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CAS No. : | 25637-18-7 | MDL No. : | MFCD06797467 |
Formula : | C5H9IO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JTRNQTFTRDPITG-UHFFFAOYSA-N |
M.W : | 212.03 | Pubchem ID : | 2795506 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 38.08 |
TPSA : | 9.23 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) : | -6.48 cm/s |
Log Po/w (iLOGP) : | 1.92 |
Log Po/w (XLOGP3) : | 1.57 |
Log Po/w (WLOGP) : | 1.6 |
Log Po/w (MLOGP) : | 1.49 |
Log Po/w (SILICOS-IT) : | 2.5 |
Consensus Log Po/w : | 1.82 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.14 |
Solubility : | 1.52 mg/ml ; 0.00718 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.37 |
Solubility : | 8.96 mg/ml ; 0.0422 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.74 |
Solubility : | 3.9 mg/ml ; 0.0184 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.97 |
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 |
---|---|---|
64.3% | With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | A RBF was charged with tetrahydro-2H-pyran-4-ol (2.0 g, 19.58 mmol), imidazole (1.600 g, 23.50 mmol), triphenylphosphine (5.39 g, 20.56 mmol), and tetrahydrofuran (39.2 ml) and cooled to 0° C. A solution of iodine (5.96 g, 23.50 mmol) in tetrahydrofuran (39.2 ml) was added slowly dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 80 g, gradient elution 0-50percent EtOAc:Heptane) to afford 4-iodotetrahydro-2H-pyran (2.67 g, 12.59 mmol, 64.3percent yield) as a clear light yellow oil. |
51% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 15℃; for 16 h; Inert atmosphere | To a solution of tetrahydropyran-4-ol (15.0 g, 146 mmol, 14.71 mL) in dichloromethane (600 mL) was added PPh3 (50.0 g, 191 mmol) and imidazole (15.0 g, 220 mmol). The mixture was stirred at 0 °C and iodine (44.7 g, 176 mmol) was added in portions under a nitrogen atmosphere. Finally, the mixture was stirred at 15 °C for 16 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to get a residue. The residue was diluted with water (150 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether: dichloromethane = 1:0 to 2:1) to give the title compound (16.0 g, 51percent yield) as a colorless oil.1H NMR (400MHz, CDCl3) δ = 4.48 - 4.41 (m, 1H), 3.80 (td, J = 4.4, 11.6 Hz, 2H), 3.56 - 3.46 (m, 2H), 2.20 - 2.09 (m, 4H). |
9.6 g | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0 - 20℃; for 2 h; Inert atmosphere | Synthesis of compound 97.2. [00609] A solution of oxan-4-ol, compound 97.1 (7.0 g, 68.54 mmol, 1.00 equiv) in dichloromethane (100 mL) was added triphenylphosphine (27.0 g, 102.94 mmol, 1.50 equiv) and imidazole (7.0 g, 102.82 mmol, 1.50 equiv) at room temperature. This was followed by addition of iodine (18.3 g, 72.05 mmol, 1.05 equiv) in several batches at 0°C. The resulting solution was stirred for 2 h at room temperature under nitrogen. After completion, the reaction was quenched with 5percent HC1 solution, extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to afford 9.6 g of 4-iodooxane, compound 97.2 as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.3% | With 1H-imidazole; iodine; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; | A RBF was charged with tetrahydro-2H-pyran-4-ol (2.0 g, 19.58 mmol), imidazole (1.600 g, 23.50 mmol), triphenylphosphine (5.39 g, 20.56 mmol), and tetrahydrofuran (39.2 ml) and cooled to 0 C. A solution of iodine (5.96 g, 23.50 mmol) in tetrahydrofuran (39.2 ml) was added slowly dropwise. The reaction was warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 80 g, gradient elution 0-50% EtOAc:Heptane) to afford 4-iodotetrahydro-2H-pyran (2.67 g, 12.59 mmol, 64.3% yield) as a clear light yellow oil. |
51% | With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 15℃; for 16h;Inert atmosphere; | To a solution of tetrahydropyran-4-ol (15.0 g, 146 mmol, 14.71 mL) in dichloromethane (600 mL) was added PPh3 (50.0 g, 191 mmol) and imidazole (15.0 g, 220 mmol). The mixture was stirred at 0 C and iodine (44.7 g, 176 mmol) was added in portions under a nitrogen atmosphere. Finally, the mixture was stirred at 15 C for 16 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to get a residue. The residue was diluted with water (150 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether: dichloromethane = 1:0 to 2:1) to give the title compound (16.0 g, 51% yield) as a colorless oil.1H NMR (400MHz, CDCl3) delta = 4.48 - 4.41 (m, 1H), 3.80 (td, J = 4.4, 11.6 Hz, 2H), 3.56 - 3.46 (m, 2H), 2.20 - 2.09 (m, 4H). |
50% | With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 45℃; for 14h; | 4-Hydroxytetrahydro-2H-pyran 33a (2.04 g, 20 mmol), triphenylphosphine (6.81 g, 26) and imidazole (2.04 g, 30 mmol) were dissolved in dichloromethane (100 mL), and cooled to 0 C., then added iodine (6.09 g, 24 mmol), and stirred at 45 C. for 14 hours, the reaction was quenched with water and then extracted with ethyl acetate (50 mL*2), the organic phases were combined and dried over anhydrous sodium sulfate, the desiccant was removed by filtering, and the reaction system was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=1/1), so as to obtain the title product 4-iodotetrahydro-2H-pyran 33b (2.12 g, white solid), and the yield was 50%. 1H NMR (400 MHz, DMSO-d6) delta 4.62 (dt, J=13.9, 4.5 Hz, 1H), 3.68-3.64 (m, 2H), 3.47-3.42 (m, 2H), 2.13-1.97 (m, 4H). |
