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CAS No. : | 17739-45-6 | MDL No. : | MFCD01321310 |
Formula : | C7H13BrO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GCUOLJOTJRUDIZ-UHFFFAOYSA-N |
M.W : | 209.08 | Pubchem ID : | 86621 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 43.69 |
TPSA : | 18.46 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) : | -6.37 cm/s |
Log Po/w (iLOGP) : | 2.51 |
Log Po/w (XLOGP3) : | 1.7 |
Log Po/w (WLOGP) : | 1.92 |
Log Po/w (MLOGP) : | 1.47 |
Log Po/w (SILICOS-IT) : | 2.22 |
Consensus Log Po/w : | 1.97 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.01 |
Solubility : | 2.05 mg/ml ; 0.00979 mol/l |
Class : | Soluble |
Log S (Ali) : | -1.7 |
Solubility : | 4.14 mg/ml ; 0.0198 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.19 |
Solubility : | 1.36 mg/ml ; 0.0065 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.45 |
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 |
---|---|---|
90% | With toluene-4-sulfonic acid In dichloromethane; water at 0℃; for 5 h; | To a solution of 2-bromoethanol 24 (50.0 g, 40 mmol) in methylene chloride (500 mL) cooled to 0 0C was added 3,4-dihydro-2H-pyran (40.32 g, 48 mmol) followed by p-TS A-H2O (100 mg) was added. Reaction mixture was stirred at 0 0C for 5.0 h. The reaction mixture was washed with aq NaHCO3 and brine, dried over Na2SO4 and evaporated to give the product 25 (75.0 g, 90percent). This crude product was taken to next step without purification. |
89% | With toluene-4-sulfonic acid In dichloromethane at 20℃; for 2 h; | To as solution of2-bromoethanol (3.8 g, 30.0 mmol) and DHP (2.5 g, 30.0 mmol) inDCM (50 mL), was added TsOH (380.0 mg, 2.2 mmol) in portions and the mixture was stirred atroom temperature for 2 hrs. The reaction was concentrated and purified by silica gel column(PE/EA '" 50/l) to g1ve 2-(2-bromoethoxy)tetrahydro-2H-pyran (5.6 g, yield: 89 percent) as acolorless oil. |
78% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; | Step 5 2-(2-Bromoethoxy)tetrahydro-2H-pyran:; 3,4-Dihydro-2H-pyran (7.80 g, 92.72 mmol) was added dropwise to a mixture of 2-bromoethanol (10.00 g, 80.03 mmol), p-toluenesulfonic acid monohydrate (1.52 g, 7.99 mmol) and dry dichloromethane (50 mL) at about 0° C. The reaction mixture was stirred at ambient temperature for about 24 hours. The volatiles were removed in vacuo to provide a crude residue. The residue was purified by silica gel column chromatography (diethyl ether) to afford the title product as a dark oil which was used in the next step without further purification (13.00 g, 78percent). 1H NMR (400 MHz, CDCl3) δ 1.48-1.91 (m, 6H), 3.44-3.55 (m, 3H), 3.72-3.81 (m, 1H), 3.83-3.93 (m, 1H), 3.96-4.04 (m, 1H), 4.67 (t, J=3.6 Hz, 1H); IR (film) ν 2943, 2885, 1448, 1353, 1274 cm-1. |
72% | With pyridinium p-toluenesulfonate In dichloromethane at 0 - 20℃; for 4 h; | Intermediate 2 2-(2-bromoethoxy)tetrahydro-2H-pyran To a solution of 2-bromoethanol (15 g, 0.12 mol) in DCM (150 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (10.6 g, 0.126 mol) was added dropwise at 0 °C. The mixture was stirred at room temperature for 4 h. It was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (50: 1) to give 2-(2-bromoethoxy)tetrahydro-2H-pyran(18.0 g, 72.0percent yield) as a light yellow oil. |
69% | With pyridinium p-toluenesulfonate In dichloromethane at 20℃; for 8 h; | 2-Bromoethanol (2 g, 16.0 mmol, 1 eq), 3,4-dihydropyran (2.15 g, 25.6 mmol, 1.6 eq) was dissolved in 40 mL of dichloromethane and PPTS (0.402 g , 1.6 mmol, 0.1 eq) was added and the reaction was stirred at room temperature for 8 hours,The reaction was carried out. After completion of the reaction, the reaction was complete and the reaction was complete. The organic phase was separated by the addition of 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and dried. Column chromatography PE: EA (v / v) = 20: 1 gave 2.3 g of product , The yield was 69percent. |
60% | With toluene-4-sulfonic acid In dichloromethane at 0 - 20℃; for 5 h; | To a solution of 2-bromo ethanol 13-1 (5 g, 40 mmol) in DCM (250 mL) was added /?-toluenesulfonic acid (760 mg, 4 mmol) followed by dihydropyran (4.3 mL, 48 mmol) at 0 °C and stirred at RT for 5 hr. The reaction mixture was diluted with EtOAc (100 mL) washed with water (100 mL), brine (10 mL) and dried over Na2S04, and concentrated under reduced pressure at 25 °C. The crude compound was purified using silica gel chromatography (5percent EtOAc in hexanes) to afford 13-2 (5 g, 24 mmol, 60percent yield) as a pale yellow color liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | at 20℃; | Step 1 (Synthesis of Compound 1-2) (0075) Compound 1-1 (12.5 g, 100 mmol) was dissolved in methanol (30 mL), and THP (12.6 g, 150 mmol), p-TsOH (250 mg, 1.3 mmol) were added at room temperature, stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure and then purified by silica gel column chromatography with an eluent system (PE: EtOAc=30:1) to obtain the product 1-2, yield: 80percent. (0076) 1H NMR (400 MHz, CDCl3) δ: 4.68 (t, J=3.6 Hz, 1H), 4.03 (td, J=6.4, 11.2 Hz, 1H), 3.90 (ddd, J=3.0, 8.4, 11.2 Hz, 1H), 3.73-3.82 (m, 1H), 3.45-3.58 (m, 3H), 1.80-1.91 (m, 1H), 1.70-1.79 (m, 1H), 1.51-1.63 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid; In dichloromethane; water; at 0℃; for 5h; | To a solution of 2-bromoethanol 24 (50.0 g, 40 mmol) in methylene chloride (500 mL) cooled to 0 0C was added 3,4-dihydro-2H-pyran (40.32 g, 48 mmol) followed by p-TS A-H2O (100 mg) was added. Reaction mixture was stirred at 0 0C for 5.0 h. The reaction mixture was washed with aq NaHCO3 and brine, dried over Na2SO4 and evaporated to give the product 25 (75.0 g, 90%). This crude product was taken to next step without purification. |
89% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 2h; | To as solution of2-bromoethanol (3.8 g, 30.0 mmol) and DHP (2.5 g, 30.0 mmol) inDCM (50 mL), was added TsOH (380.0 mg, 2.2 mmol) in portions and the mixture was stirred atroom temperature for 2 hrs. The reaction was concentrated and purified by silica gel column(PE/EA '" 50/l) to g1ve 2-(2-bromoethoxy)tetrahydro-2H-pyran (5.6 g, yield: 89 %) as acolorless oil. |
78% | With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; | Step 5 2-(2-Bromoethoxy)tetrahydro-2H-pyran:; 3,4-Dihydro-2H-pyran (7.80 g, 92.72 mmol) was added dropwise to a mixture of 2-bromoethanol (10.00 g, 80.03 mmol), p-toluenesulfonic acid monohydrate (1.52 g, 7.99 mmol) and dry dichloromethane (50 mL) at about 0 C. The reaction mixture was stirred at ambient temperature for about 24 hours. The volatiles were removed in vacuo to provide a crude residue. The residue was purified by silica gel column chromatography (diethyl ether) to afford the title product as a dark oil which was used in the next step without further purification (13.00 g, 78%). 1H NMR (400 MHz, CDCl3) delta 1.48-1.91 (m, 6H), 3.44-3.55 (m, 3H), 3.72-3.81 (m, 1H), 3.83-3.93 (m, 1H), 3.96-4.04 (m, 1H), 4.67 (t, J=3.6 Hz, 1H); IR (film) nu 2943, 2885, 1448, 1353, 1274 cm-1. |
75% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; for 5h; | Step one, dissolving 2-bromoethanol in anhydrous dichloromethane,After adding a catalytic amount of p-toluenesulfonic acid or pyridine p-toluenesulfonic acid,1.5 equivalents of 3,4-dihydro-2H-pyran was added dropwise and stirred at room temperature for 5 h.The reaction was quenched with aq.The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated.After silica gel column chromatography,2-(2-Bromoethoxy)-tetrahydropyran (IV-1, n = 1) was obtained.The product was obtained as a colorless oil in a yield of 75%. |
