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CAS No. : | 219823-47-9 | MDL No. : | MFCD27947543 |
Formula : | C11H14O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WWCNXHYRAKUQDB-SNVBAGLBSA-N |
M.W : | 242.29 | Pubchem ID : | 11149197 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; potassium iodide In acetonitrile at 50 - 55℃; | A three-necked flask was charged with 2b (35.86 g, 100 mmol)R-3-p-toluenesulfonyloxy tetrahydrofuran 3b (26.65 g, 110 mmol)Potassium carbonate (27.64 g, 200 mmol),Potassium iodide (830 mg, 5 mmol) and acetonitrile (179 mL)Stir well after heating to 50 ~ 55 reaction overnight.The reaction was terminated by direct concentration to remove part of the acetonitrile,Water (179 mL) and dichloromethane (179 mL) were added,The aqueous phase was extracted again with dichloromethane (89 mL)The organic phase saturated brine was washed once (179 mL)Sodium sulfate,After concentration, compound 4b (37.29 g, 87percent) was recrystallized from a petroleum ether ethyl acetate mixed solvent.Potassium carbonate in Example 4 can be replaced with sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine;The reaction solvent acetonitrile may be replaced by N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, toluene, isopropanol or acetone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A mixture of (3R)-tetrahydrofuran-3-o[ (18 g, 204 mmo[), TEA (42.7 m[, 306 mmo[), trimethy[amine hydroch[oride (1.95 g, 20.4 mmo[) in DCM (626 mL) was stirred at RT for 20 mi 4-methy[benzenesu[fony[ ch[oride (42.8 g, 225 mmo[) was added andthe reaction mixture stirred at RT unti[ comp[ete conversion. To the reaction mixture N,N-Dimethy[ethy[enediamine (26.4 m[, 245 mmo[) was added and stirred for 30 mm to consume the unreacted 4-methy[benzenesu[fony[ ch[oride. Water was added and the mixture was extracted with DCM (3x). The combined organic [ayers were evaporated to dryness under reduced pressure and the residue was purifiedby co[umn chromatography (si[ica ge[, hexane/ EE/ DCM/ MeOH gradient) to give41.0 g (83% yie[d) of the tit[e compound.1H NMR (400 MHz, DMSO-d6) oe [ppm] 1.79 - 1.95 (m, 1 H) 2.08 (dtd, 1 H) 2.43 (5, 3 H) 3.57 - 3.81 (m, 4 H) 5.12 (ddt, 1 H) 7.49 (d, 2 H) 7.81 (d, 2 H). | |
80% | With 1,4-diaza-bicyclo[2.2.2]octane; In dichloromethane; at 20℃; for 1h;Cooling with ice; | In an ice bath, 1,4-diazabicyclo[2.2.2]octane (2.52 g, 22.47 mmol) and p-toluenesulfonyl chloride (4.28 g, 22.45 mmol) were added to a solution of (R)-tetrahydrofuran-3-methanol (0.9 mL, 11.24 mmol) in dichloromethane (10 mL) respectively. After the addition, the reaction solution was warmed to room temperature and stirred for 1 hour. The reaction solution was diluted with dichloromethane (30 mL) and washed with water (30 mL). The organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=30:1) to give 15-c (2.17 g, yield 80%). |
59.9% | With triethylamine; In dichloromethane; at 25℃; for 3h; | Add (R) -tetrahydrofuran-3-ol (10.0 g, 113.5 mmol), p-toluenesulfonyl chloride (26.0 g, 136.4 mmol) and dichloromethane (60 mL) to a 250 mL single-necked round bottom flask at 25 C., then Add triethylamine (23mL, 165.6mmol) and continue to stir the reaction for 3 hours; stop the reaction, add saturated sodium bicarbonate solution (50mL), separate the liquid, collect the organic phase, spin dry under reduced pressure, and separate and purify by column chromatography (petroleum ether) / Ethyl acetate (v / v) = 5/1) to give the title compound as a pale yellow viscous material (16.48g, 59.9%). |
With pyridine; In dichloromethane; at 20℃; for 72h; | 4-Toluene sulfonyl chloride (1.65 g, 8.63 mmol) was added to a solution of R-3- hydroxytetrahydrofuran (0.8 g, 9.08 mmol) and pyridine (0.88 mL, 10.9 mmol) in DCM (15 mL). The reaction was stirred at RT for 72 hours. Water (10 mL) and IM hydrochloric acid (1 mL) were added and the mixture extracted with DCM (15 mL). The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow oil which was chromatograped on silica, eluting with a gradient of 0-50% ethyl acetate in isohexane, to give the desired compound (1.0 g). 1H NMR delta (CDCl3): 2.13 (m, 2H), 2.47 (s, 3H), 3.80-3.95 (m, 4H), 5.15 (m, IH), 7.37 (d, 2H), 7.81 (d, 2H). | |
With pyridine; In dichloromethane; at 20℃; for 72h; | (3i?V Tetrahydrofuran-3 -yl 4-methylbenzenesulfonate4-Toluene sulfonyl chloride (1.65 g, 8.63 mmol) was added to a solution of i?-3- hydroxytetrahydrofuran (0.8 g, 9.08 mmol) and pyridine (0.88 mL, 10.9 mmol) in DCM (15 mL). The reaction was stirred at RT for 72 hours. Water (10 mL) and IM hydrochloric acid (1 mL) were added and the mixture extracted with DCM (15 mL). The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow oil which was chromatograped on silica, eluting with a gradient of 0-50% ethyl acetate in isohexane, to give the desired compound (1.0 g). 1H NuMR delta (CDCl3): 2.13 (m, 2H), 2.47 (s, 3H), 3.80-3.95 (m, 4H), 5.15 (m, IH), 7.37 (d, 2H), 7.81 (d, 2H). | |
With pyridine; In dichloromethane; at 18 - 25℃; for 72h; | (3i?)-Tetrahydrofuran-3 -yl 4-methylbenzenesulfonate; 4-Toluene sulfonyl chloride (1.65 g, 8.63 mmol) was added to a solution of R-3- hydroxytetrahydrofuran (0.8 g, 9.08 mmol) and pyridine (0.88 mL, 10.9 mmol) in DCM (15 mL). The reaction was stirred at RT for 72 hours. Water (10 mL) and IM hydrochloric acid (1 mL) were added and the mixture extracted with DCM (15 mL). The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow oil which was chromatographed on silica, eluting with a gradient of 0-50% ethyl acetate in isohexane, to give the desired compound (1.0 g). 1H NMR delta (CDCl3): 2.13 (m, 2H), 2.47 (s, 3H), 3.80-3.95 (m, 4H), 5.15 (m, IH), 7.37 (d, 2H), 7.81 (d, 2H). | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 8h; | Step 1: Preparation of (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate To a mixture of (R)-tetrahydrofuran-3-ol (1 g, 11.4 mmole) and TEA (2.3 g, 22.8 mmole) in DCM (20 mL) at 0 C. was added dropwise 4-methylbenzene-1-sulfonyl chloride (2.2 g, 11.4 mmole). The resulting mixture was stirred at room temperature for 8 h. The mixture was washed with water, dried over MgSO4, filtered, and concentrated. The crude product was purified by ISCO (silica gel, eluting with 15% ethyl acetate in hexane) to give the title compound (2.3 g). MS (ESI) m/z: Found: 243.3 (M++1). Calc. 242.3 (M+). | |
59.5 g | With pyridine; dmap; In dichloromethane; at 0 - 20℃; for 12h; | Step 1: (R)-Tetrahydrofuran-3-yl-4-methylbenzenesulfonate To a solution of (R)-tetrahydrofuran-3-ol (25.4 g) in dichloromethane (250 mL) and pyridine (60 mL) is added at 0 C. N,N-dimethylaminopyridine (DMAP; 1 g) and p-toluene-sulfonylchloride (73 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCl solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0?95:5) to give the title compound. Yield: 59.5 g; Mass spectrum (ESI+): m/z=243 [M+H]+. |
59.5 g | With pyridine; dmap; In dichloromethane; at 0 - 20℃; for 12h; | To a solution of (R)-tetrahydrofuran-3-ol (25.4 g) in dichloromethane (250 mL) and pyridine (60 mL) is added at 0C N,N-dimethylaminopyridine (DMAP; 1 g) and p-toluene-sulfonylchloride (73 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (dichloromethane/methanol 100:0?95:5) to give the title compound. Yield: 59.5 g; Mass spectrum (ESI+): m/z = 243 [M+H]+. |
59.46 g | With pyridine; dmap; In dichloromethane; at 20℃; | Step 1 : Synthesis of [(3R)-Tetrahydrofuran-3-yl] 4-methylbenzenesulfonateTo a solution of 25.43 g (R)-tetrahydro-furan-3-ol in 60 mL pyridine and 250 mL DCM was added 73.0 g of 4-methyl-benzenesulfonyl chloride followed by 1 .0 g N,N-dimethylpyridin-4- amin. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and washed with 2M hydrochloric acid and water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (DCM ->DCM : methanol 95:5) to yield 59.46 g [(3R)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate as oil.Analysis: MS: M+H = 243 |
With 4-methyl-morpholine; 1-methyl-1H-imidazole; In toluene; at 0 - 25℃; for 2h; | To a stirred solution of (R)-tetrahydrofuran-3-ol (65 g) and toluene (325 ml), were added N-methylmorpholine (111.93 g, 1.5 eq.) and 1-methylimidazole (30.28 g, 0.5 eq.) at 15 to 20C followed by portion-wise addition of p-toluenesulfonyl chloride (187.0 g, 1.33 eq.) maintaining temperature between 0 to 10C. The reaction masswas increased to 15 to 25C followed by stirring at same temperature till completion of reaction (generally 2 hrs are taken) monitored by gas chromatography. After completion of the reaction, the reaction mass was quenched by addition of water (325 ml), maintaining temperature from 15 to 25C. The resulting layers were separated followed by back extraction of aqueous layer using toluene (195 ml). The combined toluene layer was washed by using dilute hydrochloric acid (16.25 ml conc. hydrochloric acid and 308.75 ml of water) followed by aqueous sodium bicarbonate solution (16.25 g sodium bicarbonate in 325 ml of water) followed by aqueous sodium chloride solution (32.5 g of sodium chloride in 325 ml of water). The toluene layerconcentrated under reduced pressure maintaining temperature below 40C to give 179.18 g (100.24%) of (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate as an oil.1H NMR (400 MHz, CDC13): oe: 7.75-7.77 (d, J= 8 Hz, 2H), 7.32-7.34 (d, J= 8 Hz,2H), 5.06-5.09 (m, 1H), 3.82-3.88 (q, J= 8 Hz, 2H) 3.74-3.80 (m, 2H), 2.42 (s, 3H),2.03-2.07 (m, 2H) Mass [M+Hj: 242.72Purity by GC: 98.62% area | |
42 g | With pyridine; In dichloromethane; at 5 - 28℃; for 10h; | (R)-Hydroxy-THF (20 g), dichloromethane (300 mL) and Pyridine (71 .8 g) were charged into a 1000 mL round bottom flask and the mixture was cooled to 5 C. 4- methylbenzene-1 -sulfonyl chloride (47.6 gm) was charged into the flask at 5 C and the mixture was stirred for 10 hours at 28 C. Water (500 mL) was charged to the flask and stirred for 15 minutes. Layers separated and the organic layer was washed with dilute hydrochloric acid (50 mL of HCI in 150 mL of water). The organic layer was washed with aqueous sodium bicarbonate solution (200 mL) and water (200 mL). The organic layer was concentrated under vacuum to yield 48 gm of (R)-tetrahydrofuran-3-yl-4- methylbenzenesulfonate. (0360) The crude compound was taken into another round bottom flask and ethylacetate (30 mL) was added and stirred for 10 minutes. The clear solution was cooled to 15 C and 50 mg seed compound was added. Cyclohexane (300 mL) was added slowly over a period of 30 minutes at 15 C. The obtained suspension was stirred for 1 hour at 15 C. The precipitation was filtered and wet material was washed with chilled cyclohexane (80 mL). The wet compound was dried under vacuum for 2 hours at 30 C to yield 42 gm of title compound. Purity by HPLC: 99.87%. |
With pyridine; In dichloromethane; at 20℃; for 72h; | 4-Toluene sulfonyl chloride (1.65 g, 8.63 mmol) was added to a solution of R-3- hydroxytetrahydrofuran (0.8 g, 9.08 mmol) and pyridine (0.88 mL, 10.9 mmol) in DCM (15 mL). The reaction was stirred at RT for 72 hours. Water (10 mL) and IM hydrochloric acid (1 mL) were added and the mixture extracted with DCM (15 mL). The organic layer was washed with brine (20 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow oil which was chromatograped on silica, eluting with a gradient of 0-50% ethyl acetate in isohexane, to give the desired compound (1.0 g). 1H NMR delta (CDCl3): 2.13 (m, 2H), 2.47 (s, 3H), 3.80-3.95 (m, 4H), 5.15 (m, IH), 7.37 (d, 2H), 7.81 (d, 2H). | |