9.6 g | With 1H-imidazole; iodine; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere; | Synthesis of compound 97.2. [00609] A solution of oxan-4-ol, compound 97.1 (7.0 g, 68.54 mmol, 1.00 equiv) in dichloromethane (100 mL) was added triphenylphosphine (27.0 g, 102.94 mmol, 1.50 equiv) and imidazole (7.0 g, 102.82 mmol, 1.50 equiv) at room temperature. This was followed by addition of iodine (18.3 g, 72.05 mmol, 1.05 equiv) in several batches at 0C. The resulting solution was stirred for 2 h at room temperature under nitrogen. After completion, the reaction was quenched with 5% HC1 solution, extracted with dichloromethane (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to afford 9.6 g of 4-iodooxane, compound 97.2 as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 72h; | NEt3 (1. 3mL, 9. 0MMOL) and <strong>[25637-18-7]4-iodotetrahydropyran</strong> (1.93g, 9. 0MMOL) were added to a stirred solution of ethyl (4-MERCAPTOPHENYL) acetate (1. 21g, 6. 0mmol) in anhydrous DMF (LOML) at 0 C. The mixture was allowed to warm to room temperature over 3d, then the solvents were removed under reduced pressure. The residue was partitioned between Et20 (LOOML) and saturated aqueous NH4CL (50ML), the aqueous phase being extracted further with ET20 (45mL). The combined ethereal extracts were washed with H20 (50ML), H20-SATURATED aqueous NA2C03 (1: 1, 50ML), and brine (50ML), before being dried (MGS04). Filtration, solvent evaporation, and flash chromatography (IH-ET20, 10: 1 to 2: 1) afforded the title compound: RF (IH-ET20, 2: 1) =0. 31. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With ammonium chloride; triethylamine; triphenylphosphine; In tetrahydrofuran; diethyl ether; hexane; dichloromethane; ethyl acetate; | Example 16 1-(2-(N,N-diethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indazole Rieke zinc (5 g/100 mL, 1.25 mL, 0.96 mmol) was added to a flame-dried vial containing <strong>[25637-18-7]4-iodotetrahydropyran</strong> (136.7 mg, 0.64 mmol) under argon and stirred at room temperature for 2 h. In a separate flame-dried vial under argon at 0° C., ethyl magnesium bromide in THF (1M, 0.13 mL, 0.13 mmol) was added to a mixture of NiCl2((PPh3)2 (28.8 mg, 0.044 mmol) and PPh3 (25 mg, 0.095 mmol) in Et2O (0.6 mL). The reaction was allowed to stir at 0° C. for 10 min and room temperature for 10 min. A solution of 6-bromo-1-(2-(N,N-diethylamino)ethyl)-1H-indazole (95 mg, 0.32 mmol) in Et2O was added to the catalyst solution by cannula under a positive pressure of argon, along with NMP (2 mL) to rinse vial. The prepared 4-iodozinctetrahydropyran solution was then quickly transferred by cannula under a positive pressure of argon, again using NMP (2 mL) to rinse vial. The septum was replaced with a pressure cap maintaining a steady flow of argon during replacement, and the mixture was heated at 40° C. for 18 h. The mixture was then cooled to room temperature and quenched by adding a saturated aqueous solution of ammonium chloride (5 mL). Once the zinc was completely quenched, the ammonium chloride was neutralized with aqueous sodium bicarbonate (25 mL) and the product was partitioned between 9:1 hexane: dichloromethane (150 mL) and the aqueous phase. The organic extracts were washed sequentially with water (50 mL) and brine (50 mL) and dried over anhydrous sodium sulfate. Flash chromatography (silica gel, 2-5percent 2M methanolic ammonia in dichloromethane) yielded an impure product which was further purified by flash chromatography (silica gel, 4percent triethylamine in hexane with 0-20percent added ethyl acetate) yielding 1-(2-(N,N-diethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indazole (32.6 mg, 34percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(b) 1-(2-(N,N-dimethylamino)ethyl)-6-(tetrahydropyran-4-yl)-1H-indazole (20 mg, 60percent); from <strong>[25637-18-7]4-iodotetrahydropyran</strong> (291 mg, 1.37 mmol) and of 6-bromo-1-(2-(N,N-dimethylamino)ethyl)-1H-indazole (32.8 mg, 0.12 mmol). The second flash chromatography was not required in this case. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 80℃; | Example 174: N-(5-chlorothiazol-2-yl)-3-cyclohexyl-2-(6-methyl-2-oxo-4-(tetrahydro- 2H-pyran-4-ylsulfonyl)pyridin- 1 (2H)-yl)propanamide; [0349] Compound 174 A was synthesized using the procedure described in connection with compound 3. To a solution of compound 174A (1.315 g, 3.85 mmol) in DMF (14 ml) was added a solution of sodium sulfhydrate (323.0 mg, 5.77 mmol) in H2O (3 ml). The reaction mixture was subjected to microwave heating at 100 0C for 30 minutes. The reaction solution was diluted with water and extracted with ethylacetate, dried over magnesium sulfate, concentrated under high vacuum to yield compound 174B 1.043 g. To a solution of compound 174B (500.0 mg, 1.69 mmol) in DMF (8 ml) was added sodium hydride at 00C, followed by a solution of <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong>. The mixture was <n="142"/>heated under nitrogen at 80 0C overnight. The reaction solution was diluted with water and extracted with ethylacetate, dried over magnesium sulfate, and concentrated under high vacuum to yield compound 174C (273 mg). Compound 174C was oxidized with m- chloroperoxybenzoic acid to yield compound 174D. Compound 174 was generated using the procedure described in connection with compound 9. [M+H] calc'd for C22H28ClN3O5S2 515.06; found 515. 