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CAS No. : | 101691-65-0 | MDL No. : | MFCD09475806 |
Formula : | C13H18O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | DCBKCZSYJRZBDB-UHFFFAOYSA-N |
M.W : | 270.35 | Pubchem ID : | 19077576 |
Synonyms : |
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.54 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 68.59 |
TPSA : | 60.98 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.5 cm/s |
Log Po/w (iLOGP) : | 2.68 |
Log Po/w (XLOGP3) : | 2.04 |
Log Po/w (WLOGP) : | 3.21 |
Log Po/w (MLOGP) : | 2.0 |
Log Po/w (SILICOS-IT) : | 2.16 |
Consensus Log Po/w : | 2.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.78 |
Solubility : | 0.445 mg/ml ; 0.00164 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.95 |
Solubility : | 0.304 mg/ml ; 0.00113 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.75 |
Solubility : | 0.0477 mg/ml ; 0.000177 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.85 |
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 |
---|---|---|
94% | With sodium iodide In acetone for 4 h; Reflux | Step 2 [0340] (Tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate obtained in Step 1 (1.20 g, 4.44 mmol) was dissolved in acetone (15 mL), sodium iodide (2.00 g, 13.3 mmol) was added thereto, and under reflux with heating, the mixture was stirred for 4 hours. After cooling the reaction mixture to room temperature, the precipitated solid was removed by filtration, and the filtrate was evaporated under reduced pressure. Chloroform was added to the residue, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure, whereby 4-(iodomethyl)tetrahydro-2H-pyran (0.946 g, 94percent) was obtained. 1H NMR (300 MHz, CDCl3, δ): 3.99-3.96 (m, 2H), 3.37 (td, J = 11.7, 2.1 Hz, 2H), 3.10 (d, J = 6.6 Hz, 2H), 1.81-1.65 (m, 3H), 1.37-1.24 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In 2-methyltetrahydrofuran; water; at 35℃;Cooling; | Step 2: Synthesis of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester; Prepared as described by adaptation of the following literature reference:Radziszewski, J. G. et al. J. Am. Chem. Soc. 1993, 115, 8401.To a solution of 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in 2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aqueous NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35 C. for 18 h. The suspension is poured into a mixture of ice-water (280 mL) and aqueous HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40 C. gave 216 g of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester as white crystalline solid. Yield: 99%, ES-MS: m/z 271 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm1.19-1.35 (2H, m), 1.54-1.63 (2H, m), 1.85-2.02 (1H, m), 2.45 (3H, s), 3.28-3.39 (2H, m), 3.86 (2H, d, J=6.60 Hz), 3.93 (2H, dd, J=11.37, 4.52 Hz), 7.35 (2H, d, J=9.29 Hz), 7.78 (2H, d, J=8.31 Hz) |
99% | To a solution of 97 g (810 mmol) of Compound 6 (190 mL) are added 165 mL of 50% aqueous NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35 C. for 18 h. The suspension is poured into a mixture of ice-water (280 mL) and aqueous HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40 C. gave 216 g of Compound 7 as white crystalline solid. Yield: 99%, ES-MS: m/z 271 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.19-1.35 (2H, m), 1.54-1.63 (2H, m), 1.85-2.02 (1H, m), 2.45 (3H, s), 3.28-3.39 (2H, m), 3.86 (2H, d, J=6.60 Hz), 3.93 (2H, dd, J=11.37, 4.52 Hz), 7.35 (2H, d, J=9.29 Hz), 7.78 (2H, d, J=8.31 Hz). | |
99% | With sodium hydroxide; In 2-methyltetrahydrofuran; water; at 30 - 35℃; for 18h; | Step 2: Synthesis of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester Prepared as described by adaptation of the following literature reference: Radziszewski, J.G. et al. J. Am. Chem. Soc. 1993, 115, 8401. To a solution of 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in 2- methyltetrahydrofuran (190 mL) are added 165 mL of 50% aqueous NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35 C for 18 h. The suspension is poured into a mixture of ice- water (280 mL) and aqueous HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40 C gave 216 g of toluene-4- sulfonic acid tetrahydro-pyran-4-ylmethyl ester as white crystalline solid. Yield: 99%, ES-MS: m/z 271 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.19 - 1.35 (2 H, m), 1.54 - 1.63 (2 H, m), 1.85 - 2.02 (1 H, m), 2.45 (3 H, s), 3.28 - 3.39 (2 H, m), 3.86 (2H, d, J=6.60 Hz), 3.93 (2 H, dd, J=11.37, 4.52 Hz), 7.35 (2 H, d, J=9.29 Hz), 7.78 (2 H, d, J=8.31 Hz) |
99% | Step 2: Synthesis of compound B3Prepared as described by adaptation of the following literature reference: Radziszewski, J.G. et al. J. Am. Chem. Soc. 1993, 115, 8401.To a solution of 97 g (810 mmol) of compound B2 in 2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aqueous NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35 C for 18 h. The suspension is poured into a mixture of ice- water (280 mL) and aqueous HC1 solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40 C gave 216 g of compound B3 as white crystalline solid. Yield: 99%, ES-MS: m/z 271 [M+H]; ]H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.19 - 1.35 (2 H, m), 1.54 - 1.63 (2 H, m), 1.85 - 2.02 (1 H, m), 2.45 (3 H, s), 3.28 - 3.39 (2 H, m), 3.86 (2H, d, J=6.60 Hz), 3.93 (2 H, dd, J=11.37, 4.52 Hz), 7.35 (2 H, d, J=9.29 Hz), 7.78 (2 H, d, J=8.31 Hz) | |
99% | With sodium hydroxide; In 2-methyltetrahydrofuran; water; at 30 - 35℃; for 18h; | Step 2: Synthesis of B-3Prepared as described by adaptation of the following literature reference:Radziszewski, J.G. et al. J. Am. Chem. Soc. 1993, 115, 8401.To a solution of 97 g (810 mmol) of compound B-2 in 2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aqueous NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2- methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35 C for 18 h. The suspension is poured into a mixture of ice-water (280 mL) and aqueous HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L).Drying under reduced pressure at 40 C gave 216 g of compound B-3 as white crystalline solid. Yield: 99%, ES-MS: m/z 271 [M+H]; *H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.19 - 1.35 (2 H, m), 1.54 - 1.63 (2 H, m), 1.85 - 2.02 (1 H, m), 2.45 (3 H, s), 3.28 - 3.39 (2 H, m), 3.86 (2H, d, J=6.60 Hz), 3.93 (2 H, dd, J=l 1.37, 4.52 Hz), 7.35 (2 H, d, J=9.29 Hz), 7.78 (2 H, d, J=8.31 Hz) |