In pyridine; at 20℃; | (3R)-Tetrahydrofuran-3-ol (20 mmol, 1.76 g) was dissolved in 100 mL pyridine together with 4-methylbenzenesulfonyl chloride (21 mmol, 4 g) and stirred overnight at 5 room temperature. Solvent was removed by evaporation and the residue was dissolved in dichloromethane (100 mL) and washed with IM HCl, saturated aqueous NaHCO3. The organic layer was dried, concentrated and used in the next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; | 10.3 3) Synthesis of 1,1-anhydro-1-C-[5-(4-((S)-tetrahydrofuran-3-yloxy)-phenyl)-methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose To a solution of 1,1-anhydro-1-C-[5-(4-hydroxyphenyl)methyl-2-(hydroxymethyl)phenyl]-2,3,4,6-tetra-O-acetyl-β-D-glucopyranose (190 mg, 0.35 mmol) in DMF (3 ml), (R)-p-toluenesulfonic acid tetrahydrofuran-3-yl ester (102 mg, 0.42 mmol) and cesium carbonate (137 mg, 0.42 mmol) were added and the mixture was stirred at room temperature for 12 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the solvent was concentrated under reduced pressure. The resulting residue purified by flash column chromatography (developing solution = ethyl acetate:n-hexane (1:2)) to give the titled compound (170 mg, 79%). 1H-NMR (CDCl3) δ: 1.71 (3H, s), 2.00 (3H, s), 2.04 (3H, s), 2.07 (3H, s), 2.12-2.21 (2H, m), 3.84-4.08 (7H, m), 4.22-4.36 (2H, m), 4.85-4.93 (1H, m), 5.16 (2H, dd, J=12.5, 25.7Hz), 5.24-5.33 (1H, m), 5.53-5.66 (2H, m), 6.74-6.81 (2H, m), 7.01-7.10 (2H, m), 7.11-7.19 (2H, m), 7.23 (1H, s) MS (ESI+): 635 [M+Na]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With caesium carbonate In DMF (N,N-dimethyl-formamide) at 50℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 90℃; for 84h; | EXAMPLE 47 N-(at)(2,4-Dichlorophenyllmethyl(at)-N-(tetrahydrofuran-3S-yl)-(3S)-pyrrolidine-3-yl- methylamine; L-Tartrate Step (i) N-(Tetrahydrofuran-3S-yl)-1-tert-butyloxycarbonyl-(3R)-pyrrolidine-3-yl- methylamine A solution of (R)-3-(aminomethyl)-1-N-tert-butyloxycarbonylpyrrolidine (702mg, 3.50mmol), (3R)-tetrahydrofuran-3-yl-4-methylbenzenesulphonate (849mg, 3.50mmol) and anhydrous potassium carbonate (846mg, 6.12mmol) in acetonitrile (15ml) is heated at 90C for 3.5days. The reaction mixture is cooled to room temperature, diluted with diethyl ether and filtered through celite. The filtrate is evaporated and the resulting oil purified using a combiflash on an ISCO silica cartridge (40g) by gradient elution with dichloromethane-methanol (0 to 20% over 30min). The required product is obtained as a colourless oil (596mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 21h; | Preparation example 1 preparation of according to handkerchief row only Reference Patent document WO2006/117359 A1 preparation prepared by the method of the embodiment of the net according to handkerchief row. In particular to: heating 2.85g the (R) - 3 - (4-methyl phenyl sulfonyl oxy)-tetrahydrofuran to 3.00g of 1-chloro-4 - (β-D-pyran glucose-1-yl) - 2 - (4-hydroxy-benzyl)-benzene and 4.36g cesium carbonate in 38 ml in a mixture of dimethyl formamide. The mixture for 75 °C stirring under 5 hours, then further adding 4.40g of and cesium carbonate 2.87g the (R) - 3 - (4-methyl phenyl sulfonyl oxy)-tetrahydrofuran. In the 75 °C in addition stirring 16 hours after cooling to room temperature after the mixture by adding saline. The obtained mixture is extracted with ethyl acetate, the combined organic extract is dried with anhydrous sodium sulfate. crosses the column purification of the residue (methylene chloride/methanol 1:0 → 5:1). Production of 2.1g, yield 57%. Mass spectrometric (ESI+): m/z=451/453 (Cl) [M+H]+, the net according to handkerchief row. |
49% | With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h; | Preparation of the compound A:1-chloro-4-(β-D-qlucopyranos-1-yl)-2-r4-(<fS)-tetrahvdrofuran-3-yloxy)-benzyll- benzene0.19 g (f?)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75 0C for 4 h, before another 0.29 g caesium carbonate and 0.19 g (f?)-3-(4-methylphenyl- sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75 0C the mixture is cooled to ambient temperature and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1 :0 -> 5:1 ). Yield: 0.12 g (49% of theory) Mass spectrum (ESI+): m/z = 451/453 (Cl) [M+H] + EPO Preparation of the crystalline form:Variant 1 :30 mg 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene (obtained as described above) are dissolved in 0.8 ml of ethyl acetate (containing 0.5-3% water) upon heating up to about 50 0C. The solution is allowed to cool slowly (about 1 to 3 h) to about 20 0C. After 48 h the crystalline form is isolated as white crystals by filtration. An excess of the solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 3 to 4 h at reduced pressure.Variant 2:1 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 5 ml of water/ethanol mixture (2 : 3 volume ratio) upon heating up to about 50 0C. 8 ml of water are added and the solution is allowed to cool to about 20 0C in 1 to 3 h. After 16 h the crystalline form is isolated as white crystals by filtration. Excess solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 4 to 6 h.Variant 3:1 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((S,)-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 11 ml of isopropanol upon heating up to about 50 0C. The solution is allowed to cool to about 20 0C in 1 to 3 h. After 16 h the crystalline form is isolated as white crystals by filtration. Residual solvent is removed by storing the crystals at elevated temperature (40 to 50 0C) for about 4 to 6 h.Variant 4:8,9 g 1 -chloro-4-(β-D-glucopyranos-1 -yl)-2-[4-((Sj-tetrahydrofuran-3-yloxy)-benzyl]- benzene are dissolved in 60 ml of water/ethanol mixture (2 : 3 volume ratio) upon heating up to about 50 0C. The solution is allowed to cool to about 20 0C in 3 h and the crystalline compound is isolated by filtration. The separated white solid is dried at 40 0C for 16 h to yield about 6 g of the crystalline form. |
49% | With caesium carbonate In N,N-dimethyl-formamide at 75℃; for 18h; | VI 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene 0.19 g (R)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran are added to a mixture of 0.20 g 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene and 0.29 g cesium carbonate in 2.5 ml dimethylformamide. The mixture is stirred at 75° C. for 4 h, before another 0.29 g caesium carbonate and 0.19 g (R)-3-(4-methylphenyl-sulfonyloxy)-tetrahydrofuran are added. After an additional 14 h stirring at 75° C. the mixture is cooled to ambient temperature and brine is added. The resulting mixture is extracted with ethyl acetate, the combined organic extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→5:1). Yield: 0.12 g (49% of theory) Mass spectrum (ESI+): m/z=451/453 (Cl) [M+H]+ |
With caesium carbonate at 25 - 40℃; | 9 Preparation of Compound of Formula (I) In a round bottom flask, 1.2 g compound of Formula (II), 1.2 g cesium carbonate, 0.81 (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate and 18 mL DMF or DMSO were added at 25° C. to 35° C. The reaction mixture was heated to 35 to 40° C. and stirred for 24-36 hrs. The reaction mixture then cooled to 25° C. to 35° C. 40 mL water and 20 ml toluene were added stirred for 15-20 minutes. Layers were separated. The aqueous layer was extracted with dichloromethane, dried over sodium sulfate. The solvent was distilled out under vacuum. 10 mL ethanol was added and stirred for 30 minutes. The reaction mixture was stirred at 0-5° C. for an hour. The product was filtered and washed with pre-cooled ethanol and dried to obtain empagliflozin. | |
0.55 kg | With caesium carbonate In N,N-dimethyl-formamide at 30 - 45℃; for 24h; | 36.d Preparation of Empagliflozin Tert-butyl(4-(2-chloro-5-iodobenzyl)phenoxy)dimethylsilane (1 .0 Kg), tetrahydrofuran (6.0 L) and (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl) tetrahydro-2H-pyran-2-one (1 .221 Kg) were charged into a 20 L flask under Nitrogen atmosphere. Toluene (6.0 L) was charged into the flask and the resulted mixture was cooled to -80 °C. n-Butyl Lithium in hexane (1 .6M, 2.8 Kg) was added slowly over a period of 3 hours at -80 °C. The reaction mixture was maintained for 1 hour at -80 °C. A solution of methanesulfonic acid (1 .46 Kg of methanesulfonic acid in 9.0 L of methanol) was added to the reaction mass at -70 °C. The reaction mass was heated to -10 °C and stirred for 30 minutes and heated to 30 °C and stirred for 12 hours at 30 °C. The reaction mass was cooled to 5 °C and sodium bicarbonate solution (2.0 Kg of sodium bicarbonate in 23 L of water) was added slowly. The reaction mass was stirred for 30 minutes at 30 °C. The reaction mass was washed with Toluene (6.0 Lx 3) and the reaction mass was concentrated under vacuum until 20 volumes remains in the flask. The reaction mass was extracted with ethylacetate (10.0 Lx5) and the ethylacetate layer was washed with water (3.0 L). The ethylacetate layer was charged into a 100 L reactor and concentrated under vacuum to 3 volumes remained in the reactor. The concentrated ethylacetate layer was stripped off with acetonitrile (3.0 Lx 3) then dichloromethane (7.0 L) and acetonitrile (1 .2 L) were charged into the reactor and the reaction mass was cooled to -30 °C. Triethylsilane (0.57 Kg) and Borontrifluoride etherate solution (1 .307 Kg) were charged into the reactor and the reaction mass was stirred for 3 hours at -30 °C. Temperature was raised to -5 °C and stirred for 6 hours. A solution of sodium carbonate (2.0 Kg of sodium carbonate in 20.0 L of water) was added to the reaction mass over a period of 30 minutes at 5 °C. The reaction mass was heated to 30 °C and stirred for 30 minutes. The reaction mass was concentrated under vacuum until 25 volumes remained in the reactor. The mass was washed with toluene (4.0 L) and extracted with ethylacetate (8.0 Lx2 and 4.0 Lx4) and the ethylacetate layer washed with water (2.0 Lx2) The organic layer was concentrated under vacuum until 2 volumes remained in the reactor then the crude mass was stripped off with ethylacetate (3.0 l_x2) and with DMF (1 .4 L). Tosyl-THF (0.634 Kg) and DMF (0.20 L) were charged into the reactor and the resulted mass was stirred for 30 minutes at 30 °C. Cesium carbonate lot 1 (0.57 Kg) was added to the reaction mass. Reaction mass was heated to 45 °C and stirred for 2 hours at 45 °C. Cesium carbonate lot 2 (0.57 Kg) was added to the reaction mass and the reaction mass was stirred for 2 hours. Cesium carbonate lot 3 (0.57 Kg) was added to the reaction mass the reaction mass was stirred for 20 hours at 45 °C. The reaction mass was cooled to 30 °C and water (4.0 L) was added to the mass and stirred for 30 minutes. Layers were separated and the aqueous layer was washed with toluene (4.0 L). The aqueous layer was concentrated at 70 °C under vacuum until 1 .0 volume remained in the reactor. The concentrated mass was cooled to 30 °C and water (10.0 L) and acetonitrile 1 .0 L) were charged into the reactor at 30 °C and the resulted mixture was heated to 45 °C and the mixture was stirred for 6 hours at 45 °C. The suspension was cooled to 25 °C and stirred for 7 hours at 25 °C. The precipitation was filtered and the wet solid was washed with water (3.0L) and the solid was suck dried. The wet compound and DMF (1 .0 L) were charged into another reactor and the solution was heated to 45 °C. Acetonitrile (1 .0 L) charged followed by water (10.0 L) into the reactor at 45 °C and stirred for 6 hours. The suspension was cooled to 25 °C and stirred for 6 hours. The precipitation was fileted and the wet cake was washed with water. The wet material was suck dried. The wet material was dried under vacuum at 60 °C for 6 hours to yield 0.55 Kg of crystalline empagliflozin. Purity by HPLC 99%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In propyl cyanide; at 130℃; for 3h; | A mixture of methyl 3-hydroxy-5-[phenylmethyl]oxy}benzoate (18.8 g, 72.75 mmol), (3i?)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (18.5 g, 76.4 mmol) and potassium carbonate (20.08 g, 145.5 mmol) in butyronitrile (250 mL) was heated to 130C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), 0.5M sodium hydroxide solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a colourless oil (20.1 g). 1H NMR delta (CDCl3): 2.08 - 2.26 (m, 2H), 3.78 - 4.01 (m, 4H), 3.90 (s, 3H), 4.92 - 4.96 (m, IH), 5.08 (s, 2H), 6.69 (t, IH), 7.15 (t, IH), 7.29 (t, IH), 7.34 - 7.44 (m, 5H); m/z 327 (M+H)+ | |