1H NMR (400 MHz, MeOD). delta ppm 1.04 (m, IH) 1.28 (m, IH) 1.59 (m, 5H) 1.84 (m, 6H) 2.12 (m, IH) 2.60 (m, 4H) 3.41 (m, 2H) 3.54 (m, IH) 4.03 (m, 2H) 5.29 (m, IH) 6.69 (s, IH) 6.82 (s, IH) 7.29 (s, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | The product from step 1 (3.0 g, 16.07 mmol) was added to a suspension of sodium hydride (964.3 mg, 32.14 mmol) in DMF at 0 0C. After 5 min <strong>[25637-18-7]4-iodo-tetrahydro-pyran</strong> (3.41 g, 16.07 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched with water at 0 0C and neutralized with trifluoroacetic acid. Evaporation and purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (1.385 g , 32percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a 2M solution of lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene (18 ml_, 35.9 mmol, 1.5 eq.) at -78 0C was added dropwise a solution of 1 ,4-dioxa- spiro[4.5]decane-8-carbonitrile (commercially available or via literature procedure described for example in Becker et al. Synthesis 1992, 11 , 1080-1082; 4.0 g, 23.9 mmol) in tetrahydrofuran (40 mL). After stirring for 30 min at -78 0C, 4-iodotetrahydro- 2H-pyran (5.1 g, 23.9 mmol, 1 eq.) was added carefully. The reaction mixture was allowed to warm to room temperature over night before being quenched by slow addition of ethanol (10 mL) and water (20 mL) subsequently. The resulting suspension was filtered through celite and extracted three times with dichloromethane. The combined organic phases were concentrated in vacuo and purified by flash chromatography (SiO2, 0percent --> 30percent methanol in dichloromethane) to give 2.80 g of 8- (tetrahydropyran-4-yl)-1 ,4-dioxa-spiro[4.5]decane-8-carbonitrile (5). Rt = 1.03 min (Method B). Detected mass: 252.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.6% | 0.49 mmol) in N,N-dimethylformamide (6 mL) was added to a mixture of sodium hydride (29 mg, 60percent in mineral oil, 0.74 mmol) and N,N-dimethylformamide (6 mL) under an atmosphere of argon, and the resulting mixture was stirred for 30 minutes. 4- EPO <DP n="171"/>iodotetrahydro-2H-pyran (0.16 g, 0.74 mmol) in N,N-dimethylformamide (6 mL) was then added and the reaction was heated at 60 °C for 50 hours. After cooling, the reaction mixture was concentrated and the residue diluted with water/acetonitrile (40 mL) and filtered (0.45 mum). The product was purified by preparative HPLC using a gradient of 20- 80percent acetonitrile:water (with 0.1percent formic acid and a flow rate of 45 mL/min to afford 10 mg (4.6percent) of 3-ethyl-6- { 1 -[4-methylsulfonyl)phenyl]- 1 H-pyrazol-5-yl} - 1 (tetrahydro- 2H-pyran)-lH-indazole as a yellow solid. LC/MS (EI) tR 4.54 (Method A), m/z 451.2 (M++.). 1H NMR (CDCl3) delta 1.4 (t, 3H); 1.9 (d, 2H);2.4 (m, 2H); 3.0 (m,lH); 3.1 (s, 3H); 3.6 (m, 3H); 4.1 (d, 2H); 4.5 (m, IH); 6.6 (s, IH); 6.9 (d, IH); 7.2-7.3 (m, 3H); 7.5-7.7 (m, 2H); 7.8-7.9 (m, 2H). | |
4.6% | Example 52 3-ethyl-6-{1-[4-methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1(tetrahydro-2H-pyran)-1H-indazole 3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (0.18 g, 0.49 mmol) in N,N-dimethylformamide (6 mL) was added to a mixture of sodium hydride (29 mg, 60percent in mineral oil, 0.74 mmol) and N,N-dimethylformamide (6 mL) under an atmosphere of argon, and the resulting mixture was stirred for 30 minutes. <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (0.16 g, 0.74 mmol) in N,N-dimethylformamide (6 mL) was then added and the reaction was heated at 60° C. for 50 hours. After cooling, the reaction mixture was concentrated and the residue diluted with water/acetonitrile (40 mL) and filtered (0.45 mum). The product was purified by preparative HPLC using a gradient of 20-80percent acetonitrile:water (with 0.1percent formic acid and a flow rate of 45 mL/min to afford 10 mg (4.6percent) of 3-ethyl-6-{1-[4-methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1 (tetrahydro-2H-pyran)-1H-indazole as a yellow solid. LC/MS (EI) tR 4.54 (Method A), m/z 451.2 (M++1). 1H NMR (CDCl3) delta 1.4 (t, 3H); 1.9 (d, 2H); 2.4 (m, 2H); 3.0 (m, 1H); 3.1 (s, 3H); 3.6 (m, 3H); 4.1 (d, 2H); 4.5 (m, 1H); 6.6 (s, 1H); 6.9 (d, 1H); 7.2-7.3 (m, 3H); 7.5-7.7 (m, 2H); 7.8-7.9 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere; | Commercially available (4-Mercapto-phenyl)-acetic acid methyl ester (1.8 g, 9.89 mmol) was dissolved in DMF (20 mL) at 0 °C. To this solution triethylamine (1.5 g, 14.83 mmol) was added and stirred for 15 min followed by addition of 4-iodo-tetrahydropyan (3.14 g, 14.83 mmol). The reaction mixture was stirred overnight at room temperature. Solvent was removed under reduced pressure, the resulting residue was taken into water and extracted with ethyl acetate (50 mL x 2). Combined organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by slica gel column chromatography (15percent ethyl acetate in hexanes as eluent) to provide 19b (2.1 g, 80percent). 1HNMR (CDCl3, 400 MHz): delta 1.65-1.72 (m, 2H), 1.89-1.92 (m, 2H), 3.25-3.26 (m, 1H), 3.62 (s, 2H), 3.71 (s, 3 H), 3.86-4.00 (m, 2 H), 7.39 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H); LC-MS (m/z): 267.20 (M+1). |
With triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; | (4-Mercapto-phenyl)-acetic acid methyl ester (1.8 g, 9.89 mmol) was dissolved in DMF (20 ml) at 0° C. Triethylamine (1.5 g, 14.83 mmol) was added and stirred for 15 minutes followed by addition of 4-iodo-tetrahydropyan (3.14 g, 14.83 mmol). The reaction mixture was stirred overnight at room temperature. Solvent was removed under reduced pressure, the resulting residue was taken into water and extracted with ethyl acetate (50 ml*2) washed with water and brine (50 ml each) dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product which was purified by column chromatography over silica gel using 15percent ethyl acetate in hexanes as eluent to provide [4-(Tetrahydro-pyran-4-ylsulfanyl)-phenyl]acetic acid methyl ester (2.1 gm). 1H-NMR (CDCl3, 400 MHz):-delta 1.65-1.72 (m, 2H), 1.89-1.92 (m, 2H), 3.25-3.26(m, 1H), 3.62 (s, 2H), 3.71 (s, 3H), 3.86-4.00 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H). MS (EI) m/z: 267.20 (M+1). | |
(4-Mercapto-phenyl)-acetic acid methyl ester (1.8 gm, 9.89 mmol) was dissolved in DMF (20 ml) at 0° C. Triethylamine (1.5 gm, 14.83 mmol) was added and stirred for 15 minutes followed by addition of 4-iodo-tetrahydropyran (3.14 gm, 14.83 mmol).The reaction mixture was stirred overnight at room temperature.Solvent was removed under reduced pressure, the resulting residue was taken into water and extracted with ethyl acetate (50 ml x 2) washed with water and brine (50 ml each) dried over anhydrous sodium sulfate, fliltered and concentrated to obtain a crude product which was purified by column chromatography over silica gel using 15 percent ethyl acetate in hexanes as eluent to provide [4-(Tetrahydro-pyran-4-ylsulfanyl)-phenyl]-acetic acid methyl ester (2.1 gm).1HNMR (CDCl3, 400 MHz):- delta 1.65-1.72 (m, 2H), 1.89-1.92 (m, 2H), 3.25-3.26(m, 1H), 3.41-3.46 (m, 2H), 3.62 (s, 2H), 3.71 (s, 3 H), 3.86-4.00 (m, 2 H), 7.39 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H). MS (EI) m/z: 267.20 (M+1). |
Step-II: [4-(Tetrahydro-pyran-4-ylsulfanyl)-phenyl]-acetic acid methyl ester:(4-Mercapto-phenyl)-acetic acid methyl ester (3.8 g, 20.85 mmol) was dissolved in DMF (40 mL) at 0° C. Triethylamine (3.16 g, 31.27 mmol) was added and stirred for 15 minutes followed by addition of 4-iodo-tetrahydropyan (6.63 g, 31.27 mmol). The reaction mixture was stirred overnight at room temperature. Solvent was removed under reduced pressure, the resulting residue was taken into water and extracted with ethyl acetate (2 X 100 mL) washed with water and brine (100 mL each) dried over anhydrous sodium sulfate, fliltered and concentrated under reduced pressure to obtain a crude product which was purified by column chromatography over silica gel using 15 percent ethyl acetate in hexanes as eluent to provide [4-(Tetrahydro-pyran-4- ylsulfanyl)-phenyl] -acetic acid methyl ester (2.4 g).*HNMR (CDCI3, 400 MHz):- delta 1.62-1.72 (m, 2H), 1.85-1.92 (m, 2H), 3.21-3.29 (m, 1H), 3.38- 3.46 (m, 2H) 3.60 (s, 2H), 3.70 (s, 3 H), 3.94-4.00 (m, 2 H), 7.22 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H); MS (EI) m/z: 267.20 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | EXAMPLE 6: 5-CHLORO-2-(l-(6-(TETRAHYDRO-2H-PYRAN-4-YL)PYRIMIDIN-4- YL)AZETIDTN-3 -YL)- 1 H-BENZO [ ]IMIDAZOLESTEP 1. 4-CHLORO-6-(TETRAHYDRO-2H-PYRAN-4-YL)PYRIMIDTNE; [00207] Step la. Preparation of Zinc Reagent.[00208] To a suspension of zinc dust (0.70 g, 10.75 mmol) in DMA (9 mL) was added 0.32 mL of a 7:5 v/v mixture of TMSCl/l,2-dibromoethane over 5 min. The solution was stirred for an additional 15 min and <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (1.9 g, 8.96 mmol) was added over 15 min. After the addition, the mixture was stirred for an additional 30 min before being used directly in the next step (see below).[00209] Step lb. A mixture of copper(I) iodide (0.067 g, 0.35 mmol), Pd(dppf)Cl2 (0.14 g, 0.18 mmol) , and 4,6-dichloropyrimidine (0.52 g, 3.50 mmol) in DMA (3 mL) was placed under argon atmosphere using 3 evacuation/backfill cycles. The zinc reagent prepared in Step la above (4.5 mL, about 4.5 mmol) was added dropwise via syringe and the mixture was heated to 80 °C for 4 h, then cooled to RT. Ethyl acetate and saturated aqueous ammonium chloride were added, the resulting layers were separated, and the organic layer was washed with water (2x), brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography to give 4-chloro-6-(tetrahydro-2H-pyran-4- yl)pyrimidine (0.13 g, 0.64 mmol, 14percent yield) as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; | METHOD G:Step 1: 4-(4-Bromophenyl)sulfanyltetrahydropyran[00159] 4-Iodotetrahydropyran (9 g, 42.45 mmol) was added to a stirred suspension of 4- bromobenzenethiol (7.296 g, 38.59 mmol) and potassium carbonate (10.67 g, 77.18 mmol) in DMF (15 mL) and the reaction stirred at ambient temperature for 3 hours. The mixture was diluted with Et20 and washed with water (x 2) and brine (x 1). The organic extracts was dried (MgS04) and concentrated in vacuo. Petroleum ether was added to the residue and the resultant precipitate removed by filtration. The filtrate was concentrated in vacuo to give the sub-title compound as a light yellow oil (9.0 g, 85percent Yield). XH NMR (400.0 MHz, CDC13) delta 1.63-1.73 (m, 2H), 1.89-1.93 (m, 2H), 3.23-3.30 (m, 1H), 3.45 (td, 2H), 3.99 (dt, 2H), 7.31 (d, 2H) and 7.45 (d, 2H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.8% | [0184] 7-Iodo-2H-pyrazolo[4,3-b]pyridine (50mg, 0.204 mmol), <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (43.3 mg, 0.204 mmol) and sodium hydride (9.79 mg, 0.408 mmol) were combined in DMF (5mL). The mixture was stirred at room temperature for 1 hour and then purified by preparative HPLC using a Sunfire Prep 5muiotaeta CI 8, 75 X 30 mm column eluting with a gradient of 20 - 70percent acetonitrile (containing 0.035percent TFA) in water (containing 0.05percent TFA) to afford 7-iodo-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazolo[4,3-b]pyridine as a TFA salt (22mg, 32.8 percent yield). MS [M+H] found 330.