72% | With pyridinium p-toluenesulfonate; In dichloromethane; at 0 - 20℃; for 4h; | Intermediate 2 2-(2-bromoethoxy)tetrahydro-2H-pyran To a solution of 2-bromoethanol (15 g, 0.12 mol) in DCM (150 mL) was added PPTS (891 mg, 3.6 mmol), then dihydropyran (10.6 g, 0.126 mol) was added dropwise at 0 C. The mixture was stirred at room temperature for 4 h. It was partitioned between DCM and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (50: 1) to give 2-(2-bromoethoxy)tetrahydro-2H-pyran(18.0 g, 72.0% yield) as a light yellow oil. |
69% | With pyridinium p-toluenesulfonate; In dichloromethane; at 20℃; for 8h; | 2-Bromoethanol (2 g, 16.0 mmol, 1 eq), 3,4-dihydropyran (2.15 g, 25.6 mmol, 1.6 eq) was dissolved in 40 mL of dichloromethane and PPTS (0.402 g , 1.6 mmol, 0.1 eq) was added and the reaction was stirred at room temperature for 8 hours,The reaction was carried out. After completion of the reaction, the reaction was complete and the reaction was complete. The organic phase was separated by the addition of 10 mL of water. The organic phase was dried over anhydrous sodium sulfate and dried. Column chromatography PE: EA (v / v) = 20: 1 gave 2.3 g of product , The yield was 69%. |
62% | With toluene-4-sulfonic acid; In dichloromethane; at 20℃; | A mixture of 2-bromoethanol (353 mg, 2.8 mmol),3,4-dihydro-2H-pyran (0.31 mL, 3.4 mmol), and p-TsOH monohydrate (11 mg, 0.06 mmol) in anhydrousCH2Cl2 (10 mL) was stirred at rt overnight. The reaction mixture was washed with NaHCO3, H2O,and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crudeproduct obtained was purified by column chromatography (SiO2 gel, Hexanes:EtOAc/19:1; Rf 0.52 inHexanes:EtOAc/9:1) to yield the known compound 18 [72] (362 mg, 62%) as a colorless oil: 1H NMR(400 MHz, CDCl3, Figure S61, which matches the lit. [72]) delta 4.66 (t, J = 3.6 Hz, 1H), 3.99 (dt, J1 = 11.2 Hz,J2 = 6.4 Hz, 1H), 3.87 (ddd, J1 = 11.6 Hz, J2 = 8.0 Hz, J3 = 2.8 Hz, 1H), 3.75 (dt, J1 = 11.2 Hz, J2 = 6.8 Hz,1H), 3.54-3.44 (m, 3H), 1.88-1.77 (m, 1H), 1.76-1.66 (m, 1H), 1.65-1.48 (m, 4H). |
60% | With toluene-4-sulfonic acid; In dichloromethane; at 0 - 20℃; for 5h; | To a solution of 2-bromo ethanol 13-1 (5 g, 40 mmol) in DCM (250 mL) was added /?-toluenesulfonic acid (760 mg, 4 mmol) followed by dihydropyran (4.3 mL, 48 mmol) at 0 C and stirred at RT for 5 hr. The reaction mixture was diluted with EtOAc (100 mL) washed with water (100 mL), brine (10 mL) and dried over Na2S04, and concentrated under reduced pressure at 25 C. The crude compound was purified using silica gel chromatography (5% EtOAc in hexanes) to afford 13-2 (5 g, 24 mmol, 60% yield) as a pale yellow color liquid. |
147 g (70%) | With hydrogenchloride; | EXAMPLE 10 (R)-N-(4-(2-Diphenylamino)ethoxy)-1-butyl)-3-piperidinecarboxylic acid hydrochloride 3,4-Dihydro-2H-pyran (92.5 g, 1.1 mol) was added dropwise to 2-bromoethanol (125 g, 1.0 mol) on an ice-bath. The temperature was kept between 25-30 C. during addition. When addition was complete a concentrated hydrochloric acid solution (1 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was fractionated in vacuo to give 147 g (70%) of 2-bromoethyl tetrahydropyran-2-yl ether. |
In hexane; | a. 1-Bromo-2-(tetrahydropyran-2-yloxy)ethane. To a mechanically stirred solution of dihydropyran (1L) and a strong acid ion exchange resin (10.0 g) in hexane (2L) was added 2-bromoethanol (985 g) dropwise over a period of 1.5 hours in a cold water bath to maintain an internal temperature of 35-40 C. After being stirred overnight at room temperature, the reaction mixture was chromatographed with hexane (6L). The elude was evaporated to give an amber liquid which was distilled through a 2 inch vigreux column, collecting the material boiling between 75-95 C. (3,300-4,700 Pa). This material was redistilled to give the ether as an oil (1195.5 g); bp 80-90 C. (2666 Pa); NMR: 4.68 (m, 1), 4.01 (m,1), 3.89 (m, 1), 3.77 (m,1), 3.52 (m,3), 1.75-1.50 (m, 6). | |
In hexane; | a. 2-Tetrahydropyran-2-yloxyethyl bromide To a mechanically stirred solution of dihydropyran (1000 mL) and a strong acid resin (10.0 g) in hexane (2000 mL) was added 2-bromoethanol (985 g) dropwise over a period of 1.5 hours in a cold water bath to maintain an internal temperature of 35-40 C. After being stirred overnight at room temperature, the reaction mixture was chromatographed, with hexane as the eluent. The hexane was evaporated to give an amber liquid which was distilled through a 2 inch (5 cm) diameter vigreux cole, collecting the material boiling between 75-95 C. (3,300-4,700 Pa). This material was redistilled to give the ether as an oil (1195.5 g); bp 80-90 C. (2666 Pa); NMR: 4.68 (m, 1), 4.01 (m, 1), 3.89 (m, 1), 3.77 (m, 1), 3.52 (m, 3), 1.75-1.50 (m, 6). | |
In hexane; | a. 2-Tetrahydropyran-2-yloxyethyl bromide. To a mechanically stirred solution of dihydropyran (1000 mL) and a strong acid resin (10.0 g) in hexane (2000 mL) was added 2-bromoethanol (985 g) dropwise over a period of 1.5 hours in a cold water bath to maintain an internal temperature of 35-40 C. After being stirred overnight at room temperature, the reaction mixture was chromatographed, with hexane as the eluent. The hexane was evaporated to give an amber liquid which was distilled through a 2 inch (5 cm) diameter vigreux column, collecting the material boiling between 75-95 C. (3,300-4,700 Pa). This material was redistilled to give the ether as an oil (1195.5 g); bp 80-90 C. (2666 Pa); NMR: 4.68 (m,1), 4.01 (m,1), 3.89 (m,1), 3.77 (m,1), 3.52 (m,3), 1.75-1.50 (m,6). | |
With o-toluenesulfonic acid; | EXAMPLE II Preparation of 2-Bromo-1-(tetrahydropyran-2-yloxy)ethane(4) A solution of 37.5 g (0.30 mol) of 2-bromoethanol (3) in 200 ml of dry ether was stirred under argon with ice bath cooling as 36.5 ml (0.40 mol) of dihydropyran was added followed by ca. 50 mg of toluenesulfonic acid. After 1 hour the reaction mixture was washed with saturated aqueous sodium bicarbonate solution, dried (K2 CO3) and then evaporated in vacuo over a few crystals of anhydrous K2 CO3 to yield 65 g of the desired product (4) which was stored cold over K2 CO3 and then decanted when used; tlc (CHCl3) Rf 0.30; ir (film) 810, 870, 960, 1030, 1075, 1120, 1200, 2880 and 2950 cm-1. | |
With toluene-4-sulfonic acid; In tetrahydrofuran; at -10℃; for 16h; | EXAMPLE 3 2-[4-({(1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl]-2-oxoethyl}amino)piperidin-1-yl]ethanol (compound No. 6) 3.1: 2-(2-bromoethoxy)tetrahydro-2H-pyran 3.97 ml of bromoethanol are placed in 44 ml of tetrahydrofuran. The solution is cooled to -10 C. under N2. 5.51 ml of 3,4-dihydro-2H-pyran and 0.20 g of p-toluenesulphonic acid are then added. The reaction medium is stirred for 16 h at -10 C. After dilution in diethyl ether, the organic phase is washed with a saturated aqueous sodium hydrogen carbonate solution and then with H2O, dried over Na2SO4 and concentrated to dryness, to give 11 g of 2-(2-bromoethoxy)tetrahydro-2H-pyran. 3.2: 1-[2-(tetrahydro-2H-pyran-2-yloxy)-ethyl]piperidin-4-ol | |
With toluene-4-sulfonic acid; In dichloromethane; at 20℃; | To the solution of 2-bromoethanol (5.0 g, 40 mmol) and 3,4-dihydro-2eta-pyran (8.4 g, 100 mmol) in DCM (50 mL) was added TsOH (76 mg, 0.4 mmol). The mixture was stirred at room temperature overnight, quenched with brine (2 x 50 mL), and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified via distillation at 60C under 10 mmHg to give the title compound as yellow oil (3g). | |