With potassium carbonate; In propyl cyanide; at 130℃; for 3h; | Methyl 3 - [YphenylmethyDoxy] -5 - [("3 ^-tetrahydrofuran-3 -yloxylbenzoate; A mixture of methyl 3-hydroxy-5-[phenylmethyl]oxy}benzoate (18.8 g, 72.75 mmol), (3i?)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (18.5 g, 76.4 mmol) and potassium carbonate (20.08 g, 145.5 mmol) in butyronitrile (250 mL) was heated to 130C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), 0.5M sodium hydroxide solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a colourless oil (20.1 g). 1H NMR delta (CDCl3): 2.08 - 2.26 (m, 2H), 3.78 - 4.01 (m, 4H), 3.90 (s, 3H), 4.92 - 4.96 (m, IH), 5.08 (s, 2H), 6.69 (t, IH), 7.15 (t, IH), 7.29 (t, IH), 7.34 - 7.44 (m, 5H); m/z 327 (M+H)+ | |
With potassium carbonate; In propyl cyanide; at 130℃; for 3h; | A mixture of methyl 3-hydroxy-5-[phenylmethyl]oxy}benzoate (18.8 g, 72.75 mmol), (3i?)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (18.5 g, 76.4 mmol) and potassium carbonate (20.08 g, 145.5 mmol) in butyronitrile (250 mL) was heated to 130C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), 0.5M sodium hydroxide solution (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a colourless oil (20.1 g). 1H NMR delta (CDCl3): 2.08 - 2.26 (m, 2H), 3.78 - 4.01 (m, 4H), 3.90 (s, 3H), 4.92 - 4.96 (m, IH), 5.08 (s, 2H), 6.69 (t, IH), 7.15 (t, IH), 7.29 (t, IH), 7.34 - 7.44 (m, 5H); m/z 327 (M+H)+ |
With potassium carbonate; In propyl cyanide; at 130℃; for 3h; | A mixture of methyl 3-hydroxy-5-[phenylmethyl]oxy}benzoate (18.8 g, 72.75 mmol), (3i?)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (prepared as described in Example 1) (18.5 g, 76.4 mmol) and potassium carbonate (20.08 g, 145.5 mmol) in butyronitrile (250 ml) was heated to 1300C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 ml), 0.5M sodium hydroxide solution (40 ml), brine (40 ml), dried (MgSO4), filtered and the solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 0-5% methanol in DCM, to give the desired compound as a colourless oil (20.1 g), 1H NMR delta (CDCl3): 2.08 - 2.26 (m, 2H), 3.78 - 4.01 (m, 4H), 3.90 (s, 3H), 4.92 - 4.96 (m, IH), 5.08 (s, 2H), 6.69 (t, IH), 7.15 (t, IH), 7.29 (t, IH), 7.34 - 7.44 (m, 5H); m/z 327 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 160℃; for 3h; Microwave irradiation; | A suspension of 3-hydroxy-N-(l-rnethyl-lH-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3i?)-tetrahydrofuran-3-yl 4- methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a Smith Creator microwave at 1600C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow foam which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in zso-hexane, to give the title compound as a white foam (452 mg). 1H NMR δ (CDCl3): 2.09 - 2.14 (IH, m), 2.14 - 2.24 (IH, m), 3.68 (3H, s), 3.86 - 3.91 (IH, m), 3.94 - 3.98 (3H, m), 4.89 (IH, s), 5.03 (2H, s), 6.64 (IH, t), 6.85 (IH, s), 6.96 (IH, d), 7.07 (IH, t), 7.27 (IH, m), 7.33 - 7.41 (5H, m), 9.31 (IH, s); m/z 394 (M+H)+. | |
With potassium carbonate In acetonitrile at 160℃; for 3h; Irradiation; | 7 N-α-Methyl-lH-pyrazol-S-ylVS-rrphenylmethvDoxyi-S-Cβ^-tetrahvdrofuran-S- yloxylbenzamide EPO A suspension of 3-hydroxy-N-(l-methyl-lH-pyrazol-3-yl)-5- [(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3i?)-tetrahydrofuran-3-yl 4- methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a Smith Creator microwave at 160°C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow foam which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the title compound as a white foam (452 mg). 1R ΝMR δ (CDCl3): 2.09 - 2.14 (1Η, m), 2.14 - 2.24 (1Η, m), 3.68 (3Η, s), 3.86 - 3.91 (IH, m), 3.94 - 3.98 (3H, m), 4.89 (IH, s), 5.03 (2H, s), 6.64 (IH, t), 6.85 (IH, s), 6.96 (IH, d), 7.07 (IH, t), 7.27 (IH, m), 7.33 - 7.41 (5H, m), 9.31 (IH, s); m/z 394 (M+H)+. | |
With potassium carbonate In acetonitrile at 160℃; for 3h; Microwave; | 23 A suspension of 3-hydroxy-N-(l-methyl-lH-pyrazol-3-yl)-5- [(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3i?)-tetrahydrofuran-3-yl 4- methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a Smith Creator microwave at 16O0C for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow foam which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in o-hexane, to give the title compound as a white foam (452 mg). 1H ΝMR δ (CDCl3): 2.09 - 2.14 (IH, m), 2.14 - 2.24 (IH, m), 3.68 (3H5 s), 3.86 - 3.91 (IH, m), 3.94 - 3.98 (3H, m), 4.89 (IH, s), 5.03 (2H, s), 6.64 (IH, t), 6.85 (IH, s), 6.96 (IH, d), 7.07 (IH, t), 7.27 (IH, m), 7.33 - 7.41 (5H, m), 9.31 (IH, s); m/z 394 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In acetonitrile at 160℃; for 3h; Microwave irradiation; | 2 Example 2; 3-[4-(Azetidin-l-ylcarbonv0phenylloxyl-N-(l-metliyl-ljEir-pyrazol-3-ylV5-[(3tSVtetrahvdrofuran-3-yloxylbenzamide; A mixture of 3-[4-(azetidin-l-ylcarbonyl)phenyl]oxy}-5-hydroxy-N-(l-methyl-lH- pyrazol-3-yl)benzamide (0.26 g, 0.66 mmol), (3i?)-tetrahydrofuran-3-yl 4- methylbenzenesulfonate (241 nig, 0.99 mmol) and potassium carbonate (229 mg, 1.66 mmol) in acetonitrile (5 mL) was stirred in a 'Biotage initiator Microwave'at 16O0C for 3 hours. The solvent was removed in vacuo and ethyl acetate (50 mL) added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow foam which was chromatographed on silica, eluting with a gradient of 0-5% methanol in ethyl acetate, to give the desired compound (104 mg). 1H ΝMR δ (CDCl3): 2.18 (m, IH), 2.25 (m, IH), 2.48 (quin, 2H), 3.78 (s, 3H), 3.92 (m, IH), 4.01 (m, 3H), 4.20-4.40 (m, 4H), 4.96 (m, IH), 6.72 (s, IH), 6.80 (s, IH), 7.04 (d, 2H), 7.11 (s, IH), 7.19 (s, IH), 7.28 (m, IH), 7.63 (d, 2H), 8.61 (s, IH); m/z 463 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With caesium carbonate In N,N-dimethyl-formamide at 60 - 80℃; for 22h; | 4-(β-D-glucopyranos-1-yl)-1-methyl-2-f4-(^SJ-tetrahvdrofuran-3-yloxy)-benzvn- benzene (R)-3-(4-methyIphenylsulfonyloxy)-tetrahydrofuran (4.9 g) is added to a mixture of 4- (β-D-glucopyranos-1-yl)-2-(4-hydroxy-beϖzyl)-1 -methyl-benzene (4.9 g) and cesium carbonate (6.6 g) in dimethylformamide (50 mL). The mixture is stirred at 60 0C for 8 h, before more cesium carbonate (0.7 g) and (R)-3-(4-methylphenyi-suIfonyIoxy)- tetrahydrofuran (0.5 g) are added. After an additional 14 h stirring at 80 0C, the mixture is cooled to ambient temperature, diluted with ethyl acetate and washed with brine. The organic phase is dried (sodium sulphate) and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1 :0 -> 4:1). Yield: 2.68 g (46% of theory) Mass spectrum (ESI+): m/z = 448 [IvRNH4] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16%; 56% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; | Intermediate 84-Bromo-1 -[(SHetrahvdro-furan-3-nuPi-Iota H-pyridin-2-one; A mixture of 4-bromo-1 H-pyridin-2-one (0.50 g), (/:?)-toluene-4-sulfonic acid tetrahydrofuran-3- yl ester (0.40 g), potassium carbonate (0.80 g), and dimethylsulfoxide (5 mL) was stirred at 80 'C overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgS04), and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to afford the title compound [besides, 4-bromo-2-[(S)-tetrahydro- furan-3-yloxy]-pyridine was isolated in 0.36 g (56% of theory)]. Yield: 0.1 1 g (1 6% of theory); LC (method 3): tR = 2.18 min; Mass spectrum (ESI+): m/z = 244/246 (Br) [M+H]+. |
With potassium carbonate; In dimethyl sulfoxide; at 80℃; | Intermediates E-I and E-II 4-Bwmo-l-(S)- tetrahydro-furan-3-yll-lH-pyridin-2-one and 4-bromo-2-[(S)-tetrahydro- furan-3 -yloxyl -pyridine A mixture of 4-bromo-lH-pyridin-2-one (0.50 g), (i?)-toluene-4 -sulfonic acid tetrahydro- furan-3-yl ester (0.40 g), and potassium carbonate (0.80 g) in dimethylsulfoxide (5 mL) was stirred at 80 0C overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO/O, and concentrated. The residue was purified by HPLC on reversed phase (acetonitrile/water) to afford the title compounds in separate fractions.4-Bromo-l-[(S)- tetrahydro-furan-3-yl]-lH-pyridin-2-one: Yield: 0.11 g (16% of theory); Mass spectrum (ESI+): m/z = 244/246 (Br) [M+H]+.4-Bromo-2-[(S)-tetrahydro-furan-3-yloxy]-pyridine: Yield: 0.36 g (56% of theory); Mass spectrum (ESI+): m/z = 244/246 (Br) [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 20 - 60℃; | 7.I To a solution of Acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4- hydroxy-benzyl)-phenyl]-4-oxa-spiro[2,5]oct-6-yl ester (120 mg, 0.22mmole) in DMF(3 ml_), cesium carbonate (85 mg, 0.27 mmole), Toluene-4-sulfonic acid (R)-(tetrahydro- furan-3-yl) ester (65 mg, 0.27 mmole) was added at room temperature and heated at 60 °C for 6 hours. The reaction mixture was diluted with water (20 ml_), and extracted with dichloromethane (2X50 ml_). Crude (5S,6S,7R,8S)-5-(4-chloro-3-(4-((S)- tetrahydrofuran-3-yloxy)benzyl)phenyl)-4-oxaspiro[2.5]octane-6,7,8-triyl triacetate obtained after the removal of solvent used for next step without purification. | |