99% | With sodium hydroxide; In 2-methyltetrahydrofuran; water; methyl cyclohexane; at 30 - 35℃; for 18h; | Prepared as described by adaptation of the following literature reference: Radziszewski, J. G. et al. J. Am. Chem. Soc. 1993, 115, 8401. To 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in 2-methyltetrahydrofuran (190 mL) are added 165 mL of 50% aq. NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1.46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35 C. for 18 h. The suspension is poured into a mixture of ice-water (280 mL) and aq. HCl solution (37%, 203 mL). After addition of methylcyclohexane (1.4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40 C. gave 216 g of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. Yield: 99%; ESI-MS: 271 [M+H]+ |
99% | With sodium hydroxide; In 2-methyltetrahydrofuran; water; at 30 - 35℃; for 18h; | Prepared as described by adaptation of the following literature reference: Radziszewski, J.G. et al. J. Am. Chem. Soc. 1993, 115, 8401 . To 97 g (810 mmol) of (tetrahydro-pyran-4-yl)-methanol in 2- methyltetrahydrofuran (190 mL) are added 165 mL of 50% aq. NaOH solution. To this stirred suspension is added dropwise with cooling a solution of p-toluene-sulfonylchloride (283 g, 1 .46 mol) in 2-methyltetrahydrofuran (280 mL). The reaction is stirred at 30-35 C for 18h. The suspension is poured into a mixture of ice-water (280 mL) and aq. HCI solution (37%, 203 mL). After addition of methylcyclohexane (1 .4 L) and further ice-water (0.2 L), the reaction mixture is stirred for 2 h in an ice-bath. The resulting crystalline precipitate is isolated by filtration and washed with methylcyclohexane (0.5 L) and water (0.5 L). Drying under reduced pressure at 40 C gave 216 g of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. Yield: 99%; ESI-MS: 271 [M+H]+ |
91% | Step 1 a Synthesis of Tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate To a stirred solution of (tetrahydro-2H-pyran-4-yl)methanol (300 mg, 2.58 mM) in DCM (5 ml), triethyl amine (784 mg, 7.75 mM) was added. The reaction mixture was stirred for 5 min at 0 QC followed by the addition of 4-methylbenzene-1 -sulfonyl chloride (542 mg, 2.84 mM). The reaction mixture was further stirred for 2h. RM, concentrated and purified by column chromatography to afford the title compound tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (634 mg). Yield: 91 %; 1 H NMR (CDCI3, 300 MHz): delta 7.81 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 3.97-3.86 (m, 4H), 3.36 (t, J=6.5 Hz, 2H), 2.47 (s, 3H), 1 .97-1 .94 (m, 1 H), 1 .62 (d, J=12 Hz, 2H), 1 .35-1 .23 (m, 2H), MS: m/z 293 (M+Na). | |
91% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 1h; | TsCl (7.22 g, 37.9 mmol) was added portionwise to a solution of alcohol (9) (4.0 g, 34.44 mmol), Et3N(7.0 g, 69 mmol) and DMAP (0.05 g, 0.35 mmol) in dry DCM (50 mE) at 00 C. The reaction mixture was allowed to warm to room temperature and thrther stirred for 1 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (10) as white solid. Yield (8.5 g, 91%); 1H NMR (400 MHz, DMSO-d5) delta 7.78 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.0 Hz, 2H), 3.87 (d, J=6.4 Hz, 2H), 3.78 (dd, J=11.2, 4.2 Hz, 2H), 3.22 (dt, J=11.6, 1.6 Hz, 2H), 2.42 (s, 3H),1.88-1.79 (m, 1H), 1.46 (dd, J=12.8, 1.6 Hz, 2H), 1.18-1.07 (m, 2H). |
78% | With pyridine;dmap; In dichloromethane; at 20℃; for 16h; | To a solution of (tetrahydro-2H-pyran-4-yl)methanol (5.0 g, 43.0 mmol) in CH2Cl2 (40 mL) and pyridine (30 mL) was added 4-(dimethylamino)pyridine (0.26 g, 2.2 mmol) followed by p-toluenesulfonyl chloride (8.2 g, 43.0 mmol). The mixture was allowed to stir at ambient temperature for 16 hours then was quenched with 5% aqueous HCl (15 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (9.1 g, 33.7 mmol, 78% yield). MS (DCI/NH3) m/z 288 (M+NH4)+ |
76% | With dmap; In dichloromethane; at 25℃; | [0217] A solution of (tetrahydro-pyran-4-yl)-methanol (1.0 g, 8.61 mmol, prepared according to WO 99/00385) in methylene chloride (30 mL) at 25 C. was treated with 4-(dimethylamino)pyridine (1.17 g, 9.47 mmol) and p-toluenesulfonyl chloride (1.64 g, 8.61 mmol) and then was allowed to stir at 25 C. overnight. The reaction was then transferred to a separatory funnel and washed with a 1N aqueous hydrochloric acid solution (10 mL), a saturated aqueous sodium bicarbonate solution (10 mL), and a saturated aqueous sodium chloride solution (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75/25 hexanes/ethyl acetate) afforded toluene-4-sulfonic acid tetrahydro-pyran-4-yl methyl ester (1.77 g, 76%) as a colorless oil. [0218] A solution of toluene-4-sulfonic acid tetrahydro-pyran-4-yl methyl ester (1.77 g, 6.55 mmol) and sodium iodide (2.85 g, 18.99 mmol) in acetone (26 mL) was heated to 60 C. for 16 h. The resulting suspension was then cooled to 10 C. and filtered. The salts were rinsed with cold acetone (5 mL), and the filtrate and washings were concentrated in vacuo to a thick slurry. This slurry was treated with methylene chloride (10 mL). The resulting precipitate was removed by filtration and was washed with methylene chloride (10 mL). The filtrate and washings were then dried over magnesium sulfate, filtered through a pad of silica gel, and then concentrated in vacuo to afford 4-iodomethyl-tetrahydro-pyran as a light yellow oil. [0219] A solution of diisopropylamine (0.33 mL, 2.38 mmol) in tetrahydrofuran (6 mL) cooled to -78 C. under an argon atmosphere was treated with a 2.5M solution of n-butyllithium in hexanes (0.95 mL, 2.38 mmol). The reaction mixture was stirred at -78 C. for 15 min, after which time, a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 500 mg, 2.17 mmol) in tetrahydrofuran (1 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was slowly added via a cannula. The greenish yellow solution was allowed to stir at -78 C. for 1 h, after which time, a solution of 4-iodomethyl-tetrahydro-pyran (588 mg, 2.60 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25 C., where it was stirred for 16 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL). This solution was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with a 10% aqueous sulfuric acid solution (2×50 mL) and a saturated aqueous sodium bicarbonate solution (2×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (431 mg, 61%) as a yellow oil: EI-HRMS m/e calcd for C16H21ClO3S (M+) 328.0900, found 328.0898. [0220] A solution of 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (200 mg, 0.61 mmol) in formic acid (0.23 mL) and tetrahydrofuran (0.5 mL) cooled to 0 C. was treated with a 30% aqueous hydrogen peroxide solution (0.35 mL, 3.04 mmol). The reaction was slowly warmed to 25 C. where it was stirred for 16 h. The reaction mixture was then cooled to 0 C., quenched with a saturated aqueous sodium sulfite solution, and then extracted with ethyl acetate (3×20 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 60/40 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (190 mg, 87%) as a colorless oil: (ES)+-HRMS m/e calcd for C16H21ClO5S (M+Na)+ 383.0690, found 383.0692. [0221] A |