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With nickel(II) iodide; trans-2-aminocyclohexanol hydrochloride; sodium hexamethyldisilazane; In isopropyl alcohol; at 75℃; for 15h;Inert atmosphere; | 186 mg (0.594 mmol) of nickel(II) iodide, 90 mg (0.594 mmol) of trans-2-aminocyclohexanol hydrochloride and 3.63 g (19.8 mmol) of sodium hexamethyldisilazide were added to a solution of 2.91 g (19.8 mmol) of 4-cyanophenylboronic acid [M. Nishimura et al., Tetrahedron 2002, 58 (29), 5779-5788] in 20 ml of isopropanol. The suspension obtained in this way was stirred at RT under an argon atmosphere for 5 min. 2.1 g (9.90 mmol) of <strong>[25637-18-7]4-iodotetrahydropyran</strong> [Heuberger et al., J. Chem. Soc. 1952, 910] were then added. After the reaction mixture had been stirred at a temperature of 75° C. for 15 h, it was cooled to RT and largely freed from inorganic salts with methylene chloride by filtration over approx. 50 g of silica gel. The crude product was purified byMPLC (silica gel, mobile phase: methylene chloride). 986 mg (53percent of th.) of the title compound were obtained in this way.1H-NMR (400 MHz, CDCl3, delta/ppm): 7.60 (d, 2H), 7.32 (d, 2H), 4.12-4.07 (m, 2H), 3.56-3.50 (m, 2H), 2.87-2.79 (m, 1H), 1.86-1.73 (m, 4H).GC/MS (method K, EIpos): Rt=5.97 min, m/z=187 [M]+. |
53% | 186 mg (0.594 mmol) of nickel(II) iodide, 90 mg (0.594 mmol) of trans-2-aminocyclohexanol hydrochloride and 3.63 g (19.8 mmol) of sodium hexamethyldisilazide were added to a solution of 2.91 g (19.8 mmol) of 4-cyanophenylboronic acid [M. Nishimura et al., Tetrahedron 2002, 58 (29), 5779-5788] in 20 ml of isopropanol. The suspension thus obtained was stirred at RT under an argon atmosphere for 5 min. Then 2.1 g (9.90 mmol) of <strong>[25637-18-7]4-iodotetrahydropyran</strong> [Heuberger et al., J. Chem. Soc. 1952, 910] were added. After the reaction mixture had been stirred at a temperature of 75° C. for 15 h, it was cooled to RT and substantially freed of inorganic salts with dichloromethane by filtration through approx. 50 g of silica gel. The crude product was purified by MPLC (silica gel, eluent: dichloromethane). 986 mg (53percent of theory) of the title compound were obtained.1H NMR (400 MHz, CDCl3, delta/ppm): 7.60 (d, 2H), 7.32 (d, 2H), 4.12-4.07 (m, 2H), 3.56-3.50 (m, 2H), 2.87-2.79 (m, 1H), 1.86-1.73 (m, 4H).GC/MS (method 9, ESIpos): Rt=5.97 min, m/z=187 [M]+. | |
53% | With nickel(II) iodide; sodium hexamethyldisilazane; (1S,2S)-2-hydroxycyclohexylamine hydrochloride; In isopropyl alcohol; at 20 - 75℃; for 15h;Inert atmosphere; | Step 1: 4-(Tetrahydro-2H-pyran-4-yl)benzonitrile 186 mg (0.594 mmol) of nickel (II) iodide, 90 mg (0.594 mmol) of trans-2-aminocyclohexanol hydrochloride and 3.63 g (19.8 mmol) of sodium hexamethyldisilazide were added to a solution of 2.91 g (19.8 mmol) of 4-cyanophenylboronic acid [M. Nishimura et al., Tetrahedron 2002, 58 (29), 5779-5788] in 20 ml of isopropanol. The suspension obtained in this way was stirred at RT under an argon atmosphere for 5 min 2.1 g (9.90 mmol) of <strong>[25637-18-7]4-iodotetrahydropyran</strong> [Heuberger et al., J. Chem. Soc. 1952, 910] were then added. After the reaction mixture had been stirred at a temperature of 75° C. for 15 h, it was cooled to RT and largely freed from inorganic salts with methylene chloride by filtration over approx. 50 g of silica gel. The crude product was purified by MPLC (silica gel, mobile phase: methylene chloride). 986 mg (53percent of th.) of the title compound were obtained in this way. 1H-NMR (400 MHz, CDCl3, delta/ppm): 7.60 (d, 2H), 7.32 (d, 2H), 4.12-4.07 (m, 2H), 3.56-3.50 (m, 2H), 2.87-2.79 (m, 1H), 1.86-1.73 (m, 4H). GC/MS (method L, EIpos): Rt=5.97 min, m/z=187 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
545 mg | a) (5-(Tetrahydro-pyran-4-yl)-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester Preparation of the zinc iodide reagent:A 3 -neck 25 mL flask connected to another 10 mL flask, a rubber septum, and a 2.3 mm PTFE tubing with a upside down needle covered with a filter disc, was charged with 85mg Dicalite and dried by heating in vacuo. Afterwards, zinc dust (367mg) and 3 ml of DMA dried over molecular sieves were added. The mixture was stirred at rt while a 7:5 v/v mixture of chlorotrimethylsilane (66 microliter) and 1,2-dibromoethane (45 microliter) as solution in DMA (1.5ml) was added at a rate to maintain the temperature below 65 °C (slightly exothermic at the beginning; later a warm water bath was used to increase the temperature to -45 °C). The resulting slurry was aged for 15 min. A solution of <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (1 g, 4.72 mmol, Eq: 1.48, CAN 25637-18- 7) in 5.5 ml DMA was slowly added to the mixture prepared above at a rate to maintain the temperature below 65 °C (slightly exothermic at the beginning; later a warm water bath was used to increase the temperature to ~40 °C). The resulting reaction mixture was then aged for 30 min at rt. The suspension was