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 6h; | 7.I To a solution of Acetic acid (5S,6S,7R,8S)-7,8-diacetoxy-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-4-oxa-spiro[2.5]oct-6-yl ester (120 mg, 0.22 mmole) in DMF (3 mL), cesium carbonate (85 mg, 0.27 mmole), Toluene-4-sulfonic acid (R)-(tetrahydro-furan-3-yl)ester (65 mg, 0.27 mmole) was added at room temperature and heated at 60° C. for 6 hours. The reaction mixture was diluted with water (20 mL), and extracted with dichloromethane (2×50 mL). Crude (5S,6S,7R,8S)-5-(4-chloro-3-(4-((S)-tetrahydrofuran-3-yloxy)benzyl)phenyl)-4-oxaspiro[2.5]octane-6,7,8-triyl triacetate obtained after the removal of solvent used for next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.24 g | Stage #1: methylamine; (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate In ethanol at 150℃; for 2h; Inert atmosphere; Microwave irradiation; Stage #2: With potassium hydroxide In ethanol for 0.333333h; Inert atmosphere; Microwave irradiation; Stage #3: benzyl chloroformate With triethylamine In dichloromethane at 0℃; for 0.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 10h; | Step 2) Synthesis of (S) -3- (4-bromophenoxy) tetrahydrofuran Add p-bromophenol (6.2g, 35.8mmol), (R) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (8.0g, 33.0mmol) and N, N-dimethylformamide (30mL) To a 250 mL single-necked round bottom flask, potassium carbonate (9.1 g, 66.0 mmol) was added, and the reaction was carried out at 100 ° C. for 10 hours.The reaction was stopped, and after cooling to room temperature, water (100 mL) was added, followed by addition of dichloromethane (60 mL) for extraction, liquid separation, and the organic phase was collected, spin-dried under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 5/1) The title compound was obtained as a pale yellow sticky substance (7.23g, 90.1%). |
With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 15h; | 6.2 Step 2: Preparation of (S)-3-(4-bromophenoxy)-tetrahydrofuran A mixture of 4-bromophenol (1.8 g, 10.5 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.3 g, 9.5 mmole) and K2CO3 (4.0 g, 29 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, eluting with 5% ethyl acetate in hexane) to give the title compound (690 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 15h; | 18.2 Step 2: Preparation of (S)-4,4,5,5-tetramethyl-2-(4-(tetrahydrofuran-3-yloxy)phenyl)-1,3,2-dioxaborolane A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (5 g, 22.8 mmole), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (6.6 g, 22.8 mmol) and K2CO3 (8.0 g, 58 mmole) in DMF (25 mL) was heated at 85° C. for 15 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum The residue was purified by flash chromatography (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (2.4 g, 30% yield). MS (ESI) m/z: Calc. 290.2 (M+). Found: 291.1 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With caesium carbonate In N,N-dimethyl-formamide at 20℃; | 250.5 Step 5: Preparation of 4-(methoxymethyl)-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine To a solution of 4-(4-(methoxymethyl)-2-((1s,4s)-4-methylcyclohexylamino)-6-(oxetan-3-yloxy)pyrimidin-5-yl)phenol (4) (26.0 mg, 0.065 mmol) in anhydrous DMF (1 mL) at r.t. was added Cs2CO3 (63.0 mg, 0.20 mmol). The mixture was stirred at r.t. for 10 min followed by (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (27.0 mg, 0.11 mmol). The reaction mixture was stirred at r.t. overnight, and then heated with an oil bath at 40° C. for 6 h. After this time the reaction was quenched with H2O and extracted with EtOAc. The organic layer was separated, dried (Na2SO4) and concentrated in vacuo. The residue was purified using ISCO chromatography (12 g silica gel, 0-4% MeOH in CH2Cl2 in 40 min) to give the title compound (16 mg, 52%) as a colorless gel. 1H NMR (DMSO, 500 MHz) δ 7.17 (d, 2H), 6.95 (d, 2H), 5.59 (bd, 1H), 5.07-5.03 (m, 1H), 4.91 (t, 2H), 4.63 (t, 2H), 3.93-3.89 (m, 1H), 3.88-3.74 (m, 6H), 3.41 (s, 2H), 2.28-2.20 (m, 1H), 2.02-1.95 (m, 1H), 1.77-1.66 (m, 1H), 1.45-1.11 (m, 10H), 0.82 (d, 3H); MS (Multimode, M+H+) C26H36N3O5, calcd. 470.3. found 470.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate; potassium iodide In N,N-dimethyl-formamide at 20 - 90℃; for 4.5h; | 251.4 Step 4: 4-methyl-N-((1s,4s)-4-methylcyclohexyl)-6-(oxetan-3-yloxy)-5-(4-((S)-tetrahydrofuran-3-yloxy)phenyl)pyrimidin-2-amine To a solution of 4-(4-methyl-2-((1s,4s)-4-methylcyclohexylamino)-6-(oxetan-3-yloxy)pyrimidin-5-yl)phenol (3) (130 mg, 0.35 mmol) in anhydrous DMF (4 mL) at r.t. was added Cs2CO3 (344 mg, 1.06 mmol), KI (12 mg, 0.07 mmol) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (256 mg, 1.06 mmol). The mixture was stirred at r.t. for 4 h, and then was heated at 90° C. for another 0.5 h. After this time the mixture was cooled and extracted with EtOAc. The organic layer was separated, and dried (Na2SO4) and concentrated in vacuo. The residue was purified using ISCO chromatography (12 g silica gel, 0-25% EtOAc in hexanes in 40 min) to give the title compound (46 mg, 30%) as a white solid. 1H NMR (CDCl3, 500 MHz) δ 7.16-7.14 (m, 2H), 6.90-6.85 (m, 2H), 5.95-5.51 (m, 1H), 4.97-4.95 (m, 1H), 4.90-4.84 (m, 2H), 4.62-4.66 (m, 2H), 4.05-3.90 (m, 5H), 2.24-2.18 (m, 2H), 2.15 (s, 3H), 1.79-1.75 (m, 2H), 1.51-1.65 (m, 6H), 1.27-1.21 (m, 2H), 0.93 (d, 3H). MS (ESI, M+H+) C25H34N3O4, calcd. 440.2. found 440.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: With dmap; triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: at 20 - 50℃; for 1.66667h; | 6.1 1, Preparation of p-toluenesulfonic acid _ (S) _ tetrahydrofuran-3-ol ester General procedure: A mixture of 6,61 g (75.22 mmol) of (S) -3-hydroxytetrahydrofuran,8 · 35 g (82 · 51 mmol) of triethylamine and 3.67 g (30.04 mmol)N, N-dimethylaminoP ratio was dissolved in 50 mL of dichloromethane,0 ° C after stirring lOmin,15.73 g (82.51 mmol)P-toluenesulfonyl chloride,Continue to stir lOmin,After warming to room temperature for 30 min,Heated to 50 ° C reflux lh,To the reaction system was added 50 mL of a 2 ml 1 / L HC1 aqueous solution,The organic phase is separated,The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness.The resulting black red oily liquid was chromatographed on silica gel (eluting with a 1: 6 by volume mixture of ethyl acetate and petroleum ether)To give colorless liquid p-toluenesulfonic acid (S) -tetrahydrofuran-3-ol17.45 g, the yield was 96%. |
With pyridine In dichloromethane at 0 - 20℃; for 12h; | 1 Step 4: 3-(Methylsulfonyl)propyl 4-methylbenzenesulfonate General procedure: To a solution of 3-(methylsulfonyl)propan-1 -ol (1 .0 g) in dichloromethane (10 mL) and pyridine (1 .5 mL) is added at 0°C p-toluene-sulfonylchloride (1 .38 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with dichloromethane and washed with 1 M aqueous HCI solution and brine. After drying (MgSO4) the solvent is evaporated to give the title compound. Yield: 1 .6 g; LC (method 1 ): tR = 0.82 min; Mass spectrum (ESI+): m/z = 293 [M+H]+. | |
With pyridine In dichloromethane at 0 - 20℃; for 15h; | 22.2-1 4-Methylbenzenesulfonic acid [(3S)-oxolan-3-yl] (Compound 8e) General procedure: To a dichloromethane solution (3.78 mL) of (3S)-oxolan-3-ol (Compound 8d, 500 mg, 5.68 mmol) was added pyridine (1.28 mL, 15.9 mmol) and 4-methylbenzenesulfonyl chloride (1.51 g, 7.95 mmol) at 0° C. The solution was stirred at room temperature, then 15 h. later, water and 1N hydrochloric acid were added to separate out the organic layer. The organic layer was washed sequentially with saturated sodium hydrogen carbonate solution, and brine. The solvent was removed by evaporation under reduced pressure to obtain the titled Compound 8e (1.36 g, yield 99%).LC/MS retention time: 0.96 min. (Analysis Condition: SMD-FA05-1). 1H-NMR (400 MHz, CDCl3) δ: 7.79 (2H, d, J=8 Hz), 7.35 (2H, d, J=8 Hz), 5.12 (1H, m), 3.93-3.76 (4H, m), 2.46 (3H, s), 2.13-2.05 (2H, m). |
With triethylamine In dichloromethane at 25℃; for 24h; | 3.1 Step 1) Synthesis of oxetan-3-yl 4-methylbenzenesulfonate General procedure: P-toluenesulfonyl chloride (1.0g, 5.2mmol) at 25 ° CAnd triethylamine (2.2mL, 15.7mmol) were added to a 100mL single-necked flask,Add dichloromethane (10mL),Add oxetane-3-ol (0.5g, 6.7mmol) in portions, and continue the reaction for another 24 hours; add water (40mL), then add dichloromethane (20mL), separate the liquid, collect the organic phase, reduce Spin dry and separate by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1 to 5/1) to obtain the title compound as a light yellow solid (1.02g, 85.2%). | |
With dmap; triethylamine In dichloromethane at 20 - 25℃; | Intermediate 5A: (2-oxaspiro[3.3]heptan-6-yl)methyl 4-methylbenzenesulfonate General procedure: To the solution of (2-oxaspiro[3.3]heptan-6-yl)MeOH (50 mg, 0.390 mmol), DMAP (4.77 mg, 0.039 mmol) and triethylamine (0.136 mL, 0.975 mmol) in DCM (5 mL), pTsCl (78 mg, 0.410 mmol) was added. The reaction was stirred at RT overnight and then diluted with DCM and washed with 1N HCl solution, sat. NaHCO3 solution, water and brine then dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by FCC (0-60% EtOAc/heptanes) to yield the title compound (71 mg, 0.226 mmol). LCMS: Rt: 0.92 min (LCMS Method 1). 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.66 (s, 2H), 4.54 (s, 2H), 3.95 (d, J = 5.9 Hz, 2H), 2.48 (s, 3H), 2.46 - 2.27 (m, 3H), 2.01 - 1.89 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 14h; | 1 Step 1: To a solution of toluene-4-sulfonic acid (R)-(tetrahydro-furan-3-yl) ester (1.5 g, 6.2 mmol) and Cs2C03 (1 .83 g, 5.6 mmol) in DMF (20 mL) was added 1 H-pyrazole-4-carboxylic acid ethyl ester (789 mg, 5.6 mol). The mixture was kept at 80°C for 14 h. The volatiles were removed in vacuo and the residue was extracted with EtOAc (50 mL). The combined organic layers were washed with H20, dried over Na2S04 and evaporated to dryness. Flash chromatography (silica, petroleum ether: EtOAc 3:1 ) gave reagent 2 as a solid (1.07 g, 91 %). 1H NMR (CDCI3) δ 7.97 (s, 1 H), 7.90 (s, 1 H), 4.95-5.00 (m, 1 H), 4.27 (q, J = 6.4 Hz, 2 H), 4.01 -4.15 (m, 3 H), 3.90-3.96 (m, 1 H), 2.43-2.52 (m, 1 H), 2.27-2.34 (m, 1 H), 1.33 (t, J = 6.4 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.7% | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 4h; | 4.a Synthesis of 4'-[(R)-(tetrahydro-furan-3-yI)oxy]-biphenyl-4-carboxylic acid a) A mixture of 4'-hydroxy-biphenyl-4-carboxylic acid (R)-l-methyl-heptyl ester (269.5 mg; 0.825 mmol), toluene-4-sulfonic acid (R)-(tetrahydro-furan-3- yl) ester (200 mg; 0.825 mmol) and cesium carbonate (350 mg; 1.07 mmol) in of N,N-dimethylformamide (5 mL) is heated to 60 °C for 4 hours. The reaction mixture is diluted with 10 ml water and extracted 3x with 10 ml ethyl acetate. The organic layer is dried over Na2SO4, filtered and the solvent removed in vacuo. The residue is crystallized with methanol, filtered with suction, washed with cold methanol and dried at 40°C under vacuo to give 300 mg (91 ,7%) 4'- [(R)-(tetrahydro-furan-3-yl)oxy]-biphenyl-4-carboxylic acid (R)-1 -methyl-heptyl ester as white powder; LC/MS: M+Na = 419. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.9% | With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 2h; Inert atmosphere; | 2 (S)-4-(3-(3-Fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 1e (80 mg, 0.19 mmol) was placed in a reaction flask, followed by addition of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 2a (92 mg, 0.38 mmol, prepared by a well known method "Journal of Medicinal Chemistry, 2011, 54 (12), 4092-4108"), cesium carbonate (186 mg, 0.57 mmol) and 3 mL of N,N-dimethylacetamide successively. The reaction solution was warmed up to 60°C. After reacting for 2 hours, the reaction solution was cooled down to room temperature, mixed with 15 mL of water and extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under the reduced pressure and the residue was purified by thin layer chromatography with elution system B to obtain the title compound (S)-4-(3-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy) phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 2 (73 mg, yield 77.9%) as a pale yellow solid. MS m/z (ESI): 494.4 [M+1] 1H NMR (400 MHz, CDCl3): δ 8.00-7.06 (m, 2H), 7.84 (q, 1H), 7.08 (d, 1H), 7.04-7.03 (m, 2H), 5.04-5.02 (m, 1H), 4.07-3.94 (m, 4H), 2.29-2.24 (m, 2H), 1.60 (s, 6H). |
