a N2 atmosphere. The mixture was stirredat 120 oC for 24 h and cooled to room temperature. The resultingsolid was washed by diethyl ether, recrystallized from CH2Cl2/hexane,and dried in vacuum to give 0.66 g of (E)-ethene-1,2-diylbis(triphenylphosphonium)ditriflate (3a) as a white solid (0.78 mmol, 78%).2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | No. I.21-4: Methyl 5-(2,2-difluoroethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-4-carboxylate Methyl 2-(4-methoxyphenyl)-5-hydroxy-2,3-dihydro-1-benzofuran-4-carboxylate (200 mg, 0.67 mmol) was dissolved in abs. acetonitrile (5 ml) under argon in a baked-out round-bottom flask. This was followed by the addition of N,N-diisopropylamine (0.1 ml, 0.77 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After cooling to 0 C., 2,2-difluoroethyl trifluoromethanesulfonate (214 mg, 1.0 mmol) was added. The reaction mixture was stirred at a temperature of 60 C. for 5 hours, cooled down to room temperature and then admixed with water. After thorough repeated extraction of the aqueous phase with dichloromethane, the combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification (ethyl acetate/n-heptane gradient) of the remaining residue gave methyl 5-(2,2-difluoroethoxy)-2-(4-methoxyphenyl)-2,3-dihydro-1-benzofuran-4-carboxylate (229 mg, 63% of theory) in the form of a colorless solid. 1H NMR (400 MHz, CDCl3 delta, ppm) 7.31 (d, 2H), 6.91 (d, 2H), 6.89 (d, 1H), 6.84 (d, 1H), 6.23-5.95 (tt, 1H), 5.72 (t, 1H), 4.21 (m, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.76 (dd, 1H), 3.38 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In tetrahydrofuran; acetonitrile; at 55℃;Sealed tube; | A mixture of <strong>[281235-04-9]methyl 4-(piperidin-4-yl)benzoate</strong> (1.6 g, 7.3 mmol) , 2,2- difluoroethyl trifluoromethanesulfonate (2.03 g, 9.5 mmol), K2C03 (6.05 g, 44 mmol) in a mixture of MeCN (60 ml.) and THF (7 ml.) in a sealed tube was heated at 55 C overnight. The mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to give crude product as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Ethyl 3-propyl-1H-pyrazole-5-carboxylate (1 g, 5.49 mmol) and potassium tert-butoxide (660 mg, 5.76 mmol) were combined with tetrahydrofuran (23.1 ml). After 10 mi 2,2-difluoroethyltrifluoromethanesulfonate (1.56 g, 968 jil, 7.13 mmol) was added. The reaction mixture was stilTed at rt overnight. Water and ethyl acetate were added. The organic layer was dried over magnesium sulfate, filtered and evaporated.The crude material was purified by flash chromatography (silica gel, 20g, 0% to 30% Ethyl acetate in heptane) to yield a colourles liquid(1.02g, 76%). MS (ISP): 247.1 ([M+H]j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36%; 53% | With caesium carbonate; In acetonitrile; at 60℃; for 2h; | Methyl 1H-pyrazole-3-carboxylate (0.500 g, 3.96 mmol) was dissolved in dry MeCN (30 mL), then 2,2-difluoroethyl trifluoromethanesulfonate (0.633 mL, 4.76 mmol) was added, followed by cesium carbonate (1.94 g, 5.95 mmol), and the reaction mixturewas stirred at 60 C for 2 h. The reaction mixture was cooled to rt, diluted with EtOAc. Then CELITE was added, and solvent was removed under reduced pressure. The residue was purified by flash chromatography (solid loading on CELITE): 0-60% EtOAc/Hex affording two products.Intermediate 7A (0.27 1 g, 36% yield) as a colorless syrup: peak 1 eluted at 25%EtOAc. MS(ESI) m/z: 190.9 (M+H) ?H NMR: (400 MHz, CDC13) oe ppm 7.57 (d, J2.0Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.31 - 5.95 (m, 1H), 4.98 (td, J13.1, 4.4 Hz, 2H), 3.91 (s, 3H); ?9F-NMR: (376 MHz, CDC13) oe ppm -122.87 (s, 2F).Intermediate 8A: (0.398 g,53% yield) as a colorless syrup: peak 2 eluted at 45% EtOAc. MS(ESI) m/z: 190.9 (M+H) ?H NMR: (400 MHz, CDC13) oe ppm 7.51 (d, J2.4Hz, 1H), 6.87 (d, J=2.4 Hz, 1H), 6.29 - 5.94 (m, 1H), 4.55 (td, J13.4, 4.3 Hz, 2H), 3.94 (s, 3H); ?9F-NMR: (376 MHz, CDC13) oe ppm -122.42 (s, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13%; 7% | With caesium carbonate; In acetonitrile; at 60℃; for 2h; | Ethyl 3-methyl-1H-pyrazole-4-carboxylate (0.300 g, 1.95 mmol) was dissolved in dry MeCN (15 mL), then 2,2-difluoroethyl trifluoromethanesulfonate (0.3 11 mL, 2.34 mmol) was added, followed by cesium carbonate (0.951 g, 2.92 mmol) and the reaction mixture was stirred at 60 C for 2 h. The reaction mixture was cooled to rt and dilutedwith EtOAc. Then CELITE was added, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography and was further purified by chiral SFC to afford two products.Intermediate 20A (0.056 g, 13% yield) as a colorless oil, which solidified upon standing. MS(ESI) 219.0 (M+H) ?H NMR (400MHz, DMSO-d6) oe ppm 7.89 (s, 1H),6.29 - 5.90 (m, 1H), 4.38 (td, J13.4, 4.4 Hz, 2H), 4.28 (q, J=7.0 Hz, 2H), 2.46 (s, 3H),1.34 (t, J=7.2 Hz, 3H); ?9F-NMR: (376 MHz, CDC13) oe ppm -122.64 (s, 2F). Intermediate 21A (0.032 g, 7% yield) as a colorless oil. MS(ESI) 219.0 (M+H)?H NMR (400MHz, DMSO-d6) oe ppm 7.90 (s, 1H), 6.29 - 5.91 (m, 1H), 4.41 (td, J13.2,4.4 Hz, 2H), 4.30 (q, J7.1 Hz, 2H), 2.58 (s, 3H), 1.35 (t, J=7.2 Hz, 3H); ?9F-NMR: (376MHz, CDC13) oe ppm -122.36 (s, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Ethyl 6-hydroxypyrazolo [1,5 -a]pyridine-3 -carboxylate (0.080 g, 0.388 mmol) was suspended in MeCN (3.0 mL), then 2,2-difluoroethyl trifluoromethanesulfonate (0.062mL, 0.466 mmol) and cesium carbonate (0.379 g, 1.16 mmol) were added. The reaction mixture was stirred under microwave irradiation at 120 C for 15 mm. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1.5 mL)/THF (1.5 mL), and LiOH (1 M aq.) (1.94 mL, 1.94 mmol) was added. The reaction mixture was stirred under microwave irradiation at 120 C for 15 mm. Thereaction mixture was acidified with TFA, DMF was added, and the obtained solution was purified by preparative HPLC to afford Intermediate 34 (0.064 g, 68% yield) as a white solid. MS(ESI) m/z: 243.0 (M+H) ?H NMR (500MHz, DMSO-d6) oe ppm 12.41 (s, 1H), 8.72 (d, J1.7 Hz, 1H), 8.32 (s, 1H), 7.99 (d, J10.2 Hz, 1H), 7.43 (dd, J=9.6, 2.5 Hz, 1H), 6.45 (tt, J=54.3, 3.5 Hz, 1H), 4.44 (td, J=14.6, 3.4 Hz, 2H); ?9F-NMR: (471 MHz,DMSO-oe6) oe ppm -125.92 (s, 2F). | |
68% | Ethyl 6-hydroxypyrazoio[ i,5-a]pvridine-3-carhoxy]ate (0.080 g, 0389mmo1) was suspended in MeCN (3.0 ml.), then 2,2difluoroethyI trifluoromethanesuifonate (0.062 mL, 0.47 rnrnoi) and cesium carbonate (0.379 g, 1 16 mrnoi) were added. The reactionmixture was stirred under microwave irradiation at 120 for 15 mi The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1.5 inL)/THF (1.5 mL), and LiOH (1 M aq.) (1.94 mL, 1.94 mrnoi) was added. The reaction mixture was stirred under microwave irradiation at 120 C for 15 mi The reaction mixture was purified by preparative FIPLC to afford 6-(2,2difluoroethoxy)pyrazoio[ 1 ,5-a]pyridine3carboxviic acid (0.064 g, 68 % yield) as awhite solid. MS (ES) in/z: 243.0 (M+H). ?WNMR: (500 MHz, DMSO-d6) d ppm 12.41(s, IH), 8.72 (d, .J:l.7 Hz, 1H). 832 (s. 1H). 799 (d, J=10.2 -lz. 1H). 7.43 (dd, J:::9.6, 2.5Hz, 1H), 6.45 (tI, J=543, 3.5 Hz. 1H), 4.44 (td, .J=14.6, 3.4 Hz. 2H). ?9F-NMR: (471MHz, DMSO-d6) oe ppm 125.92 (s, 2F). | |