52% | With sodium hydroxide; In tetrahydrofuran; water; at 20℃; | Step 1 [0339] (Tetrahydro-2H-pyran-4-yl)methanol (1.00g, 8.61 mmol) was dissolved in THF (3.0 mL), a solution of sodium hydroxide (0.689 g, 17.2 mmol) dissolved in water (0.69 mL) and a solution of p-toluenesulfonyl chloride (3.28 g, 17.2 mmol) dissolved in THF (3.0 mL) were added thereto, and the mixture was stirred at room temperature overnight. Then, 12 mol/L hydrochloric acid (2.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane/ethyl acetate = 80/20 to 50/50), whereby (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (1.22 g, yield 52%) was obtained. 1H NMR (300 MHz, CDCl3, delta): 7.82-7.76 (m, 2H), 7.37-7.33 (m, 2H), 3.98-3.90 (m, 2H), 3.86 (d, J = 6.6 Hz, 2H), 3.34 (td, J = 11.7, 2.2 Hz, 2H), 2.46 (s, 3H), 2.01-1.87 (m, 1H), 1.61-1.56 (m, 2H), 1.30-1.24 (m, 2H) |
47% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; | To a ooc solution of (tetrahydro-2H-pyran-4-yl)methanol (1.1 g, 9.47mmol) in anhydrous DCM was added DMAP (-3 mg, cat.) and TEA (1.9 g, 18.94 mmol),followed by TsCI (1.8 g, 9.5mmol). The mixture was stirred at room temperature overnight.The solvent was removed and the residue purified by flash chromatography (silica gel, 0-40% ethyl acatate in petroleum ether) to afford tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (1.2 g, yield,47%) as a white solid.LCMS (ESI) m/z: 271.17 (M +1t. |
35% | With dmap; triethylamine; In dichloromethane; at 0 - 20℃; for 24h; | 3.1.22a (1 g, 8.62 mmol, 1.0 equiv) was dissolved in dichloromethane (20 mL), TEA (4.36 g, 43.1 mmol, 5.0 equiv), DMAP (0.21 g, 1.72 mmol, 0.2 equiv) were added and cooled toO C. 4-methylbenzenesulfonyl chloride (2.46 g, 12.9 mmol, 1.5 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The crude residue was purified by silica gel column chromatography (30-35 % EtOAc/Hexane) to afford the desired product 3.1.22b (0.8 g, 35 % yield). LCMS (mlz): 271.1 [M+H]. 1H NMR (400 MHz, DMSO) 6 7.80 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 3.89 (dd, J = 11.9, 6.4 Hz, 2H), 3.80 (dd, J = 14.4, 6.9 Hz, 2H), 3.24 (dd, J = 22.0, 12.0 Hz, 2H), 2.43 (s, 3H), 1.90-1.71 (m, 2H), 1.51 (dd, J= 31.2, 12.6 Hz, 3H). |
With pyridine; In dichloromethane; at 20℃; for 16.25h; | Example 203A (tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate To a solution of tetrahydro-2H-pyran-4-ylmethanol (Combi-Blocks, 2.0 g, 17.2 mmol) in 10 mL of of CH2Cl2 and 10 mL of of pyridine was added p-toluenesulfonyl chloride (3.5 g, 18.1 mmol) in portions over 15 minutes. The mixture stirred at ambient temperature for 16 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 10 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) delta ppm 1.05-1.25 (m, 2 H), 1.40-1.53 (m, 2 H), 1.73-1.94 (m, 1 H), 2.43 (s, 3 H), 3.14-3.28 (m, 2 H), 3.71-3.84 (m, 2 H), 3.88 (d, J=6.4 Hz, 2 H), 7.48 (d, J=8.5 Hz, 2 H), 7.79 (d, J=8.5 Hz, 2 H); MS (DCI/NH3) m/z 288 (M+NH4)+. | |
With pyridine; In dichloromethane; at 20℃; for 17h; | I: Toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester Intermediate p-Toluenesulfonyl chloride (29.8 g, 157 mmol) was added portionwise to a mixture of tetrahydro-2H-pyran-4-yl-methanol (20.0 g, 172 mmol) and pyridine (25.2 ml, 313 mmol) in dichloromethane (200 ml). The mixture was stirred at room temperature for 17 h, then quenched with aqueous hydrochloric acid (2 M; 100 ml). The layers were separated and the aqueous layer extracted 2 with dichloromethane (2*100 ml). The organic layers were combined and concentrated in vacuo. Recrystallisation from dichloromethane:n-heptane (5:1) afforded toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. The mother liquors were further purified by silica gel column chromatography eluding with 50% dichloromethane in n-heptane to yield a further quantity of toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester (total yield 41.6 g, 154 mmol). | |
With dmap; triethylamine; In dichloromethane; | EXAMPLE 85b; Preparation of intermediate toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester; At room temperature, a mixture of (tetrahydro-pyran-4-yl)-methanol (2.4 g, 20.7 mmol), p-toluenesulfonyl chloride (6.73 g, 35.4 mmol), triethylamine (6.6 mL, 47.6 mmol) and DMAP (0.288 g, 2.36 mmol) in DCM (50 mL) was stirred overnight. The solution was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound as an oil (4.2 g). | |
With pyridine; In dichloromethane; at 20℃; for 16.25h; | To a solution of tetrahydro-2H-pyran-4-ylmethanol (Combi-Blocks, 2.0 g, 17.2 mmol) in 10 mL of of CH2CI2 and 10 mL of of pyridine was added p- toluenesulfonyl chloride (3.5 g, 18.1 mmol) in portions over 15 minutes. The mixture stirred at ambient temperature for 16 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 10 mL portions OfCH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) delta ppm 1.05 - 1.25 (m, 2 H), 1.40 - 1.53 (m, 2 H), 1.73 - 1.94 (m, 1 H), 2.43 (s, 3 H), 3.14 - 3.28 (m, 2 H), 3.71 - 3.84 (m, 2 H), 3.88 (d, J=6.4 Hz, 2 H), 7.48 (d, J=8.5 Hz, 2 H), 7.79 (d, J=8.5 Hz, 2 H); MS (DCI/NH3) m/z 288 (M+NH4)+ | |
With pyridine; In dichloromethane; at 20℃; for 17h; | I: Toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester intermediate p-Toluenesulfonyl chloride (29.8 g, 157 mmol) was added portionwise to a mixture of tetrahydro-2/-/-pyran-4-yl-methanol (20.0 g, 172 mmol) and pyridine (25.2 ml, 313 mmol) in dichloromethane (200 ml). The mixture was stirred at room temperature for 17 h, then quenched with aqueous hydrochloric acid (2 M; 100 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2 x 100 ml). The organic layers were combined and concentrated in vacuo. Recrystallisation from dichloromethane: n-heptane (5:1 ) afforded toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. The mother liquors were further purified by silica gel column chromatography eluting with 50% dichloromethane in n-heptane to yield a further quantity of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (total yield 41.6 g, 154 mmol). | |
