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CAS No. : | 26272-83-3 | MDL No. : | MFCD08544401 |
Formula : | C10H12O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UMFWNFVHKAJOSE-UHFFFAOYSA-N |
M.W : | 228.26 | Pubchem ID : | 13153907 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 54.17 |
TPSA : | 60.98 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.8 cm/s |
Log Po/w (iLOGP) : | 2.12 |
Log Po/w (XLOGP3) : | 1.26 |
Log Po/w (WLOGP) : | 2.18 |
Log Po/w (MLOGP) : | 1.16 |
Log Po/w (SILICOS-IT) : | 1.33 |
Consensus Log Po/w : | 1.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.15 |
Solubility : | 1.63 mg/ml ; 0.00713 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.14 |
Solubility : | 1.66 mg/ml ; 0.00726 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.8 |
Solubility : | 0.363 mg/ml ; 0.00159 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.55 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine In water at 20℃; for 18 h; | Scheme 613 Step 1 14 Step 2 15Step 1To a solution of 1.00 g (13.5 mmol) of compound 13 and 7.6 mL (54.0 mmol) of triethylamine in 27 mL of methylene chloride was added 5.15 g (27.0 mmol) of p- toluenesulfonyl chloride. The reaction mixture was stirred at room temperature overnight. After this time, the reaction was quenched with saturated 150 mL of aqueous sodium bicarbonate and extracted with three 50 mL portions of methylene chloride. The combined extracts were concentrated and the resulting residue was purified by column chromatography (silica, 0-25percent EtOAc/hexanes) to give 1.22 g (94percent) of 14 as white solid: NMR (CDCI3 500 MHz) δ 7.78 (d, J= 8.5 Hz, 2H), 7.36 (d, J= 9.0 Hz, 2H), 5.29 (m, 1H), 4.69 (m, 4H), 2.46 (s, 3H). |
85% | With sodium hydroxide In water at 0℃; for 3 h; | At 0° C., aqueous NaOH solution (2 N, 15 mL) was added dropwise to a solution of oxetan-3-ol (1.48 g, 20 mmol) and p-toluene sulfonyl chloride (4.18 g, 22 mmol) in water (50 mL). After stirred for 3 hours, the mixture was treated with water (100 mL), extracted with dichloromethane (100 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 39-c (3.9 g, yield: 85percent). LC-MS (ESI): m/z=229 [M+H]+. |
78% | at 20℃; Inert atmosphere | ;To a 50 mL two-neck flask were added oxetan-3-ol (1.00 g, 13.0 mmol) and anhydrous pyridine (25 mL), then paratoluensulfonyl chloride (3.10 g, 16.0 mmol) was added to the mixture under nitrogen protection. The reaction mixture was stirred at rt overnight. The reaction was mornitored by TLC until oxetan-3-ol consumed completely, then the mixture was concentrated in vacuo to remove pyridine. To the residue was added saturated brine (60 mL). The resulting mixture was extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated brine (30 mL*2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica-gel column chromatography (PE:EtOAc=10:1, V/V) to give a white solid (2.40 g, 78.0percent). MS(ESI, pos.ion)m/z:229.1 (M+1); |
65% | With sodium hydroxide In water at 50℃; for 1 h; | To a well-stirred 50° C. solution of Part D compound (7 g, 94 mmol) and p-TsCl (12.8 g, 67.1 mmol) in water (15 mL) was added dropwise a solution of NaOH (2.69 g, 67.1 mmol) in water (15 mL). The reaction was heated for 1 h at 50° C., then cooled to RT and toluene (10 mL) was added. The aqueous layer was extracted with toluene (5 mL.x.2). The combined organic extracts were washed with conc NH4OH (3.x.) and water (2.x.), then concentrated in vacuo. Hexane (50 mL) was added to the residue and a solid was formed, which was collected by filtration and then was dried in vacuo for 1 h to give Part E compound (10 g, 65percent yield) as a white solid. [M+H]+=229.1; 1H NMR (400 MHz, CDCl3) δ ppm 2.46 (s, 3 H), 4.64-4.75 (m, 4 H), 5.27-5.34 (m, 1 H), 7.37 (d, J=8.25 Hz, 2 H), 7.78 (d, J=8.25 Hz, 2 H). |
62% | at 20℃; for 18 h; | Preparation of toluene-4-sulfonic acid oxetan-3-yl ester; To a solution of oxetan-3-ol (1.0 g, 13.0 mmol) in anhydrous pyridine (25 ml_) at room temperature was added 4-toluene sulfonyl chloride (3.09 g, 16.2 mmol). After stirring the reaction mixture for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30percent ethyl acetate in heptane to afford 1.9 g (62percent yield) of the desired product as a white solid.1H NMR (400 MHz, chloroform-d) delta ppm 2.46 (s, 3 H), 4.63 - 4.75 (m, 4 H), 5.26 - 5.34 (m, 1 H), 7.36 (d, J=8.00 Hz, 2 H), 7.78 (d, J=8.40 Hz, 2 H). |
50% | With triethylamine In dichloromethane at 20℃; for 15 h; | Step 1: To a stirred mixture of oxetan-3-ol (0.85 g, 11.5 mmol) in DCM (38 mL) were added TEA (3.3 mL, 23mmol) and 4-methylbenzene-1-sulfonyl chloride (2.7 g, 13.8 mmol). The reaction mixture was stirred at rt for 15 h. Themixture was partitioned between water and DCM. The organic layer was separated, dried over Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradientof 30percent DCM in petroleum ether to 100percent DCM to afford oxetan-3-yl 4-methylbenzenesulfonate (1.3 g, 50percent) as a whitesolid. 1H NMR (300 MHz, CDCl3) δ 7.77 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 5.30 (m, 1H), 4.66 - 4.74 (m, 4H),2.46 (s, 3H); LCMS (ESI) m/z 229 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In water; at 20℃; for 18h; | Scheme 613 Step 1 14 Step 2 15Step 1To a solution of 1.00 g (13.5 mmol) of compound 13 and 7.6 mL (54.0 mmol) of triethylamine in 27 mL of methylene chloride was added 5.15 g (27.0 mmol) of p- toluenesulfonyl chloride. The reaction mixture was stirred at room temperature overnight. After this time, the reaction was quenched with saturated 150 mL of aqueous sodium bicarbonate and extracted with three 50 mL portions of methylene chloride. The combined extracts were concentrated and the resulting residue was purified by column chromatography (silica, 0-25% EtOAc/hexanes) to give 1.22 g (94%) of 14 as white solid: NMR (CDCI3 500 MHz) delta 7.78 (d, J= 8.5 Hz, 2H), 7.36 (d, J= 9.0 Hz, 2H), 5.29 (m, 1H), 4.69 (m, 4H), 2.46 (s, 3H). |
86% | With dmap; triethylamine; In dichloromethane; at 20℃; for 16h; | In a round bottom flask, oxetan-3-ol (3.00 g, 40.5 mmol) in dichloromethane (DCM) (25 mL),Triethylamine (8.47 mL, 60.7 mmol) and 4-toluenesulfonyl chloride (8.49 g, 44.5 mmol) were added to give a colorless solution.4-Dimethylaminopyridine (0.247 g, 2.025 mmol) was added and the mixture was stirred at room temperature for about 16 hours.The reaction was quenched with saturated aqueous NH 4 Cl (20 mL) and the layers were separated. Extract the aqueous with DCM (2 × 20 mL),The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL).The organic layer is dehydrated with MgSO4,Concentrate under reduced pressure to give a residue,This was purified by silica gel chromatography eluting with 10-100% ethyl acetate / heptane,The product (7.98 g, 86% yield) was obtained. |