filtered through the filter disc under argon to remove all solids. In a second 25 mL two-necked flask, methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate(1 g, 3.18 mmol, Eq: 1.00, CAN 1211589-51-3) was combined with DMA (4 mL) to give a colorless solution. Copper (I) iodide (60.6 mg, 318 ?????, Eq: 0.1) and PdCl2(DPPF)-CH2Cl2 adduct (116 mg, 159 ?????, Eq: 0.05) were added. The reaction mixture was 3x degassed and purged with argon, then the above prepared solution containing the organozinc reagent was added (3x degassed and purged with argon) and the reaction mixture was stirred over night at 95°C. After cooling, the reaction mixture was quenched with sat. NH4C1 (30 mL) and extracted with EtOAc (2 x 50 mL) .The organic layers were washed with H20/NaCl solution. The organic layers were combined, dried over Na2S04, and concentrated in vacuo. The crude material was purified twice by flash chromatography (silica gel, 70g, 15percent to 35percent EtOAc in heptane) and (silica gel, 70g, 100percent DCM) to finally afford 545 mg of the title compound as white semisolid; MS (EI) 320.0 (M+H)+. | |
545 mg | [0380] Preparation of the zinc iodide reagent:A 3-neck 25 mL flask connected to another 10 mL flask, a rubber septum, and a 2.3 mm PTFE tubing with a upside down needle covered with a filter disc, was charged with 85 mg Dicalite and dried by heating in vacuo. Afterwards, zinc dust (367 mg) and 3 ml of DMA dried over molecular sieves were added. The mixture was stirred at rt while a 7:5 v/v mixture of chlorotrimethylsilane (66 microliter) and 1,2-dibromoethane (45 microliter) as solution in DMA (1.5 ml) was added at a rate to maintain the temperature below 65° C. (slightly exothermic at the beginning; later a warm water bath was used to increase the temperature to ?45° C.). The resulting slurry was aged for 15 min. A solution of <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (1 g, 4.72 mmol, Eq: 1.48, CAN 25637-18-7) in 5.5 ml DMA was slowly added to the mixture prepared above at a rate to maintain the temperature below 65° C. (slightly exothermic at the beginning; later a warm water bath was used to increase the temperature to ?40° C.). The resulting reaction mixture was then aged for 30 min at rt. The suspension was filtered through the filter disc under argon to remove all solids.[0381]In a second 25 mL two-necked flask,methyl 5-bromo-6-(2,2,2-trifluoroethoxy)nicotinate (1 g, 3.18 mmol, Eq: 1.00, CAN 1211589-51-3) was combined with DMA (4 mL) to give a colorless solution. Copper (I) iodide (60.6 mg, 318 mumol, Eq: 0.1) and PdCl2(DPPF)-CH2Cl2 adduct (116 mg, 159 mumol, Eq: 0.05) were added. The reaction mixture was 3× degassed and purged with argon, then the above prepared solution containing the organozinc reagent was added (3× degassed and purged with argon) and the reaction mixture was stirred over night at 95° C.[0382]After cooling, the reaction mixture was quenched with sat. NH4Cl (30 mL) and extracted with EtOAc (2×50 mL). The organic layers were washed with H2O/NaCl solution. The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The crude material was purified twice by flash chromatography (silica gel, 70 g, 15percent to 35percent EtOAc in heptane) and (silica gel, 70 g, 100percent DCM) to finally afford 545 mg of the title compound as white semisolid; MS (EI) 320.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2 g | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere; | Synthesis of compound 97.3 [00611] To a solution of 4-nitro-lH-pyrazole (2.45 g, 21.67 mmol, 1.00 equiv) in freshly distilled DMF (70 mL) was added <strong>[25637-18-7]4-iodooxane</strong>, compound 97.2 (9.2 g, 43.39 mmol, 2.00 equiv) and cesium carbonate (22.2 g, 68.14 mmol, 3.00 equiv) and the resulting solution was stirred for 3 h at 80 °C under nitrogen. The resulting mixture was diluted with 200 mL of water, extracted with CH2CI2 (100 mL x 3) and the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. Crude was purified via flash column chromatography to give 2.0 g of 4-nitro-l-(oxan-4-yl)-lH-pyrazole, compound 97.3 as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With C26H32Cl2FeN3O2; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere; | General procedure: Alkyl halide (Method A: 0.5 mmol, Method B: 0.25 mmol) was dissolved in THF [3.0 mL (A)/1.5 mL (B)] and a stock solution (25 mM) of [Fe(Bopa-tBu)Cl2] (1d) [1.0 mL (A)/0.5 mL (B)] was added. Afterwards PhMgCl (1.00 M) [0.5 mL (A)/0.25 mL (B)] was added over a time period of 15 min. The solution was stirred for another 45 min. Method A: The reaction was then quenched with H2O (20 mL), acidified with aq 1 M HCl, and extracted with CH2Cl2 (3 × 20 mL). The crude extract was dried (Na2SO4) and further purified by chromatography on silica gel (eluent: 1percent to 45percent EtOAc in hexanes). Method B: The reaction was quenched by adding EtOH (0.5 mL). The reaction mixture was transferred on a preparative TLC plate and then further separated (eluent:EtOAc?hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With chloro-trimethyl-silane; iodine; ethylene dibromide; lithium chloride; In tetrahydrofuran; at 50℃; for 18h;Inert atmosphere; | An oven-dried round-bottom flask equipped with a magnetic stir bar and a rubber septum was charged with lithium chloride (0.740 g, 17.45 mmol). The vessel was heated with a heat gun for 10 min under high vacuum and