I: Toluene-4-sulfonic acid tetrahydropyran-4-ylmethyl ester intermediate p-Toluenesulfonyl chloride (29.8 g, 157 mmol) was added portionwise to a mixture of tetrahydro-2H-pyran-4-yl-methanol (20.0 g, 172 mmol) and pyridine (25.2 ml, 313 mmol) in dichloromethane (200 ml). The mixture was stirred at room temperature for 17 h, then quenched with aqueous hydrochloric acid (2 M; 100 ml). The layers were separated and the aqueous layer extracted with dichloromethane (2*100 ml). The organic layers were combined and concentrated in vacuo. Recrystallisation from dichloromethane: n-heptane (5:1) afforded toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester. The mother liquors were further purified by silica gel column chromatography eluding with 50% dichloromethane in n-heptane to yield a further quantity of toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester (total yield 41.6 g, 154 mmol). |
Yield | Reaction Conditions | Operation in experiment |
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91% | With 1,4-diaza-bicyclo[2.2.2]octane; In dichloromethane; at 20℃; for 1h;Cooling with ice; | General procedure: In an ice bath, to a solution of commercially purchased compound 28-d (1.72 g, 10 mmol) and DAI3CO (2.24g, 20 mmol) in dichloromethane (30 mE) was added slowly TsC1 (2.86 g, 15 mmol). The reaction solution was warmed to normal temperature and stirred for about 1 hour, followed by washing with 2N HC1 solution (30 mE), water (30 mE) and saturated solution of sodium bicarbonate (30 mE) in sequence. The organic phase was dried over anhydrous sodium sulphate and concentrated. The crude product was purified with silica column chromatograph (petroleum ether ethyl acetate10/1 -3/1) to give 28-c (2.94 g, 90%) which was white solid. EC-MS (ESI): m/z344.1 (M+NH4). |
Yield | Reaction Conditions | Operation in experiment |
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With tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 85℃; for 24h; | Example 203B 5-methyl-3-((tetrahydro-2H-pyran-4-yl)methyl)thiazol-2(3H)-imine A mixture of Example 203A (1.9 g, 7.0 mmol), 2-amino-5-methylthiazole (0.80 g, 7.0 mmol) and tetrabutylammonium iodide (1.3 g, 3.5 mmol) in 3 mL of N,N-dimethylformamide was warmed to 85 C. and was allowed to stir for 24 hours. The mixture was diluted with 10 mL of CH2Cl2, washed with 10% aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 10% methanol in ethyl acetate then 9:1:0.1 CH2Cl2:methanol:NH4OH) afforded the title compound. MS (DCI/NH3) m/z 213 (M+H)+. | |
With tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 85℃; for 24h; | A mixture of Example 203A (1.9 g, 7.0 mmol), 2-amino-5-methylthiazole (0.80 g, 7.0 mmol) and tetrabutylammonium iodide (1.3 g, 3.5 mmol) in 3 mL of N,N- dimethylformamide was warmed to 85 0C and was allowed to stir for 24 hours. The mixture was diluted with 10 mL OfCH2Cl2, washed with 10% aqueous NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 10% methanol in ethyl acetate then 9:1 :0.1 CH2Cl2 : methanol : NH4OH) afforded the title compound. MS (DCI/NH3) m/z 213 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
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14% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | 2-(6-(1 ,4-Diazepan-1-yl)-2-(4-fluoro-3-methoxyphenyl)-4-oxoquinazolin-3(4/-/)-yl)-lambda/- isopropylacetamide (EXAMPLE 1 i) (30 mg, 0.064 mmol), (tetrahydro-2/-/-pyran-4-yl)methyl 4-methylbenzenesulfonate (35 mg, 0.128 mmol) and DIPEA (17 mg, 21 mul, 0.128 mmol) were dissolved in DMF (1 ml_) and stirred at room temperature overnight. Purification by preparative HPLC afforded 2-{2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-[4-(tetrahydropyran-4- ylmethy^perhydro-IA-diazepin-i-ylJ^H-quinazolin-S-ylj-N-isopropylacetamide (EXAMPLE 11a) (5 mg, 0.0088 mmol, 14%).Data for 2-{2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-[4-(tetrahydropyran-4-ylmethyl) perhydro- 1,4-diazepin-1-yl]-4H-quinazolin-3-yl}-N-isopropylacetamide (EXAMPLE 11a): MS (ESI) m/z: |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 24h; | 3- {2- [5-Chloro-2- (hydroxy)-phenyi]-5-methyl-pyrrol-1-yl}-benzoic acid ethyl ester (27mg) was heated in DMF at [60C] with potassium carbonate (25mg) and toluene-4-sulfonic acid [TETRAHYDRO-PYRAN-4-YL-METHYL] ester (21 mg) for 24 hours. The mixture was then diluted with [ET20] and water. The organic phase was separated, dried (Na2SO4), filtered and concentrated to give the title compound (27mg). LC/MS t=3.98 min [MH+] 454,456. |
Yield | Reaction Conditions | Operation in experiment |
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A mixture of methyl 6-(5'-bromo-2'-hydroxy-2-biphenylyl)-2-pyridinecarboxylate (200mg, 0.52mmol), tetrahydro-2H-pyran-4-ylmethyl-4-methylbenzene sulphonate (430mg, 1.5mmol) and potassium cabonate (200mg) in dimethylformamide (4ml) was heated to reflux for 3 hours under nitrogen. The reaction mixture was then filtered through celite, washed with ethyl acetate (10mls) and evaporated to an oil which was flash chromatographed eluting with diethyl ether/isohexane (1/5). The product was dissolved in methanol (10ml), treated with 2N sodium hydroxide (2ml) and heated at 70C for 15min. The solution was evaporated and partitioned between water and ethyl acetate. After drying with anhydrous sodium sulphate the ethyl acetate solution was evaporated to give the title compound (130mg). LC/MS [M+H] 470.3, 471.4, Rt=3.65min. |
Yield | Reaction Conditions | Operation in experiment |
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With caesium carbonate; In N,N-dimethyl-formamide; at 90℃; | Reference Example 4: Synthesis of 7-[4-(tetrahydropyran-4-ylmethoxy)phenyl]-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine 7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylamine (the compound obtained in Reference Example 3; 295 mg) was dissolved in N,N-dimethylformamide (8 ml). Thereafter, tetrahydropyran-4-ylmethyl p-toluenesulfonate (460 mg) and cesium carbonate (556 mg) were added to the obtained solution, and the obtained mixture was stirred at 90C overnight. After the reaction solution was cooled to a room temperature, distilled water (18 ml) was added thereto. The generated precipitate was collected by filtration, and the obtained product was then washed by successive suspension in a 20% ethanol solution, ethanol, and acetone to obtain the captioned compound (310 mg). |
Yield | Reaction Conditions | Operation in experiment |
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PREPARATION 45 (Tetrahydropyran-4-yl)-methyl p-toluenesulfonate (Formula K-3) Refer to Chart K To a cold (0), stirred solution of 5 mmol of the title compound of Preparation 44 and 0.81 ml of pyridine in 5 ml of dichloromethane is added 1.05 g of p-toluenesulfonyl chloride, and the solution is allowed to warm to room temperature. After 18 hours the mixture is partitioned between ethyl acetate and dilute aqueous hydrochloric acid, and the organic phase is washed with brine and dried over magnesium sulfate. Following removal of solvent under reduced pressure, the residue is flash chromatographed on silica using 50% ethyl acetate in hexane to afford 1.23 g of the title compound as a colorless liquid. Physical characteristics are as follows: 1 H NMR delta1.2-1.4, 1.6, 1.9-2.0, 2.46, 3.34, 3.85, 3.95, 7.3, 7.8 ppm. MS: 270 |