In dichloromethane; | EXAMPLE 161 N-(1-trans-(2-(3-(4-(2-hydroxyethoxy)phenoxy)phenyl) cyclopropyl)methyl)-N-hydroxyurea To a solution of 2-bromoethanol (10.00 g, 80 mmol) and 3,4-dihydro-2H-pyran (10.1 g, 120 mmol) in CH2 Cl2 (400 mL) was added a spatula of Amberlyst-15 ion exchange resin and the reaction was stirred for 18 hrs. It was then filtered through Celite and concentrated. Distillation (40 mm Hg, b.p.=102 C.) afforded tetrahydro-2-(2-bromoethoxy)-2H-pyran (8.49 g). | |
With pyridinium p-toluenesulfonate; In dichloromethane; for 2.5h; | Combine 2-bromoethanol (14.2 mL, 200 mmol) and dihydropyrane (18.25 mL, 200 mmol) in dichloromethane (20 mL). Add pyridinium p-toluenesulfonic acid (5 g, 20 mmol). After 2.5 hours, dilute the reaction mixture with diethyl ether and extract with water, 1/1 water/brine, water, and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue. Distill the residue to give the title compound: bp; 80-90C at 15-20 mm Hg. | |
With toluene-4-sulfonic acid; In diethyl ether; at 20℃; for 16h; | To a stirred solution of 2-bromoethanol (10 g, 80.6 mmol) in diethyl ether (150 mL) was added PTSA (1.54 g, 8.0 mmol, 0.1 eq) followed by addition of 3,4-dihydro-2H-pyran (8.83 g, 96.5 mmol, 1.2 eq) and the resultant mixture was stirred at RT for 16 h. Reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (350 mL).The organic layer was washed with saturated NaHCO3solution (100 mL), water (200 mL), brine (100 mL) dried over Na2SO4,filtered and concentrated under reduced pressure to afford the title compound as a yellowish liquid which was taken to next-step without further purification.1H NMR (400 MHz, DMSO-d6) d 4.66 (t, J = 3.3 Hz, 1H), 3.93-3.85 (m, 1H), 3.82-3.66 (m, 2H), 3.66-3.57 (m, 2H), 3.49-3.39 (m, 1H), 1.72 (d, J = 9.2 Hz, 1H), 1.62 (d, J = 2.2 Hz, 1 H), 1.53-1.40 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | To a solution of 4-methoxyphenol (700 mg, 5.64 mmol) in methylsulfoxide (5 mL) was added potassium hydroxide (634 mg, 11.3 mmol).The reaction mixture was stirred at room temperature for 10 min. Then,2-(2-bromoethoxy)-tetrahydro-2H-pyrane (1.18 g, 5.64 mmol) wasadded and the reaction mixture was stirred at room temperatureovernight. The reaction was worked up as described for the preparationof 18 yielding 1.34 g (94% yield) of 26 (colorless oil), which was usedas such in the next step: Rf=0.50 (hexane-EtOAc, 4:1); 1H NMR(300.18 MHz, CDCl3) delta 1.52-1.68 (m, 4H, H-4?, H-5?), 1.71-1.77 (m,1H, H-3?a), 1.79-1.89 (m, 1H, H-3?b), 3.54 (m, 1H, H-6?a), 3.77 (s, 3H,OCH3), 3.83 (m, 1H, H-6?b), 3.89 (m, 1H, H-1a), 3.92 (m, 1H, H-1a),4.05 (m, 1H, H-1b), 4.13 (m, 2H, H-2), 4.70 (dist t, J=3.6 Hz, 1H, H-2?), 6.84 (d, J=9.4 Hz, 1H, H-2?), 6.90 (d, J=9.4 Hz, 1H, H-3?); 13CNMR (75.48 MHz, CDCl3) delta 19.4 (C-4?), 25.4 (C-5?), 30.5 (C-3?), 55.7(OCH3), 62.2 (C-1), 65.9 (C-6?), 68.1(C-2), 99.0 (C-2?), 114.6 (C-3?),115.7 (C-2?), 153.1 (C-1?), 153.9 (C-4?). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; | 2-[2-(4-Bromophenoxy)ethoxy]tetrahydro-2H-pyran N,N-Dimethylformamide (150 mL) was added to 4-bromophenol (18.2 g, 104 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (26.9 mL, 178 mmol), and potassium carbonate (36.0 g, 260 mmol), followed by stirring at 60C overnight. The resulting mixture was left to cool, and the solvent was distilled off under reduced pressure. Ethyl acetate and water were added for extraction. The resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and then filtered. The solvent was then distilled off under reduced pressure and the residue thus obtained was purified by silica gel chromatography (hexane : ethyl acetate, 90 : 10 - 30 : 70, V/V) to give the desired title compound (28.86 g, yield 86%). 1H-NMR (CDCl3) delta: 1.47-1.67 (4H, m), 1.69-1.89 (2H, m), 3.49-3.56 (1H, m), 3.77-3.84 (1H, m), 3.85-3.92 (1H, m), 4.00-4.07 (1H, m), 4.07-4.17 (2H, m), 4.67-4.72 (1H, m), 6.79-6.84 (2H, m), 7.33-7.39 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Add 2-bromo-phenol (10 g, 57.80 mmol) to a suspension of sodium hydride (60% dispersion in mineral oil, 2.77 g, 69.36 mmol) in DMF (6 mL). Stir the mixture for 1 h. Add 2-(2-bromo-ethoxy)-tetrahydropyran (13.54 g, 64.74 mmol). Stir the solution at RT overnight. Dilute the mixture with ethyl acetate and water. Wash the organic layer with aqueous saturated sodium chloride and water. Dry the mixture over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (10 % ethyl acetate in hexane) to give the title compound (13.9 g, 80 %) as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride; In water; dimethyl sulfoxide; at 20℃; for 24h; | [57] Example 1[58] 1-(1) Synthesis of monomer[59] 5 g of 2-(2-bromoethoxy)tetrahydro-2H-pyran and 3 g of 2,7-dibromofluorene were reacted in an equivalent ratio of 1:2.4 in a 50 wt% aqueous solution of DMSO/ NaOH at room temperature for 24 hours. At this time, benzyltriethylammonium chloride was used as a phase transfer catalyst. After the reaction was completed, the resultant was extracted with methylene chloride to remove the solvent. The residue was purified with a SiO column chromatography (EA:n-Hexane) to obtain 4 g of 2-[2-(2,7-dibromofluoren-9,9'-yl)ethoxy]perhydro-2H-pyran (yield: 50%).[60] NMR data: 1.25-1.46 (m, 12H), 2.35-2.37 (t, 4H), 2.70-2.72 (m, 2H), 3.13-3.15 (m,2H), 3.24-3.26 (m, 2H), 3.45-3.47 (m, 2H), 4.10-4.27 (t, 2H), 1 AA-1.62 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 20 - 60℃; for 22h; | A mixture of the phenol from example 22 (1.29 g, 2.65 mmol), potassium carbonate (690 mg, 5 mmol), and 2-(2-bromoethoxy)tetrahydro-2H-pyran (840 mg, 4 mmol) in 1-methyl-2-pyrrolidinone (10 ml), was heated at 60 C. for 4 hours, followed by a further 18 hours at room temperature. The mixture was diluted with ethyl acetate and washed with water (*3), then brine, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as the eluant to afford the title compound as a white foam, 1.20 g. 1H-NMR (CDCl3, 400 MHz) delta: 1.37 (m, 2H), 1.46 (m, 2H), 1.61 (m, 4H), 1.76 (m, 4H), 1.92 (m, 4H), 2.33 (s, 3H), 2.43 (m, 2H), 2.72 (m, 4H), 3.39 (m, 1H), 3.72 (m, 1H), 3.86 (m, 1H), 4.13 (m, 3H), 4.30 (t, 2H), 4.54 (m, 1H), 5.24 (m, 1H), 6.87 (d, 1H), 7.21 (d, 1H), 8.04 (m, 3H), 8.13 (d, 1H), 8.26 (dd, 1H). LRMS: m/z APCI- 614 [M-H-] |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; lithium iodide; In 1-methyl-pyrrolidin-2-one; at 80℃; for 17h; | A mixture of indazole-3-carboxylic acid ethyl ester (Chem. Ber. 52; 1919; 1345) (1.9 g, 10 mmol), 2-(2-bromoethyloxy)tetrahydropyran (2.25 g, 10.8 mmol), potassium carbonate (1.43 g, 10.4 mmol) and lithium iodide (67 mg, 0.5 mmol) in 1-methyl-2-pyrrolidinone (20 ml) was heated at 80 C. for 17 hours. The mixture was partitioned between water (250 ml) and ethyl acetate (250 ml), and the layers separated. The organic phase was washed with water (3*200 ml), dried (MgSO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (91:9 to 50:50) to afford the title compound as a pale yellow oil, 1.88 g. 1H-NMR (DMSOd6, 400 MHz) delta: 1.20-1.53 (m, 6H), 1.35 (t, 3H), 3.30 (m, 2H), 3.80 (m, 1H), 4.00 (m, 1H), 4.37 (q, 2H), 4.48 (m, 1H), 4.70 (m, 2H), 7.32 (m, 1H), 7.80 (d, 1H), 8.05 (d, 1H). LRMS: m/z ES+ 341 [MNa+] | |