77.9% | With caesium carbonate In N,N-dimethyl acetamide; water at 60℃; for 2h; | 2 (S)-4-(3-(3-Fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1e (80 mg, 0.19 mmol) was placed in a reaction flask, followed by addition of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 2a (92 mg, 0.38 mmol, prepared by a well known method described in Journal of Medicinal Chemistry, 2011, 54 (12), 4092-4108), cesium carbonate (186 mg, 0.57 mmol), and 3 mL of N,N-dimethylacetamide, successively. The reaction solution was warmed up to 60° C. After reacting for 2 hours, the reaction solution was cooled down to room temperature, mixed with 15 mL of water, and extracted with ethyl acetate (25 mL*3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL*3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by thin layer chromatography with elution system B to obtain the title compound (S)-4-(3-(3-fluoro-4-((tetrahydrofuran-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 2 (73 mg, yield 77.9%) as a pale yellow solid. MS m/z (ESI): 494.4 [M+1]; 1H NMR (400 MHz, CDCl3): δ 8.00-7.06 (m, 2H), 7.84 (q, 1H), 7.08 (d, 1H), 7.04-7.03 (m, 2H), 5.04-5.02 (m, 1H), 4.07-3.94 (m, 4H), 2.29-2.24 (m, 2H), 1.60 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.6% | With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 2h; Inert atmosphere; | 24 Example 24 (S)-4-(4,4-Dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimida zolidin-1-yl)-2-(trifluoromethyl)benzonitrile Example 24 (S)-4-(4,4-Dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimida zolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(6-Hydroxypyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 10c (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 2a (116 mg, 0.48 mmol), cesium carbonate (235 mg, 0.72 mmol) and 3 mL of N,N-dimethylacetamide successively. The reaction solution was warmed up to 60°C and stirred for 2 hours. The reaction solution was cooled down to room temperature, mixed with 10 mL of saturated sodium chloride solution, and extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under the reduced pressure and the residue was purified by thin layer chromatography with elution system A to obtain the title compound (S)-4-(4,4-dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy) pyridin-3-yl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 24 (60 mg, yield 52.6%) as a white solid. |
52.6% | With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 2h; | 24 (S)-4-(4,4-Dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 4-(3-(6-Hydroxypyridin-3-yl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 10c (100 mg, 0.24 mmol) was placed in a reaction flask, followed by addition of (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate 2a (116 mg, 0.48 mmol), cesium carbonate (235 mg, 0.72 mmol), and 3 mL of N,N-dimethylacetamide, successively. The reaction solution was warmed up to 60° C. and stirred for 2 hours. The reaction solution was cooled down to room temperature, mixed with 10 mL of saturated sodium chloride solution, and extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with elution system A to obtain the title compound (S)-4-(4,4-dimethyl-5-oxo-3-(6-((tetrahydrofuran-3-yl)oxy)pyridin-3-yl)-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 24 (60 mg, yield 52.6%) as a white solid. MS m/z (ESI): 477.2 [M+1]; 1H NMR (400 MHz, CDCl3): δ 8.09-8.08 (m, 1H), 8.00-7.96 (m, 2H), 7.86-7.84 (m, 1H), 7.54-7.51 (m, 1H), 6.92-6.90 (m, 1H), 5.63-5.60 (m, 1H), 4.14-3.91 (m, 4H), 2.35-2.16 (m, 2H), 1.60 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
476 mg | With caesium carbonate In N,N-dimethyl-formamide at 65℃; | Step 2: Synthesis of 4-Bromo-1 -[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6 Step 2: Synthesis of 4-Bromo-1 -[(3S)-tetrahydrofuran-3-yl]pyrazole 3.6A mixture of 650 mg [(3R)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate, 400 mg 4-bromo- 1 H-pyrazole and 1 .40 g cesium carbonate in 10 mL Ν,Ν-dimethylformamide (DMF) was stirred at 65 °C for 6 h. Additional 20 mg 4-bromo-1 H-pyrazole were added and the reaction mixture was stirred at 65 °C overnight. The reaction mixture was diluted with ethyl acetate and washed with brine. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (cyclohexane/ethyl acetate 9:1 ->1 :1 ) to yield 476 mg of 4-bromo-1 -[(3S)-tetrahydrofuran-3- yl]pyrazole 3J3 as solid.Analysis: MS: M+H = 217 / 219 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.96 g | To a stirred solution of <strong>[185456-26-2]tri-tert-butyl hydrazine-1,1,2-tricarboxylate</strong> (58.5 g, 0.95 eq., prepared as per Angew. Chem. Tnt. Ed. 1996, 35, No. 22, 2626-2627) in dimethylsulfoxide (180 ml), was added cesium carbonate (90.77 g, 1.5 eq.), followed by stirring for 30 minutes at 20 to 30C. (R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (45.0 g, 1.0 eq.) was added into the reaction mass, followed by increase of temperature to 50 to 55C. The resulting reaction mass was stirred at 50 to 55C till <strong>[185456-26-2]tri-tert-butyl hydrazine-1,1,2-tricarboxylate</strong> is less than 0.25% monitored by HPLC area %. After completion of the reaction, the reaction mass was cooled to 20 to 25C, followed by addition of water (225 ml) and methyl tert-butyl ether (450 ml). The resulting biphasic mixture was stirred for 10 minutes followed by layer separation. The resulting organic layer was washed with an aqueous sodium chloride solution (225m1) followed by solvent evaporation under reduced pressure to give crude (5)-tri-tert-butyl 2-(tetrahydrofuran-3-yl)hydrazine- 1,1 ,2-tricarboxylate (68.34 g). The crude material was recrystallized using a mixture of methyl tert-butyl ether and n-heptane (22.5 ml:112.50 ml) to give pure (5)-tri-tert-butyl2-(tetrahydrofuran-3-yl)hydrazine- 1,1 ,2-tricarboxylate (57.96 g , 77.53%).Mass [M+Hj: 402.80Purity by HPLC: 99.59% areaSpecific Optical Rotation (C=1, Methanol): -8.553Melting point (DSC method): 62.7 1C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 36h; | 4C methyl 3-(5-methyl-1,3-thiazol-2-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate Intermediate 3 (4.5 g, 18.2 mmo[), Intermediate 6C (5.3 g , 21.8 mmo[) and caesium carbonate (8.9 g, 27.3 mmo[) were stirred in DMF (100 mL) at 90°C for 36h. The reaction mixture was filtered and the filtrate concentrated under reducedpressure. Crude material was purified by column chromatography (silica gel, hexane/ EE gradient) to give 3.9 g (67 % yield) of the title compound.1H NMR (400 MHz, DMSO-d6) 6 [ppm] 1.96 - 2.05 (m, 1 H) 2.20 - 2.31 (m, 1 H) 3.743.82 (m, 1 H) 3.82 - 3.94 (m, 6 H) 5.19 - 5.26 (m, 1 H) 7.48 (dd, J=2.41, 1.39 Hz,H) 7.61 (dd, J=2.28, 1.52 Hz, 1 H) 7.66 (d, J=1.27 Hz, 1 H) 8.00 (t, J=1.39 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; | 95 methyl 3-bromo-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate A mixture of Intermediate 1 (3.00 g, 13.0 mmo[), Intermediate 6AZ (4.72 g, 19.5 mmo[) and C52CO3 (6.35 g, 19.5 mmo[) in DMF 25 m[ was stirred at 80°C unti[ comp[ete conversion. The reaction mixture was coo[ed to RT and the so[id was filtered through Celite and washed with DMF. The filtrate was evaporated and the residue purified by column chromatography (silica gel, hexane/ EE gradient) to give 2.63 g (67% yield) of the title compound.LCMS, method 1, rt: 1.17 mm, MS ES+ m/z = 301 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; potassium iodide; In acetonitrile; at 50 - 55℃; | A three-necked flask was charged with 2b (35.86 g, 100 mmol)R-3-p-toluenesulfonyloxy tetrahydrofuran 3b (26.65 g, 110 mmol)Potassium carbonate (27.64 g, 200 mmol),Potassium iodide (830 mg, 5 mmol) and acetonitrile (179 mL)Stir well after heating to 50 ~ 55 reaction overnight.The reaction was terminated by direct concentration to remove part of the acetonitrile,Water (179 mL) and dichloromethane (179 mL) were added,The aqueous phase was extracted again with dichloromethane (89 mL)The organic phase saturated brine was washed once (179 mL)Sodium sulfate,After concentration, compound 4b (37.29 g, 87%) was recrystallized from a petroleum ether ethyl acetate mixed solvent.Potassium carbonate in Example 4 can be replaced with sodium carbonate, cesium carbonate, potassium tert-butoxide, triethylamine or diisopropylethylamine;The reaction solvent acetonitrile may be replaced by N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, toluene, isopropanol or acetone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol; (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate With caesium carbonate at 25 - 50℃; Stage #2: <i>L</i>-proline In water at 75 - 80℃; for 0.5h; | 11 Preparation of Co-Crystal of Empagliflozin and L-Proline from Compound of Formula (II-SH-A) In a round bottom flask, 15 g compound of Formula (II-SH-A), 17.96 g cesium carbonate, 11.45 g (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate and 150 mL DMSO or DMF were added at 25° C. to 35° C. The reaction mixture was heated to 35 to 40° C. and stirred for 4-5 hours. 2.86 g (R)-tetrahydrofuran-3-yl-4-methylbenzenesulfonate and 6.41 g cesium carbonate were added and the reaction mixture was stirred at 40-50° C. for 24-36 hours. The reaction mixture then cooled to 25° C. to 35° C. 300 mL water was taken in another flask and cooled to 0-10° C. The reaction mixture was added into the water at 0-10° C. The reaction mixture was stirred at 25° C.-35° C. 75 mL toluene was added into the reaction mixture stirred for 30 minutes. The layers were separated and the aqueous layer was washed 2 to 3 times with toluene. In another flask, the aqueous layer and 450 mL methylene dichloride were taken and stirred for 30 minutes. Layers were separated. Organic layer was treated with 75 mL of 5% NaOH solution for 30 minutes and the layers were separated. The organic layer then treated with brine solution and then dried over sodium sulphate. The solvent was distilled out under vacuum to get a residue. 150 mL ethanol, 8 gm L-proline and 0.75 mL water were added into the flask having the residue and the reaction mixture was stirred for 30 minutes at 75-80° C. The reaction mixture then cooled and 75 mL toluene was added and stirred for 2 hours at 25-30° C. The solid was filtered and washed with ethanol and then dried to obtain co-crystal of empagliflozin and L-proline. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In acetonitrile at 20℃; | 17 (4R-3), 4-chloro-3- (4 - (((S) -tetrahydrofuran-3-yl) oxy)Benzyl) phenyl) tetrahydro-2H-pyran-3,4,5-triol triacetate A 10-necked flask was charged with 10 (54.90 g, 100 mmol) and acetonitrile (275 mL)Add potassium carbonate(27.64 g, 200 mmol) and(3R) -tetrahydrofuran-3-p-toluenesulfonate(29.07 g, 120 mmol),Room temperature reaction overnight. The reaction was terminated by removing part of the acetonitrile, adding water (275 mL) andEthyl acetate (275 mL) and the aqueous phase was extracted again with ethyl acetate (137 mL)Combined with organic saturated brine washed twice (137mL), dried over sodium sulfate,After concentration, the crude key intermediate compound 11 (53.86 g, 87%) was re-crystallized with petroleum ether ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With caesium carbonate In N,N-dimethyl acetamide at 60℃; for 0.5h; Inert atmosphere; | 13 (S) - 6 - ((4 - ((tetrahydrofuran-3-yl) oxy) - 1,2-dihydro-furo [3,2-f] quinolin-9-yl) oxy)-N-methyl-1-naphthalene carboxamide Under the protection of argon gas, the 6 - (4-hydroxy -1,2-dihydro-furo [3,2-f] quinoline-9-yloxy)-N-methyl-1-naphthalene carboxamide 1p (20 mg, 0 . 052mmol), (R)-tetrahydrofuran-3-yl tosylates 13a (under WO2007007886 relates to the method of preparing) (63 mg, 0 . 26mmol), cesium carbonate (127 mg, 0 . 39mmol) and 2 ml in dimethyl acetamide is put into the reaction bottle, for 60 °C reaction under 30 minutes. Cooling, adding 2 ml water and 5 ml ethyl acetate, separating, the aqueous phase is extracted with ethyl acetate (3 ml × 2), combined with the phase, saturated sodium chloride solution used for washing, drying by anhydrous magnesium sulphate, filtered, filtrate concentrated under reduced pressure, in order to thin-layer chromatography for purification of the resulting product A developing agent system, to obtain the title product (S) - 6 - ((4 - ((tetrahydrofuran-3-yl) oxy) - 1,2-dihydro-furo [3,2-f] quinolin-9-yl) oxy)-N-methyl-1-naphthalene carboxamide 13 (40 mg, pale yellow solid), yield: 67.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | At room temperature, <strong>[102127-34-4]3-methoxy-4-bromophenol</strong> (0.4 g, 1.97 mmol) and cesium carbonate (0.96 g, 2.96 mmol) were added to a solution of compound 15-c (0.43 g, 1.78 mmol) in N,N-dimethylformamide (4 mL) respectively. After the addition, the reaction solution was stirred at 80 C. for 16 hours. The reaction solution was diluted with ethyl acetate (10 mL), washed sequentially with water (10 mL×3) and brine (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=10:1) to give compound 15-b (0.31 mg, yield 64%). (0265) 1H-NMR (400 MHz, CDCl3) delta: 7.40 (d, J=8.4 Hz, 1H), 6.48 (d, J=2.8 Hz, 1H), 6.33 (dd, J=2.8, 8.8 Hz, 1H), 4.85-4.94 (m, 1H), 3.94-4.05 (m, 3H), 3.87-3.94 (m, 1H), 3.86 (s, 3H), 2.07-2.29 (m, 2H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With potassium carbonate In acetonitrile at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate at 110℃; for 16h; | Description 2885-methyl-I -(tetrahydro-2H-pyran-2-yl)-6-(3-((S)-tetrahydrofuran-3-yP)-3-azabicycl-o[3.I .01 hexan-6-yl)-1 H-indazole (D288) To a stirred solution of 6-(3-azabicyclo[3. 1 .0]hexan-6-yl)-5-methyl-1 -(tetrahydro-2H-pyran-2- yl)-l H-indazole (300 mg, 1.0 mmol) in MeCN (40 ml) were added (R)-tetrahydrofuran-3-yl 4- methylbenzenesulfonate (726 mg, 3.0 mmcl) and K2C03 (342 mg, 3.0 mmol). Then thereaction mixture was stirred at 110°C for 16 h, filtered and extracted with EtOAc (2 x 50 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (EtOAc:PE 2:1) to give the desired product as a pale yellow oil (150 mg, yield: 40%).LC-MS [mobile phase: from 60% water (0.1% FA) and 40% MeCN (0.1% FA) to 5% water (0.1% FA) and 95% MeCN (0.1% FA) in 2.6 mm]: Rt = 0.79 mm; MS Calcd: 367.23; MSFound: 368.3 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With potassium carbonate In acetonitrile at 110℃; for 24h; Inert atmosphere; | 179 Example 179(1 R,4R)-5-(2-methyl-6-(5-methyl-6-(3-((S)-tetrahydrofuran-3-yl)-3-azabicyclo- [3.1.0] hexan-6-yl)-1 H-indazol-1-yl)pyrimidin-4-yI)-2-oxa-5-azabicyclo[2.2. 1] heptane To a solution of (1 R,4R)-5-(6-(6-(3-azabicyclo[3. 1 .0]hexan-6-yl)-5-methyl-1 H-indazol-1 -yl)-2- methylpyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2. 1 ]heptane (150 mg, 0.37 mmol) in MeCN (20 mL) was added (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (271 mg, 1.12 mmcl) and K2C03 (154 mg, 1.12 mmcl) at ii under N2. The reaction mixture was stirred at 110 °C for 24h. The mixture was purified by silica gel chromatography eluted with EtOAc and flash columnto give the product as a white solid (35 mg, yield: 19%).IH NMR (400 MHz, CDCI3) ö 8.52 (s, 1H), 8.03 (s, IH), 7.46 (s, 1H), 6.66 (s, 1 H), 5.25 (m,0.65H), 4.73 (s, 1H), 3.97-3.93 (m, 1H), 3.92-3.90 (m, 2H), 3.88-3.83 (m, 2H), 3.79-3.77 (m,1H), 3.65-3.52 (m, 2H), 3.29-3.27 (m, 1H), 3.18-3.16 (m, IH), 3.07-3.03 (m, 1H), 2.61-2.50(m, 5H), 2.42 (s, 3H), 2.41-2.40 (m, 1H), 2.06-1.91 (m, 4H), 1.88 (m, 2H).LC-MS [mobile phase: from 90% water (0.1% FA) and 10% MeCN (0.1% FA) to 5% water (0.1% FA) and 95% MeCN (0.1% FA) in 2.6 mm]: Rt 1.12 mm; MS Calcd: 472.26, MS Found: 473.5 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine In acetonitrile at 95℃; for 48h; | 172 Synthesis of (2R,4R)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4-amine Int-172- 13 A mixture of Int-172-1 (1.0 g, 4.6 mmol), Int-172-11 (3.3 g, 14 mmol) and DIPEA (2.44 mL, 14 mmol) in acetonitrile (10 mL) was heated 95oC for 48 h. The mixture was concentrated under reduced pressure and purified by column chromatography using CH2Cl2/MeOH as mobile phase to give 1.0 g of pale grey solid (76 % yield). LCMS: (M+1) m/z = 285. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 12h; Microwave irradiation; | 237 Synthesis of Compound 237a (2R,4S)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl- 1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4- amine and Compound 237b (2S,4R)-1-(8-fluoro-6-methoxy-4-methyl-3-(3-methyl- 1,2,4-oxadiazol-5-yl)quinolin-2-yl)-2-methyl-N-((S)-tetrahydrofuran-3-yl)piperidin-4- amine A microwave vessel was charged with 1-[8-fluoro-6-methoxy-4-methyl- 3-(3-methyl-1,2,4-oxadiazol-5-yl)quinolin-2-yl]-trans-2-methylpiperidin-4-amine (Int- 236-4, 58 mg, 0.15 mmol), (3R)-oxolan-3-yl 4-methylbenzene-1-sulfonate (Int-172-11, 146 mg, 0.56 mmol), DIPEA (0.105 mL, 0.56 mmol) and CH3CN (0.9 mL). The mixture was heated for 12 hours at 120oC in a microwave reactor. The mixture was partitioned between EtOAc and an aqueous Na2CO3 solution, drying the organic fraction over sodium sulfate, and concentrating to 170 mg of an orange oil. The crude product was purified by column chromatography eluting with a gradient of 0-60% EtOAc/hexanes, followed by a gradient of 0-10% MeOH/DCM to give the mixture of diastereomers as a yellow solid (38 mg, 56% yield). The mixture can be separated to give the individual diasteromers using a phenomenex Lux 5μ cellulose-4 column (250mmx4.6mm, hexane:ethanol:DEA (73:27:0.1), 1 mL/min, retention time: 7.2 min, 8.9 min. LCMS: (M+1) m/z = 356.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 2h; | 4.1 (S)-2-Methyl-6-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)pyridine 4b 1e (328 mg, 2.06 mmol) was dissolved in 10 mL of N,N-dimethylformamide, then (R)-tetrahydrofuran-3-yl toluene-4-sulfonate 4a (500 mg, 2.06 mmol, prepared according to the method disclosed in the patent application "WO2016021192") and cesium carbonate (1.3 g, 4.12 mmol) were added, and the reaction solution was stirred at 60° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was added with water, and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound 4b (370 mg, colorless transparent oil), which was used directly in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With potassium carbonate In acetonitrile at 70℃; for 24h; | a a) ethyl 1-r(3S)-tetrahvdrofuran-3-vnpiperidine-4-carboxylate A mixture of 1.93 g (7.97 mmol) of (3R)-tetrabydrofuran-3-yl 4- methylbenzenesulfonate (WO 2016/91776 A1 (16.06.2016) EVOTEC AG), 2.46 mL (15.9 mmol) of ethyl piperidine-4-carboxyiate, 39 mL of acetonitrile and 4.4 g (31.9 mmol) of K2CO3 was stirred at 70°C for 24 h, then cooled to room temperature and diluted with ethyl acetate. The so obtained mixture was washed with water and this water phase was discarded. The organic layer was washed with 1 M HCI solution and this acidic water phase was alkaiified with 10% K2CO3 solution, extracted with ethyl acetate, the combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane : methanol = 91 :9 as eluent to yield 603 mg (27%) of the title compound. GC-MS (El) m/z 227. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide for 5h; Overall yield = 55percent; Overall yield = 63 mg; | 49-51 Example 49: 5-(4-fluoro-2-[(3S)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (mixture of stereoisomers 5-(4-fluoro-2-hydroxyphenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl]-1,3,9- triazaspiro[5.5]undecan-2-one (100 mg, 202 pmol, Intermediate 10), (3R)-oxolan-3-yl 4- methylbenzene-1 -sulfonate (73.4 mg, 303 pmol) and potassium carbonate (1 12 mg, 0.81 mmol) were mixed in dimethylformamide (1.2 ml_) and heated to 100 13 for 5 hours. The reaction was cooled down to room temperature, filtered and purified by preperative HPLC (Method 1 1) to give the title compound 63.0 mg (55 % yield). LC-MS (Method 4): Rt = 1.16 min; MS (ESIpos): m/z = 566 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.015 (0.45), 0.059 (0.74), 0.077 (0.64), 0.297 (0.51), 0.318 (0.77), 0.350 (0.51), 0.877 (1.92), 0.91 1 (1.73), 1.200 (1.80), 1.218 (2.18), 1.230 (2.15), 1.341 (1.60), 1.479 (1.35), 1.508 (0.93), 1.598 (0.93), 1.631 (0.80), 1.874 (1.57), 1.892 (1.99), 1.907 (2.15), 1.942 (0.48), 2.140 (0.45), 2.161 (1.06), 2.176 (1.38), 2.195 (1.41), 2.21 1 (1.22), 2.233 (1.47), 2.253 (1.44), 2.268 (1.35), 2.287 (0.93), 2.302 (0.48), 2.518 (7.02), 2.522 (4.49), 2.888 (0.51), 2.913 (0.67), 2.947 (1.35), 2.955 (1.54), 2.963 (1.60), 2.974 (1.22), 2.987 (1.70), 3.027 (0.80), 3.070 (1.35), 3.106 (1.70), 3.1 18 (1.44), 3.131 (2.05), 3.143 (1.89), 3.158 (1.38), 3.188 (0.83), 3.221 (1.70), 3.233 (1.96), 3.270 (2.12), 3.305 (2.92), 3.367 (3.46), 3.413 (3.78), 3.453 (6.09), 3.486 (2.60), 3.570 (16.00), 3.663 (0.74), 3.684 (2.12), 3.701 (2.24), 3.713 (1.92), 3.726 (3.17), 3.745 (5.10), 3.755 (3.72), 3.763 (5.29), 3.778 (5.23), 3.784 (5.77), 3.799 (7.60), 3.809 (4.78), 3.818 (2.34), 3.829 (1.96), 3.844 (1.28), 3.855 (1.38), 3.868 (0.71), 3.883 (0.48), 3.894 (0.42), 4.070 (0.83), 4.105 (0.77), 4.179 (1.03), 4.213 (0.99), 4.951 (1.80), 5.030 (1.47), 5.084 (1.06), 6.366 (2.47), 6.395 (2.89), 6.459 (2.40), 6.535 (5.58), 6.716 (0.51), 6.722 (0.61), 6.744 (1.47), 6.765 (2.63), 6.785 (2.37), 6.799 (1.86), 6.805 (2.05), 6.820 (1.06), 6.827 (1.09), 6.846 (1.41), 6.865 (2.12), 6.873 (2.12), 6.880 (1.96), 6.903 (3.82), 6.910 (3.46), 6.920 (1.44), 6.926 (1.41), 6.932 (2.24), 6.939 (1.99), 7.075 (1.86), 7.094 (4.30), 7.113 (3.05), 7.176 (6.22), 7.197 (5.10), 7.214 (2.63), 7.234 (2.50), 7.244 (10.52), 7.253 (6.80), 7.329 (0.67), 7.341 (0.90), 7.350 (1.03), 7.367 (2.82), 7.385 (4.07), 7.404 (1.35), 7.423 (2.73), 7.429 (2.28), 7.438 (2.15), 7.446 (1.76), 7.461 (5.64), 7.467 (4.36), 7.478 (2.57). The title compund was separated into its diastereoisomers by preparative chiral HPLC to give stereoisomer 1 (17 mg, Example 50), and stereoisomer 2 (18 mg, Example 51). For the isolation of stereoisomer 1 and stereoisomer 2 the following method was used. Preparative chiral HPLC method: Instrument: Labomatic HD5000, Labocord-5000; Gilson GX- 241, Labcol Vario 4000, column: Chiralpak IA 5m 250x30mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 20 min; flow 40.0 mUmin; UV 220 nm. Analytical chiral HPLC method: Instrument: Agilent HPLC 1260; column: Chiralpak IA 3m 100x4, 6mm; eluent A: hexane + 0.1 Vol-% diethylamine (99%); eluent B: 2-propanol; gradient: 20 - 50% B in 7 min; flow 1.4 mUmin; temperature: 25 O; DAD 220 nm. Example 50, Example 51 (5R)-5-(4-fluoro-2-[(3S)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (5S)-5-(4-fluoro-2-[(3S)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2- phenylpropanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one Example 50 5-(4-fluoro-2-[(3S)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (stereoisomer 1) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 49. Analytical chiral HPLC (method see Example 49): Rt = 2.4 min; ee > 99.9% Optical rotation (method OR1) = 35.9°+/- O.SODMS O). 