backfilled with nitrogen after cooling to room temperature. Zinc (1.141 g, 17.45 mmol) was added. The vessel was again heated with a heat gun for 10 minutes under high vacuum and backfilled with nitrogen after cooling to room temperature. THF (17.45 ml) and 1,2-dibromoethane (0.038 ml, 0.436 mmol) were added via syringe and the reaction mixture was heated at 60° C. until bubbling occurred. After cooling to room temperature, TMS-Cl (0.033 ml, 0.262 mmol) and a solution of iodine (0.011 g, 0.044 mmol) in THF (0.2 mL) were added via syringe. The reaction mixture was heated at 60° C. for 20 min and then cooled to room temperature. <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (1.011 ml, 8.73 mmol) was added and the reaction was stirred at 50° C. for 18 h. The reaction mixture was allowed to stand at RT for 1 h and the solution was taken up in a syringe. The syringe was fitted with a 0.45 muM filter and the solution was filtered into an oven-dried screw top vial with teflon septum. The solution was titrated by adding dropwise to a 0° C. solution of iodine (0.0204 g, 0.080 mmol) in lithium chloride, 0.5 m in anhydrous tetrahydrofuran (1.0 ml, 0.500 mmol) until the orange color disappeared. 0.29 mL of solution was used, corresponding to a concentration of 0.28 M. | |
With chloro-trimethyl-silane; In N,N-dimethyl acetamide; ethylene dibromide; at 60℃; for 1h;Inert atmosphere; | To a suspension of zinc powder (1.85 g, 28.3 mmol) in redistilled DMA (3.00 mL) under a nitrogen atmosphere was cautiously added a mixture of 1,2-dibromoethane (442 mg, 2.36 mmol, 178 uL) and TMSCl (256 mg, 2.36 mmol, 298 uL) over 10 min at 20 °C. The temperature of the reaction mixture rose to about 60 °C during this period. After stirring for 15 min, a solution of <strong>[25637-18-7]4-iodotetrahydropyran</strong> (5.00 g, 23.5 mmol) in redistilled DMA (8.00 mL) was added over 30 min and stirring was continued for an additional 30 min. The temperature of reaction mixture rose to 70 °C during this period. On completion, the reaction mixture was filtered and the filtrate was used into the next step directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With dmap; N-ethyl-N,N-diisopropylamine; at 75℃; | A mixture of methyl (E)-3-(5-oxo-4,5-dihydro-lH-tetrazol-l-yl)acrylate (50 mg, 0.3 mmol), <strong>[25637-18-7]4-iodotetrahydropyran</strong> ( 0.5 g, 2.4 mmol), DIEA (0.5 mL, 371 mg, 2.9 mmol) and DMAP (50 mg, 0.4 mmol) was allowed to stir at 75 °C overnight. The reaction mixture was cooled down to room temperature, diluted with brine (20 mL) and extracted with DCM (3x20 mL). The combined organic layer was then dried (MgS04), filtered and concentrated to give 560 mg of a brown residue. Column chromatography (Combiflash Isco; 24 g Redisep column; eluted with hexanes for 5 min, 50percent EtOAc/hexanes over 15 min till compound eluted) provided 17 mg (23percent) of compound 12 as a white solid. 1H NMR (300 MHz, CDC13) delta 7.89 (d, / = 14.4 Hz, 1H), 6.68 (d, / = 14.4 Hz, 1H), 4.37 (tt, / = 11.5, 4.3 Hz, 1H), 4.19 - 4.07 (m, 2H), 3.82 (s, 3H), 3.54 (td, / = 11.9, 2.2 Hz, 2H), 2.27 - 2.13 (m, 2H), 2.04 - 1.94 (m, 2H). 13C NMR (75 MHz, CDC13) delta 166.41, 132.38, 108.97, 105.36, 66.90, 52.99, 52.43, 31.41. MS m/e: 255 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With copper(l) iodide; water; zinc; In ethanol; at 20℃; for 5h;Inert atmosphere; Sonication; | Example 7 3-(oxan-4-yl)-A'-[4-oxo-3-(trifluoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]dodeca- l(12),6,8,10-tetraen-3-yl]propanamide (ABR 238816) To a stirred solution of N-[4-oxo-3-(trifiuoromethyl)-2,5,7-triazatricyclo[6.4.0.02'6]-dodeca- 1(8),6,9,1 l-tetraen-3-yl]prop-2-enamide (25 mg, 0.08 mmol) and <strong>[25637-18-7]4-iodooxane</strong> (80 mg, 0.26 mmol) in an EtOH (5 mL) and water (1.5 mL) mix was added zinc dust (101.0 mg, 1.54 mmol) and copper iodide (98.2 mg, 0.51 mmol) under nitrogen. The reaction mixture was sonicated at room temperature for 5 h. The reaction mixture was filtered through celite and washed with EtO Ac (3 x 25 mL). The filtrate was washed with brine (50 mL), dried (MgSO^, filtered and concentrated. The crude product was purified by automated reverse phase HPLC (low pH Method A) to afford the title compound as a white solid (17 mg, 16percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | A solution of compound 152-a (50mg, 0.11 mmol) and cesium carbonate (30 mg, 0.22 mmol) in DMF (4 mE) was stirred at room temperature for 10 minutes, and thereafter compound 152-b (35 mg, 0.17 mmol) was added. The reaction solution was stirred at 70° C. overnight. The reaction solution was quenched with water (20 mE), extracted with ethyl acetate (20 mE), and washed with saturated brine (3*20 mE). The organic phase was dried over anhydrous sodium sulfate, and concentrated. The crude was separated and purified by Prep-HPEC to obtain compound 152 (7 mg, 12percent).EC-MS (ESI): mIz536.2 (M+H). ?H NMR (400 MHz,CDC13): oe8.73 (1H, d, J2.0Hz), 8.39 (1H, d, J2.4 Hz), 6.83(1H, s), 4.87-4.97 (1H, m), 4.11 (3H, s), 4.01-4.09 (2H, m),3.86-3.94 (4H, m), 3.79-3.86 (4H, m), 3.53 (1H, dd, J2.8,8.8 Hz), 3.51 (1H, dd, J2.8, 8.8 Hz), 3.08 (3H, s), 2.49 (3H,s), 1.97-2.09 (2H, m), 1.79-1.92 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | (Step 1) 4-Nitro-2-tetrahydropyran-4-yl-pyridine (0323) (0324) Zinc (19.2 g, 293 mmol) was heated at 210° C. for 10 minutes, cooled to 