85% | With sodium hydroxide; In water; at 0℃; for 3h; | At 0 C., aqueous NaOH solution (2 N, 15 mL) was added dropwise to a solution of oxetan-3-ol (1.48 g, 20 mmol) and p-toluene sulfonyl chloride (4.18 g, 22 mmol) in water (50 mL). After stirred for 3 hours, the mixture was treated with water (100 mL), extracted with dichloromethane (100 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=10:1) to give compound 39-c (3.9 g, yield: 85%). LC-MS (ESI): m/z=229 [M+H]+. |
80% | With potassium carbonate; In acetonitrile; at 70℃; | Add oxetan-3-ol (740 mg, 10 mmol) and potassium carbonate (2.7 g, 20 mmol) to the reaction flask, and then add 40 ml of anhydrous acetonitrile as the solvent. With stirring, p-toluenesulfonyl chloride (2.3 g, 12 mmol) was added in portions. After the addition, the reaction was heated to 70 C and stirred overnight. The reaction was quenched with water, extracted with ethyl acetate, the organic phase was dried and concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain the compound oxetan-3-yl 4-methylbenzene Sulfonate (1.8g, yield 80%).[1354]1H NMR (400MHz, d-CDCl3) delta 7.78 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 5.33-5.27 (m, 1H), 4.74 - 4.65 (m, 4H), 2.46 (s, 3H). |
78% | With pyridine; at 20℃;Inert atmosphere; | To a 50 mL two-neck flask were added oxetan-3-ol (1.00 g, 13.0 mmol) and anhydrous pyridine (25 mL), then paratoluensulfonyl chloride (3.10 g, 16.0 mmol) was added to the mixture under nitrogen protection. The reaction mixture was stirred at rt overnight. The reaction was mornitored by TLC until oxetan-3-ol consumed completely, then the mixture was concentrated in vacuo to remove pyridine. To the residue was added saturated brine (60 mL). The resulting mixture was extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated brine (30 mL*2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica-gel column chromatography (PE:EtOAc=10:1, V/V) to give a white solid (2.40 g, 78.0%). MS(ESI, pos.ion)m/z:229.1 (M+1); |
65% | With sodium hydroxide; In water; at 50℃; for 1h; | To a well-stirred 50 C. solution of Part D compound (7 g, 94 mmol) and p-TsCl (12.8 g, 67.1 mmol) in water (15 mL) was added dropwise a solution of NaOH (2.69 g, 67.1 mmol) in water (15 mL). The reaction was heated for 1 h at 50 C., then cooled to RT and toluene (10 mL) was added. The aqueous layer was extracted with toluene (5 mL×2). The combined organic extracts were washed with conc NH4OH (3×) and water (2×), then concentrated in vacuo. Hexane (50 mL) was added to the residue and a solid was formed, which was collected by filtration and then was dried in vacuo for 1 h to give Part E compound (10 g, 65% yield) as a white solid. [M+H]+=229.1; 1H NMR (400 MHz, CDCl3) delta ppm 2.46 (s, 3 H), 4.64-4.75 (m, 4 H), 5.27-5.34 (m, 1 H), 7.37 (d, J=8.25 Hz, 2 H), 7.78 (d, J=8.25 Hz, 2 H). |
62% | With pyridine; at 20℃; for 18h; | Preparation of toluene-4-sulfonic acid oxetan-3-yl ester; To a solution of oxetan-3-ol (1.0 g, 13.0 mmol) in anhydrous pyridine (25 ml_) at room temperature was added 4-toluene sulfonyl chloride (3.09 g, 16.2 mmol). After stirring the reaction mixture for 18 hours at room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30% ethyl acetate in heptane to afford 1.9 g (62% yield) of the desired product as a white solid.1H NMR (400 MHz, chloroform-d) delta ppm 2.46 (s, 3 H), 4.63 - 4.75 (m, 4 H), 5.26 - 5.34 (m, 1 H), 7.36 (d, J=8.00 Hz, 2 H), 7.78 (d, J=8.40 Hz, 2 H). |
50% | With triethylamine; In dichloromethane; at 20℃; for 15h; | Step 1: To a stirred mixture of oxetan-3-ol (0.85 g, 11.5 mmol) in DCM (38 mL) were added TEA (3.3 mL, 23mmol) and 4-methylbenzene-1-sulfonyl chloride (2.7 g, 13.8 mmol). The reaction mixture was stirred at rt for 15 h. Themixture was partitioned between water and DCM. The organic layer was separated, dried over Na2SO4, filtered, andconcentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradientof 30% DCM in petroleum ether to 100% DCM to afford oxetan-3-yl 4-methylbenzenesulfonate (1.3 g, 50%) as a whitesolid. 1H NMR (300 MHz, CDCl3) delta 7.77 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 5.30 (m, 1H), 4.66 - 4.74 (m, 4H),2.46 (s, 3H); LCMS (ESI) m/z 229 (M+H)+ |
With sodium hydroxide; In water; at 20 - 65℃; for 2.5h; | Step 1: Combine oxetan-3-ol (prepared according to J. Org. Chem. 1983, 2953, 3.64 g, 52 mmol) and ptoluenesulfonyl chloride (11.9 g, 62 mmol) in water (10 ml) and add NaOH (3.3 g, 83 mmol) in water (4 ml). Stir 2 h at RT, then 0.5 h at 65 C. Filter and chromatograph the solid on silica to obtain the tosylate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | A mixture of Example 67 Part A compound (450 mg, 1.396 mmol), Part E compound (500 mg, 2.190 mmol), and K2CO3 (2.7 g, 19.54 mmol) in DMF (5 mL) was stirred in a sealed tube at 110 C. for 18 h, then was cooled to RT. The reaction was filtered, the solids were washed with DMF, and the combined filtrates were concentrated in vacuo. The residue was neutralized with TFA and purified by preparative HPLC(Phenomenex AXIA 5u C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% A to 100% B over 10 min +1 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to give the Part F compound (220 mg, 42% yield) as a white solid. [M+H]+=365.2; 1H NMR (400 MHz, CDCl3) delta 3.08 (s, 3 H), 4.78 (dd, J=7.15, 4.95 Hz, 2 H), 5.02 (t, J=6.87 Hz, 2 H), 5.23-5.31 (m, 1 H), 6.75 (t, J=1.92 Hz, 1 H), 7.13 (d, J=8.79 Hz, 2 H), 7.18 (s, 1 H), 7.39 (s, 1 H), 7.93 (d, J=8.24 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.0% | A mixture of methyl 3,5-dihydroxybenzoate (200 mg, 1.189 mmol), Example 71 Part E compound (600 mg, 2.63 mmol), and K2CO3 (2 g, 14.47 mmol) in DMF (10 mL) was stirred in a sealed tube at 115 C. for 18 h, then was cooled to RT. Solids were removed by filtration and were washed with DMF. The combined filtrates were concentrated in vacuo. The residue was neutralized with TFA and was purified by preparative HPLC (Phenomenex AXIA 5u C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% A to 100% B over 10 min+1 min hold time at 100% B, where A=90:10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to give Part A compound (60 mg, 19.0 %) as a white solid. [M+H]+=267.2; 1H NMR (400 MHz, CD3OD) delta 4.68 (dd, J=7.15, 4.95 Hz, 4 H), 5.02 (t, J=6.60 Hz, 4 H), 5.26-5.35 (m, 2 H), 6.46 (t, J=2.20 Hz, 1 H), 6.98 (d, J=2.20 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | A mixture of methyl 3-hydroxy-5-isopropoxybenzoate (100 mg, 0.476 mmol), Example 71 Part E compound (180 mg, 0.789 mmol), and K2CO3 (1 g, 7.24 mmol) in DMF (5 mL) was stirred in a sealed tube at 115 C. for 18 h, then was cooled to RT. Solids were filtered off and washed with DMF. The combined filtrates were concentrated in vacuo. The residue was neutralized with TFA and purified by preparative HPLC (Phenomenex AXIA 5 mum C18 30×100 mm column; detection at 220 nm; flow rate=40 mL/min; continuous gradient from 30% A to 100% B over 10 min+1 min hold time at 100% B, where A=90: 10:0.1 H2O:MeOH:TFA and B=90:10:0.1 MeOH:H2O:TFA) to give Part A compound (100 mg, 83% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta 1.35 (d, J=6.05 Hz, 6 H), 4.59 (dt, J=12.09, 6.05 Hz, 1 H), 4.77 (dd, J=7.42, 5.22 Hz, 2 H), 5.01 (t, J=6.60 Hz, 2 H), 5.19-5.27 (m, 1 H), 6.52 (t, J=2.47 Hz, 1 H), 6.94 (s, 1 H), 7.27 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; sodium iodide; In N,N-dimethyl acetamide; at 130℃; for 2h; | A mixture OF 2-(4-MERCAPTOPHENYL)-3-(TEKAHYDROPYRAN-4-YL)-N-THIAZOL-2- ylpropionamide (see EXAMPLE 146,349mg, L. Ommol), K2C03 (152mg, L. lmmol), NaI (150mg, L. OMMOL), and 3- (tosyloxy) oxetane (274mg, 1. 