68% | ethyl 6-hydroxypyi"azolo[ls5-o]pyridine-3-carboxylate (0.080 g, 0.39 mmol) was suspended in MeCN (3.0 mL), then 2,2-difluoroetbyl ti-ifluoromethanesulfonate (0.062 mL, 0.47 mmol) and cesium carbonate (0.379 g, 1.16 mmol) were added. The reaction mixture was stirred under microwave irradiation at 120 C for 15 min. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH (1.5 mL)/THF (1.5 mL), and LiOH (1 M aq.) (1.94 mL, 1.94 mmol) was added. The reaction mixture was stirred under microwave irradiation at 120 C for 15 min. The reaction mixture was purified by preparative HPLC to afford Intermediate 7 (0.064 g, 68 % yield) as a white solid. MS (ESI) m/z 243.0 (M+H)+. 1H-NMR: (500 MHz, DMSO-d6) delta ppm 12.41 (s, IH), 8.72 (d, J=1.7 Hz, IH), 8.32 (s, IH), 7.99 (d, J=10.2 Hz, IH), 7.43 (dd, J-9.6, 2.5 Hz, IH), 6.45 (tt, J-54.3, 3.5 Hz, IH), 4.44 (td, .7=14.6, 3.4 Hz, 2H). 19F-NMR: (471 MHz, DMSO-d6) delta ppm -125.92 (s, 2F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.65 g | With potassium carbonate; In acetone; at 20℃; for 3h; | Step 1: To a solution of <strong>[4874-33-3]2-(methylthio)pyrimidin-5-ol</strong> (CAS 4874-33-3, 2 g) in acetone (50 ml) were added potassium carbonate (2.92 g) and 2,2-difluoroethyl trifluoromethanesulfonate (3.46 g) and the mixture was stirred for 3h at room temperature.Diethyl ether (200 ml) was added and the mixture was filtered.The filtrate was concentrated and the crude material was purified by flash chromatography (silica gel, 0% to 50% EtOAc in n-heptane) to give 5-(2,2-difluoroethoxy)-2-(methylthio)pyrimidine (2.65 g) as light yellow solid. MS: m/z = 207.0 [M+H]+. |
2.65 g | With potassium carbonate; In acetone; at 20℃; for 3h; | Step 1 : To a solution of <strong>[4874-33-3]2-(methylthio)pyrimidin-5-ol</strong> (CAS 4874-33-3, 2 g) in acetone (50 ml) were added potassium carbonate (2.92 g) and 2,2-difluoroethyl trifluoromethanesulfonate (3.46 g) and the mixture was stirred for 3h at room temperature. Diethyl ether (200 ml) was added and the mixture was filtered. The filtrate was concentrated and the crude material was purified by flash chromatography (silica gel, 0% to 50% EtOAc in n- heptane) to give 5-(2,2-difluoroethoxy)-2-(methylthio)pyrimidine (2.65 g) as light yellow solid. MS: m/z = 207.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; | To a stirred solution of Compound 1 (25 mg, 0.053 mmol) in DMF (0.5 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (16.99 mg, 0.079 mmol) and DIPEA (0.018 mL, 0.106 mmol) and the resulting reaction mixture was heated at 60 C overnight. The reaction completion was monitored by LCMS. The reaction mixture was diluted with water (10 mL) and the aqueous layer was back extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with sodium bicarbonate solution, brine, dried over Na2S04, filtered and concentrated. Crude product was purified by preparative HPLC to afford Compound 32 as pale yellow solid (17 mg, 60%). MS(ES): m/z = 537 [M+H]+; HPLC Ret. Time 16.28 min and 14.75 min (HPLC Methods E and F, respectively). 1H NMR (400 MHz, DMSO-d6) delta ppm 11.84 (s, 1H), 8.45 - 8.51 (m, 2H), 7.92 - 7.99 (m, 2H), 7.80 (s, 1H), 7.49 - 7.55 (m, 2H), 7.21 - 7.29 (m, 2H), 6.85 (d, J = 9.54 Hz, 1H), 6.09 - 6.41 (m, 1H), 4.25 (t, J= 5.52 Hz, 2H), 4.10 (s, 2H), 3.20 (t, J= 5.52 Hz, 2H), 3.09 (td, J= 15.44, 4.27 Hz, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;Microwave irradiation; | A mixture of 2,2-difluoroethyl trifluoromethanesulfonate 1b (8.23 g, 0.38 mol), <strong>[936250-20-3]3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (500 mg, 1.92 mmol) and CS2CO3 (1.25 g, 3.84 mmol) in DMF (10 mL) was heatedin microwave at 100C for 1 h. The reaction mixture was cooled to room temperature quenched with H2O (30 mL) andextracted with EA (20 mL*3), the organic layers were combined and washed with water (10 mL*2) and brine (10 mL*2),dried over Na2SO4, evaporated. The residue was purified by silica column to afford 1-(2,2-difluoroethyl)-3-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazole (117 mg, white solid), yield: 17.8 %.1H NMR (400 MHz, CDCl3) delta 7.63 (s, 1H), 6.23-5.89 (m, 1H), 4.41-4.31 (m, 1H), 2.36 (s, 3H), 1.28 (s, 12H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With pyridine; In tetrahydrofuran; at 20℃; for 6h;Cooling with ice; | Under ice-cooling, 160g of the compound (IV of), inter-trifluoromethylphenol 90. 8g of pyridine and 55g of dry tetrahydrofuran was added to the lmL, warmed to room temperature stirred for 6 hours. Was cooled to 0 C, the reaction mixture was added water and methylene chloride each 1000mL. The organic phase was separated, washed with water, brine, and dried, to give the crude spin dry, to give the compound (II) (117g, 90%) after distillation. 1H - NMR (400MHz, CDC13) delta: 3 · 76 (dt, J = 3Hz, J = 13Hz, 2H), 5 89 (tt, J = 3Etazeta, J = 55Etazeta, 1Eta), 7 14 (d.. , 2Eta, J = 8. 0Etazeta), 7. 19 (s, 1Eta), 7. 33 (d, 2Eta, J = 8. 0Etazeta), 7. 45 (d, 2Eta, J = 8. 0Etazeta) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydride; In tetrahydrofuran; mineral oil; at -10 - 20℃; for 2h; | Sodium hydride (60% oil, 0.563 g, 14.07 mmol) was slowly added to a solution of 2,2-difluoroethyl trifluoromethanesulfonate (3.01 g, 14.07 mmol) and 2-(2-fluoro-4-nitrophenyl)-2-methylpropan-1-ol (2.5 g, 11.73 mmol) in THF (100 mL) at -10C, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 0?20% ethyl acetate/hexane) to give 1-(1-(2,2-difluoroethoxy)-2-methylpropan-2-yl)-2-fluoro-4-nitrobenzene (2.88 g, 10.39 mmol, 89%) as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With diisopropylamine; at 80℃; for 3h; | A mixture of (2R)-l-(lH-indol-3-yl)propan-2-amine (4.2 g, 24.1 mmol), 2,2- difluoroethyl trifluoromethanesulfonate (5.16 g, 24.1 mmol) and diisopropylamine (8.41 mL, 48.2 mmol) was heated to 80 C for 3 hours. The reaction was cooled to room temperature, diluted with iPrOAc (150 mL) and was washed with water, brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography over silica gel, eluting with 0-5% MeOH/DCM to yield the title compound (5.6 g, 97% yield). 1H NMR (400 MHz, Chloroform-d) delta 8.03 (s, 1H), 7.63 - 7.54 (m, 1H), 7.36 (dt, J = 8.1, 0.9 Hz, 1H), 7.27 - 7.17 (m, 1H), 7.12 (ddd, J = 8.0, 7.1, 1.1 Hz, 1H), 5.78 (tdd, J = 56.6, 4.7, 4.1 Hz, 1H), 3.11 - 2.76 (m, 5H), 1.12 (d, J = 6.2 Hz, 3H); LCMS: 239.15 [M+H]+. |
96% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dichloromethane; at 17 - 25℃;Inert atmosphere; | 2,2-Difluoroethyl trifluoromethanesulfonate (0.4M in DCM, 253 mL, 101 mmol) was added dropwise over 10 minutes to a stirred solution of (R)-1-(1H-indol-3-yl)propan-2-amine (16 g, 91.82 mmol) and DIPEA (19.83 mL, 114.78 mmol) in 1,4-dioxane (95 mL). The reaction was stirred at room temperature overnight, then was washed with brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 50% EtOAc in heptane. Product containing fractions were evaporated to dryness to afford (R)-N-(2,2-difluoroethyl)- 1 -(1 H-indol-3 -yl)propan-2-amine (20.94 g, 96%) as a pale yellow oil. ?H NMR (500 MHz, CDC13, 27 C) 1.13 (3H, d),2.75 - 3.18 (5H, m), 5.78 (1H, tt), 7.04 (1H, d), 7.12 (1H, ddd), 7.20 (1H, ddd), 7.36 (1H, dt), 7.60 (1H, dd), 8.02 (1H, s); m/z: ES+ [M+H]+ 239. |
90% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; dichloromethane; at 20℃; for 2h; | Intermediate 6b: (R)-N-(2,2-Difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine Trifluoromethanesulfonic anhydride (9.4 mL, 55.87 mmol) was added to a cooled solution of 2,2-difluoroethane-1-ol (3.37 mL, 53.21 mmol) in DCM (110 mL). 2,6-Dimethylpyridine (6.82 mL, 58.54 mmol) in DCM (11 mL) was then added dropwise and the reaction was stirred at 0 C. for 1 hour. 2N HCl (200 mL) was added and the layers were separated. The organic phase was dried over Na2SO4 to afford a 0.4 M solution of 2,2-difluoroethyl trifluoromethanesulfonate in DCM (133 mL, 53 mmol) which was added in portions (over 20 minutes) to a stirred suspension of (R)-1-(1H-indol-3-yl)propan-2-amine (7.70 g, 44.17 mmol) and DIPEA (10.68 mL, 61.83 mmol) in 1,4-dioxane (68.8 mL). The reaction was stirred at RT for 2 hours. The mixture was washed with sat. NH4Cl solution, dried over MgSO4, filtered and evaporated. The crude product was purified by flash column chromatography, elution gradient 20 to 60% EtOAc in heptane to afford the title compound (9.45 g, 90%) as a pale yellow oil; 1H NMR (400 MHz, DMSO-d6) 0.97 (3H, d), 1.76 (1H, s), 2.59 (1H, dd), 2.84 (1H, dd), 2.88-3.02 (3H, m), 5.96 (1H, m), 6.97 (1H, m), 7.06 (1H, m), 7.14 (1H, d), 7.33 (1H, m), 7.52 (1H, d), 10.79 (1H, s); m/z: ES+ [M+H]+ 239.2. |
62% | With N-ethyl-N,N-diisopropylamine; In chloroform; at 60℃; for 16h; | (R)-1-(1H-Indol-3-yl)propan-2-amine (5 g, 28.69 mmol) was added to a solution of 2,2-difluoroethyl trifluoromethanesulfonate (7.07 g, 33.00 mmol) and DIPEA (7.44 mL, 43.04mmol) in chloroform (100 mL) and the reaction was stirred at 60 C for 16 hours. The reaction mixture allowed to cool and concentrated in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in heptane to afford (R)-N-(2,2- difluoroethyl)-1-(1H-indol-3-yl)propan-2-amine (4.22 g, 62%) as a yellow oil.?H NMR (500 MHz, CDC13, 27 C): 1.12 (3H, d), 2.73 - 3.17 (5H, m), 3.47 (1H, s), 5.77 (1H, tt), 7.01 (1H, d), 7.06-7.17 (1H, m), 7.17-7.23 (1H, m), 7.3-7.42 (1H, m), 7.59 (1H, d), 8.11 (1H, s). m/z: ES- [M-H]- 237. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In neat (no solvent); at 120℃; for 48h;Inert atmosphere; Sealed tube; | General procedure: Diaryl, dialkyl, or aryl(alkyl) sulfides and fluoroalkyl trifluoromethanesulfonate were placed in a sealed tube under a N2 atmosphere with vigorous stirring. The mixture was reacted at a temperature for 5-72 h (see Tables 1 and 3), cooled to room temperature, washed with diethyl ether or hexane (till the excess sulfide or sulfonate was completely removed), and dried in vacuum to give the title compounds. In some cases (see below), the product was decolored by activated charcoal in CH2Cl2 (refluxing for 0.5h) to afford a light color oil. |
90% | at 150℃; for 48h;Inert atmosphere; | General procedure: A mixture of TfOCH2CF3 (3.0 g, 12.9 mmol) and diphenyl sulfide (14.4 g, 77.4 mmol) was placed in a closed Schlenk flask under a N2 atmosphere with stirring. The mixture was heated at 150 C for 48 h, cooled to room temperature, and washed with diethyl ether (till the excess sulfide was completely removed). The resulting solid was then dried in vacuum to give 2.5 g of [Ph2SCH2CF3][OTf] (2e) 0,15b as a white solid (6.0 mmol, 47%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | To a solution of intermediate 296A? (800 mg, 3.65 mmol) in anhydrous THF (20 mL) at 0 C. was added LiHMDS (7.30 mL, 7.30 mmol, 1M solution in THF) dropwise. The reaction mixture was stirred at 0 C. for 15 min and 2,2-difluoroethyl trifluoromethanesulfonate (0.485 mL, 3.65 mmol) was added. The mixture was stirred at 0 C. for an additional 2 h, quenched with saturated aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give the crude residue, which was purified by silica gel chromatography (24 g CombiFlash column, eluting with a gradient of 30-50% EtOAc in petroleum ether). Fractions containing the desired product were combined and evaporated to afford intermediate 296A? (600 mg, 58.0% yield). LCMS: m/z=282.0 [M-H]+; HPLC Ret. Time 1.410 min. (HPLC Method J). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In neat (no solvent) at 100℃; for 24h; Inert atmosphere; Sealed tube; | 4.2. General procedure for the synthesis of alkyl and fluoroalkyl sulfonium salts General procedure: Diaryl, dialkyl, or aryl(alkyl) sulfides and fluoroalkyl trifluoromethanesulfonate were placed in a sealed tube under a N2 atmosphere with vigorous stirring. The mixture was reacted at a temperature for 5-72 h (see Tables 1 and 3), cooled to room temperature, washed with diethyl ether or hexane (till the excess sulfide or sulfonate was completely removed), and dried in vacuum to give the title compounds. In some cases (see below), the product was decolored by activated charcoal in CH2Cl2 (refluxing for 0.5h) to afford a light color oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In neat (no solvent) at 20℃; for 24h; Inert atmosphere; Sealed tube; | 4.2. General procedure for the synthesis of alkyl and fluoroalkyl sulfonium salts General procedure: Diaryl, dialkyl, or aryl(alkyl) sulfides and fluoroalkyl trifluoromethanesulfonate were placed in a sealed tube under a N2 atmosphere with vigorous stirring. The mixture was reacted at a temperature for 5-72 h (see Tables 1 and 3), cooled to room temperature, washed with diethyl ether or hexane (till the excess sulfide or sulfonate was completely removed), and dried in vacuum to give the title compounds. In some cases (see below), the product was decolored by activated charcoal in CH2Cl2 (refluxing for 0.5h) to afford a light color oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 24h; | Prepared according to procedure in boronate ester 3 step using 5-bromo-7-fluoro-1,3-benzoxazol-2(3H)-one (boronate ester 6 step i) and <strong>[74427-22-8]2,2-difluoroethyl trifluoromethane sulfonate</strong> to afford the subtitled compound as a brown solid(2.49 g, 89%). ?H NMR (400 MHz, CDC13): oe 7.16 (dd, iH),7.05 (s, iH), 6.08 (tt, 1H), 4.16 (td, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; for 4h; | A stirred solution of 449A Diastereomer 2 (40 mg, 0.099 mmol) in ACN (5 mL) was cooled at 0 C. and DIPEA (0.052 mL, 0.297 mmol) was added followed by <strong>[74427-22-8]2,2-difluoroethyl trifluoromethane sulfonate</strong> (31.8 mg, 0.148 mmol). The reaction suspension was stirred at room temperature for 4 h. After evaporation of volatiles, the residue was diluted with ethyl acetate (20 mL), and washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford the crude residue. The crude residue was purified via silica gel flash chromatography to afford 450A Diastereomer 2 (absolute and relative stereochemistry not confirmed, brown solid, 37 mg, 0.079 mmol, 80% yield). LC-MS Anal. Calc'd. for C26H30F2N4O2, 468.234. found [M+H] 469.4, Tr=3.77 (Method U). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | 3,4-Dihydroquinolin-2(1H)-one (1.54 g, 7.66 mmol) was added to conc. acetic acid (10 mL) and then cautiously admixed with fuming nitric acid (0.42 mL, 10.12 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then diluted with ice-water. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), <strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (1.09 g, 69% of theory) was isolated as a colorless solid. 6-Nitro-3,4-dihydroquinolin-2(1H)-one (2000 mg, 2.60 mmol) was dissolved under argon in abs. N,N-dimethylformamide, cooled down to a temperature of 0 C. and admixed with sodium hydride (458 mg, 11.45 mmol, 60% purity). After stirring at room temperature for 30 min, a solution of 2,2-difluoroethyl trifluoromethanesulfonate (223 mg, 10.41 mmol) in abs. N,N-dimethylformamide was slowly added dropwise, again while cooling with ice. The resulting reaction mixture was stirred at room temperature for 3 h, and water and ethyl acetate were then added. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 1-(2,2-difluoroethyl)-<strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (1.80 g, 64% of theory) was isolated as a colorless solid. In the next step, 1-(2,2-difluoroethyl)-<strong>[22246-16-8]6-nitro-3,4-dihydroquinolin-2(1H)-one</strong> (1.80 g, 7.03 mmol) was added together with tin(II) chloride dihydrate (6.34 g, 28.10 mmol) to abs. ethanol and the mixture was stirred under argon at a temperature of 60 C. for 4 h. After cooling to room temperature, the reaction mixture was poured into ice-water and then adjusted to pH 12 using aqueous NaOH. The aqueous phase was then repeatedly extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), 6-amino-1-(2,2-difluoroethyl)-3,4-dihydroquinolin-2(1H)-one (1.56 g, 93% of theory) was isolated as a colorless solid. 6-Amino-1-(2,2-difluoroethyl)-3,4-dihydroquinolin-2(1H)-one (142 mg, 0.63 mmol) was dissolved together with (3-methylphenyl)methanesulfonyl chloride (167 mg, 0.82 mmol) in abs. acetonitrile (105 mL) in a baked-out round-bottom flask under argon, then pyridine (0.16 mL, 1.95 mmol) was added and the mixture was stirred at a temperature of 70 C. for 3 h. The reaction mixture was then concentrated under reduced pressure, the remaining residue was admixed with dil. HCl and dichloromethane, and the aqueous phase was extracted repeatedly with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. By column chromatography purification of the crude product obtained (ethyl acetate/heptane gradient), N-[1-(2,2-difluoroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl]-1-(3-methylphenyl)methanesulfonamide (181 mg, 69% of theory) was isolated as a colorless solid. 1H-NMR (400 MHz, CDCl3 delta, ppm) 7.25 (m, 1H), 7.20 (m, 1H), 7.13-7.05 (m, 3H), 7.00 (m, 1H), 6.94 (m, 1H), 6.25-5.97 (tt, 1H), 6.18 (s, 1H, NH), 4.30 (s, 2H), 4.28-4.19 (m, 2H), 2.91 (m, 2H), 2.70 (m, 2H), 2.34 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.3% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 0 - 20℃; | To a solution of tert-butyl 4-(2-(azetidin-3 -yl)ethyl)piperidine- 1 -carboxylate (300 mg, 1.11 mmol) in MeCN (6 mL) was added DIPEA (0.46 mL, 2.79 mmol) and 2,2- difluoroethyl trifluoromethanesulfonate (310 mg, 1.44 mmol) at 0C. The mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was partitionedbetween DCM (20 mL) and water (10 mL). The organic layer was dried over anhydrousNa2SO4 and concentrated. The residue was purified by silica gel column chromatography(DCM: MeOH = 100: 1) to give tert-butyl 4-(2-(1-(2,2-difluoroethyl)azetidin-3-yl)ethyl)piperidine-1-carboxylate (250 mg, 67.3% yield) as aayellow oil. LC-MS m/z:333 [M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | at 100℃; for 24h; Inert atmosphere; | 5 Example 5: Under nitrogen protection, TfOCH2CF2H (0.128 g, 0.6 mmol) was mixed with dibutyl sulfide (0.263 g, 1.8 mmol)The reaction was stirred at 100 ° C for 24 h,After the reaction system was cooled to room temperature,The resulting liquid was washed with n-hexane,And then pumped dry, [(n-Bu)3S][OTf] (white solid, 0.353 g, 0.58 mmol)Yield: 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 72h; | 2,2-Difluoroethyl trifluoromethanesulfonate (1 .00 g, 4.67 mmol) was added to a mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.91 mg, 4.67 mmol) and caesium carbonate (3.04 g, 9.34 mmol) in dry N,N-dimethylformamide (18 mL). The resulting mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with brine (3x100 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (Method L7; 12 g; heptane, 10%-30% ethyl acetate) afforded 0.44 g (1.68 mmol; 36% of theory) of the title compound.GO-MS (Method L9): R1 = 3.58 mm; mlz = 258 M1H NMR (300 MHz, Ohloroform-d, Method M2) 6 7.83 (s, 1H), 7.76 (s, 1H), 6.09 (tt, J = 55.5,4.3 Hz, 1H), 4.47 (td, J = 13.5, 4.3 Hz, 2H), 1.32 (s, 12H). |
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; | 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.00 g) was dissolved in 9.9 m L DMF and potassium carbonate (2.14 g) and 2,2-difluoroethyl trifluoromethanesulfonate (970 p1) were added. This mixture was stirred at 80 D overn ight. The reaction mixture was diluted with ethyl acetate and water. The layers were seperated and the aqueous layer was extracted withethyl acetate. The combined organic layers were dried using a water resistant filter. The filtrate was concentrated under reduced pressure. The crude product was used without further purification.Yield: 1.8 g of 69% pure target compound.LC-MS (Method 2): R = 0.82 mm; MS (ESIpos): m/z = 259 [M+HJ 1H-NMR (400 MHz, DMSO-d6)oe [ppm] = 1.25 (s, 12H), 4.64 (td, 2H), 6.17- 6.53(m, IH), 7.65 (s, IH), 7.99 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 65℃; for 3h;Inert atmosphere; | 2,2-Difluoroethyl trifluoromethanesulfonate (0.789 g, 3.68 mmol) was added to a stirred solution of (R)-3-(2-aminopropyl)-2-methylaniline (0.55 g, 3.4 mmol) and DIPEA (0.760 ml, 4.35 mmol) in 1,4-dioxane (10 mL). The reaction was heated at 65 C. for 3 hours and then cooled to room temperature. The reaction was concentrated under reduced pressure, and the resulting residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous sodium hydrogen carbonate. The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a red liquid. This oil was purified by flash silica chromatography, elution gradient 30 to 90% ethyl acetate in hexanes to give (R)-3-(2-((2,2-difluoroethyl)amino)propyl)-2-methylaniline (0.52 g, 68%) as a gum. 1H NMR (400 MHz, CDCl3, 27 C.) 1.06 (3H, d), 2.09 (3H, s), 2.60 (1H, dd), 2.77 (1H, dd), 2.81-2.99 (3H, m), 3.56 (2H, br s) 5.78 (1H, tt), 6.58 (2H, d), 6.94 (1H, t). m/z: ES+ [M+H]+ 229. |
68% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 65℃; for 3h; | 2,2-Difluoroethyl trifluoromethanesulfonate (0.789 g, 3.68 mmol) was added to a stirred solution of (i?)-3-(2-aminopropyl)-2-methylaniline (0.55 g, 3.4 mmol) and DIPEA (0.760 ml, 4.35 mmol) in 1,4-dioxane (10 mL). The reaction was heated at 65 C for 3 hours and then cooled to room temperature. The reaction was concentrated under reduced pressure, and the resulting residue was dissolved in EtOAc (30 mL) and washed with saturated aqueous sodium hydrogen carbonate. The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give a red liquid. This oil was purified by flash silica chromatography, elution gradient 30 to 90% ethyl acetate in hexanes to give (i?)-3-(2-((2,2-difluoroethyl)amino)propyl)-2-methylaniline (0.52 g, 68%) as a gum. H NMR (400 MHz, CDCb, 27 C) 1.06 (3H, d), 2.09 (3H, s), 2.60 (1H, dd), 2.77 (1H, dd), 2.81 - 2.99 (3H, m), 3.56 (2H, br s) 5.78 (1H, tt), 6.58 (2H, d), 6.94 (1H, t). m/z: ES+ [M+H]+ 229. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; triethylamine; In acetonitrile; at 120℃; | To a solution of <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (300 mg, 95% purity, 3.43 mmol) in acetonitrile(17 mL) were added 2,2-difluoroethyl trifluoromethanesulfonate (690 p1, 5.1 mmol, CASRN 74427-22-8), powdered potassium carbonate (1 .06 g, 7.65 mmol), and triethylamine (720 pL, 5.1 mmol). The mixture was heated to 12000 overnight. For work-up, it was filtered, and the solid was rinsed with ethyl acetate. Concentraction of the filtrate in vacuo followed by flash chromatography led to the title compound (505 mg, 90% yield, 90%purity).LC-MS (Method B): Rt = 0.43 mm MS (ESIpos): mlz = 148 (M--H)1HNMR (400MHz, DMSO-d6) oe [ppm]: 3.23 (tdd, 2H), 4.72 (t, 1H), 6.05 (tt, 1H), 7.12 (s,2H), 12.10 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.41% | To a solution of tert-butyl 8- hydroxy- 10-m ethyl- 11-oxo-l, 3,4,7,8, 9-hexahydropyrido [2,3]pyrazolo[2,4-b][l,4]diazepine-2- carboxylate (100.00 mg, 297.27 muiotaetaomicron, 1.00 eq) in THF (3.00 mL) was added NaH (35.67 mg, 891.82 mupiiotaomicron, 22.70 muChi, 60% purity, 3.00 eq) with stirring at 0 C for 0.5 h under N2. Then 2, 2-difluoroethyl trifluoromethanesulfonate (2.97 mmol, 10.00 eq) in DCM (7.4 mL) was added. The mixture was stirred at 15 C for 2 h. TLC showed that the starting material was consumed completely and one main spot formed. The mixture was poured into 10 mL of ice water and extracted with EtOAc (10 mL*3). The organic layers was combined and dried over anhydrous Na2S04, filtered and concentrated. The resulting residue combined with another batch reaction mixture (50 mg of starting material) was purified by prep-TLC (PE: EtOAc = 1 :5) to afford the title compound (140.00 mg, 349.63 muiotaetaomicron, 78.41% yield) as off-white oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.01% | To a mixture of tert-butyl (3R,8R)-8-(hydroxymethyl)-3, 10-dimethyl-l l-oxo-1,3,4,7,8,9,10, 11- octahydro-2H-pyrido[4',3':3,4]pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (100.00 mg, 274.39 mupiiotaomicron, 1 eq) in THF (1 mL) was added NaH (21.95 mg, 548.79 mupiiotaomicron, 60% purity, 2 eq) in one portion at -20 C under N2. The mixture was stirred at -20 C for 30 min, then 2,2-difluoroethyl trifluoromethanesulfonate (176.25 mg, 823.18 mupiiotaomicron, 3 eq) was added to the mixture. The mixture was stirred at -20 C for 2 hours. The mixture was poured into water (15 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (25 mL*2). The combined organic layers were washed with brine (10 mL*2), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Ethyl acetate : Petroleum ether=2/l) to afford the title compound (107 mg, 249.72 muiotaetaomicron, 91.01% yield, 100% purity) as a yellow solid. LCMS: 429 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.26% | To a solution of tert-butyl (3R,8S)-8-(hydroxymethyl)-3,10-dimethyl-l l-oxo-1,3,4,7,8,9,10, 11- octahydro-2H-pyrido[4',3':3,4]pyrazolo[l,5-a][l,4]diazepine-2-carboxylate (230 mg, 631.11 muiotaetaomicron, 1 eq) in THF (10 mL) was added NaH (50.49 mg, 1.26 mmol, 60% purity, 2 eq) at -20 C. The solution was stirred at -20 C for 30 min. Then 2, 2,2-difluoroethyl (1907) trifluoromethanesulfonate (405.38 mg, 1.89 mmol, 3 eq) was added, the solution was stirred at - 15 C for 2 hr. The solution was poured into water (30 mL). The mixture extracted with ethyl acetate (20 mL*2). The combined organic layers were washed with brine (20 mL*3), dried with anhydrous Na2S04, filtered and concentrated. The residue was purified by prep-TLC. The title compound (190 mg, 443.44 mupiiotaomicron, 70.26%) yield) was obtained as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.41% | To a solution of tert-butyl (3R)-3-methyl-l l-oxo-3,4,7,8,9,10-hexahydro-lH-pyrido [2,3]pyrazolo[2,4-b][l,4]diazepine-2- carboxylate (700.00 mg, 2.18 mmol, 1.00 eq) in DMF (7.00 mL) was added NaH (261.60 mg, 6.54 mmol, 60% purity, 3.00 eq) at -10 C. The mixture was stirred at -10 C for 30 min. Then a solution of 2,2-difluoroethyl trifluoromethanesulfonate (1.40 g, 6.54 mmol, 3.00 eq) in DMF (800.00 uL) was added dropwise at -10 C. The mixture was stirred at 0 C for 1 hr. TLC (1524) (PE:EtOAc = 1 : 1) showed one main spot appeared. The mixture was added into ice-water (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layer was washed with H2O (50 mL*3), dried over Na2S04, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EtOAc = 30% ~ 50%) to afford the title compound (800.00 mg, 2.08 mmol, 95.41% yield) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.55% | To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl- 1 -oxo- 1,4,5,8,9,11- hexahydropyrido[4?,3?:3 ,4]pyrazolo[5, 1 -d] [1 ,2,5]oxadiazepine- 1 0(2H)-carboxylate (Intermediate 18, 70 mg, 1.91 mmol, 1.0 eq, single diastereomer separated by SFC) in DMF (5.0 mL) wasadded NaH (152.80 mg, 3.82 mmol, 60% purity, 2.0 eq) at -400 C. The mixture was stirred at -400 C for 30 mm. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (1.23 g, 5.73 mmol,3.0 eq) in was added dropwise at -400 C. The mixture was stirred at -20 C for 0.5 hr. TLC(PE:ethyl acetate = 1:1) showed the starting material consumed nearly and a new spot formed.The mixture was added into ice-water (50 mL) and extracted with ethyl acetate (50 mL*3). Thecombined organic layer was washed with H20 (50 mL*3), dried over Na2504, filtrated. Thefiltrate ws concentrated in vacuum. The residue was purified through colunm chromatography (PE:ethyl acetate: 30%50%) to get the title 0 (580.0 mg, 1.35 mmol, 70.55% yield) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In a 250 mL round bottomed flask, <strong>[7411-23-6]3,5-dibromo-1H-1,2,4-triazole</strong> (Int-1, 2.00 g, 8.82 mmol) was dissolved in DMF (60 mL) and potassium carbonate (2.72 g, 19.5 mmol) was added. The resulting suspension was stirred for 20 min at room temperature. Then, 2,2-difluoroethyl trifluoromethanesulfonate (2.08 g, 1.29 mL, 9.7 mmol) was added and the reaction mixture was stirred for 6 h at room temperature. After that, it was concentrated in vacuo, the residue was diluted with MTBE (100 mL) and ice water (100 mL), the aqueous phase was extracted with MTBE (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (1 x 100 mL), dried (sodium sulfate) and concentrated in vacuo. The resulting crude product, a white solid, was used in the next step without further purification (2.402 g, 94 %). HPLC (method LCMS_fastgradient) tR = 0.88 min. 1H NMR (CDCl3, 300 MHz): delta 4.52 (dt, J = 4.2, 12.6 Hz, 2 H), 6.16 (tt, J= 4.2, 54.8 Hz, 1 H). MS (ES+) m/z 289.9, 291.9, 293.9 [M+H, 2 Br isotopes] . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | A solution ofExample 209.12 (0.5g, 1.06 mmol) in THF (5.30 mL) was cooled to -78 C. To this wasadded potassium bis(trimethylsilyl)amide solution, (1M in THF, 1.27 mL, 1.27 mmol)dropwise, and the reaction was stirred at -78 C for 15 mins. 2,2-Difluoroethyltrifluoromethanesulfonate (0.056 mL, 0.42 mmol) was added to the mixture dropwise.The reaction was then stirred for another 15 mins at -78 C after which LCMS indicatedcomplete conversion to product. The mixture was poured onto a solution ofNH4Cl andextracted with DCM, dried over Na2S04 and concentrated in vacuo. The material waspurified by silica gel 0-75% EtOAc:Heptanes to yield Example 209.1 (0.4 g, 0.75 mmol,70% yield). LCMS-ESI (pos.) m/z: 472.2 (M+Ht.- |
Yield | Reaction Conditions | Operation in experiment |
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99.7% | To a suspension of Reactant 1 (0.2 g, 0.56 mmol) and 2-lodo- 1,1 -difluoroethane (0.15 g,0.78 mmol) in 1,4-Dioxane (3 ml) were added Cesium carbonate 99.95% (0.21 g, 3.35 mmol). The mixture was stirred at 60C overnight. Cooled to room temperature and 2,2-Difluoroethyl trifluoromethane sulfonate(98%min) (0.17 g, 0.78 mmol) was added. The mixture was warmed up to 60C for 8 h. Quenched with brine, extracted with EtOAc. The organic layer was dried over Na2504, filtered, concentrated and purified by silica column chromatography (10% EtOAcHex). The product was dissolved in Methanol (3 ml), potassium carbonate (0.11 g, 0.82 mmol)was added and after 1 h the mixture was concentrated diluted with EtOAc, washed with water,dried over Na2504, filtered concentrated to yield S63 (76 mg, 99.7%). MS (ESI) mlz 278.2[M+Hj + |
Yield | Reaction Conditions | Operation in experiment |
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72% | NaH (120 mg, 3.0 mmol, 2.0 eq) was added to a solution of compound 85-A (450 mg, 1.50 mmol, 1.0 eq) in DMF 10 mL at 0C. The mixture was stirred at 0C for 1 hour. (2167) Subsequently, 2,2-difluoroethyl trifluoromethanesulfonate (480 mg, 2.3 mmol, 1.5 eq) was added to the mixture. The resulting mixture was stirred at 20C for 14 hours. LCMS showed compound 85-A was consumed completely. The mixture was poured into water 50 mL, and filtered. The cake was dried to get compound 88-A (480 mg, 72.0% in yield) as yellow solid. ^NMR: (400 MHz, Methanol-d4) delta: 7.55-7.57 (m, 2H), 7.32-7.36 (m, 2H), 7.26-7.38 (m, 1H), 5.72-6.02 (m, 1H), 3.93-3.96 (m, 4H), 3.72-3.76 (m, 1H), 3.69-3.70 (m, 1H), 3.27-3.29 (m, 1H), 3.08-3.11 (m, 1H), 2.56-2.58 (m, 1H), 2.13-2.15 (m, 1H), 2.02-2.11 (m, 2H), 1.97- 1.99 (m, 2H), 1.62-1.65 (m, 1H), 1.23-1.29 (m, 3H), 0.98 (d, 7 = 6.8 Hz, 3H), 0.86-0.88 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.66 g | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 70℃; for 18.0h; | To a mixture of 2,2-difluoroethyl trifluoromethanesulfonate ( 1.0 g, 4.67 mmol), 2- methyl-2-(methylamino)propan-l-o3 (0.48 g, 4.67 mmol) in THF (10 mL) was added DIPEA (0.65 g, 4.8 mmol). The resulted mixture was stirred at 70 °C for 18 h, then concentrated to dryness. The residue was stirred in EtOAc (40 mL) for 5 min, then filtered. The filtration was concentrated in vacuo. The crude residue was purified via silica chromatography and a gradient of 10percent- 100percent EtOAc in hexanes to afford 2- ((2,2~difluoroethyl)(methyi)aniino)-2-methyipropan-l-ol as a colorless oil (0.66 g). |
Yield | Reaction Conditions | Operation in experiment |
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71% | To a stirred solution of 7-Bromo-4-chloro-lH-indazol-3 -amine A4 (2.0 g, 8.16 mmol, 1.0 equiv.) in dry THF (20 mL) at 0 C was added TiuOK (1.20 g, 10.61 mmol, 1.3 equiv.) in portions. After being stirred for 10 min at 0 C, 2,2-Difluoroethyl (0613) trifluoromethanesulfonate (1.92 g, 8.98 mmol, 1.10 equiv.) was added slowly at the same temperature. Then it was slowly raised to room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), it was diluted with ice cold water (20 mL) and MTBE (40 mL). The organic layer was separated, washed with water (2 x 20 mL), dried over Na2S04, filtered and concentrated in vacuum. Column chromatographic purification (eluting with 5% EA/hexanes to 10% EA hexanes) of this crude led to 7- Bromo-4-chloro-l-(2,2-difluoroethyl)-lH-indazol-3-amine A5 as a light yellow solid.Yield: 1.8 g, T /o^H MR (400 MHz, DMSO-c): delta 7.53 (d, J= 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.30 (tt, Ji = 3.9 Hz, J2 = 7.7 Hz, Js = 55.2 Hz, 1H), 5.61 (s, 2H), 4.92 (td, Ji = 3.8 Hz, J2 = 14.1 Hz, 2H) | |
71% | Step-4: Synthesis of 7-bromo-4-chloro- 1 -(2.2-difluorocthyl)- 1H-indazol-3-amine To a stirred solution of 7-Bromo-4-chloro-li/-indazol-3 -amine (2.0 g, 8.16 mmol,1.0 equiv.) in dry THF (20 mL) at 0 C was added ThtOK (1.20 g, 10.61 mmol, 1.3 equiv.) in portions. After being stirred for 10 min at 0 C, 2,2-Difluoroethyl trifluoromethanesulfonate (1.92 g, 8.98 mmol, 1.10 equiv.) was added slowly at the same temperature. Then it was slowly raised to room temperature and stirred for 2 h. After completion of the reaction (monitored by TLC), it was diluted with ice cold water (20 mL) and MTBE (40 mL). The organic layer was separated, washed with water (2 x 20 mL), dried over NaiSOr. filtered and concentrated in vacuum. Column chromatographic purification (eluting with 5% EA/hexanes to 10% EA/hexanes) of this crude led to 7- Bromo-4-chloro- 1 -(2.2-difluorocthyl)- l//-indazol-3-aminc as a light yellow solid.Yield: 1.8 g, 71%;. NMR (400 MHz, DMSO- d): d 7.53 (d, J= 8.0 Hz, 1H), 6.94 (d, J= 8.0 Hz, 1H), 6.30 (tt, Ji = 3.9 Hz, J2 = 7.7 Hz, J3 = 55.2 Hz, 1H), 5.61 (s, 2H), 4.92 (td, Ji = 3.8 Hz, J2 = 14.1Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Nortriptylene HC1 (1.80 