Yield | Reaction Conditions | Operation in experiment |
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Step B: 7-Chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid To a solution of 7-chloro-1H-indole-3-carboxylic acid (7.5 g, 38.0 mmol) in dimethyl-formamide (100 ml) at 10 C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 3.1 g, 76.0 mmol) portionwise over 10 mins, maintaining the temperature below 15 C. The cooling bath was removed and the suspension stirred for 90 mins. Toluene-4-sulfonic acid tetrahydropyran-4-ylmethylester (14.6 g, 53.0 mmol) was added. The mixture was heated at 50 C. with stirring for 6 h. Dimethylformamide was removed by evaporation and the residue was dissolved in water (500 ml). The emulsion was washed with dichloromethane (2*100 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 7-chloro-1-(tetrahydropyran-4-yl)methyl-1H-indole-3-carboxylic acid (15.0 g, 51.0 mmol) as a white solid. | ||
Step B: 1 -(Tetrahvdropyran-4-yl)methyl-7-chloro-1 /-/-indole-3-carboxylic acid To a solution of 7-chloro-1 /-/-indole-3-carboxylic acid (7.5 g, 38.0 mmol) in di- methylformamide (100 ml) at 10 C under nitrogen was added sodium hydride (60% dispersion in mineral oil, 3.1 g, 76.0 mmol) portionwise over 10 mins, maintaining the temperature below 15 C. The cooling bath was removed and the suspension stirred for 90 mins. Toluene-4-sulfonic acid tetrahydopyran-4-ylmethylester (14.6 g, 53.0 mmol) was added. The mixture was heated at 50 C with stirring for 6 h. Dimethylformamide was removed by evaporation and the residue was dissolved in water (500 ml). The emulsion was washed with dichloromethane (2 x 100 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 1-(tetrahydropyran-4- yl)methyl-7-chloro-1 /-/-indole-3-carboxylic acid (15.0 g, 51.0 mmol) as a white solid. | ||
Step B: 1-(Tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid To a solution of 7-chloro-1H-indole-3-carboxylic acid (7.5 g, 38.0 mmol) in dimethylformamide (100 ml) at 10 C. under nitrogen was added sodium hydride (60% dispersion in mineral oil, 3.1 g, 76.0 mmol) portionwise over 10 mins, maintaining the temperature below 15 C. The cooling bath was removed and the suspension stirred for 90 mins. Toluene-4-sulfonic acid tetrahydopyran-4-ylmethylester (14.6 g, 53.0 mmol) was added. The mixture was heated at 50 C. with stirring for 6 h. Dimethylformamide was removed by evaporation and the residue was dissolved in water (500 ml). The emulsion was washed with dichloromethane (2*100 ml). The aqueous phase was acidified to pH 1 using 5 M hydrochloric acid and the precipitate filtered off, washed with water to neutrality and dried to afford 1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid (15.0 g, 51.0 mmol) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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Tetrahydropyran-4-yl-carboxylic acid (207mg, 1. [59MMOL)] was dissolved in THF (3.2mL). 1 M borane-THF (3.2mL) was added and the mixture was stirred at room temperature for 6 hours, after which time water was added. The mixture was extracted twice with EtOAc. The combined extracts were dried [(NA2SO4),] filtered and concentrated. The residue was dissolved in DCM-pyridine (1: 1,3. 2mL). [TOSYL] chloride (327mg, 1. 71mmol) was added to this solution. Stirring was continued overnight, after which time the mixture was diluted with DCM and washed sequentially with 2M HCI and saturated NaHCO3, dried [(NA2SO4),] filtered and concentrated. The residue was purified on silica gel with iso-hexane containing EtOAc (20%), as eluant, to give the title compound (66mg). Rf 0.49 (50% EtOAc in iso-hexane). 'H NMR [(400MHZ,] [CDCI3)] 1.17 (2H, m's excess), 1.51-1. 66 (2H, m's excess), 1.86-2. 01 (1 H, m), 2.47 (3H, s), 3.34 (2H, t, [J=12HZ),] 3.86 (2H, d, J=6Hz), 3.95-4. 00 (2H, m), 7.35 (2H, d, J=8Hz), 7.78 (2H, d, J=8Hz). |
Yield | Reaction Conditions | Operation in experiment |
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0.998 mmol of NaH (60% dispersion in oil) are added to a solution of 0.832 mmol of (3S,4S)-4-hydroxy-4-[4-(2-methoxy-ethoxymethyl)-phenyl]-3-[4-(3-nnethoxy-propyl)- 3,4-dihydro-2H-benzo[1 ,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1 b) in 2 ml of DMF. The mixture is stirred at 400C for 25 min, then a solution of 1.248 mmol of <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> [101691-65-0] in 1 ml of DMF is added. The reaction mixture is stirred at 400C for 24 h then 0.2 mmol of <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> and 0.45 mmol of NaH (60% dispersion in oil) are added. The reaction mixture is stirred at 40C for 60 h an is then cooled to RT. The mixture is diluted with TBME (100 ml), washed successively with aqueous saturated NaHCO3 (20 ml) and brine (20 ml), dried over Na2SO4 and evaporated under reduced pressure. The title compound is obtained from the residue by flash chromatography (SiO2 60F) as a colorless solid. Rf (EtOAc/heptane 1 :1 ) = 0.21 ; Rt = 5.57 (gradient I). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; | EXAMPLE 85c; Preparation of intermediate 5-chloro-2-(tetrahydro-pyran-4-yl-methoxy)-benzaldehyde; A mixture of 5-chlorosalicylaldehyde (5.0 g, 32 mmol), <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> (8.6 g, 32 mmol) and K2CO3 (9.5 g, 68.8 mmol) in DMF (50 mL) was heated at 75 C. overnight. After cooled to room temperature, the mixture was poured into water. The aqueous phase was extracted with EtOAc twice. The combined organic phases were washed with water and brine, dried and concentrated. The residue was purified by column chromatography to give the title compound (7.0 g). |
Yield | Reaction Conditions | Operation in experiment |
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96% | In 4-methyl-2-pentanone; at 70℃; for 4.5h; | Step 3: Synthesis of Thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester; Prepared as described by adaptation of the following literature reference:Watson, R. J. et al. Tetrahedron Lett. 2002, 43, 683-685.To a solution of 224 g (0.83 mol) of <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70 C. for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through celite (20 g), activated charcoal (20 g) and Na2SO4 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl)ester as a yellow-orange oil (CAUTION: Stench.). Yield: 96%; ES-MS: m/z 175 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.23-1.40 (2H, m), 1.59-1.78 (3H, m), 2.33 (3H, d, J=4.16 Hz), 2.82 (2H, dd, J=6.24, 3.79 Hz), 3.27-3.39 (2H, m), 3.88-4.02 (2H, m) |