2MMOL) in anhydrous DMAC (20mL) was heated for 2h at 130 C. The solvent was evaporated off under reduced pressure, then the residue was partitioned between CH2C12 (75mL) and 2% aqueous citric acid (20mL). The organic layer was washed with H20 (20mL), saturated aqueous Na2CO3 (20ML), and brine (20mL), before being dried (MGS04). Filtration and solvent evaporation afforded 2- [4- (OXETAN-3-YLSULFANYL) phenyl] -3- (tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide : NILZ (ES+) = 405.2 [M+ H] +. This thioether was oxidised employing the protocol outlined in EXAMPLE 148 to give the title compound: RTA = 3. 04MIN ; m/z (ES+) = 437. 2 [M+ H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With caesium carbonate; In N,N-dimethyl-formamide; at 125℃; for 14h; | Step 3. Preparation of 3-(fH2-hvdroxv-1-(hvdroxvmethvl)ethvnpiperidin-3-vl)methyl)-2-(2-methvlphenvl)-6-(trifluoromethoxy)quinazolin-4(3H)-one; -OH[165] To a mixture of 2-(2-methylphenyl)-3-(piperidin-3-ylmethyl)-6-(trifluoromethoxy)quinazolin-4(3H)-one (200 mg, 0.48 mmol) (step 2) and Cs2CO3(624 mg, 1.92 mmol) in DMF (8 mL) wasadded <strong>[26272-83-3]oxetan-3-yl-4-methylbenzenesulfonate</strong> (164 mg, 0.72 mmol). The reaction mixture wasstirred at 125C for 14 h, then cooled to rt, and concentrated under reduced pressure. The residuewas diluted with water and extracted with EtOAc (2 x 20 mL). The solvent was removed underreduced pressure and the crude mixture purified by HPLC with 5% to 80% acetonitrile in water(0.1% TFA) to give the product (14 mg, 6 %) as light yellow solid. 1H NMR (400 MHz, CD3OD) 58.10-8.11 (m, 1 H), 7.75-7.76 (m, 2 H), 7.47-7.51 (m, 2 H), 7.39-7.42 (m, 2 H), 4.06-4.25 (m, 1 H),3.42-3.73 (m, 4 H), 2.77-2.85 (m, 2 H), 2.38-2.46 (m, 2 H), 2.25-2.26 (d, 3 H), 1.94-1.99 (m, 2 H),471.29-1.64 (m, 4 H), 0.87-0.92 (m, 1 H); ES-MS m/z 492.4 (MH+); HPLC RT (min) 2.80. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | EXAMPLE 14-(3,5-Dicyclopropyl-1-oxetan-3-yl-1H-pyrazol-4-yloxy)-2,6-dimethyl-benzonitrile Sodium Hydride (60% dispersion in mineral oil, 16.4 mg, 0.41 mmol) was added to a solution of the compound obtained from Preparation 12 (100 mg, 0.341 mmol) in tetrahydrofuran (0.75 mL). This mixture was heated to 50 C. A solution of toluene-4-sulfonic acid oxetan-3-yl-ester (93.4 mg, 0.41 mmol) in tetrahydrofuran (0.75 mL) was then added, and this new mixture was stirred at 50 C. for 12 hours. This mixture was partitioned between water (5 mL) and diethyl ether (2×5 mL). The combined organics were washed with saturated brine (5 mL) dried over magnesium sulphate filtered and evaporated under reduced pressure. This residue was purified by purified by preparative high performance liquid chromatography to give the title compound as an off white gum (5 mg, 4%). 1H NMR (400 MHz, CDCl3): delta 0.55-1.70(m, 10H), 2.45(m, 6H), 4.90(m, 2H), 5.20(m, 2H), 5.60(m, 1H), 6.60(s, 2H); APCI MS m/z 294 [M-CH(CH2)2O]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.4% | (R)-tert-bntyl 4-(3-methoxy-4-(oxetan-3-yloxy)phenyl)-2-methylpiperazine-l- carboxylate(R)-tert-buty{ 4-(4-hydroxy-3-methoxyphenyl)-2-methylpiperazine-l -carboxylate (0.645 g, 2.00 mmol) was dissolved in NMP (5 mL) and sodium hydride (0.088 g, 2.20 mmol) added portionwise and the reaction stirred for 10 minutes. Oxetan-3-yl A- methylbenzenesulfonate (0.548 g, 2.40 mmol) was added in one portion and the reaction was heated to 120 0C for 17 hours and then allowed to cool. Poured into water (50 ml) and extracted with EtOAc (3 x 50 mL), the combined organic extracts were washed with water (100 mL) and then saturated brine (100 mL), dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford (R)-tert-bvXy A- <n="144"/>(3-methoxy-4-(oxetan-3-yloxy)phenyl)-2-methylpiperazine-l-carboxylate (0.306 g, 40.4%) as a cream solid.MS (+ve ESI) : Rt = 2.46 min, 379 (M+H)+IH NMi? (400.132 MHz, CDC13) delta 1.31 (3H, d), 1.48 (9H, s), 2.63 - 2.72 (IH, m), 2.83 -2.89 (IH, m), 3.19 - 3.25 (2H, m), 3.33 - 3.40 (IH, m), 3.86 (3H, s), 3.90 - 3.97 (IH, m),4.29 - 4.38 (IH, m), 4.83 (2H, t), 4.89 (2H, t), 5.08 - 5.15 (IH, m), 6.33 - 6.37 (IH, m),6.48 (IH, d), 6.52 (IH, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 0 - 120℃; | To a solution of crude 4-(5-bromo-2-chlorobenzyl)phenol (3.0 g, 10 mmol) and cesium carbonate (4.9 g, 15 mmol) in Lambda/,Lambda/-dimethylformamide (77.5 ml_) at room temperature was added a solution of toluene-4-sulfonic acid oxetan-3-yl ester (3.5 g, 15 mmol) in Lambda/,Lambda/-dimethylformamide (8 ml_). The mixture was heated to 65C for 22 hours whereupon an additional aliquot of cesium carbonate (3.3 g, 10 mmol) was added. The reaction mixture was stirred for a further 12 hours at 120C, cooled to room temperature whereupon water and ethyl acetate were added and the mixture was carefully acidified with 1 N aqueous hydrochloric acid solution. The organic layer was separated, washed with brine (3 times), and concentrated in vacuo. Purification via Biotage MPLC (silica gel, eluting with a gradient of 0 to 25% ethyl acetate in heptane) afforded 3-(4-(5-bromo-2- chlorobenzyl)phenoxy)oxetane (2.5 g, 70% yield) as a white solid.1H NMR (400 MHz, dichloromethane-d2) delta ppm 7.34 - 7.28 (m, 2 H), 7.26 (d, J=8.4 Hz, 1 H), 7.14 - 7.09 (m, 2 H), 6.69 - 6.35 (m, 2 H), 5.22 - 5.16 (m, 1 H), 4.96 - 4.91 (m, 2H), 4.72 - 4.68 (m, 2H), 4.01 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 65℃; for 18h; | Preparation of starting material 3-[4-(5-bromo-2-fluoro-benzyl)-Dhenoxyl-oxetane; To a solution of 4-(5-bromo-2-fluoro-benzyl)-phenol (1.1 g, 3.9 mmol) and cesium carbonate (1.91 g, 5.87 mmol) in Lambda/.Lambda/-dimethylformamide (15.0 ml_) at room temperature was added a solution of toluene-4-sulfonic acid oxetan-3-yl ester (1.34 g, 8.0 mmol) in N,N- dimethylformamide (10.0 ml_). The reaction mixture was then stirred overnight at 65C.After a total of 18 hours, the reaction mixture was cooled to room temperature, diluted with brine and extracted 3 times with ethyl acetate. The combined organic layers were washed twice with water and once with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography over silica gel eluting with a gradient of 0 to 30% ethyl acetate in heptane to afford 0.948 g (72% yield) of the desired product as a white solid.1H NMR (400 MHz, chloroform-d) delta ppm 3.88 (s, 2 H), 4.76 (dd, J=7.22, 5.3 Hz, 2 H), 4.95 (t, J=6.6 Hz, 2 H), 5.14 - 5.21 (m, 1 H), 6.63 (d, J=8.4 Hz, 2 H), 6.92 (dd, 1 H), 7.10 (d, J=8.6 