With potassium carbonate;lithium iodide; In 1-methyl-pyrrolidin-2-one; at 80℃; for 17h; | Indazole-3-ethyl-carboxylate (prepared according to the method of Synthesis, 1984, (11), 982-983, page 983 product 6ca) (1.90 g, 10.0 mmol), 2-(2-bromoethoxy)tetrahydropyran (2.25 g, 10.8 mmol), potassium carbonate (1.43 g, 10.4 mmol) and lithium iodide (67 mg, 0.50 mmol) was dissolved in 1-methyl-2-pyrrolidinone (20 mL) and the reaction mixture stirred at 80 C. for 17 hours. The reaction mixture was partitioned between ethyl acetate (250 mL) and water (250 mL) and the organic layer washed with water (3×200 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane:ethyl acetate 10:1 to 5:1 to 3:1 to 2:1 to 1:1 to yield the title product, 1.88 g. [0289] 1HNMR (DMSO-D6, 400 MHz): 1.20-1.53(m, 6H), 1.35)t, 3H), 3.30(m, 2H), 3.80(m, 1H), 4.00(m, 1H), 4.37(m, 2H), 4.48(m, 1H), 4.70(m, 2H), 7.32(t, 2H), 7.80(d, 1H), 8.05(d, 1H), [0290] MS ES+ m/z 341 [MNa]+ |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 18h; | A mixture of <strong>[78208-72-7]ethyl 5-isopropyl-1H-pyrazole-3-carboxylate</strong> (Chem. and Pharm. Bull. 1984; 32(4);1568) (509 mg, 2.8 mmol), 2-(2-bromoethoxy)tetrahydro-2-pyran (732 mg, 3.5 mmol) and potassium carbonate (483 mg, 3.5 mmol) in 1-methyl-2-pyrrolidinone (5 ml) was stirred at 80° C. for 18 hours. The cooled mixture was poured into ethyl acetate and washed with water and brine, then dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (20:80 to 40:60) to afford the title compound of preparation 34 as a clear oil, 663 mg. [0469] 1HNMR (CDCl3, 400 MHz) delta: 1.25 (d, 6H), 1.37 (t, 3H), 1.44-1.71 (m, 6H), 2.97 (m, 1H), 3.42 (m, 1H), 3.54 (m, 1H), 3.75 (m, 1H), 4.00 (m, 1H), 4.32 (q, 2H), 4.54 (t, 1H), 4.68 (m, 1H), 4.76 (m, 1H), 6.64 (s, 1H). [0470] LRMS: m/z ACPI+ 311 [MH]+ [0471] Further elution provided the title compound of preparation 35, 242 mg. [0472] 1HNMR (CDCl3, 400 MHz) delta: 1.25 (d, 6H), 1.38 (t, 3H), 1.46-1.72 (m, 6H), 3.15 (m, 1H), 3.45 (m, 1H), 3.65 (m, 1H), 3.81 (m, 1H), 4.10 (m, 1H), 4.34 (m, 2H), 4.39 (m, 2H), 4.49 (t, 1H), 6.57 (s, 1H). [0473] LRMS: m/z ACPI+ 311 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With potassium carbonate; potassium iodide; In acetonitrile; at 90℃; for 72.0h; | Preparations 7 to 13 Potassium carbonate (2eq) and potassium iodide (0. 1 EQ) were added to a solution of the appropriate PHENOL (1EQ) in acetonitrile (1. 25MLMMOL-1), and the mixture warmed to 90C. 2- (2-Bromoethoxy) tetrahydro-2H-pyran (1.3eq) was added and the reaction stirred at 90C for 72 hours. The cooled reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 10% citric acid solution, and the layers separated. The organic phase was washed with water, sodium bicarbonate solution and brine, then dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane (5: 95 to 50: 50) to yield the appropriate product |
With potassium carbonate; potassium iodide; In acetonitrile; at 90℃; for 72.0h; | Potassium carbonate (2eq) and potassium iodide (0.1 eq) were added to a solution of the appropriate phenol (1 eq) in acetonitrile (1.25 mlmmol-1), and the mixture warmed to 90 C. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.3 eq) was added and the reaction stirred at 90 C. for 72 hours. The cooled reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate and 10% citric acid solution, and the layers separated. The organic phase was washed with water, sodium bicarbonate solution and brine, then dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:pentane (5:95 to 50:50) to afford the title compounds as clear oils |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; lithium iodide; In 1-methyl-pyrrolidin-2-one; at 80℃; for 24h; | Preparation 18 2-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-2H-pyrazole-3-carboxylic acid ETHVL ester Ethyl-pyrazole-3-carboxylate (980mg, 7. 0MMOL), 2- (2-bromoethoxy)-tetrahydro- 2H-pyran (1.57g, 7. 5MMOL), potassium carbonate (1. 01G, 7. 3MMOL) and lithium iodide (46. 8mg, 0. 35MMOL) were dissolved in 1-METHYL-2-PYRROLIDINONE (1 OML) and the reaction mixture heated to 80°C for 24 hours. The reaction mixture was allowed to cool for 17 hours and then diluted with a mixture of ethyl acetate: water 1: 1 (500mL). The organic layer was washed with water (3X250ML), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with cyclohexane : ethyl acetate 90: 10 to 80 : 20 to 75: 25 to 50: 50. The appropriate fractions were combined and concentrated in vacuo to yield the title product. HNMR (CDCI3, 400MHZ) : 1.40 (t, 3H), 1.42-1. 80 (m, 6H), 3.43 (m, 1H), 3.60 (m, 1H), 3. 78 (m, 1H), 4.04 (m, 1H), 4.35 (q, 2H), 4.55 (m, 1H), 4.82 (m, 2H), 6.81 (m, 1 H), 7. 48 (m, 1 H). MS ES+ m/z 291 [MNa] + |
Yield | Reaction Conditions | Operation in experiment |
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76% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 18h; | Preparation 14 5-ISOPROPYL-1-R2- (TETRAHVDRO-PVRAN-2-YLOXV)-ETHYLL-1 H-PYRAZOLE-3-CARBOXYLID ethyl ester The ester of preparation 6 (509mg, 2. 8MMOL), 2- (2-bromoethoxy) tetrahydro-2H- pyran (732mg, 3. 5MMOL) and potassium carbonate (483mg, 3. 5MMOL) were dissolved in 1-methyl-2-pyrrolidinone (5mL) and the reaction mixture heated to 80°C for 18 hours. The reaction mixture was cooled, poured into ethyl acetate, washed with water (x 2) and brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with pentane: ethyl acetate 80: 20 to 60: 40 to yield the title product, 663mg (76percent). HNMR (CD3, 400MHZ) : 1.25 (d, 6H), 1.37 (t, 3H), 1.44-1. 71 (m, 6H), 2.97 (m, 1 H), 3.42 (m, 1 H), 3.54 (m, 1 H), 3.75 (m, 1 H), 4.00 (m, 1 H), 4.32 (m, 2H), 4.54 (t, 1 H), 4.68 (m, 1 H), 4.76 (m, 1 H), 6.64 (s, 1 H). MS ES+ M/Z 227 [MH] + |
Yield | Reaction Conditions | Operation in experiment |
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58% | With ammonium chloride; In tetrahydrofuran; hexane; | (a) 2-[[3-Cyano-3-(3,4-difluorophenyl)]propyloxy]-2H-tetrahydropyran. To a stirred cooled (0 C.) mixture of 60% sodium hydride (4.12 g, 103 mmol) in THF (95 mL) was added dropwise a solution of <strong>[658-99-1]3,4-difluorobenzyl cyanide</strong> (15.0 g, 98 mmol) in THF (25 mL) and the solution was stirred at room temperature for 3 h. The solution was cooled (ice bath) and 2-(2-bromoethoxy)-2H-tetrahydropyran (20.5 g, 98 mmol) was added dropwise and the solution stirred at room temperature overnight. Saturated ammonium chloride was added and the mixture was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Chromatography (20%, 90% and 95% DCM in hexane) provided the title compound (16.05 g, 58%) as a yellow oil. 1H-NMR (CDCl3) delta 1.55-1.63 (m, 4H, CH2) 1.75-1.80 (m, 2H, CH2) 2.10-2.19 (m, 2H, CH2) 3.52-3.58 (m, 2H, CH2) 3.82-4.06 (m, 2H, CH2) 4.08-4.11 (t, 1H, CH) 4.56-4.60 (m, 1H, CH) 7.08-7.27 (m, 3H, ArH). |
58% | With ammonium chloride; In tetrahydrofuran; hexane; | (a) 2-[[3-Cyano-3-(3,4-difluorophenyl)]propyloxy]-2H-tetrahydropyran. To a stirred cooled (0 C.) mixture of 60% sodium hydride (4.12 g, 103 mmol) in THF (95 mL) was added dropwise a solution of <strong>[658-99-1]3,4-difluorobenzyl cyanide</strong> (15.0 g, 98 mmol) in THF (25 mL) and the solution was stirred at room temperature for 3 h. The solution was cooled (ice bath) and 2-(2-bromoethoxy)-2H-tetrahydropyran (20.5 g, 98 mmol) was added dropwise and the solution stirred at room temperature overnight. Saturated ammonium chloride was added and the mixture was extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. Chromatography (20%, 90% and 95% DCM in hexane) provided the title compound (16.05 g, 58%) as a yellow oil. 1H-NMR (CDCl3) delta 1.55-1.63 (m, 4H, CH2) 1.75-1.80 (m, 2H, CH2) 2.10-2.19 (m, 2H, CH2) 3.52-3.58 (m, 2H, CH2) 3.82-4.06 (m, 2H, CH2) 4.08-4.11 (t, 1H, CH) 4.56-4.60 (m, 1H, CH) 7.08-7.27 (m, 3H, ArH). |