96% | In 4-methyl-2-pentanone; at 70℃; for 4.5h; | To a solution of 224 g (0.83 mol) of Compound 7 in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70 C. for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through Celite (20 g), activated charcoal (20 g) and Na2SO4 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of Compound 8 as a yellow-orange oil. Yield: 96%; ES-MS: m/z 175 [M+H]; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.23-1.40 (2H, m), 1.59-1.78 (3H, m), 2.33 (3H, d, J=4.16 Hz), 2.82 (2H, dd, J=6.24, 3.79 Hz), 3.27-3.39 (2H, m), 3.88-4.02 (2H, m). |
96% | In 4-methyl-2-pentanone; at 70℃; for 4.5h; | Step 3: Synthesis of Thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester Prepared as described by adaptation of the following literature reference:Watson, R.J. et al. Tetrahedron Lett. 2002, 43, 683-685. To a solution of 224 g (0.83 mol) of toluene-4- sulfonic acid tetrahydro-pyran-4-ylmethyl ester in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70 C for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through celite (20 g), activated charcoal (20 g) and Na2S04 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester as a yellow-orange oil (CAUTION: Stench.). Yield: 96%; ES-MS: m/z 175 [M+H]; 1H NMR (400 MHz,CHLOROFORM-d) delta ppm 1.23 - 1.40 (2 H, m), 1.59 - 1.78 (3 H, m), 2.33 (3 H, d, 7=4.16 Hz), 2.82 (2 H, dd, 7=6.24, 3.79 Hz), 3.27- 3.39 (2 H, m), 3.88 - 4.02 (2 H, m) |
96% | In 4-methyl-2-pentanone; at 70℃; for 4.5h; | Step 3: Synthesis of Compound B4Prepared as described by adaptation of the following literature reference:Watson, RJ. et al. Tetrahedron Lett. 2002, 43, 683-685.To a solution of 224 g (0.83 mol) of compound B3 in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70 C for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through celite (20 g), activated charcoal (20 g) and Na2S04 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n- heptanes (250 mL) to afford 138 g of compound B4 as a yellow-orange oil (CAUTION: Stench.). Yield: 96%; ES-MS: m/z 175 [M+H]; ]H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.23 - 1.40 (2 H, m), 1.59 - 1.78 (3 H, m), 2.33 (3 H, d, 7=4.16 Hz), 2.82 (2 H, dd, 7=6.24, 3.79 Hz), 3.27- 3.39 (2 H, m), 3.88 - 4.02 (2 H, m) |
96% | In 4-methyl-2-pentanone; at 70℃; for 4.5h; | Step 3: Synthesis of B-4Prepared as described by adaptation of the following literature reference:Watson, R.J. et al. Tetrahedron Lett. 2002, 43, 683-685. To a solution of 224 g (0.83 mol) of compound B-3 in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The beige suspension is stirred at 70 C for 4.5 h. The reaction mixture is cooled to room temperature and water (1.8 L) is added. The organic layer is washed with 10% aqueous K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through celite (20 g), activated charcoal (20 g) and Na2S04 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of compound B-4 as a yellow-orange oil (CAUTION: Stench.). Yield: 96%; ES-MS: m/z 175 [M+H]; *H NMR (400 MHz, CHLOROFORM-d) delta ppm 1.23 - 1.40 (2 H, m), 1.59 - 1.78 (3 H, m), 2.33 (3 H, d, 7=4.16 Hz), 2.82 (2 H, dd, 7=6.24, 3.79 Hz), 3.27- 3.39 (2 H, m), 3.88 - 4.02 (2 H, m) |
96% | at 70℃; for 4.5h; | Prepared as described by adaptation of the following literature reference: Watson, R. J. et al. Tetrahedron Lett. 2002, 43, 683-685. To 224 g (0.83 mol) of <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> in methyl isobutylketone (1.6 L) are added 189 g (1.66 mol) of potassium thioacetate. The suspension is stirred at 70 C. for 4.5 h. The reaction mixture is cooled to RT and water (1.8 L) is added. The organic layer is washed with 10% aq. K2CO3 solution (1.8 L) and water (1 L). The organic layer is filtered through Celite (20 g), activated charcoal (20 g) and Na2SO4 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of thioacetic acid S-(tetrahydro-pyran-4-ylmethyl) ester. Yield: 96%; ESI-MS: 175 [M+H]+ |
96% | at 70℃; for 4.5h; | Prepared as described by adaptation of the following literature reference: Watson, R.J. et al. Tetrahedron Lett. 2002, 43, 683-685. To 224 g (0.83 mol) of <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> in methyl isobutylketone (1.6 L) are added 189 g (1 .66 mol) of potassium thioacetate. The suspension is stirred at 70 C for 4.5 h. The reaction mixture is cooled to RT and water (1 .8 L) is added. The organic layer is washed with 10% aq. K2C03 solution (1.8 L) and water (1 L). The organic layer is filtered through Celite (20 g), activated charcoal (20 g) and Na2S04 (20 g) and the filtrate is concentrated under reduced pressure. The residual oil is azeotroped with methylcyclohexane (200 mL) and n-heptanes (250 mL) to afford 138 g of thioacetic acid S-(tetrahydro-pyran-4- ylmethyl) ester. Yield: 96%; ESI-MS: 175 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
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65% | To a solution of Example 95A (9.1 g, 33.7 mmol) in EtOH (50 mL) was added hydrazine hydrate (3.3 mL, 67.3 mmol). The mixture was warmed to reflux (85 C.) and was allowed to stir for 20 hours. The mixture was cooled to ambient temperature then 4,4-dimethyl-3-oxopentanenitrile (8.4 g, 67.3 mmol) was added and the mixture was again warmed to reflux (85 C.) and was allowed to stir for 6 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (30 mL) and saturated aqueous NaHCO3 (20 mL) was added slowly. The layers were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) provided the title compound (5.2 g, 21.9 mmol, 65% yield). MS (DCI/NH3) m/z 238 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 45℃; for 15.5h;Inert atmosphere;Product distribution / selectivity; | To a solution of (3-bromo-4-fluoro-phenyl)-carbamic acid tert-butyl ester (300 mg, 1.03 mmol) and <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> (335 mg, 1.24 mmol) in DMF (4 mL) under argon was added sodium hydride (60 wt.%, 83 mg). The mixture was stirred at ambient temperature for 30 min and at 45 C for 15 hrs. The reaction mixture was cooled to room temperature and was diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (3-bromo-4-fluoro-phenyl)-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (320 mg) as yellow oil, which was directly used in the next step without purification. LCMS (m/z): 288/290 [M+H, loss of t-Bu]; Retention time = 1.11 min | |