Hz, 2 H), 7.23 (dd, J=6.6, 2.15 Hz, 1 H), 7.26 - 7.31 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 8h; | To a solution of methyl 6-(2,6-difluoro-4-hydroxyphenyl)-5-fluoropicolinate (1.0 equiv.) in DMF (0.08 M) was added potassium carbonate (10.1 equiv.) and <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (1.3 equiv.). The mixtures were stirred at 110 C. in an oil bath for 8 hrs and cooled to room temperature. The reaction was diluted with ethyl acetate and water. The organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and heptanes (0-50%). The pure fractions were concentrated to give methyl 6-(2,6-difluoro-4-(oxetan-3-yloxy)phenyl)-5-fluoropicolinate in 36% yield. LC/MS=340.0 (MH+), Rt=0.82 min. 1H NMR (400 MHz, <cdcl3>) delta ppm 4.00 (s, 3H), 4.77 (dd, J=7.63, 5.28 Hz, 2H), 5.00 (t, J=6.85 Hz, 2H), 5.22 (quin, J=5.48 Hz, 1H), 6.38 (d, J=9.00 Hz, 2H), 7.63 (t, J=8.61 Hz, 1H), 8.24 (dd, J=8.61, 3.91 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.7% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h;Sealed tube; | To a 20 mL sealed tube were added 4-bromophenol (590 mg, 3.41 mmol), potassium carbonate (1.28 g, 9.28 mmol), <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (700 mg, 3.06 mmol) and DMF (6 mL), and the sealed tube was pluged with a polytetrafluoroethylene plug. The mixture was stirred at 100C for 16 h in sealed tube. After the reaction was completed, the reaction mixture was cooled to rt and to the mixture was added saturated brine (20 mL). The resulting mixture was extracted with EtOAc (20 mL*3). The combined organic layers were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica-gel column chromatography (DCM:EtOAc=2:1, V/V) to give a white solid (700 mg, 69.7%). MS(ESI, pos.ion)m/z:229.01 (M+1); |
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h; | Step A) 3-(4-Bromophenoxy)oxetane4-Bromophenol (2.5 g, 14.5 mmol) and K2CO3 (5.45 g, 39.4 mmol) were added to a solution of <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (3.00 g, 13.1 mmol) in DMF (10 mL) in a sealed tube. The reaction was heated to 100 C. and stirred at this temperature for 24 h. The reaction was diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to afford the title compound. MS (GCMS) m/z 228. This material was used in subsequent steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Step 2A solution of 0.50 g (2.19 mmol) of compound 14 and 0.75 g (6.57 mmol) of potassium thioacetate in 5 mL of N.N-dimethylformamide was stirred at 100 C for 2 h. After this time the reaction mixture was cooled to room temperature and diluted with 100 mL of 5% aqueous lithium chloride. The resulting mixture was extracted with three 50 mL portions of methylene chloride. The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica, 0-50%EtOAc hexanes) to give 0.28 g (97%) of 15 as a yellow oil: 1H NMR (CDC13 500 MHz) delta 5.06 (t, J= 12.0 Hz, 2H), 4.61 (m, 3H), 2.34 (s, 3H). Scheme 7 . AC 16 17a 18a |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃; | Example 94 6-[4-[2 6-difluoro-4-(oxetan-3-yloxy)phenyl]piperazin- 1 -yl]- 1 -methyl-5H-pyrazolo[3 4- d]pyrimidin-4-one (1-85) Condensation of <strong>[26272-83-3]3-(4-methylbenzenesulfonate)-3-oxetanol</strong> (CASRN 26272-83-3) and 4- bromo-3,5-difluorophenol under Mirsunobu conditions (PPh3,DIAD, DCM, RT) afforded 3-(4- bromo-3,5-difluoro-phenoxy)-oxetane which was condensed teri-butyl piperazine-l-carboxylate utilizing palladium coupling described in Intermediate I. Removal of the boc (TFA/DCM) and condensation with Intermediate A (DIPEA, EtOH, 140 C) affords the title compound: H NMR (300MHz, DMSO-i delta ppm 10.96 (s, 1H), 7.80 (s, 1H), 6.61 (d, J = 10.8 Hz, 2H), 5.30-5.26 (m, 1H), 4.95-4.91 (m, 2H), 4.54-4.50 (m, 2H), 3.76-3.74 (m, 7H), 3.10-3.09 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The following Preparations were prepared according to Method H (Preparation 122) using 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole and the appropriate alkyl electrophile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 90℃; for 12h; | Step 2. 2-(Difluoromethoxy)-5-methyl-3-(3-(oxetan-3-yloxy)phenyl)pyridine. To a solution of 3-(2-(difluoromethoxy)-5-methylpyridin-3-yl)phenol (502.5 mg, 2.0 mmol), in DMF, was added <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (685 mg, 3.0 mmol), and potassium carbonate (553 mg, 4.00 mmol). The reaction mixture was stirred at 60 C. for 8 h. LC-MS suggested about 50% conversion. The temperature was raised to 90 C. and the reaction mixture was stirred an additional 4 h. Sat. aq. NaCl was added, and the mixture was extracted with DCM (3*). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. Purification (FCC, SiO2, 10-30% EtOAc/hexanes) afforded the title compound (310 mg, 50%) as a colorless solid. [M+H]=308.11 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With caesium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 130℃; for 4h; | Example 230 N-[4-(2,4-difluorophenoxy)-3-(1,5-dimethyl-6-oxopyridin-3-yl)phenyl]-N-(oxetan-3-yl)methanesulfonamide The title compound of Example 102 (46 mg, 0.11 mmol), Cs2CO3 (150 mg, 0.46 mmol), KI (10 mg, 0.06 mmol) and <strong>[26272-83-3]oxetan-3-yl-4-methylbenzenesulfonate</strong> (30 mg, 0.13 mmol) in DMF (0.9 mL) were microwaved at 130 C. for 2 h. Additional <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (65 mg, 0.29 mmol) and Cs2CO3 (126 mg, 0.39 mmol) were added and microwave resumed at 130 C. for 2 h more. The mixture was purified by silica gel chromatography (EA) to give the title compound (20 mg, 0.04 mmol) as cream solids in 38% yield. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.03 (s, 3H) 2.98 (s, 3H) 3.50 (s, 3H) 4.41 (t, J=6.82 Hz, 2H) 4.58 (t, J=6.95 Hz, 2H) 5.30 (quin, J=7.01 Hz, 1H) 6.83 (d, J=8.84 Hz, 1H) 7.06-7.20 (m, 1H) 7.22-7.35 (m, 2H) 7.39 (d, J=2.53 Hz, 1H) 7.43-7.57 (m, 1H) 7.60 (s, 1H) 7.83 (d, J=2.27 Hz, 1H). LCMS (M+H)+ 477 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.7% | With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 12h;Inert atmosphere; | 4-(3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluor omethyl)benzonitrile 14c (100 mg, 0.25 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, followed by addition of <strong>[26272-83-3]oxetan-3-yl-4-methylbenzenesulfonate</strong> 40a (114 mg, 0.50 mmol, prepared by a well known method "Organic Letters, 2008, 10(15), 3259-3262") and potassium carbonate (103 mg, 0.75 mmol). The reaction solution was warmed up to 80C. After reacting for 12 hours, the reaction solution was cooled down to room temperature, mixed with 20 mL of H2O, and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), 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 4-(4,4-dimethyl-3-(4-((oxetan-3-yl)oxy)phenyl)-5-oxo-2-thioxoimidazolidin-1-yl)-2-(tri fluoromethyl)benzonitrile 40 (20 mg, yield 17.7%) as a yellow solid. MS m/z (ESI): 462.3 [M+1] 1H NMR (400 MHz, CDCl3): delta 7.99-7.96 (m, 2H), 7.86-7.83 (m, 1H), 7.23-7.20(m, 2H), 6.86-6.83 (m, 2H), 5.27-5.24 (m, 1H), 5.03-4.99 (m, 2H), 4.83-4.80 (m, 2H), 1.58 (s, 6H). |