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.298 (0.67), 0.319 (1.00), 0.349 (0.60), 0.851 (0.60), 0.881 (1.20), 0.910 (1.00), 1.026 (3.80), 1.042 (3.73), 1.180 (1.20), 1.201 (1.73), 1.213 (1.93), 1.232 (3.07), 1.340 (2.07), 1.375 (0.67), 1.598 (1.20), 1.629 (1.00), 1.859 (0.60), 1.875 (1.20), 1.893 (1.93), 1.908 (1.73), 1.926 (1.20), 1.944 (0.53), 2.198 (0.47), 2.218 (0.93), 2.233 (1.53), 2.253 (1.80), 2.268 (1.73), 2.287 (1.13), 2.302 (0.60), 2.331 (2.87), 2.336 (1.27), 2.518 (16.00), 2.522 (10.13), 2.673 (2.87), 2.678 (1.27), 2.888 (0.47), 2.914 (0.73), 2.940 (0.53), 3.070 (1.67), 3.137 (1.00), 3.159 (1.47), 3.187 (1.00), 3.221 (2.00), 3.233 (2.27), 3.269 (2.53), 3.304 (3.47), 3.392 (1.80), 3.405 (2.20), 3.452 (7.00), 3.576 (13.67), 3.712 (2.13), 3.727 (3.00), 3.742 (4.87), 3.763 (5.73), 3.778 (4.33), 3.783 (4.00), 3.800 (6.93), 3.808 (4.60), 3.818 (2.33), 3.829 (2.40), 3.844 (1.53), 3.854 (1.33), 4.070 (1.07), 4.104 (1.00), 4.344 (0.53), 4.355 (0.53), 5.030 (1.80), 5.071 (1.07), 6.361 (3.07), 6.447 (2.27), 6.527 (3.33), 6.744 (1.60), 6.759 (2.40), 6.765 (3.40), 6.780 (1.47), 6.786 (1.93), 6.846 (1.73), 6.864 (2.27), 6.874 (2.27), 6.880 (2.33), 6.891 (1.87), 6.898 (2.00), 6.902 (2.13), 6.908 (1.93), 6.920 (1.53), 6.926 (1.40), 7.213 (1.60), 7.231 (2.73), 7.234 (3.13), 7.244 (13.27), 7.253 (8.53), 7.278 (0.73), 7.365 (1.80), 7.374 (2.27), 7.383 (2.20), 7.424 (0.87), 7.432 (1.40), 7.438 (1.53), 7.446 (1.93), 7.462 (6.87), 7.468 (5.53), 7.478 (3.20). Example 51 5-(4-fluoro-2-[(3S)-oxolan-3-yl]oxy}phenyl)-9-[(2R)-3,3,3-trifluoro-2-methoxy-2-phenyl- propanoyl]-1,3,9-triazaspiro[5.5]undecan-2-one (stereoisomer 2) For the preparation of the diastereomeric mixture and the separation in the corresponding stereoisomers, see Example 49. Analytical chiral FIPLC (method see Example 49): Rt = 3.1 min; ee = 86.8% Optical rotation (method OR1) = -18.9°+/- OODM SO) 1H-NMR (400 MHz, DMSO-d6) d [ppm]: -0.016 (0.52), 0.000 (0.66), 0.016 (0.92), 0.028 (0.92), 0.045 (0.79), 0.061 (0.59), 0.819 (0.66), 0.843 (1.51), 0.876 (1.31), 0.995 (3.34), 1.010 (3.34), 1.164 (1.18), 1.187 (1.84), 1.199 (3.15), 1.218 (1.44), 1.227 (1.31), 1.446 (1.64), 1.477 (1.18), 1.827 (0.66), 1.839 (1.05), 1.857 (1.18), 1.865 (1.18), 1.874 (1.31), 1.960 (0.39), 2.108 (0.52), 2.129 (1.25), 2.144 (1.64), 2.150 (0.98), 2.157 (0.98), 2.164 (1.51), 2.178 (1.18), 2.199 (0.59), 2.300 (2.75), 2.304 (1.31), 2.486 (16.00), 2.490 (10.10), 2.642 (2.89), 2.646 (1.38), 2.914 (1.25), 2.924 (1.77), 2.931 (1.97), 2.943 (1.44), 2.956 (1.97), 2.989 (0.92), 3.073 (1.51), 3.086 (1.57), 3.098 (2.10), 3.1 11 (1.77), 3.205 (0.46), 3.241 (0.52), 3.334 (3.87), 3.381 (3.41), 3.415 (1.70), 3.454 (3.02), 3.536 (15.15), 3.631 (0.79), 3.652 (2.36), 3.669 (2.49), 3.691 (2.43), 3.703 (1.97), 3.713 (3.15), 3.724 (3.15), 3.734 (2.03), 3.742 (3.74), 3.752 (3.48), 3.767 (3.48), 3.778 (2.43), 3.825 (0.72), 3.836 (0.79), 3.851 (0.52), 3.862 (0.46), 4.147 (1.25), 4.180 (1.18), 4.313 (0.46), 4.323 (0.46), 4.919 (2.16), 5.062 (0.52), 6.358 (3.41), 6.418 (1.1 1), 6.489 (4.13), 6.685 (0.59), 6.691 (0.66), 6.705 (0.39), 6.712 (0.52), 6.747 (1.1 1), 6.753 (1.44), 6.768 (2.16), 6.774 (2.49), 6.788 (1.25), 6.795 (1.31), 6.834 (0.72), 6.840 (0.79), 6.871 (2.82), 6.878 (2.62), 6.901 (2.56), 6.907 (2.36), 7.042 (2.23), 7.063 (5.18), 7.081 (3.67), 7.144 (7.54), 7.165 (6.03), 7.183 (2.10), 7.212 (1.05), 7.221 (0.66), 7.297 (0.79), 7.308 (0.98), 7.317 (1.05), 7.335 (2.03), 7.354 (3.34), 7.372 (1.57), 7.391 (2.56), 7.397 (2.16), 7.405 (1.31), 7.430 (0.59). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 5h; | 52 Example 52: 5-(4-fluoro-2-[(3S)-oxolan-3-yl]oxy}phenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9-triaza- spiro[5.5]undecan-2-one (mixture of stereoisomers) (4-fluoro-2-hydroxyphenyl)-9-[2-(trifluoromethoxy)phenyl]acetyl}-1,3,9-triazaspiro[5.5]- undecan-2-one (100 mg, 208 pmol, Intermediate 15), (3R)-oxolan-3-yl 4-methylbenzene-1 - sulfonate (75.5 mg, 312 pmol) and potassium carbonate (1 15 mg, 0.831 mmol) were mixed in dimethylformamide (1.2 ml_) and heated to 100 13 for 5 hours. The reaction was cooled down to room temperature, filtered and purified by preperative HPLC (Method 1 1) to give the title compound 65.0 mg (52 % yield). LC-MS (Method 4): Rt = 1.09 min; MS (ESIpos): m/z = 552 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 1.153 (0.98), 1.201 (1.22), 1.237 (2.54), 1.267 (2.20), 1.359 (2.88), 1.382 (2.54), 1.533 (1.66), 1.565 (1.46), 1.598 (1.56), 1.631 (1.32), 1.833 (0.83), 1.849 (1.12), 1.866 (1.37), 1.883 (1.17), 1.898 (1.07), 1.916 (1.12), 1.935 (1.37), 1.951 (1.71), 1.967 (1.80), 1.996 (0.88), 2.026 (0.78), 2.041 (0.73), 2.047 (1.32), 2.062 (1.71), 2.068 (0.73), 2.076 (0.59), 2.083 (1.46), 2.097 (0.98), 2.103 (0.59), 2.1 18 (0.54), 2.187 (1.41), 2.202 (2.00), 2.220 (2.29), 2.238 (1.90), 2.428 (16.00), 2.518 (11.56), 2.522 (7.02), 2.673 (2.05), 2.947 (1.22), 2.967 (1.17), 3.1 19 (0.88), 3.154 (1.61), 3.183 (2.29), 3.212 (1.27), 3.285 (3.37), 3.343 (7.22), 3.375 (4.00), 3.489 (0.68), 3.521 (1.71), 3.544 (3.41), 3.553 (4.15), 3.583 (4.10), 3.594 (3.85), 3.636 (2.88), 3.646 (7.37), 3.652 (10.29), 3.663 (5.66), 3.667 (3.46), 3.673 (5.02), 3.677 (3.27), 3.681 (4.10), 3.684 (4.73), 3.688 (4.10), 3.714 (3.80), 3.719 (4.24), 3.728 (3.32), 3.740 (4.59), 3.757 (8.05), 3.761 (6.34), 3.778 (8.00), 3.793 (6.98), 3.834 (3.46), 3.844 (3.76), 3.859 (1.85), 3.877 (2.34), 3.886 (2.29), 3.903 (1.90), 3.915 (1.66), 3.946 (1.71), 3.987 (2.05), 4.023 (0.88), 5.063 (2.39), 5.101 (2.29), 5.106 (2.15), 5.1 1 1 (2.29), 5.1 16 (2.15), 5.121 (1.41), 5.125 (1.12), 6.440 (6.15), 6.665 (5.66), 6.732 (1.46), 6.738 (1.80), 6.752 (3.85), 6.759 (3.66), 6.766 (2.93), 6.773 (3.80), 6.780 (2.20), 6.787 (1.61), 6.794 (1.51), 6.886 (3.12), 6.891 (3.17), 6.898 (2.88), 6.908 (2.63), 6.915 (3.22), 6.920 (3.22), 6.927 (2.63), 7.207 (6.10), 7.215 (12.34), 7.226 (9.85), 7.253 (10.68), 7.259 (8.68), 7.279 (3.66), 7.331 (2.00), 7.339 (4.00), 7.345 (4.00), 7.354 (3.56), 7.363 (3.95), 7.376 (1.76), 7.382 (1.22), 7.481 (3.61), 7.483 (4.20), 7.502 (4.68), 7.799 (5.95), 7.804 (1.80), 7.816 (1.76), 7.820 (5.32). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 5h; | 53 Example 53: 5-(4-fluoro-2-[(3S)-oxolan-3-yl]oxy}phenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]- propanoyl}-1,3,9-triazaspiro[5.5]undecan-2-one (mixture of stereoisomers) (5-(4-fluoro-2-hydroxyphenyl)-9-{2-methyl-2-[3-(trifluoromethyl)phenyl]propanoyl}-1,3,9- triazaspiro[5.5]undecan-2-one (50.0 mg, 101 mihoI, Intermediate 16), (3R)-oxolan-3-yl 4- methylbenzene-1 -sulfonate (36.8 mg, 152 pmol) and potassium carbonate (56 mg, 0.405 mmol) were mixed in dimethylformamide (0.6 ml_) and heated to 100 13 for 5 hours. The reaction was cooled down to room temperature, filtered and purified by preperative HPLC (Method 1 1) to give the title compound 42.0 mg (74 % yield). LC-MS (Method 4): Rt = 1.15 min; MS (ESIpos): m/z = 564 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) d [ppm]: 0.429 (0.64), 0.984 (1.48), 1.306 (5.33), 1.470 (5.72), 1.938 (1.48), 2.152 (1.35), 2.173 (2.57), 2.187 (3.08), 2.206 (2.70), 2.221 (1.80), 2.331 (2.70), 2.518 (16.00), 2.522 (10.15), 2.673 (2.83), 2.729 (0.58), 2.888 (2.83), 3.142 (3.28), 3.172 (4.18), 3.207 (3.98), 3.316 (2.44), 3.343 (3.08), 3.497 (1.22), 3.737 (5.85), 3.761 (8.55), 3.813 (3.73), 3.828 (2.76), 4.033 (0.84), 5.028 (2.44), 6.359 (8.80), 6.485 (5.40), 6.498 (4.76), 6.758 (4.24), 6.867 (3.41), 6.873 (3.53), 6.895 (4.95), 6.901 (4.31), 6.919 (1.80), 7.176 (1.67), 7.279 (3.41), 7.379 (7.26), 7.396 (6.30), 7.583 (3.73), 7.595 (5.53), 7.613 (3.28). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.68% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; | 27.1 Step 1: (6aS,8S)-4-iodo-8-(((S)-tetrahydrofuran-3-yl)oxy)-6a,7,8,9-tetrahydro-6H- pyrido[3 ,2-b]pyrrolo[ 1 ,2-d] [ 1 ,4]oxazine To a stirred solution of (3R)-oxolan-3-yl 4-methylbenzenesulfonate (457 mg, 1.886 mmol, 3 equiv) and (6aS,8S)-4-iodo-6a,7,8,9-tetrahydro-6H-pyrido[3,2-b]pyrrolo[l,2- d][l,4]oxazin-8-ol (200 mg, 0.629 mmol, 1.00 equiv) in DMF (2.00 mL) was added NaH (88 mg, 2.200 mmol, 3.5 equiv, 60%) in portions at 0 °C under nitrogen atmosphere and the resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. After cooling at 0 °C, the reaction was quenched with water and the resulting mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by Prep-TLC (EtOAc 100%) to afford the title compound (70 mg, 28.68%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 14h; | 7.1 Step 2) Synthesis of 3- (oxetan-3-yloxy) benzaldehyde General procedure: M-hydroxybenzaldehyde (1.5g, 12.3mmol),Oxetan-3-yl 4-methylbenzenesulfonate (2.0g, 8.7mmol) and N, N-dimethylformamide (10mL) were added to a 100mL single-necked round bottom flask, and potassium carbonate (2.6 g, 18.8 mmol), reaction at an oil bath at 100 ° C for 14 hours; stop the reaction, cool to room temperature, add water (50 mL) to quench, then add ethyl acetate (30 mL), separate the liquid, collect the organic phase, and spin dry under reduced pressure , Column chromatography separation and purification (petroleum ether / ethyl acetate (v / v) = 8/1) to give the title compound as a yellow oil (1.1g, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With caesium carbonate In N,N-dimethyl-formamide at 70℃; for 12h; | 5.1 Step 8) (R)-Methyl 4-(3-(3-(2-((tert-butoxycarbonyl)amino)-2-phenylethyl)-1-(2-fluoro-6-(trifluoro (Methyl)benzyl)-6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-fluorophenoxy)butyrate General procedure: Add (R)-tert-butyl(2-(5-(2-fluoro-3-hydroxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl- 2,6-dioxo-2,3-dihydropyrimidine-1(6H)-yl)-1-phenylethyl)carbamate (0.5g, 0.79mmol) andN,N-dimethylformamide (8.0mL) was added to a 100mL single-neck round bottom flask, potassium carbonate (221mg, 1.58mmol) andMethyl 4-bromobutyrate (286mg, 1.58mmol), react at 70°C for 12 hours;Stop the reaction, add water (50mL) after cooling to room temperature, and then add ethyl acetate for extraction (50mL×2),The organic phases were combined, spin-dried under reduced pressure, and separated and purified by column chromatography (petroleum ether/ethyl acetate (v/v)=3/1) to obtain the title compound as a viscous liquid (456 mg, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; potassium carbonate In N,N-dimethyl-formamide at 118℃; for 18h; | 29.1 The first step Compound 7-1(250.0 mg, 470.56 mmol) was dissolved in N,N-dimethylformamide (4 mL). To the reactionsolution were added potassium fluoride (65.6 mg, 1.13 mmol), potassium carbonate (130.07 mg, 941.11 mmol) andcompound L-1 (171.0 mg, 705.83 mmol). The reaction solution was stirred at 118 °C for 18 hours. The reaction solutionwas concentrated under reduced pressure to remove the solvent, and the residue was isolated by preparative thin-layerchromatography (ethyl acetate) to afford compound 29-2. LC-MS: m/z = 601.3 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 3h; | 26.1 The first step Compound 20-5 (200.0 mg, 364.02 umol) was added to N,N-dimethylformamide (5 mL) at room temperature,and then to the mixture were added cesium carbonate (55.8 mg, 1.09 mmol) and compound L-1 (97.0 mg, 400.42 mmol).The reaction solution was heated to 100 °C, and stirred for 3 hours. The reaction solution was cooled to room temperature,quenched with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washedsequentially with water (5 mL x 3) and saturated brine (5 mL), dried over sodium sulfate, and filtered. The filtrate wasconcentrated under reduced pressure, and the residue was isolated by preparative thin-layer chromatography (dichloromethane:methanol = 20:1) to afford compound 26-2. LC-MS: m/z = 619.