With sodium hydride; In N,N-dimethyl-formamide; at 20 - 45℃; for 15.5h;Inert atmosphere; | To a solution of (3-bromo-4-fluoro-phenyl)-carbamic acid tert-butyl ester (300 mg, 1.03 mmol) and <strong>[101691-65-0]toluene-4-sulfonic acid tetrahydro-pyran-4-ylmethyl ester</strong> (335 mg, 1.24 mmol) in DMF (4 mL) under argon was added sodium hydride (60 wt.%, 83 mg). The mixture was stirred at ambient temperature for 30 min and at 45 C for 15 hrs. The reaction mixture was cooled to room temperature and was diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure providing crude (3-bromo-4-fluoro-phenyl)- (tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (320 mg) as yellow oil, which was directly used in the next step without purification. LCMS (m/z): 288/290 [M+H, loss of t-Bu]; Rt = 1.11 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of sodium hydride (60 wt.% in mineral oil, 15.74 mg) in DMF (0.7 mL) was added to a solution of tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (213 mg, 0.596 mmol) in DMF (0.70 mL) at 0 C. The resulting mixture was stirred at 0 C for 30 min. To this stirred mixture was then added (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (161 mg, 0.596 mmol) in one portion. The mixture was warmed to 40 C and maintained at this temperature for 16 hrs. The reaction mixture was diluted with EtOAc, washed with IN aqueous sodium hydroxide solution, water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by preparative TLC [silica gel, 1 mm; EtO Ac/heptane = 15/85] providing [2-chloro-5-(5-chloro-2-fluoro- pyridin-4-yl)-phenyl]-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (176 mg) as a colorless oil. LCMS (m/z): 355.0/356.9 [M+H, loss of t-Bu]; Retention time = 1.21 min. | ||
A mixture of sodium hydride (60 wt.% in mineral oil, 15.74 mg) in DMF (0.7 mL) was added to a solution of tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (213 mg, 0.596 mmol) in DMF (0.70 mL) at 0 C. The resulting mixture was stirred at 0 C for 30 min. To this stirred mixture was then added (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (161 mg, 0.596 mmol) in one portion. The mixture was warmed to 40 C and maintained at this temperature for 16 hrs. The reaction mixture was diluted with EtOAc, washed with 1 N aqueous sodium hydroxide solution, water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by preparative TLC [silica gel, 1 mm; EtOAc/heptane = 15/85] providing [2-chloro-5- (5-chloro-2-fluoro-pyridin-4-yl)-phenyl]-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (176 mg) as a colorless oil. LCMS (m/z): 355.0/356.9 [M+H, loss of t-Bu]; Rt = 1 .21 min. | ||
A mixture of sodium hydride (60 wt.% in mineral oil, 15.74 mg) in DMF (0.7 mL) was added to a solution of tert-butyl 2-chloro-5-(5-chloro-2-fluoropyridin-4- yl)phenylcarbamate (213 mg, 0.596 mmol) in DMF (0.70 mL) at 0 C. The resulting mixture was stirred at 0 C for 30 min. To this stirred mixture was then added<strong>[101691-65-0](tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate</strong> (161 mg, 0.596 mmol) in one portion. The mixture was warmed to 40 C and maintained at this temperature for 16 hrs. The reaction mixture was diluted with EtOAc, washed with IN aqueous sodium hydroxide solution, water and brine, dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by preparative TLC [silica gel, 1 mm; EtO Ac heptane = 15/85] providing [2-chloro-5-(5-chloro-2-fluoro- pyridin-4-yl)-phenyl]-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (176 mg) as a colorless oil. LCMS (m/z): 355.0/356.9 [M+H, loss of t-Bu]; Rt = 1.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (270 mg, 0.837 mmol) in DMF (3 rriL) was added slowly sodium hydride (60 wt.% in mineral oil, 40.1 mg) at 0 C. The ice bath was removed and the crude mixture was stirred for 20 min at room temperature. To the crude mixture was added <strong>[101691-65-0](tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate</strong> (271 mg, 1.004 mmol) and stirring was continued at 40 C for 40 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc (150 mL). The mixture was washed saturated aqueous sodium bicarbonate solution (2x), water (2x) and brine (lx), dried with sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 24 g, EtO Ac/heptane = 0/100 to 30/70] providing [3-(5-chloro-2- fluoro-pyridin-4-yl)-phenyl]-(tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (205 mg). LCMS (m/z): 421.2 [M+H]+; Retention time = 1.19 min. | ||
To tert-butyl 3-(5-chloro-2-fluoropyridin-4-yl)phenylcarbamate (270 mg, 0.837 mmol) in DMF (3 mL) was added slowly sodium hydride (60 wt.% in mineral oil, 40.1 mg) at 0 C. The ice bath was removed and the crude mixture was stirred for 20 min at room temperature. To the crude mixture was added <strong>[101691-65-0](tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate</strong> (271 mg, 1.004 mmol) and stirring was continued at 40 C for 40 hrs. The reaction mixture was cooled to room temperature and diluted with EtOAc (150 mL). The mixture was washed saturated aqueous sodium bicarbonate solution (2x), water (2x) and brine (lx), dried with sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [silica gel, 24 g, EtO Ac/heptane = 0/100 to 30/70] providing [3-(5-chloro-2-fluoro-pyridin-4-yl)-phenyl]- (tetrahydro-pyran-4-ylmethyl)-carbamic acid tert-butyl ester (205 mg). LCMS (m/z): 421.2 [M+H]+; Rt = 1.19 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To tert-butyl 5'-chloro-2'-fluoro-6-morpholino-3,4'-bipyridin-5-ylcarbamate (120 mg, 0.294 mmol) in DMF (1.8 ml) was added sodium hydride (60% in mineral oil, 14.09 mg, 0.352 mmol). The resulting mixture was stirred for 20 minutes at room temperature. Then to the mixture was added (tetrahydro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (95 mg, 0.352 mmol) and the reaction mixture was stirred at room temperature for 18 hours. To the resulting reaction mixture was added 50 ml of ethyl acetated. The mixture was then washed with saturated sodium bicarbonate (lx), water (2x) and brine (lx), dried with sodium sulfate, filtered and concentrated to give the crude intermediate which was used as is. To the intermediate was added 4M HC1 in dioxane (3 ml, 12.00 mmol) and the reaction mixture was stirred at room temperature for 1 hour. This mixture was concentrated to dryness, dissolved in DMSO, filtered and purified by HPLC. After lyophilization, 50 mg of the title compound, as a TFA salt was obtained. LCMS (m/z): 407.1 (MH+), retention time = 0.75 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | To a scintillation vial containing 5-bromo-2-chloropyridin-3-amine (1.3 g, 6.27 mmol) was added DMF (20 ml) and NaH (0.301 g, 7.52 mmol). After 20 min stirring at room temperature, <strong>[101691-65-0](tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate</strong> (1.694 g, 6.27 mmol) was added. The reaction mixture was stirred at room temperature for 58 hours. The reaction mixture was diluted with EtOAc and washed with H20 and brine. The organic layer was dried Na2S04, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel (22% EtOAc/Hexane) to yield 5-bromo- 2-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-3-amine (1.27g, 4.16 mmol, 66.3% yield) as brown oil. LCMS (m/z): 305.0 (MH+), retention time = 0.89 min. | |