g, 6.00 mmol) was suspended in anhydrous THF (20 mL), DIEA (2.30 mL, 13.2 mmol) was added at room temperature (RT) to give a suspension. The reaction mixture was briefly heated to gentle reflux after which the suspension remained. The suspension was cooled to 5 C, Trifluoro-methanesulfonic acid 2,2-difluoro-ethyl ester (1.414 mL, 6.60 mmol) was added dropwise at 5 C, then the reaction mixture was allowed to slowly warm to RT, and stirred at RT for 14 h after which there was an amber solution with a small amount of suspension. The solvent was evaporated in vacuo to give a solid which was extracted with diethyl ether (Et^O) (200 mL), washed with water (40 mL), brine (40 mL), dried with MgS04, solvent was evaporated in vacuo to give an oil which was dissolved in dichloromethane (DCM) (6 mL) and purified by SiC chromatography using Hex-EtOAc (ethyl acetate) to give an amber oil (1.05 g, 3.2 mmol). This oil was dissolved in Et20 (3.0 mL), cooled to 5 C, 1 M HC1 in Et^O (6.4 mL, 6.4 mmol) was added dropwise while stirring to give a gum. The solvent was evaporated in vacuo to give a gum which was further evaporated in vacuo (0.5 mm Hg) to give the title compound (1.150 g, 53%) as a hygroscopic foam. LCMS: mass expected for C21H23F2N: 327.18. Found: 328.2 (M+H). NMR (dmso-d6): 6.60 (1H, t, J=54 Hz), 5.78 (1H, t, J=7 Hz), TLC: DCM-MeOH-HNEt2, 90: 10:3, SM, Rf 0.35, product, Rf 0.80. TLC: Hex-EtOAc, 80:20, SM. Rf 0.0, product, Rf 0.38. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Norcyclobenzaprine (1.57 g, 6.00 mmol), was suspended in anhydrous tetrahydrofuran (THF) (20 mL), Nu,Nu-diisopropylethylamine (DIEA) (1.25 mL, 7.20 mmol) was added at RT to give a suspension. The reaction mixture was briefly heated to gentle reflux to give a turbid solution which was cooled to 5C, Trifluoro-methanesulfonic acid 2,2- difluoro-ethyl ester (1.414 mL, 6.60 mmol) was added dropwise at 5C, then the reaction mixture was allowed to slowly warm to RT, and stirred at RT for 15 h after which there was a suspension. The solvent was evaporated in vacuo to give an oil which was extracted with Et20 (120 mL), washed with water (20 mL), brine (20 mL), dried with MgSCk The solvent was evaporated in vacuo to give an oil which was dissolved in DCM (6 mL) and purified by S1O2 chromatography using Hex-EtOAc to give an amber oil (1.70 g, 5.21 mmol). This oil was dissolved in Et20 (5.0 mL), cooled to 5C, 1 M HC1 in Et^O (12 mL, 12 mmol) was added dropwise while stirring to give a gum. The solvent was evaporated in vacuo to give a gum which was further evaporated in vacuo (0.5 mm Hg) to give the title compound (1.514 g, 70%) as a hygroscopic foam. LCMS: mass expected for C21H23F2N: 325.16. Found: 326.2 (M+H). NMR (dmso-d6): 6.5 (1H, br), 5.47 (1H, t, 7 Hz), TLC: DCM-MeOH-HNEt2, 95:5:3, SM, Rf 0.30, product, Rf 0.85. TLC: Hex-EtOAc, 80:20, SM. Rf 0.0, product, Rf 0.40. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | To a 25 mL round bottomed flask were added methyl (0501) (4aR,6R,7R,8R,8aR)-8-(4-(4-bromo-3,5-difluorophenyl)-1H-1,2,3-triazol-1-yl)-7- hydroxy-2-phenylhexahydropyrano[3,2-d][1,3]dioxine-6-carboxylate (0.40 g, 0.72 mmol) and DMF (15 mL). The reaction was cooled to 0 C, then NaH (60% dispersion in mineral oil) (0.087 g, 2.2 mmol) was added. After stirring at this temperature for 45 min, 2,2-difluoroethyl trifluoromethanesulfonate (0.29 ml, 2.2 mmol) was added and the reaction was continued at 0 C. After stirring at this temperature for 1 h, the reaction was quenched with sat. NH4Cl (100 mL) and extracted with EtOAc (2x50 mL). The organic phase was combined, washed with brine, dried over Na2SO4, filtered and concentrated. The solid was triturated with ether, the product was collected by vacuum filtration, and dried in vacuo to provide the title compound (0.43 g, 0.70 mmol, 96 % yield) as an off white solid. LC-MS, [M+1]+ = 618.0, (Method F: tR = 1.07 min). 1H NMR (500 MHz, DMSO-d6) delta 9.19 - 9.12 (m, 1H), 7.75 - 7.70 (m, 2H), 7.39 - 7.36 (m, 5H), 5.74 - 5.69 (m, 1H), 5.62 - 5.58 (m, 1H), 5.53 - 5.46 (m, 1H), 4.66 - 4.58 (m, 1H), 4.56 - 4.47 (m, 2H), 4.38 - 4.33 (m, 1H), 4.20 - 4.10 (m, 2H), 4.02 - 3.97 (m, 1H), 3.79 (s, 3H), 3.69 - 3.59 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | The compound 1a (200 mg, 0.76 mmol) was dissolved in DMF (4 mL). To the solution were added 2,2-difluoroethyl trifluoromethanesulfonate (324 mg, 1.51 mmol) and potassium carbonate (282 mg, 2.04 mmol). The mixture was stirred at room temperature overnight. To the reaction solution, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed by brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane-ethyl acetate) to give a compound 2a (225 mg, yield 91%).1H-NMR (CDCl3) delta: 1.49 (s, 9H), 2.81 (m, 2H), 3.02 (m, 2H), 3.56 (m, 4H), 4.51 (td, J=13.6, 4.3 Hz, 2H), 6.12 (tt, J=55.8, 4.3 Hz, 1H), 6.57 (d, J=8.3 Hz, 1H), 7.34 (d, J=8.3 Hz, 1H). |
91% | With potassium carbonate; In N,N-dimethyl-formamide; | Compound 1a (200 mg, 0.76 mmol) was dissolved in DMF (4 mL), and 2,2-difluoroethyl trifluoromethanesulfonate (324 mg, 1.51 mmol) and potassium carbonate (282 mg, 2.04 mmol) were added. Stir overnight. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 2a (225 mg, yield 91%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4.5h; | A compound 12b (212 mg, 0.618 mmol) was dissolved in DMF (4.24 mL). To the solution were added potassium carbonate (256 mg, 1.85 mmol) and <strong>[74427-22-8]2,2-difluoroethyl triflate</strong> (264 mg, 1.24 mmol). The mixture was stirred at room temperature for 4.5 hours. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed by water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane-ethyl acetate) to give a compound 13b (189 mg, yield 75%).1H-NMR (CDCl3) delta: 1.49 (s, 9H), 2.77-2.80 (br, 2H), 2.99-3.01 (brm, 2H), 3.54-3.59 (brm, 4H), 4.56 (td, J=13.3, 4.3 Hz, 2H), 6.15 (tt, J=55.6, 4.4 Hz, 1H), 7.57 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.5h;Inert atmosphere; | Under nitrogen atmosphere, to a solution of compound 31 (45.4 mg, 0.18 mmol) in DMF (2 mL) was added potassium carbonate (50.1 mg, 0.36 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (58.3 mg, 0.27 mmol). Then, the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed by brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica-gel column chromatography (hexane-ethyl acetate) to give a compound 32 (43.8 mg, yield 77%). 