Yield | Reaction Conditions | Operation in experiment |
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With acetic acid; In tetrahydrofuran; N-methyl-acetamide; water; | Step A 1-Carbobenzoxy-4-(2-hydroxyethyl)piperazine-3-one To a solution of 1-carbobenzoxypiperazin-3-one (234 mg, 1.0 mmol) in dimethylformamide (10 ml) under nitrogen was added in one portion, 50% sodium hydride (48 mg, 1 mmol). After stirring at 20-25 for 30 minutes until all of the sodium hydride had reacted, a solution of 2-(2-bromoethoxy)-tetrahydropyran (209 mg, 1 mmol) in dimethylformamide (2 ml) was added and the reaction mixture stirred at 20-25 for 20 hours. Solvent was removed at 40-45 and 0.1 mm and the residue chromatographed over silica gel. Elution with 2% isopropanol -98% methylene chloride gave the pure protected alcohol as an oil. The tetrahydropyranyl blocking group was removed by heating a solution of the protected alcohol (200 mg, 0.55 mmol) in a mixture of acetic acid (8 ml), tetrahydrofuran (4 ml) and water (2 ml) at 50 for 4 hours. After removing solvents under reduced pressure, the residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated. Chromatography of the residue over silica gel and elution with 5% methanol-95% chloroform gave pure 1-carbobenzoxy-4-(2-hydroxyethyl)piperazine-3-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In dimethyl sulfoxide; at 70℃; for 3h; | Dispersion synergist SYN-1 0; The compound SYN-10 having a quinacridone structure but with a hydroxyethyl group was used as a comparative dispersion synergist. [Show Image] Synthesis scheme of SYN-10: [Show Image] 25 g (80 mmol) PV19 was suspended in 200 mL DMSO. 17.9 g (160 mmol) KOtBu was added and the suspension was heated to 70C. 21.64 g (104 mmol) 2-(2-bromoethoxy)-tetrahydro-2H-pyran was added and the reaction was allowed to continue for 3 hours at 70C. After cooling down to room temperature, 300 mL of water is added. The crude intermediate was isolated by filtration, washed with water and dried. The crude intermediate was suspended in 500 mL acetone. 8.0 mL HCI (conc.) was added and the reaction was allowed to continue for 1 hour at room temperature. N-hydroxyethyl-quinacridone was isolated by filtration, washed with aceton, resuspended in aceton, again isolated by filtration and dried. The crude product was used for polymer modification without further purification. The yield was 92 %. | |
Chromophore MAG-1; [0142] 25 g (80 mmol) PV19 was suspended in 200 mL DMSO. 17.9 g (160 mmol) KOtBu was added and the suspension was heated to 70C. 21.64 g (104 mmol) 2-(2-bromoethoxy)-tetrahydro-2H-pyran was added and the reaction was allowed to continue for 3 hours at 70C. After cooling down to room temperature, 300 mL of water is added. The crude intermediate was isolated by filtration, washed with water and dried. The crude intermediate was suspended in 500 mL acetone. 8.0 mL HCI (cone.) was added and the reaction was allowed to continue for 1 hour at room temperature. N-hydroxyethyl-quinacridone was isolated by filtration, washed with aceton, resuspended in aceton, again isolated by filtration and dried. The crude product was used for polymer modification without further purification. The yield was 92 %. | ||
With potassium tert-butylate; In dimethyl sulfoxide; at 70℃; for 3h; | Chromophore MAG-1; [0215] 25 g (80 mmol) PV19 was suspended in 200 ml_ DMSO. 17.9 g (160 mmol) KOtBu was added and the suspension was heated to 70C. 21.64 g (104 mmol) 2-(2-bromoethoxy)-tetrahydro-2H-pyran was added and the reaction was allowed to continue for 3 hours at 7O0C. After cooling down to room temperature, 300 ml_ of water is added. The crude intermediate was isolated by filtration, washed with water and dried. The crude intermediate was suspended in 500 ml_ acetone. 8.0 mL HCI (cone.) was added and the reaction was allowed to continue for 1 hour at room temperature. N-hydroxyethyl-quinacridone was isolated by filtration, washed with aceton, resuspended in aceton, again isolated by filtration and dried. The crude product was used for polymer modification without further purification. The yield was 92 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate; In water; toluene; at 40℃; for 17h; | (i) Production of 2-methyl-4- [ 2- ( tetrahydro-2H-pyran-2- yloxy) e+/-hoxy] butan-2-olTo the- solution of 2- ( 2-bromoethoxy) tetrahydro-2H- pyran (3 mL) and 3-methylbutane-l, 3-diol (2.08 g) in 0 toluene (40 mL) were added 50% aqueous sodium hydroxide solution (10 mL) and tetra-n-butylammonium hydrogen sulfate (673 mg) , and the mixture was stirred at 400C for 17 hr . Water was added to the reaction mixture and the mixture was extracted with toluene. The organic 5 layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane: ethyl acetate = 90 : /10?33/ : 67) to give the title compound (3.41 g) 0 as a colorless oil.1H-NMR (CDCl3) delta: 1-25 (6H, s), 1.44-1.91 (8H, m) , 3.34 (IH, s), 3.46-3.68 (4H, m) , 3.75 (2H, t, J = 6 Hz), 3.80-3.94 (2H, m) , 4.56-4.70 (IH, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Example 181-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole To a solution of 4-pyrazole boronic acid pinacol ester (2.0 g, 10.3 mmol) in anhydrous DMF (20 mL) was added cesium carbonate (4.03 g, 12.4 mmol) and the mixture stirred at RT for 10 minutes. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.87 mL, 12.4 mmol) was added in two portions and the mixture was heated to 70 C. After heating for 18 hours the mixture was allowed to cool to RT and partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was washed with EtOAc (3×20 mL) and the combined organic layers washed with water (3×100 mL) followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (2.15 g, 65%). LCMS: RT=3.97 min, [M+Na]+=345 | |
With caesium carbonate; In acetonitrile; | prepared by reaction of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and <strong>[17739-45-6]2-(2-bromoethoxy)tetrahydropyran</strong> with caesium carbonate in acetonitrile | |
With potassium carbonate; In acetonitrile; at 20℃; | A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.20 g, 1.0 mmol) (Aldrich Cat. No. 525057), 2-(2-bromoethoxy)tetrahydro-2H-pyran (170 muL, 1.1 mmol) (Aldrich Cat. No. 475394) and potassium carbonate (0.21 g, 1.5 mmol) in acetonitrile (2 mL) was stirred at r.t. overnight. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5-Methoxy-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1-H-pyrrolo[2,3-b]pyridine; Into a solution of compound I (296 mg, 2.0 mmol) in DMF (40 mL) was added NaH (160 mg, 4 mmol). The mixture was stirred at room temperature for 10 min. 2-(2-bromoethoxy)tetrahydropyran (1.5 mL, 10 mmol) was then added into the above mixture. After being continuously stirred at room temperature for 12 hours, the reaction was quenched with water (1 mL) to give a crude mixture of the desired product, which was used directly in the next step. |
Yield | Reaction Conditions | Operation in experiment |