17.7% | With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 12h; | 4-(3-(4-Hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 14c (100 mg, 0.25 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, followed by addition of <strong>[26272-83-3]oxetan-3-yl-4-methylbenzenesulfonate</strong> 40a (114 mg, 0.50 mmol, prepared by a well known method described in Organic Letters, 2008, 10(15), 3259-3262) and potassium carbonate (103 mg, 0.75 mmol). The reaction solution was warmed up to 80 C. After reacting for 12 hours, the reaction solution was cooled down to room temperature, mixed with 20 mL of H2O, and extracted with ethyl acetate (20 mL*2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL*2), 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 4-(4,4-dimethyl-3-(4-((oxetan-3-yl)oxy)phenyl)-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 40 (20 mg, yield 17.7%) as a yellow solid. MS m/z (ESI): 462.3 [M+1]; 1H NMR (400 MHz, CDCl3): delta 7.99-7.96 (m, 2H), 7.86-7.83 (m, 1H), 7.23-7.20 (m, 2H), 6.86-6.83 (m, 2H), 5.27-5.24 (m, 1H), 5.03-4.99 (m, 2H), 4.83-4.80 (m, 2H), 1.58 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.5% | With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 4h;Inert atmosphere; | 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2 -(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, followed by addition of <strong>[26272-83-3]oxetan-3-yl-4-methylbenzenesulfonate</strong> 40a (110 mg, 0.48 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was warmed up to 80C. After reacting for 4 hours, the reaction solution was cooled down to room temperature, mixed with 20 mL of H2O, and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×2), 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 4-(3-(3-fluoro-4-((oxetan-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 41 (30 mg, yield 26.5%) as a white solid. MS m/z (ESI): 480.3 [M+1] 1H NMR (400 MHz, CDCl3): delta 8.00-7.95 (m, 2H), 7.84-7.82 (m, 1H), 7.12-7.09(m, 1H), 7.01-7.00 (m, 1H), 6.75-6.71 (m, 1H), 5.32-5.30 (m, 1H), 5.03-4.99 (m, 2H), 4.89-4.86 (m, 2H), 1.59 (s, 6H). |
26.5% | With potassium carbonate; In N,N-dimethyl acetamide; at 80℃; for 4h; | 4-(3-(3-Fluoro-4-hydroxyphenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 1e (100 mg, 0.24 mmol) was dissolved in 5 mL of N,N-dimethylacetamide, followed by addition of <strong>[26272-83-3]oxetan-3-yl-4-methylbenzenesulfonate</strong> 40a (110 mg, 0.48 mmol) and potassium carbonate (100 mg, 0.72 mmol). The reaction solution was warmed up to 80 C. After reacting for 4 hours, the reaction solution was cooled down to room temperature, mixed with 20 mL of H2O, and extracted with ethyl acetate (20 mL*2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL*2), 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 4-(3-(3-fluoro-4-((oxetan-3-yl)oxy)phenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile 41 (30 mg, yield 26.5%) as a white solid. MS m/z (ESI): 480.3 [M+1]; 1H NMR (400 MHz, CDCl3): delta 8.00-7.95 (m, 2H), 7.84-7.82 (m, 1H), 7.12-7.09 (m, 1H), 7.01-7.00 (m, 1H), 6.75-6.71 (m, 1H), 5.32-5.30 (m, 1H), 5.03-4.99 (m, 2H), 4.89-4.86 (m, 2H), 1.59 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In dimethyl sulfoxide; at 60℃; | <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (1.185 g, 6.20 mmol), oxetan-3-yl 4-methyl-benzenesulfonate (1.77 g, 7.75 mmol) and cesium carbonate (5.05 g, 15.51 mmol) were dissolved in DMSO (7.75 mL) and heated to 60 OC overnight. The reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 2% to 50% EtOAc:Hexane to give the desired product. 1H NMR delta (ppm) 7.39 (t, 1H), 6.50 (d, 1H), 6.40 (d, 1H), 5.17-5.12 (m, 1H), 4.97 (t, 2H), 4.73 (t, 2H). | |
With caesium carbonate; In dimethyl sulfoxide; at 60℃; | <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (1.185 g, 6.20 mmol), oxetan-3-yl 4-methyl-benzenesulfonate (1.77 g, 7.75 mmol) and cesium carbonate (5.05 g, 15.51 mmol) were dissolved in DMSO (7.75 mL) and heated to 60 C. overnight. The reaction mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 2% to 50% EtOAc:Hexane to give the desired product. 1H NMR delta (ppm) 7.39 (t, 1H), 6.50 (d, 1H), 6.40 (d, 1H), 5.17-5.12 (m, 1H), 4.97 (t, 2H), 4.73 (t, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-bromothiophenol (1.15 g, 6.08 mmol), <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (1.66 g, 7.3 mmol), and cesium carbonate (3.96 g, 12.16 mmol) were suspended in DMSO (6 ml). The reaction mixture was stirred for 2 days at rt, then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chormatogaphy on a Biotage 50 g column by eluting with 5% to 75% EtOAc:Hexane. The major peak was isolated, concentrated and dissolved in MeOH (10 mL), THF (10 mL) and water (5 mL). Oxone (4.05 g, 6.59 mmol) was added and the reaction was stirred overnight at rt, and then diluted with water and EtOAc. The EtOAc phase was washed with water, Na2S2O3, and brine, and then dried over Na2SO4, filtered and concentrated to provide the desired product. 1H NMR delta 7.80-7.75 (m, 4H), 4.96 (t, 2H), 4.82 (t, 2H), 4.46 (pentet, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 116h; | 5.16 g (17.5 mmol) of the compound of intermediate 68 and 6.86 g (21.0 mmol) of cesium carbonatewere provided in 60 mL of DMF. A solution of 4.80 g (21.0 mmol) of oxetan-3-yl-4- methylbenzenesulfonate in 40 mL of DMF was added and it was stirred for 116 h at 50 C. The reaction mixture was concentrated. The remaining material was triturated with water and ethanol and stirred for 30 minutes. The precipitate was collected by filtration, washed with ethanol and dried under reduced pressure. The remaining material was triturated with ethanol under reflux. Theprecipitate was collected by filtration at room temperature, washed with ethanol and dried under reduced pressure to give 2.30 g (37% of theory) of the title compound.?H-NMR (400MHz, DMSO-d6): 6 [ppm]: 2.523 (0.88), 2.566 (3.27), 2.577 (4.64), 2.589 (3.42), 3.193(9.40), 3.661 (3.68), 3.673 (5.05), 3.685 (3.62), 3.821 (16.00), 4.612 (1.97), 4.624 (2.26), 4.629 (2.28),4.632 (2.32), 4.643 (2.27), 5.000 (2.07), 5.017 (3.36), 5.020 (2.49), 5.035 (2.08), 5.473 (0.91), 5.488(1.50), 5.500 (0.87), 5.503 (0.84), 6.830 (2.63), 6.851 (2.77), 7.638 (1.70), 7.644 (1.66), 7.659 (1.60),7.664 (1.65), 8.902 (2.83), 8.907 (2.88), 9.850 (2.27).LC-MS (Method 4): R = 0.64 mm; MS (ESIpos): m/z = 351 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | Compound 39-c (3.9 g, 17 mmol) was added to a solution of 4-nitropyrazole (1.13 g, 10 mmol) and cesium carbonate (6.5 g, 20 mmol) in DMF (15 mL), and then was heated to 120 C. and stirred for 12 hours. After cooled to room temperature, the mixture was treated with water (60 mL), extracted with ethyl acetate (20 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=5:1) to give compound 