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33 mg | With caesium carbonate In N,N-dimethyl-formamide at 60℃; for 12h; | 323.a (a) (((2-nitro-1,3-phenylene)bis(oxy))bis(methylene))dibenzene General procedure: 5 g of 2-nitroresorcinol was dissolved in N,N-dimethylformamide (88 mL), and then benzylbromide (8.4 mL, 2.2equivalents) and caesium carbonate (25 g, 2.4 equivalents) were added thereto, followed by stirring at room temperaturefor 12 hours. The formation of the product was confirmed by TLC, and then ethyl acetate was added thereto. The organicphase was washed by 1% aqueous solution of hydrochloric acid and then washed again by distilled water. The organicphase was dried over anhydrous magnesium sulfate, followed by filtration. Hexane was added to the residue obtainedby vacuum concentration of the filtrate and the precipitated solid was collected by filtration, thus obtaining 10 g of thetitle compound. MS (ESI) m/z: 336 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.01% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 1h; Sealed tube; | 109 Example - 109: N-((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)- tetrahydrofuran-3-yl)oxy)-8,9-dihydro-7H-cyclopenta[h]quinazolin-4-amine (Compound - 109) To a stirred solution of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl- 8,9-dihydro-7H-cyclopenta[h]quinazolin-6-ol (170 mg, 0.422 mmol) in DMF (10 ml) were added (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (123 mg, 0.507 mmol) and Cs2CO3(206 mg, 0.634 mmol) at room temperature and then reaction mixture heated at 80°C for 1 h in a sealed vial. After completion of reaction, reaction mixture was allowed to room temperature and diluted with ethyl acetate (50 ml). The organic layer was washed with water (20 ml x 2) and brine (20 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude mass was purified by flash column chromatography by using 80 - 90% ethyl acetate in Hexane as eluent to get afford N-((R)-1-(3-amino-5- (trifluoromethyl)phenyl)ethyl)-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)-8,9-dihydro-7H- cyclopenta[h]quinazolin-4-amine (10 mg, 5.01% yield). MS (ES+) m/z = 473.23 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.03 - 7.98 (m, 1H), 7.53 (s, 1H), 6.88 (s, 1H), 6.86 - 6.84 (m, 1H), 6.71 - 6.68 (m, 1H), 5.64 - 5.57 (m, 1H), 5.55 (s, 2H), 5.25 - 5.20 (m, 1H), 4.05 - 4.00 (m, 1H), 3.93 - 3.86 (m, 1H), 3.85 - 3.78 (m, 2H), 3.16 - 3.09 (m, 2H), 2.95 - 2.88 (m, 2H), 2.38 (s, 3H), 2.35 - 2.28 (m, 1H), 2.15 - 1.98 (m, 3H), 1.57 (d, J = 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 1h; | 111.2 Step - 2: N-(R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)- tetrahydrofuran-3-yl)oxy)furo[2,3-h]quinazolin-4-amine To a stirred solution of (R)-4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2,8- dimethylfuro[2,3-h]quinolin-6-ol (0.2 g, 0.481 mmol) in DMF (10 ml) were added Cs2CO3(0.173 g, 0.530 mmol) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (0.128 g, 0.530 mmol) at room temperature and heated at 90°C for 1 h. After completion of reaction, the reaction mass was allowed to room temperature and diluted with ethyl acetate (60 ml), washed it with water (30 ml x 2) and brine (30 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. This residue (200 mg) was purified by flash column chromatography using gradient elution (0 - 5% ) of methanol in dichloromethane to afford N-((R)1-(3-amino- 5-(trifluoromethyl)phenyl)ethyl)-2,8-dimethyl-6-(((S)-tetrahydrofuran-3-yl)oxy)furo[2,3- h]quinazolin-4-amine (0.15 g, 64.0% yield) as an off white solid. MS (ES+) m/z: 487.17 (M+1).1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.59 (s, 1H), 6.99 (d, J = 1.3 Hz, 1H), 6.89 (s, 1H), 6.87 (s, 1H), 6.71 (d, J = 1.9 Hz, 1H), 5.64 (p, J = 7.3 Hz, 1H), 5.56 (s, 2H), 5.42 - 5.38 (m, 1H), 4.06 - 4.02 (m, 1H), 3.99 - 3.89 (m, 2H), 3.87 - 3.82 (m, 1H), 2.50 (s, 3H), 2.44 (s, 3H), 2.41 - 2.32 (m, 1H), 2.18 - 2.09 (m, 1H), 1.58 (d, J = 7.1 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; | 38 Compound 38B At room temperature, compound 38A (3.40 g, 14.0 mmol) was dissolved in N,N-dimethylformamide (20.0 mL).Subsequently, 4-amino-3-nitrophenol (3.23 g, 21.0 mmol) and cesium carbonate (9.12 g, 28.2 mmol) were added to the above solution.The reaction system was heated to 80 degrees Celsius and stirred for 3 hours.After LCMS monitoring showed that the raw materials disappeared, the reaction system was cooled to room temperature.Water (10 mL) was added to the reaction system to quench.The mixture was extracted with ethyl acetate (30 ml×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (10 ml×3 times), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure.The obtained residue was slurried with ether (10 ml), filtered, and the filter cake was dried to obtain 1.10 g of dark brown solid compound 38B (yield: 35.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate for 2h; Heating; | B.63.2 Step 2: A mixture of 63c (650 mg, 2.85 mmol, 1 eq), 63b (1.04 g, 4.27 mmol, 1.5 eq) and CS2CO3 (2.78 g, 8.54 mmol, 3 eq) in DMF (10 mL) was stirred at 110°C for 2 h. LCMS showed that 63d was present. The solution was quenched by water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (neutral condition, column: Phenomenex Gemini-NX C1875*30mm*3um; mobile phase: [water(10mM NH4HC03)-ACN]; B%: 26%-46%,10.5min) to afford the titled product Ex.63 (140 mg, 16.5% yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67 mg | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 70℃; for 12h; | 21.1 Example 21: Synthesis of S-14 Step 1: Add (R)-3-hydroxytetrahydrofuran p-toluenesulfonate (260mg), potassium iodide (30mg) and potassium carbonate (300mg) to a solution of S-2 (190mg) in DMF (6mL), and react at 70 After 12h, pour into water, extract with EA, wash the EA layer with saturated brine, dry with anhydrous sodium sulfate, spin-dry the organic phase under reduced pressure, and then column chromatography to obtain S-14-1 (67mg) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate In N,N-dimethyl-formamide at 75℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With cesium fluoride In N,N-dimethyl-formamide at 90℃; for 2h; | 7-1.G [0491] Step G: To a solution of /'/Y-butyl (f?)-(2-(5-(N-((Rhydroxy-4-methylphthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)carbamate (13.0 mg, 25.8 pmol, 1.00 eq.) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (9.16 mg, 30.9 pmol, 1.20 eq.) in DMF (0.10 mL) was added cesium fluoride (15.0 mg, 98.8 pmol, 3.64 pL, 3.83 eq ). The mixture was stirred at 90 °C for 2 hours then poured into water (5.00 mL) and filtered. The filtrate was extracted with ethyl acetate (10 mL c 2) and the combined organic layers were washed with brine (10.0 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue tert-butyl methyl(2-(5-((R)-1-((4-methyl-7-(((V)-tetrahydrofuran-3-yl)oxy)phthalazin-1-yl)amino)ethyl)thiophen-2-yl)benzyl)carbamate (14.8 mg, 25.8 pmol, 100% yield) was obtained as a yellow oil which was used without further purification. LCMS [M+l]+: 575.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h; | 15-1.C [0578] Step C: To a solution of (R)-1-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)phthalazin-6-ol (16.0 mg, 40.8 pmol, 1.00 eq.) in DMF (1.50 mL) was added cesium carbonate (39.9 mg, 122 pmol, 3 00 eq.) and (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (14.8 mg, 61.2 pmol, 1.50 eq.). The mixture was stirred at 80 °C for 12 hours. The residue was diluted with water (2.00 mL) and extracted with ethyl acetate (3.00 mL x 3). The combined organic layers were washed with brine (5.00 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The crude product 4-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-7-(((5)-tetrahydrofuran-3-yl)oxy)phthalazin-1-amine (18.0 mg, 38.93 pmol, crude) as a brown oil used into the next step without further purification. LCMS [M+l] +: 463.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.6% | With Cs2CO3 In N,N-dimethyl-formamide at 65℃; for 15h; | (R)-3-(2-(5-Bromo-2-chlorobenzyl)phenoxy)tetrahydrofuran (6) To a solution of 6a (4 g, 13.5 mmol) and 6b (3.3 g, 13.5 mmol) in DMF (65 mL), wasadded Cs2CO3 (8.8 g, 27.0 mmol) at rt. The mixture was stirred at 65 C for 15 h, thencooled to rt, quenched by water (100 mL), and extracted into ethyl acetate (EA,150 mL), and dried with Na2SO4. After filtration and evaporation of the solvent thecrude product was purified by column chromatography (silica gel, petroleum ether/EA 30:1) to get 6 (3.8 g, 76.6% yield). 1H NMR (600 MHz, CDCl3) d (ppm): 7.24-7.20(m, 4H), 7.12 (d, J7.2 Hz, 1H), 6.92-6.89 (m, 1H), 6.78 (d, J8.4 Hz, 1H), 4.93 (s,1H), 4.05-3.97 (m, 3H), 3.93-3.82 (m, 3H), 2.18-2.06 (m, 2H); 13C NMR (150 MHz,CDCl3) d (ppm): 155.1, 140.6, 133.5, 133.2, 131.0 130.6,130.3, 127.9, 127.7, 120.7, 120.2,111.9, 73.1, 67.1, 33.8, 33.0 HRMS (ESI) calcd for C17H16BrClNaO2[MNa]388.9914, found 388.9919.Anal. Calcd for C17H16BrClO2: C, 55.54; H, 4.39. Found: C, 55.54; H, 4.38. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With Cs2CO3 In N,N-dimethyl-formamide at 60℃; for 3h; | 3.2 The second step: dissolve 102-1 (10g, 47.62mmol), (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (13.9g, 57.14mmol) and cesium carbonate (23.3g, 71.43mmol) Stir in N,N-dimethylformamide (80 mL) at 60°C for 3 hours.The reaction was cooled, filtered through celite, the filter cake was washed with ethyl acetate (100 mL), water was added to the filtrate, the layers were separated, and the aqueous phase was extracted with ethyl acetate (3×100 mL), followed by saturated sodium chloride The solution was washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by slurrying with ethyl acetate to obtain compound 102-2 (8.9 g) as an off-white solid.Yield 67%. |
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P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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