1H-NMR (CDCl3) delta: 1.50 (s, 9H), 2.74 (t, J=5.0 Hz, 2H), 3.66 (t, J=5.0 Hz, 2H), 4.46-4.55 (m, 4H), 6.12 (tt, J=55.7, 4.0 Hz, 1H), 6.63 (d, J=8.4 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | To a stirred suspension of K2CO3 (3.33 g, 24.1 mmol) in DMSO (12.0 mL) was added methyl 3-methylsalicylate (2.0 g, 12.0 mmol) at room temperature. After 5 minutes at 50 C, 2,2-difluoroethyltrifluoromethanesulfonate (3.1 g, 14.4 mmol) was added dropwise. After 1 h at 50 C, more 2,2-difluoroethyltrifluoromethanesulfonate (1.1 g, 5.1 mmol) was added dropwise. After 1h30 at the same temperature, LC-MS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and quenched by addition of 1N aq. HCl (100 mL). The mixture was extracted with MTBE (2 × 50 mL). The combined organic layers were washed with sat. aq. Na2CO3 (50 mL) and sat. aq. NaCl (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0% to 20% EtOAc in hexane) to afford methyl (2158) 2-(2,2-difluoroethoxy)-3-methylbenzoate (2.57 g, 93%) as a colorless liquid. 1H NMR (500 MHz, Chloroform-d) d 7.69 (dd, J = 7.8, 1.2 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 6.16 (tt, J = 55.4, 4.1 Hz, 1H), 4.15 (td, J = 13.5, 4.1 Hz, 1H), 3.91 (s, 2H), 2.34 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h; | Preparation of 4-chloro- 1 -(2.2-difluorocthyl)-7-nitro- l /-indazol-3-aminc To a stirred solution of 4-chloro-7-nitro-1H-indazol-3 -amine (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (CS2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2- difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 C (until the moisture content was below 1.0%). The isolated material, 4-chloro- l-(2,2-difluoroethyl)-7-nitro-1H-indazol-3 -amine (160 g, 71% yield), was used in the next step without further purification. NMR (400MHz, CDCb): d 8.05 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.00 (tt, Ji = 3.9 Hz, J2 = 7.7 Hz, 1H), 4.76 - 4.84 (m, 4H). |
71% | With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h; | Preparation of 4-chloro- 1 -(2.2-difluorocthyl)-7-nitro- l /-indazol-3-aminc To a stirred solution of 4-chloro-7-nitro-1H-indazol-3 -amine (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (CS2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2- difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 C (until the moisture content was below 1.0%). The isolated material, 4-chloro- l-(2,2-difluoroethyl)-7-nitro-1H-indazol-3 -amine (160 g, 71% yield), was used in the next step without further purification. NMR (400MHz, CDCb): d 8.05 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.00 (tt, Ji = 3.9 Hz, J2 = 7.7 Hz, 1H), 4.76 - 4.84 (m, 4H). |
71% | To a stirred solution of 4-chloro-7-nitro- l//-indazol-3-amine (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (CS2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2- difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 C (until the moisture content was below 1.0%). The isolated material, 4-chloro- 1 -(2.2-difluorocthyl)-7-nitro- 1 //-indazol- 3-amine (160 g, 71% yield), was used in the next step without further purification. NMR (400MHz, CDCL): d 8.05 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.00 (tt, Ji = 3.9 Hz, J2 = . Hz, 1H), 4.76 - 4.84 (m, 4H). |
71% | To a stirred solution of 4-chloro-7-nitro- l//-indazol-3-aminc (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (CS2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2- difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 C (until the moisture content was below 1.0%). The isolated material, 4-chloro- 1 -(2.2-difluorocthyl)-7-nitro- 1 //-indazol- 3-amine (160 g, 71% yield), was used in the next step without further purification. NMR (400MHz, CDCb): d 8.05 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.00 (tt, Ji = 3.9 Hz, J2 = . Hz, 1H), 4.76 - 4.84 ( | |
71% | To a stirred solution of 4-chloro-7-nitro-1H-indazol-3-amine (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (Cs2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2- difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50oC (until the moisture content was below 1.0%). The isolated material, 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol- 3-amine (160 g, 71% yield), was used in the next step without further purification.1H NMR (400MHz, CDCl3): d 8.05 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.00 (tt, J1= 3.9 Hz, J2 = 7.7 Hz, 1H), 4.76 - 4.84 (m, 4H). | |
71% | To a stirred solution of 4-chloro-7-nitro-1H-indazol-3-amine (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (Cs2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2-difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 oC (until the moisture content was below 1.0%). The isolated material, 4-chloro-1-(2,2-difluoroethyl)-7-nitro-1H-indazol-3-amine (160 g, 71% yield), was used in the next step without further purification.1H NMR (400MHz, CDCl3): d 8.05 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.00 (tt, J1 = 3.9 Hz, J2 = 7.7 Hz, 1H), 4.76 -4.84 (m, 4H). | |
71% | To a stirred solution of 4-chloro-7-nitro- 1H-indazol-3-amine (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (CS2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2- difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 C (until the moisture content was below 1.0%). The isolated material, 4-chloro- 1 -(2.2-difluorocthyl)-7-nitro- 1 //-indazol- 3-amine (160 g, 71% yield), was used in the next step without further purification. NMR (400MHz, CDCb): d 8.05 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.00 (tt, Ji = 3.9 Hz, J2 = . Hz, 1H), 4.76 - 4.84 (m, 4H) | |
To a stirred solution of 4-chloro-7-nitro-li7-indazol-3 -amine (180 g, 0.85 mol, 1.0 equiv.) in DMF (1.8 L, 10.0 V) at 10-15 C was added cesium carbonate (CS2CO3) (551 g, 1.70 mol, 2.0 equiv.) at a rate necessary to maintaining the reaction mass below 20 C. The mixture was stirred for 5-10 min, then to the stirred mixture at 10-15 C was added 2,2- difluoroethyl trifluoromethanesulfonate (133 mL, 0.93 mol, 1.1 equiv.) at a rate necessary to maintain the reaction mass below 20 C (Note: Slow addition is preferred to obtain more favorable regio-selectivity). The reaction mass was allowed to slowly warm to room temperature and was then stirred at the same temperature for 3 h. After completion of the reaction (monitored by TLC), the reaction mass was quenched by the addition of ice-cold water (5.4 L, 30.0 V) and the resulting mixture was allowed to warm to room temperature with stirring for 6-8 h. The solids were isolated via filtration and were then washed with water (540 mL, 3.0 V). The wet solid was washed with hexanes (0.9 L, 5.0 V). Bulk residual water was removed from the solids by maintaining vacuum filtration for 60-90 min. The wet solid was dried in a hot air oven for 7-8 h at 50 C (until the moisture content was below 1.0%). The isolated material, 4-chloro- 1 -(2.2-difluorocthyl)-7-nitro- l//-indazol-3-aminc (160 g, 71% yield), was used in the next step without further purification. NMR (400MHz, CDCb): S 8.05 (d, J= 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 6.00 (tt, Ji = 3.9 Hz, J2 = 7.7 Hz, 1H), 4.76 - 4.84 (m, 4H). |
Tags: 74427-22-8 synthesis path| 74427-22-8 SDS| 74427-22-8 COA| 74427-22-8 purity| 74427-22-8 application| 74427-22-8 NMR| 74427-22-8 COA| 74427-22-8 structure
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