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Preparation 20 5-METHYL-1-R2- (TETRAHVDRO-PVRAYLOXY)-ETHYLL-1 H-PYRAZOLE-3-CARBOXVLIC acid ethyl ester A solution of sodium hydride (934mg, 23. 4MMOL) in tetrahydrofuran (50mL) was treated with ethyl 3-METHYLPYRAZOLE-5-CARBOXYLATE (3. 00G, 19. 5MMOL) and the reaction mixture stirred at room temperature for 30 minutes. 2- (2- Bromoethoxy) tetrahydro-2H-pyran (3.5mL, 19. 5MMOL) and lithium iodide (50mg, 0. 39MMOL) were added and the reaction mixture refluxed for 16 hours. The reaction mixture was cooled and taken up in ethyl acetate and water. The organics were separated and washed with 10% citric acid solution, water, saturated sodium hydrogencarbonate solution and brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with DICHLOROMETHANE : methanol 99: 1 to 95: 5 to yield the title product, 4.47g. HNMR (CD3, 400MHZ) : 1.36 (T, 3H), 1.42-1. 77 (m, 6H), 2.37 (s, 3H), 3.41 (m, 1H), 3.58 (m, 1H), 3.77 (m, 1H), 4.03 (m, 1H), 4.30 (m, 2H), 4.40 (m, 2H), 4.47 (m, 1 H), 6.49 (m, 1 H). MS ES+ m/z 283 [MH] + |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With caesium carbonate; In acetonitrile; at 20℃; for 18h;Inert atmosphere; | In a 1 L 3 -neck flask equipped with magnetic stir bar, nitrogen blanket and internal temperature probe dissolve 2-(2-bromoethoxy)tetrahydro-2H-pyran (34 g, 156 mmol) in acetonitrile (ACN, 400 mL). Add 4-iodopyrazole (29.34 g, 149.74 mmol) followed by cesium carbonate (73.4 g, 223.02 mmol). Stir the mixture at RT for 18 hours. Filter the reaction mixture through CELITE, wash the filter cake with ACN and concentrate the filtrate to a golden oil. Use without further purification. Yield: 47.819 g (99%). MS (ES) m/z 323 [M+ 1]+. |
66.2% | With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; | A solution of 4-iodopyrazole (20g, 0.10 mol) in anhydrous DMF (300 mL) was treated with Cs2C03 (32.5g, 0.10 mol) and 2-(2-bromoethoxy)tetrahydro-2H pyran. The resultant reaction mixture was stirred at 70 C overnight. The cooled mixture was diluted with EtOAc (500 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water, dried over Na2SC>4, and concentrated to afford yellow oil. Purification on a silica gel provided 4- iodo-l-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-lH-pyrazole (22g, 66.2 % yield). 1H-NMR (300 MHz, CDC13): delta 7.55 (s, 1H), 7.50 (s, 1H), 4.53 (s, 1 H), 4.33 (m, 2 H), 4.03 (m, 1 H), 3.74 (m, 1 H), 3.61 (m, 1 H), 3.46 (m, 1 H), 1.60-1.48 (m, 6 H). |
64% | (Example 162) 2-(4-{2-Fluoro-5-[3-(6-methylpyridin-2-yl)-1H-pyrazol-4-yl]phenyl}-1H-pyrazol-1-yl)ethanol (Compound No. 2-662) (162a) 4-Iodo-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole Sodium hydride (55% oil, 0.51 g, 12 mmol) was added to an N,N-dimethylformamide solution (15 mL) of 4-iodo-1H-pyrazole (1.5 g, 7.7 mmol). The resulting solution was stirred at room temperature for 15 min, and then 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.5 mL, 9.9 mmol) was added thereto. The resulting mixture was stirred at room temperature for 5 hr. Water was added to the reaction solution to terminate the reaction. After extraction with ethyl acetate, the organic layer was washed with water and brine, and then dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (Biotage, eluting solvent: hexane/ethyl acetate) to obtain 1.6 g (yield: 64%) of the title compound as a light yellow gum-like material. 1H-NMR (500 MHz, CDCl3) delta ppm: 7.55 (1H, s), 7.51 (1H, s), 4.52 (1H, m), 4.36-4.29 (2H, m), 4.04 (1H, m), 3.72 (1H, m), 3.61 (1H, m), 3.45 (1H, m), 1.80-1.47 (6H, m). |
With caesium carbonate; at 70℃; for 17h; | To a mixture of 4-iodopyrazole (Aldrich, Buchs. Switzerland, 10 g, 51 6 mmol) and Cs2CO3 (20.16 g 61 9 mmol) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (Aldrich, Buchs, Switzerland, 9 IA ml, 61.9 mmol) The RM was stirred at 70 C for 17h. Then the RM was quenched with water (100 ml) and extracted with EtOAc (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (hexane/EtOAc 0 % to 30 %) The fractions containing product were combined and evaporated to dryness to give the title compound as a colorless oil (HPLC tR 3 12 mm (Method A), M+H = 323 MS-ES). | |
With caesium carbonate; In acetonitrile; at 20℃; for 18h;Inert atmosphere; | In a 1 L 3-neck flask equipped with magnetic stir bar, nitrogen blanket and internal temperature probe dissolve 2-(2-bromoethoxy)tetrahydro-2H-pyran (34 g, 156 mmol) in acetonitrile (ACN, 400 mL). Add 4-iodopyrazole (29.34 g, 149.74 mmol) followed by cesium carbonate (73.4 g, 223.02 mmol). Stir the mixture at RT for 18 hours. Filter the reaction mixture through CELITE, wash the filter cake with ACN and concentrate the filtrate to a golden oil. Use without further purification. Yield: 47.819 g (99%). MS (ES) m/z 323 [M+1]+. | |
0.12 g | With caesium carbonate; In acetonitrile; at 20℃; | At r.t. to a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (210 muL, 1.4 mmol) (Aldrich Cat. No. 475394) in acetonitrile (6 mL) was added 4-iodo-1H-pyrazole (0.25 g, 1.3 mmol) (Aldrich Cat. No. 213993), followed by cesium carbonate (0.63 g, 1.9 mmol). The mixture was stirred at r.t. over a weekend. The solid was filtered off, then washed with acetonitrile. The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g). LCMS (M-84)+=239.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 3h; | To a solution of <strong>[7411-23-6]3,5-dibromo-1H-1,2,4-triazole</strong> (10 g, 44.1 mmol) in acetonitrile (100 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (8.0 mL, 52.9 mmol) and N,N-diisopropylethylamine (8.45 mL, 48.5 mmol). The mixture was stirred at 90 C. for 3 h and concentrated under reduced pressure. The residue was diluted with ethyl acetate (300 mL), washed saturated sodium bicarbonate (2*50 mL), brine (2*50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 3,5-dibromo-1-(2-tetrahydropyran-2-yloxyethyl)-1,2,4-triazole (13 g, 83%) as a colorless oil, used as is in the next step. |
77% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 3h; | To a solution of 3,5-dibromo-lH-l,2,4-triazole (5.00 g, 22.04 mmol) in CH3CN (50 ml) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (5.07 g, 24.24 mmol) and DIPEA (4.00 ml, 24.24 mmol). The resulting solution was heated at 90 C for 3 h.Subsequently, the mixture was cooled and diluted with EtOAc (100 ml). The resulting solution was then washed with a sat. aq. solution of NaHC03 and brine. The organic layer was dried (MgSC^) and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel (eluent: DCM/MeOH(NH3) from 100/0 to 97/3). The product fractions were collected and concentrated in vacuo, yielding 6.00 g of intermediate 56 (77 %). |
77% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃; for 3h; | To a sol. of 3,5-dibromo-lH-l,2,4-triazole (60 g, 264.48 mmol) in CH3CN (600 mL) were added 2-(2-bromoethoxy)tetrahydro-2H-pyran (48.01 mL, 317.38 mmol) and DIPEA (48.08 mL, 290.93 mmol). The r.m. was stirred at 90 C for 3 h. The mixture was then diluted with EtOAc and washed with a sat. aq. NaHC03 sol. and brine. The separated o.l. was dried (MgS04), filtered and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; eluent: DCM/(7 N NH3 in MeOH) from 100/0 to 97/3). The product fractions were collected and the solvent evaporated in vacuo. Yield: 72 g of intermediate 45 (77% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With dichloro bis(acetonitrile) palladium(II); potassium carbonate; norbornene; In N,N-dimethyl acetamide; water; at 70℃; for 14h;Schlenk technique; Inert atmosphere; | General procedure: A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze-pump-thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 C or 90 C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in arotary evaporator (60 C water bath, 8-10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dichloro bis(acetonitrile) palladium(II); potassium carbonate; norbornene; In N,N-dimethyl acetamide; water; at 70℃; for 14h;Schlenk technique; Inert atmosphere; | General procedure: A 50-mL Schlenk flask equipped with a magnetic stirring bar and a rubber septum was charged with 1H-indole substrate 1 (1.00 mmol), norbornene (188 mg, 2.00 mmol), the base [K2CO3 (276 mg, 2.00mmol), KHCO3 (300 mg, 3.00 mmol), or K2HPO4 (522 mg, 3.00mmol) as indicated], and PdCl2(MeCN)2 (25.9 mg, 0.100 mmol). A 0.5 M solution of H2O in DMA (5 mL) was added. The alkyl bromide 2 (2.00 mmol) was then added from a syringe, and the resulting mixture was degassed by three freeze-pump-thaw cycles with liquid nitrogen under high vacuum. The flask was then placed in an oil bath preheated to 70 C or 90 C, as indicated, and the mixture was stirred vigorously under balloon pressure of argon. Upon completion of the reaction (TLC), the mixture was cooled to r.t., diluted with Et2O (30 mL), and filtered. The filtrate was concentrated in arotary evaporator (60 C water bath, 8-10 mbar) to remove the Et2O and most of the DMA. The residue was purified directly by flash column chromatography [silica gel (dry loading)] to give the alkylation product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In dimethyl sulfoxide; at 60℃; for 29h; | <Example 1>Production ofN-(( 1 R,2R)- 1 ,2-diphenyl-2-(2-(tetrahydro-2H-pyran-2-yloxy^amideThe target compound (B) was produced by the reaction shown below.[Chem. 8]In a 50-ml Schlenk tube, 5.0 g (13.65 mmol) of (R,R>TsDPEN and 2.85 g (2.07 ml) (13.65 mmol) of an alkyl bromide (A) were mixed with 10 ml of DMSO, and the mixture was allowed to react for 29 hours at 60C. Subsequently, 50 ml of dichloromethane and 50 ml of a saturated aqueous solution of NaHC03 were introduced into the reaction mixture, and the resulting mixture was stirred. Subsequently, the organic layer was separated and was washed two more times with 50 ml of a saturated aqueous NaHCC>3. Dichloromethane was recovered, and the residue was purified by silica gel column chromatography. Thus, 4.94 g (72% yield) of the desired compound (B) was obtained.'H-NMR(CDCl3, 300MuEtazeta)delta:1.43-1.80(m, 6H), 2.32(s, 3H), 2.42-2.70(m, 2H), 3.40-3.55(m, 2H), 3.70-3.85(m, 2H), 3.77(d, 1H), 4.30(m, 1H), 4.45 (d, 1H), 6.93-7.38(m, 14H) |
72% | In dimethyl sulfoxide; at 60℃; for 29h;Schlenk technique; | [Synthesis l]Production of N-((lR,2R)-l,2-diphenyl-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethylamino)ethyl)-4- methylbenzenesulfonamideThe target compound (B) was produced by the following reaction.In a 50-ml Schlenk tube, 5.0 g (13.65 mmol) of (R,R)-TsDPEN and 2.85 g (2.07 ml) (13.65 mmol) of alkyl bromide (A) were mixed with each other in 10 ml of DMSO, and the reaction was allowed to proceed at 60C for 29 hours. Then, 50 ml of dichloromethane and 50 ml of a saturated aqueous NaHCOs solution were added to the reaction mixture. After stirring, the organic layer was separated, and further washed twice with 50 ml of a saturated aqueous NaHC03 solution. The dichloromethane was recovered, and the residue was purified by silica gel column chromatography. Thus, 4.94 g of the target compound (B) was obtained. Yield: 72%.?-NMR (CDCls, 300 MHz) 5-1.43- 1.80 (m, 6H), 2.32 (s, 3H), 2.42-2.70 (m, 2H), 3.40-3.55 (m, 2H), 3.70-3.85 (m, 2H), 3.77 (d, 1H), 4.30 (m, 1H), 4.45 (d, 1H), 6.93-7.38 (m, 14H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In acetonitrile; at 80℃; | A solution of 3-bromo-5-methoxy phenol (3.12g; 15.4 mmol), 2-(2- bromoethoxy)tetrahydro-2H-pyran (2.66 mL; 16.9 mmol) and K2C03 (1 .63g; 1 1.8 mmol) was heated at 80C in CH3CN (40 mL) overnight. The solution was cooled and the mixture was poured into cooled water, the product was extracted with EtOAc, the organic layer was washed with H20 and dried (MgS04), filtered and evaporated to dryness (5.5g). The residue was purified by chromatography over silica gel (irregular SiOH, 15-40 m, 200 g; mobile phase 80 % cyclohexane, 20 EtOAc). The product fractions were collected and the solvent was evaporated, yielding 3.7g (73%) of intermediate 42. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(2) The following reagent and solvent were put into a reaction container. sodium hydride: 1.4 g N,N-dimethylformamide: 200 ml After the reaction solution was cooled to 0 C., the compound obtained in the item (1) was added gradually. Subsequently, the reaction solution was agitated for 2 hours while the temperature of the reaction solution was raised to room temperature. Then, 6.4 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran was added, the reaction solution was heated to 60 C., and agitation was performed at this temperature (60 C.) for 5 hours. At this time, the degree of proceeding of the reaction was ascertained with TLC appropriately. Thereafter, the reaction was terminated with an ammonium chloride aqueous solution, and an organic phase was extracted with ethyl acetate. The resulting organic phase was washed with water and saturated saline solution in that order and was dried with anhydrous magnesium sulfate. A crude product obtained by concentrating the organic phase under reduced pressure was refined through column chromatography. The thus obtained product was used as-is in the following step |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.8% | With potassium carbonate; In N,N-dimethyl-formamide; for 3h;Heating; | <strong>[896139-85-8]Imidazo[1,2-a]pyridin-7-ol</strong> (3 g, 0.023 mol), 2-(2-bromo-ethoxy)tetrahydro-2H-Pyran (3.6 mL, 0.023 mol) and K2CO3 (6.32 g, 0.05 mol) were heated in DMF (100 ml) for 3 hours. The solution was cooled and evaporated to dryness. The residue was taken up with DCM+MeOH, the solution was filtered through a celite layer and the filtrate was evaporated to dryness. The residue was purified by Normal phase on E 5424(Irregular SiOH 15-40 mum 300 g MERCK). Mobile phase (0.3% NH4OH, 97% DCM, 3% MeOH), yielding 1.49 g (24.8%) of intermediate shown. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium hydroxide;tetra(n-butyl)ammonium hydrogensulfate; In water; at 65℃; for 7h; | (R,S)-N-ter/-Butoxycarbonyl- 1 -amino-2-[ 1 -(4-fluorophenyl)-2-methyl-5-(4- methylsulphonylphenyl)-lH-pyrrolo-3-yl]ethanol (6g, 0.0123 mol) and 3-bromoethanol- tetrahydropyranyl ether (16.43 g, 0.0736 mol) are heated at 65C for 7 hours, in a 50% aqueous NaOH solution (19.8 ml, 0.2456 mol) containing tetrabutylammonium hydrogen sulphate (600 mg). Then it is extracted with DCM, the extracts are washed with NaCl s.s., with H20, then dried and concentrated. The residue is purified by chromatography (silica, hexane-EtOAc 1 :5), 4.5 g, yield 64%. MS: 639.2 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In dimethyl sulfoxide at 60℃; for 30h; | 3 Production ofN-(( 1 S,2S)- 1 ,2-diphenyl-2-(2-(teti^ydro-2H^yran-2-yloxy)em^The target compound (D) was produced by the reaction shown below.