39-b (1.3 g, yield: 77%). LC-MS (ESI): m/z=170 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With caesium carbonate; In acetonitrile; at 80℃; | Example 403 6-(2,3-Difluoro-4-(oxetan-3-yloxy)benzyl)-9-hydroxy-5-methyl-7-oxo-N-(4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide 6-[(2,3-Difluoro-4-hydroxyphenyl)methyl]-9-hydroxy-5-methyl-7-oxo-N-[4-(trifluoromethyl)-2-[6-(trifluoromethyl)pyrimidin-4-yl]phenyl]-5,6-diazaspiro[3.5]non-8-ene-8-carboxamide (Reference Example 107) was dissolved in acetonitrile (200 muL), then <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (14.2 mg, 0.062 mmol) and cesium carbonate (30.4 mg, 0.093 mmol) were added, and the mixture was stirred at 80 C. overnight. After the reaction mixture was diluted with N,N-dimethyl formamide and water, the resultant was purified by HPLC to obtain the title compound (14.1 mg, 65%). LCMS: m/z 700[M+H]+ HPLC retention time: 1.62 minutes (analysis condition SMD-TFA05) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With potassium carbonate; sodium iodide; In N,N-dimethyl acetamide; at 130℃; for 2h;Inert atmosphere; | To a 50 mL two-neck flask were added 4-bromo thiophenol (380 mg, 2.00 mmol) and anhydrous N,N-dimethylacetamide (20 mL), and oxetan-3-yl 4-benzenemethylsulfonate (551 mg, 2.40 mmol) was added under nitrogen protection. Then sodium iodide (304 mg, 2.00 mmol) and potassium carbonate (310 mg, 2.20 mmol) were added in turn. The resulting mixture was stirred at 130C for 2 h. The reaction mixture was cooled to rt and to the mixture was added saturated brine (60 mL). The resulting mixture was extracted with EtOAc (20 mL*3). The combined organic layers were washed with saturated brine (30 mL*2), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica-gel column chromatography (PE:EtOAc=10:1, V/V) to give light yellow oil (0.41 g, 83.0%). MS(ESI, pos.ion)m/z:245.1 (M+1); |
With caesium carbonate; In N,N-dimethyl-formamide; at 85℃; for 3h; | To a solution of 4-bromothiophenol (6.65 g, 35.2 mmol) in DMF (35 mL) was added <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (8.83 g, 38.7 mmol) and cesium carbonate (15.5 g, 47.5 mmol) , and the resulting mixture was heated at 85 for 3 h. The mixture was cooled, diluted with ethyl acetate (200 mL) , and washed with water (3 x 200mL) . The organic layer was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel, eluting with 0-30EtOAc/hexane, to give the title compound. MS: m/z 244.87 (M + 1) . | |
With caesium carbonate; In dimethyl sulfoxide; at 20℃; for 48h; | 4-bromothiophenol (1.15 g, 6.08 mmol), <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (1.66 g, 7.3 mmol), and cesium carbonate (3.96 g, 12.16 mmol) were suspended in DMSO (6 ml). The reaction mixture was stirred for 2 days at rt, then diluted with water and EtOAc. The aqueous phase was extracted with EtOAc (×2); and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage 50 g column by eluting with 5% to 75% EtOAc:Hexane. The major peak was isolated, concentrated and dissolved in MeOH (10 mL), THF (10 mL) and water (5 mL). Oxone (4.05 g, 6.59 mmol) was added and the reaction was stirred overnight at rt, and then diluted with water and EtOAc. The EtOAc phase was washed with water, Na2S2O3, and brine, and then dried over Na2SO4, filtered and concentrated to provide the desired product. 1H NMR delta 7.80-7.75 (m, 4H), 4.96 (t, 2H), 4.82 (t, 2H), 4.46 (pentet, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.46% | STEP 2: 7-isopentyl-l,3-dimethyl-8-(4-(oxetan-3-yloxy)phenoxy)-lH-purine-2,6(3HJH)-dione, TFA (Cpd. 91) To a mixture of 8-(4-hydroxyphenoxy)-7-isopentyl-l,3-dimethyl-lH-purine-2,6(3H,7H)- dione (35.8 mg, 0.1 mmol) and K2C03 (27.6 mg, 0.200 mmol) was added N,N-Dimethylformamide (Volume: 1). The mixture was stirred at rt for 5 min and <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (45.7 mg, 0.200 mmol) was added. The mixture was sealed and heated at 120 C for overnight. The mixture was filtered through a filter and submitted for purification to give 7-isopentyl-l,3-dimethyl-8-(4- (oxetan-3-yloxy)phenoxy)-lH-purine-2,6(3H,7H)-dione, TFA (8.7 mg, 0.016 mmol, 16.46 % yield). MS (M+H)+= 415. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate; In acetonitrile; at 100 - 110℃; for 10h;Sealed tube; | Intermediate 3 (300 mg, 1.2 mmo[), oxetan-3-yl. tosylate (357 mg, 1.56 mmo[) and cesium carbonate (588 mg, 1.81 mmo[) were combined in acetonitrile (5 mL) and stirred at 100 C in a sealed tube for 6 h, then at 110 C for 4 h. The reaction mixture was cooled to RT and filtered through celite, washing with EtOAc. Thefiltrate was concentrated under reduced pressure and purified by Biotage IsoleraTM chromatography (silica gel eluting with heptanes - ethyl acetate 9:1 to 2:3) to give 163.5 mg (43 % yield) of the title compound as a colourless gum.1H NMR (500MHz, Chloroform-d): 6 [ppm] = 8.12 (t, J = 1.4 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 7.51 (dd, J = 2.5, 1.6 Hz, 1H), 7.37 (dd, J = 2.5, 1.3 Hz, 1H), 5.33 (p, J =5.6 Hz, 1H), 5.07 - 4.98 (m, 2H), 4.78 (dd, J = 7.9, 5.1 Hz, 2H), 3.94 (5, 3H), 2.53 (d, J = 1.1 Hz, 3H).LCMS (Analytical Method A) Rt = 1 .29 mm, MS (ESIpos): m/z = 309.95 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With caesium carbonate; sodium iodide; In 1-methyl-pyrrolidin-2-one; at 145℃; for 15h; | Step 2: A stirred mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol 6-yl)methyl)-1H-benzo[d]imidazol-5-ol (100 mg, 0.23 mmol) from Step 1 of Example 171, <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong>(420 mg, 1.84 mmol) from the previous step, Cs2CO3 (225 mg, 0.69 mmol), sodium iodide (276 mg, 0.69mmol) and NMP (4 mL) was heated at 145 C for 15 h. The mixture was diluted with EtOAc and washed with brine. Theorganic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified bysilica gel flash chromatography eluting with 40:1 DCM/MeOH to afford (3aR,7aR)-2,2-dimethyl-3-(6-((5-(oxetan-3-yloxy)-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)octahydrobenzo[d]oxazole (35 mg, 31%) as a yellow solid. 1HNMR (300 MHz, CDCl3) delta 7.90 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.17 - 7.20 (m, 2H), 6.94 (s, 1H), 6.84 (m,1H), 5.35 (s, 2H), 5.24 (m, 1H), 5.00 (m, 2H), 4.79 (m, 2H), 3.66 (m, 1H), 3.08 (m, 1H), 2.81 (m, 1H), 2.15 (m, 1H), 1.84- 1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.30 - 1.45 (m, 4H); LCMS (ESI) m/z 491 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Step 1: To a stirred solution of 4-amino-3-nitrophenol (1.37 g, 8.91 mmol) in DMF (15 mL) at rt was addedcesium carbonate (5.79 g, 17.82 mmol) and the mixture was stirred for 30 min. Oxetan-3-yl-4-methylbenzenesulfonate(3.05 g, 13.36 mmol) was added and the mixture was heated at 80 C for 6 h. The mixture was cooled to rt and partitionedbetween EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc.The combined organic layers were washed with brine. The organic layer was separated, dried over MgSO4, filtered, andconcentrated under reduced pressure. The solid residue was purified by trituration with diethyl ether to afford 2-nitro-4-(oxetan-3-yloxy)aniline (1.33 g, 71%) as a brown solid. 