A solution of 5-bromo-2-chloropyridin-3-amine (1.3 g, 6.27 mmol) in DMF (20 ml_) was added slowly sodium hydride (60 wt.% in mineral oil, 0.301 g) was stirred for 20 min, followed by addition of <strong>[101691-65-0](tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate</strong> (1.694 g, 6.27 mmol). The resulting reaction mixture was stirred at room temperature for 58 hrs, diluted with EtOAc, washed with water, brine, dried over sodium sulphate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane = 22/78) providing 5-bromo-2-chloro-N- ((tetrahydro-2H-pyran-4-yl)methyl)pyridin-3-amine (1.27 g). LCMS (m/z): 305.0 [M+H]+; Rt = 0.89 min. | ||
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 58h; | A solution of 5-bromo-2-chloropyridin-3-amine (1 .3 g, 6.27 mmol) in DMF (20 mL) was added slowly sodium hydride (60 wt.% in mineral oil, 0.301 g) was stirred for 20 min, followed by addition of <strong>[101691-65-0](tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate</strong> (1.694 g, 6.27 mmol). The resulting reaction mixture was stirred at room temperature for 58 hrs, diluted with EtOAc, washed with water, brine, dried over sodium sulphate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, EtOAc/hexane = 22/78) providing 5-bromo-2-chloro-N-((tetrahydro-2H-pyran-4- yl)methyl)pyridin-3-amine (1 .27 g). LCMS (m/z): 305.0 [M+H]+; Rt = 0.89 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To DMF (1.5 ml) was added NaH (60% in mineral oil, 46.1 mg, 1.152 mmol) and then 5-bromo-2-fluoropyridin-3 -amine (200 mg, 1.047 mmol). The reaction mixture was stirred at room temperature for 15 minutes. Then (tetrahy dro-2H-pyran-4-yl)methyl 4- methylbenzenesulfonate (283 mg, 1.047 mmol) was added and stirred at 40 C for 40 hours. The reaction was cooled to room temperature and 100 ml of ethyl acetate was added. The resulting mixture was washed with saturated sodium bicarbonate (2x), water (2x), brine, dried sodium sulfate, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (40g column eluting with 0-40% ethyl acetate in heptane). The desired fractions were concentrated to yield 104 mg of the title compound as free base. LCMS (m/z): 288.9/290.9 (MH+), retention time = 0.88 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49.2% | With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 50℃; for 4h; | Step 1 b Ethyl 2-(3-(4-((2',6'-dimethyl-4'-((tetrahydro-2H-pyran-4-yl)methoxy)-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate To a solution of ethyl 2-(3-(4-((4'-hydroxy-2',6'-dimethyl-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of Step 1 c of Example 39, 150 mg, 0.336 mM) and <strong>[101691-65-0](tetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate</strong> (136 mg, 0.504 mM, compound of Step 1 a) in anhydrous DMF (2 ml), cesium carbonate (219 mg, 0.672 mM) was added at RT and stirred at 50 QC for 2h. The reaction mixture was then stirred at RT for 2h. The reaction was quenched with the addition of water (5 ml), further stirred for 10 min and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash column chromatography (eluted with 40% ethyl acetate in n-hexane) to obtain the title compound, ethyl 2-(3-(4-((2',6'-dimethyl-4'-((tetrahydro-2H-pyran-4- yl)methoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (90 mg) as colorless oil. Yield: 49.2 %. 1 H NMR (CDCI3, 300 MHz): delta 7.47 -7.42 (m, 2H), 7.19 (s, 1 H), 7.1 1 (d s, J=8.7 Hz, 3H), 6.96 (d, J=8.7 Hz, 2H), 6.67 (s, 2 H), 5.1 1 (s, 2H), 5.00 (d, J=6.1 Hz, 2 H), 4.87 (d, J=6.1 Hz, 2 H), 4.05-3.57 (m, 4H), 3.84 (d, J=6.1 Hz, 2 H), 3.51 -3.44 9 (m, 3H), 3.10 (s, 2H), 2.00 (s, 6 H), 1 .82 (d, J=12.9 Hz, 2H), 1 .49- 1 .46 (m, 2 H), 1 .13 (t, J=8.7 Hz, 3H); MS: m/z 567 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.8% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | Example 71 Ethyl 2-(3-(4-((2'-chloro-4'-((tetrahydro-2H-pyran-4-yl)methoxy)-[1 ,r-biphenyl]-3-yl) methoxy)phenyl)oxetan-3-yl)acetate (Compound 71 ) To a stirred solution of ethyl 2-(3-(4-((2'-chloro-4'-hydroxy-[1 ,1 '-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of Example 60,100 mg, 0.221 mM) and (tetrahydro-2H-pyran-4-yl)methyl4-methylbenzenesulfonate (compound of Step 1 a of Example 42, 71 .6 mg, 0.265 mM) dissolved in DMF (5 ml), cesium carbonate (144 mg, 0.442 mM) was added and stirred at 60 QC for 2 h. The reaction mixture was quenched with water and extracted with ethyl acetate, concentrated and purified by column chromatography to obtain the title compound, ethyl 2-(3-(4-((2'- chloro-4'-((tetrahydro-2H-pyran-4-yl)methoxy)-[1 ,1 '-biphenyl]-3-yl)methoxy)phenyl) oxetan-3-yl) acetate (80 mg, 0.145 mM). Yield: 65.8 %; 1 H NMR (300 MHz, CDCI3,): delta 7.49-7.41 (m, 4 H), 7.26-7.25 (m, 1 H), 7.13 (d, J = 8.4 Hz, 2 H), 7.02 (bs, 1 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.89 (dd, J = 8.4 Hz, 2.5 Hz, 1 H), 5.1 1 (s, 2 H), 5.01 (d, J = 5.7 Hz, 2 H), 4.87 (d, J = 5.7 Hz, 2 H), 4.10-3.98 (m, 4 H), 3.86 (d, J = 5.7 Hz, 2 H), 3.47 (t, J = 1 1 .38 Hz, 2 H), 3.1 1 (s, 2 H), 1 .81 (d, J= 12.3 Hz, 2 H), 1 .58-1 .47 (m, 3 H), 1 .13 (t, J = 6.5 Hz, 3 H); MS: (m/z) 552 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h; | K2C03 (8.2 g, 59.2 mmol) was added to a stirred solution of methyl 3-hydroxybenzoate (11) (3.0 g, 19.72 mmol) sulfonate (10) (5.33 g, 19.72 mmol) in DMF (30 mE) and the reaction mixture was stirred at 90 C. for 16 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 30% EtOAc in hexanes) gave methyl 3-((tetrahydro- 2H-pyran-4-yl)methoxy)benzoate (12) as a light yellow solid. Yield (4.8 g, 97%); ?H NMR (400 MHz, DMSO-d5) oe 7.53 (d, J=7.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.22 (dd, J=8.4, 2.4 Hz, 1H), 3.88-3.82 (m, 7H), 3.32 (t, J=1 .2Hz, 2H), 2.02-1.96 (m, 1H), 1.69-1.66 (m, 2H), 1.38-1.28 (m, 2H). |
Tags: 101691-65-0 synthesis path| 101691-65-0 SDS| 101691-65-0 COA| 101691-65-0 purity| 101691-65-0 application| 101691-65-0 NMR| 101691-65-0 COA| 101691-65-0 structure
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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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