70° C., then heated to 210° C. again, and the resulting mixture was stirred for 10 minutes. The reaction mixture was cooled to room temperature, then a solution of N,N-dimethylformamide (100 ml) and dibromoethane (6.87 g, 33.6 mmol) in N,N-dimethylformamide (10.0 ml) was added thereto, and the resulting mixture was stirred at 90° C. for 30 minutes. The reaction mixture was cooled to room temperature, then trimethylsilyl chloride (800 mg, 7.30 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 10 minutes. A solution of 4-iodine tetrahydropyran (10.4 g, 49.2 mmol) in N,N-dimethylformamide (60.0 ml) was added to the reaction liquid, and the resulting mixture was stirred at 35° C. for 90 minutes. This zinc derivative was added to a suspension of 2-bromo-4-nitro-pyridine (5.00 g, 24.6 mmol) and Pd(PPh3)2Cl2 (2.60 g, 3.70 mmol) in N,N-dimethylformamide (80.0 ml), and the resulting mixture was stirred in the presence of nitrogen gas at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, then the reaction solution was filtered, and the obtained filtrate was diluted with water (600 ml) and extracted with ethyl acetate (200 ml×3). The extracts were combined, washed with a saturated saline solution, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1 to 5:1) to obtain the title compound (900 mg, 17percent). (0325) 1H NMR (CDCl3, 400 MHz): delta 8.85 (d, J=5.6 Hz, 1H), 7.90-7.86 (m, 2H), 4.15-4.11 (m, 2H), 3.61-3.54 (m, 2H), 3.16-3.10 (m, 1H), 2.00-1.91 (m, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h; | A solution of the compound <strong>[25637-18-7]4-iodo-tetrahydro-2H-pyran</strong> (3.18 g, 15 mmol) was added to ethyl 3-methyl-1H-pyrazole-5-carboxylate (770 mg, 5 mmol) and C52CO3 in DMF (30 mL) was stirred for 18 hours at 60 C. It was quenched by H20 (50 mL) and extracted with EA (3x), dried Na2504, filtered and purified by reverse phase C18 column chromatography(MeCN/H20) to give ethyl 3-methyl-i -(tetrahydro-2H-pyran-4-yl)- 1H-pyrazole-5-carboxylate as a brown oil. (143 mg, 12 %). |
12% | With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h; | A solution of the compound <strong>[25637-18-7]4-iodo-tetrahydro-2H-pyran</strong> (3.18 g, 15 mmol) was added to ethyl 3-methyl-1H-pyrazole-5-carboxylate (770 mg, 5 mmol) and Cs2CO3 in DMF (30 mL) was stirred for 18 hours at 60°C. It was quenched by H2O (50 mL) and extracted with EA (3x), dried Na2SO4, filtered and purified by reverse phase C18 column chromatography (MeCN/H2O) to give ethyl 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-5-carboxylate as a brown oil. (143 mg, 12 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium azide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃; for 2h; | 95b) Methyl 1 -(3'-((S)-1 -cyclohexylethoxy)-[1 ,1 '-biphenyl]-3-yl)-5-((1 R,2R)-2-(1 - (tetrahydro-2H-pyran-4-yl)-1 H-1 ,2,3-triazol-4-yl)cyclopropyl)-1 H-pyrazole-4- carboxylate A mixture of <strong>[25637-18-7]4-iodotetrahydro-2H-pyran</strong> (122 mg, 0.576 mmol), sodium azide (49.9 mg, 0.768 mmol), and DIPEA (0.101 ml_, 0.576 mmol) in Nu,Nu-dimethylformamide (DMF) (1 .2 ml_) was stirred for 2.0 hours at 80°C. The resulting organic azide intermediate solution was transferred to a microwave reaction tube, and it was diluted with Tert-Butanol (1 .5 mL) and Water (0.5 ml_). Methyl 1 -(3'-((S)-1 -cyclohexylethoxy)-[1 ,1 '-biphenyl]-3-yl)-5- ((1 R,2R)-2-ethynylcyclopropyl)-1 H-pyrazole-4-carboxylate (90 mg, 0.192 mmol) and copper(l) iodide (7.32 mg, 0.038 mmol) were added. The reaction mixture was irritated via microwave reactor for 40 min at 70°C. After cooled to the room temperature, the mixture was diluted with brine and extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous magnesium sulfate. It was filtered and the filtrate was concentrated. The crude product was purified on the Combiflash eluting with a gradient of 0-60percent ethyl acetate in hexanes. The title compound was obtained as white solid (88 mg, 0.148 mmol, 77 percent yield). LC-MS m/z 596.2 (M+H)+, 1 .46 min (ret. time). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (±)-allyl 2-[4-[3-[tert-butylsulfinyl(2- trimethylsilylethoxymethyl)amino]oxetan -3-yl]phenyl]acetate (200 mg, 415 umol, synthesized via Steps 1-2 of Intermediate BT) in N,N-dimethylformamide (5 mL) was added LiHMDS (1 M, 1.25 mL) dropwise at 0 °C. After the reaction mixture was stirred for 1 hr, a solution of 4- iodotetrahydropyran (440 mg, 2.08 mmol) in N,N-dimethylformamide (1 mL) was added dropwise and the reaction mixture was stirred at rt for 6.5 hrs. On completion, the reaction mixture was poured into 100 mL cool water and extracted with ethyl acetate (3 X 30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 20: 1- 10: 1) to give the title compound. LCMS: (ES+) m/z (M+23)+ = 588.4, tR = 1.071. |
Tags: 25637-18-7 synthesis path| 25637-18-7 SDS| 25637-18-7 COA| 25637-18-7 purity| 25637-18-7 application| 25637-18-7 NMR| 25637-18-7 COA| 25637-18-7 structure
[ 4677-18-3 ]
2-(Tetrahydro-2H-pyran-4-yl)ethanol
Similarity: 0.61
[ 101691-94-5 ]
4-(Iodomethyl)tetrahydro-2H-pyran
Similarity: 0.72
[ 4677-18-3 ]
2-(Tetrahydro-2H-pyran-4-yl)ethanol
Similarity: 0.61
Precautionary Statements-General | |
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P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
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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