1H NMR (500 MHz, DMSO-d6) delta 7.29 (br s, 2H), 7.15 (dd, J =9.2, 3.0 Hz, 1H), 7.10 (d, J = 3.0 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 5.24 (pentet, J = 4.9 Hz, 1H), 4.87 - 4.93 (m, 2H),4.51 - 4.53 (m, 2H); LCMS (ESI) m/z 211 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.4% | With caesium carbonate; In N,N-dimethyl-formamide; at 65 - 80℃; for 26h; | (Step 5) 5-Chloro-N-{4-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-2,2-dimethyl-4-oxobutyl}-2-(oxetan-3-yloxy)benzamide (0373) 5-Chloro-N-{4-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-2,2-dimethyl-4-oxobutyl}-2-hydroxybenzamide (0.131 g, 0.27 mmol) synthesized in step 4 was dissolved in N,N-dimethylformamide (4.0 mL). To the solution, cesium carbonate (0.132 g, 0.41 mmol) and 3-tosyloxyoxetane (0.124 g, 0.54 mmol) were added, and the mixture was reacted at 65C for 6 hours. 3-Tosyloxyoxetane (0.100 g, 0.44 mmol) was further added thereto, and the mixture was reacted at 80C for 20 hours. The reaction solution was brought back to room temperature, and water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the obtained crude product was purified by amino silica gel column chromatography (Biotage Japan Ltd., eluting solvent: hexane/ethyl acetate/methylene chloride ? ethyl acetate/methanol/methylene chloride = 67/28/5 to 0/95/5 ? 95/0/5 to 81/14/5) and concentrated, and the obtained solid was suspended in ethyl acetate, then collected by filtration, and dried to obtain the title compound (0.096 g, yield: 67.4%) as a solid. 1H-NMR (CDCl3) delta: 8.44 (1H, s), 8.21 (1H, d, J = 2.7 Hz), 8.17 (1H, t, J = 6.8 Hz), 7.46-7.42 (4H, m), 7.35-7.33 (1H, m), 7.29-7.28 (1H, m), 6.40 (1H, d, J = 8.8 Hz), 5.35-5.30 (1H, m), 5.02-5.01 (2H, m), 4.85-4.83 (2H, m), 3.58 (2H, d, J = 6.8 Hz), 3.09 (3H, s), 2.30 (2H, s), 2.27 (3H, s), 1.13 (6H, s). MS (ESI) m/z : 527 [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With 1-methyl-pyrrolidin-2-one; tetra-(n-butyl)ammonium iodide; caesium carbonate; at 150℃; for 2h;Sealed tube; Microwave irradiation; | To a solution of 4-(benzyloxy)-1H-indole 1 (550 mg, 2.45 mmol) in N-methyl-2- pyrrolidone (5 mL) were added <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (840 mg, 3.68 mmol), Cs2CO3 (1.6 g, 4.91 mmol) and tetrabutylammonium iodide (453 mg, 1.23 mmol). The reaction mixture was sealed, placed in a microwave synthesizer, and heated at 150 C for 2 h. The reaction mixture was cooled to RT, diluted with ice cold water (30 mL) and extracted with Et20 (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 2-4% EtOAc in hexanes), to afford compound 2 (200 mg, 32%) as pale yellow sticky liquid. ?HNMR (500MHz, CDC13): 7.50 (d, J= 7.2 Hz, 2H), 7.40 (t, J= 7.5 Hz, 2H), 7.36-7.31 (m, 2H), 7.16-7.07 (m, 2H), 6.78 (d, J= 3.2 Hz, 1H), 6.61 (d, J= 7.5 Hz, 1H), 5.60-5.53 (m, 1H), 5.24 (s, 2H), 5.16 (t, J 7.2 Hz, 2H), 5.09 (t, J= 6.1 Hz, 2H); LCMS Mass: 279.9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
118 mg | To a solution of 3-hydroxybenzaldehyde (0.16 g, 1 .31 mmol) in DMF (4 mL) was added Cs2C03 (0.64 g, 1 .97 mmol). The mixture is stirred 10 minutes, and 3-tosyloxyoxetane (0.45g, 1 .97 mmol) was added in one portion, followed by heating to 100C overnight. The reaction mixture was then cooled, filtered through a pad of celite and the filter pad was rinsed with ethyl acetate. The organics were then diluted with ethyl acetate, washed 3X with water, dried with brine and Na2S04, and evaporated. The crude residue was purified by flash chromatography on silica using 7:3 hexanes:ethyl acetate as eluent, providing 1 18 mg of the title compound as a pale green liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 48h; | Example 261: Preparation of 3-(3-chloro-4-fluorophenyl)-5-(2-(3-fluoropyrrolidin-1-yl)- 2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one: (0447) (0448) [00195] To a solution of 3-(4-fluoro-3-(trifluoromethyl)phenyl)-5-(2-(3-fluoropyrrolidin- 1-yl)-2-oxoethyl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.1 g, 0.25 mmol) in N,N- dimethylformamide (5 mL), <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (0.14 g, 0.64 mmol) and cesium carbonate (0.25 g, 0.77 mmol) were added. The reaction mixture was heated at 100 C for 48 h. After completion of the reaction, the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated to afford the crude product which was purified by silica gel column chromatography using 2% methanol in dichloromethane to afford the title compound 3-(3-chloro-4-fluorophenyl)-5-(2-(3- fluoropyrrolidin-1-yl)-2-oxoethyl)-1-(oxetan-3-yl)-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.0055 g, 5% yield) as pale yellow solid.1H-NMR (DMSO-d6, 400 MHz) delta (ppm): 8.19 (dd, J = 2 Hz, 7.2 Hz, 1H), 7.95 (s, 1H), 7.9-7.87 (m, 1H), 7.37-7.32 (m, 2H), 6.62 (d, J = 7.2 Hz, 1H), 5.69-5.65 (m, 1H), 5.49-5.25 (m, 1H), 4.99-4.71 (m, 6H), 3.89-3.32 (m, 4H), 2.31-1.94 (m, 2H). Calculated (M+H): 448.12, Found (M+H): 448.1, HPLC purity: 97.34%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28 mg | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h; | to the DMF solution (1.0 mL) of {1-[6-(3-cyano-2-methoxymethoxy-phenyl)-3-(3-fluoro-5-hydroxy-phenyl)-quinolin-4-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (0.16 mmol, 100 mg) was added 3-tosyloxyoxetane (10 eq., 1.6 mmol, 365 mg) and K2CO3 (10 eq., 1.6 mmol, 220 mg) portion-wise. The resulting mixture was heated at 80 C. for 5 hrs. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was separated, dried with MgSO4 and concentrated. The residue obtained was purified by silica gel chromatography eluting with ethyl acetate/hexane (0?50%) to give 28 mg of the desired product as white solid. MS (M+H)+=655.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 12h; | To a mixture of <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (800 mg, 3.50 mmol) and pyridin- 4-ol (367 mg, 3.86 mmol) in N,N-dimethylformamide (10 mL) was added K2CO3 (1453 mg, 10.51 mmol). The mixture was heated to 80 C and stirred for 12 hours. The mixture was poured onto water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were concentrated to give crude 4-(oxetan-3-yloxy) pyridine which was combined with a batch of material that was prepared in a similar manner and purified by column chromatography (PE/EA = 2/1) to give 4-(oxetan-3-yloxy)-pyridine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h; | To a solution of 4- (4-hydroxyphenyl) cyclohexan-1-one (19 g, 100 mmol) in DMF (100 mL) was added <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (23 g, 100 mmol) and Cs2CO3 (33 g, 100 mmol) and the mixture was heated at 80 for 24 hours. Thenthe solvent was evaporated under reduced pressure, the crude product was purified by column chromatography (PE: EA=5: 1) to give product as white solid (19 g in 70% yield). 1H NMR (DMSO-d6) deltaH 7.21 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 5.21-5.26 (m, 1H), 4.91 (t, J = 6.8 Hz, 2H), 4.53 (dd, J = 4.8, 7.2 Hz, 2H), 2.97-3.02 (m, 1H), 2.50-2.60 (m, 2H), 2.23-2.27 (m, 2H), 2.00-2.04 (m, 2H), 1.77-1.88 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h; | To a solution of 121 (1 equiv) in DMF (10 vol) was added potassium carbonate (3 equiv) and <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (2 equiv). The reaction mixture was heated to 100 C for 12 hours. The reaction mixture was quenched with water and the resulting mixture wasextracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by preparative purification to afford 208. ?H NMR (400 MHz, DMSO-d6) 10.33 (s, 1H), 8.94 (d, J= 2.6 Hz, 1H), 8.42 (d, J 2.3 Hz, 1H), 8.21 (s, 1H), 7.62 (d, J= 8.0 Hz, 1H), 7.51 (s, 1H), 7.44 (d, J 8.0 Hz, 1H), 6.02 (d, J = 17.3 Hz, 1H), 5.65 (d, J= 18.0 Hz, 1H), 5.41 - 5.38 (m, 1H), 4.93 - 4.84 (m, 4H), 4.34 - 4.32 (m, 1H), 3.593.58 (m, 1H), 2.65 (s, 3H), 2.64 - 2.63 (m, 1H), 2.58 (s, 3H), 2.04 (s, 3H), 2.01 - 1.98 (m, 1H),1.32 (s, 3H), 1.01 - 0.94 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere; | To a solution of D33 (200 mg, 0.576 mmol) and <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (263 mg, 1 .15 mmol) in DMF (3.0 mL) under argon at room temperature was added CS2CO3 (563 mg, 1 .73 mmol). The reaction was stirred under argon at 90 C overnight. The mixture was diluted with water (25 mL), extracted with EtOAc (3x25 mL). The combined organics were washed with brine (20 mL), dried over anhydrous Na2S04, filtered. The filtrate was concentrated and the crude was purified by prep-TLC (CH2CI2: EtOAc = 3: 1 ) to give the title compound as a white solid (50 mg, yield 21 %).1 H NMR (400 MHz, CDCI3) delta 8.00 (s, 1 H), 5.98 (s, 1 H), 5.40 (t, J= 7.0 Hz, 1 H), 5.15 (t, J= 6.2 Hz, 2H), 4.94 (t, J= 6.8 Hz, 2H), 4.54 (t, J = 5.4 Hz, 2H), 3.79 (dd, J= 1 1.8, 5.4 Hz, 2H), 2.58 (s, 3H), 2.26-2.20 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41.6% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | 1e (749 mg, 4.7 mmol) was dissolved in 15 mL of N,N-dimethylformamide, then <strong>[26272-83-3]oxetan-3-yl toluene-4-sulfonate</strong> 6a (1.61 g, 7.05 mmol, prepared according to the method disclosed in the patent application "WO2013056070") and cesium carbonate (3.06 g, 9.4 mmol) were added, and the reaction solution was stirred for 3 hours at 60 C. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by CombiFlash rapid preparation instrument with elution system A to obtain the title compound 6b (420 mg, light yellow oil, yield: 41.6%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | (R) -2-Chloro-6- (3-methoxytetrahydrofuran-3-yl) pyridin-4-ol (0.300 g, 1.306 mmol) cooled to about 0 C.Dimethylformamide (DMF) of (Preparation Example 21)To a solution in (10.89 mL), NaH (60% dispersion in mineral oil) (0.063 g, 1.568 mmol) was added.The reaction is stirred for about 10 minutes,Then a solution of <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (0.358 g, 1.568 mmol) in 1 mL DMF was added slowly.The reaction was heated to about 100 C. for about 16 hours.The temperature was then raised to 115 C. for about 2 hours.The reaction was cooled to room temperature and then brine (30 mL) and ethyl acetate (50 mL) were added. Separate the aqueous layer,The organic layer was washed with brine (20 mL).The organic layer is dried over MgSO4, filtered,Concentrate under reduced pressure to give a residue that isPurification by silica gel chromatography eluting with 10-70% ethyl acetate / heptane gave the product (0.325 g, 87% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.2% | To a mixture of tert-butyl 4-(5-chloro-lH-indol-3-yl)piperidine-l-carboxylate (1 g, 2.99 mmol, BB9, intermediate step b) in DMF (20 mL) was added NaH 60% in mineral oil (143.35 mg, 3.58 mmol) at 0C. The mixture was stirred at 20C for 1 hour, and then <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (1022.55 mg, 4.48 mmol; CAS RN 26156-48-9) was added and the mixture was stirred at 85C for 12 hours. The mixture was poured into 1120 (60 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and concentrated over vacuum to afford the title compound as light yellow solid (1.1 g, 2.81 mmol, 94.2%). MS (ESI): m/z = 291.1 [M-Boc+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h; | To a suspension of the product of Example 1H (0.100 g, 0.249 mmol) and cesium carbonate (0.324 g, 0.994 mmol) in dimethylformamide (1 mL) was added oxetan-3-yl-4- methylbenzenesulfonate (0.170 g, 0.746 mmol) and the resulting mixture was heated to 60 C. After 2 hours, the reaction mixture was cooled to ambient temperature, quenched with 1 M hydrochloric acid (2 mL) and diluted with ethyl acetate (2 mL). The aqueous layer was extracted with ethyl acetate (2 x 2 mL). The organic layers were combined and washed with saturated aqueous ammonium chloride (4 x 1 mL) followed by a 4:1 mixture of brine and 1 M hydrochloric acid, dried over anhydrous sodium sulfate, then filtered and concentrated under reduced pressure to give 5-{3-(benzyloxy)-l-fluoro-7-[(oxetan-3-yl)oxy]naphthalen-2-yl}- 1 /',2,5-thiadiazolidinc- 1, 1,3-trione , which was used without purification for the next reaction. MS (EST) m/z 457 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate; In dimethyl sulfoxide; at 60℃;Inert atmosphere; | Using 3-bromo-4-fluorothiophenol (1 g, 5 mmol) in Example 33 as a raw material, under a nitrogen atmosphere, this was mixed with cyclobutyl bromide (810 mg, 6 mmol) and potassium carbonate (1.36 g, 10 mmol). ) Reaction at 60 degrees in 10 ml of dimethyl sulfoxide overnight. The system was diluted with water, extracted with ethyl acetate, the organic phase was washed with water, washed with saturated brine, dried, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain the compound (3-bromo-4 -Fluorophenyl) (cyclobutyl) sulfane (1.2 g, 92%).[1260]1H NMR (400MHz, d-CDCl 3): delta 7.47 (dd, J = 2.4, 6.4 Hz, 1H), 7.22-7.18 (m, 1H), 7.07 (t, J = 8.4 Hz, 1H), 3.35- 3.47 (m, 1H), 2.01-1.65 (m, 6H).; Taking 3-bromo-4-fluorothiophenol as a raw material, referring to the first step of Example 74, replacing cyclobutyl bromide with m-butyl-3-yl 4-methylbenzenesulfonate to obtain compound 3-( (3-Bromo-4-fluorophenyl)thio)oxabutyl ring (90%).[1358]1H NMR (400MHz, d-CDCl3): delta 7.47 (dd, J = 2.4, 6.4 Hz, 1H), 7.22 - 7.18 (m, 1H), 7.07 (t, J = 8.4 Hz, 1H), 5.07 (t , J = 7.6 Hz, 1H), 4.62 (t, J = 6.4 Hz, 2H), 4.44 - 4.37 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 14h; | 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%). |
Tags: 26272-83-3 synthesis path| 26272-83-3 SDS| 26272-83-3 COA| 26272-83-3 purity| 26272-83-3 application| 26272-83-3 NMR| 26272-83-3 COA| 26272-83-3 structure
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P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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