[Chem. 10]h a 50-ml Schlenk tube, 7.0 g (24.1 mmol) of (S,S)-MsDPEN and 5.04 g (3.64 ml, 24.1 mmol) of an alkyl bromide (A) were mixed with 17.6 ml of DMSO, and the mixture was allowed to react for 30 hours at 60°C. Subsequently, 50 ml of dichloromethane and 50 ml of a saturated aqueous solution of NaHCC>3 were introduced into the reaction mixture, and the resulting mixture was stirred. Subsequently, the organic layer was separated and was washed two more times with 50 ml of a saturated aqueous NaHCOa. Dichloromethane was recovered, and the residue was purified by silica gel column chromatography. Thus, 5.06 g (50% yield) of the desired compound (D) was obtained.1.42-1.90(m, 6H), 2.20(d, 3H), 2.50-2.75(m, 2H), 3.40-3.50(m, 2H), 3.70-3.83(m, 2H), 3.90(d, 1H) , 4.45(m, 1H), 4.50(d, 1H), 7.10-7.30(m, 10H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With copper(l) iodide; lithium methanolate; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; | A mixture of 2-(2-bromoethoxy)tetrahydro-2H-pyran (84.0 g, 402 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (153 g, 602 mmol), lithium methoxide (30.5 g, 803 mmol), copper(l) iodide (7.65 g, 40.2 mmol), and polymer- bound triphenylphosphine (equivalent to 10.5 g, 40.0 mmol) in /V,/V-dimethylformamide (2.0 L) was stirred for 20 hours at room temperature. It was then diluted with dichloromethane (2 L) and filtered through a pad of diatomaceous earth; the filter pad was rinsed with dichloromethane (2 x 500 mL) and the combined filtrates were concentrated in vacuo. The residue was poured into saturated aqueous ammonium chloride solution (1.0 L) and the resulting mixture was extracted with diethyl ether (4 x 500 mL). After the combined organic layers had been washed with water (2 x 500 mL) and saturated aqueous sodium chloride solution (500 mL), they were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the product as a colorless oil. Yield: 85 g, 330 mmol, 82%. 1H NMR (400 MHz, CDCI3) delta 4.60 (dd, J=4.1, 2.8 Hz, 1H), 3.92-3.84 (m, 2H), 3.56-3.44 (m, 2H), 1.87-1.76 (m, 1H), 1.73-1.64 (m, 1H), 1.62-1.44 (m, 4H), 1.23 (s, 12H), 1.17 (t, J=7.9 Hz, 2H). |
70% | With copper(l) iodide; lithium methanolate; In N,N-dimethyl-formamide; at 20℃; | To a stirred solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran (10 g, 0.048 mol) in dry DMF (240 mL), were added bis(pinacolato)diboron (18.31 g, 0.071 mol), polymer-bound PPh3 (1.2 g, 0.004 mol), LiOMe (3.63 g, 0.096 mol), Cul (0.91 g, 0.004 mol) at RT. The reaction mixture was stirred at RT for overnight. Completion of the reaction was monitored by TLC. After completion, the mixture was filtered through a celite-bed and washed with DCM (2 x 10 mL). The filtrate was poured into sat. NH4CI solution (50 mL) and exacted with EtOAc (3 x 100 mL). The combined organic layer was washed with ice-cold water (2 x 50 mL), brine (50 mL), dried over Na2S04 and concentrated under reduced pressure to get the title compound. Yield: 70% (8.5 g, colorless liquid). 1H NMR: 1 H-NMR (400 MHz, CDCI3): d 4.64 (t, J = 4.0 Hz, 1 H), 3.94-3.88 (m, 2H), 3.56-3.52 (m, 2H), 1.90-1.75 (m, 1 H), 1.73-1.65 (m, 1 H), 1.61-1 .52 (m, 4H), 1.28 (s, 12H), 1.21 (t, J = 8.0 Hz, 2H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.08 g | With tetrabutylammomium bromide; sodium hydroxide; In toluene; at 60℃; | i) tert-butyl 5-(2-tetrahydropyran-2-yloxyethoxy)-2-azabicyclo[2.2.1]heptane-2- carboxylate Tert-butyl-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.5 g, 7.0 mmol) and tetrabutylammonium bromide (0.35 g, 0.70 mmol) were stirred in sodium hydroxide (10 M) (30 mL, 1600 mmol) / toluene (30 mL) and heated to 60 C. 2-(2- Bromoethoxy)tetrahydropyran (4.4 g, 21 mmol) was added in 4 portions over 2 hours and heating continued overnight. Further 2-(2-bromoethoxy)tetrahydropyran (1 eq) was added and the reaction heated for a further 3 hours. The reaction mixture was diluted with DCM, washed with water, dried over Na2S04 and concentrated in vacuo to afford a yellow oil. The reaction mixture was purified by flash chromatography, eluting with DCM then 90/10 DCM/MeOH to afford tert-butyl-5-(2-tetrahydropyran-2-yloxyethoxy)-2- azabicyclo[2.2.1]heptane-2-carboxylate (1.08 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h; | a. 6-Fluoro-l-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-lH-indazole (Intermediate 11a) A mixture of 6-fluoro-lH-indazole (2.0 g, 14.7 mmol), and 2-(2-bromo- ethoxy)-tetrahydro-pyran (3.38 g, 16.2 mmol) in DMF (25 mL) was treated with caesium carbonate (6.1 g, 18.7 mmol) and stirred at RT for 18 h. The solvent volume was reduced in vacuo, and the residue partitioned between EtOAc (100 mL) and water (100 mL). The aqueous layer was extracted into EtOAc (3 x). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated in vacuo. The residue was purified by FCC, using 0-50% cyclohexane in EtOAc, to afford the title product and a yellow oil. LCMS (Method 1): Rt 3.42 min, m/z 181 [MH+] (M-THP). 1H NMR (300 MHz; CDC13) 1.52- 1.56 (6 H, m), 3.39- 3.49 (1 H, m), 3.57-3.68 (1 H, m), 3.89-3.91 (1 H, m), 4.19-4.21 (1 H, m), 4.56-4.57 (3 H, m), 6.88 (1 H, td, J 9.15 and 2.26), 7.30 (1 H, m), 7.62 (1 H, m), 8.04 (1 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; | Preparation 5 2-Fluoro-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine Add cesium carbonate (3 Eq, 53.05 mmoles; 17.2 g) to a solution of <strong>[55758-32-2]2-fluoro-5-hydroxypyridine</strong> (2.0 g, 1.00 Eq, 17.68 mmoles) in dimethylformamide (0.3 M; 762.37 mmoles; 59.0 mL), followed by 2-(2-bromoethoxy)tetrahydro-2H-pyran (17.7 mmoles, 3.7 g) and stir at room temperature overnight. Transfer to a separatory funnel and add EtOAc (500 mL). Wash organic layer, wash with water (300 mL) followed by brine (200 mL). Dry over Na2SO4, filter and concentrate. Purify the crude mixture by HPLC eluting with hexanes/EtOAc 7/3 to give 2-fluoro-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine as a pale yellow oil (3.9 g, 16.2 mmoles; 91% yield). LCMS (Low) rt=1.8 min., M+1=242. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To a solution of <strong>[1149388-19-1]methyl 4-bromo-3-hydroxy-2-methylbenzoate</strong> (1 .Og, 4.08 mmol) in anhydrous DMF (20 ml) under argon was added anhydrous K2C03 (1.12 g, 8.16 mmol), and the reaction mixture was stirred at room temperature for 2 h. To this stirred mixture was added 2-(2-bromoethoxy) tetrahydro-2H-pyran (1.28g, 6.12 mmol). The reaction mixture was heated at 60C for 4 h. LCMS showed a single peak with the expected product mass. The heating was stopped and stirring was continued overnightroom temperature. After aqueous work up and extraction with EtOAc, the organic fractions dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified using an ISCO system (40 g silica column, hexane/EtOAc gradient). The product eluted with --10% EtOAc in hexane. The product fractions were collected and concentrated to give 1.48 g (97% yield) of SKC-02-034. ?H NMR (400 MHz, CDC13)7.53 (d, J= 8.5 Hz, 1H), 7.46 (d, J 8.5 Hz, 1H), 4.78 (t, J 3.5 Hz, 1H), 4.22 -4.03 (m, 3H), 4.07-3.76 (m, 5H), 3.60-3.52 (m, 1H), 2.61 (s, 3H), 1.98- 1.38 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With caesium carbonate; In acetonitrile; at 60℃; for 3.5h; | c. 4-Iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole-3-carboxylic acid ethyl ester (Intermediate 74c) A suspension of Intermediate 74b (2.72 g, 10.2 mmol) in acetonitrile (27 mL) was treated with caesium carbonate (5.0 g, 15.3 mmol) then 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.70 mL, 11.2 mmol) and the mixture was stirred at 60 C. for 3.5 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2*). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, isolating the lower running spot to give the title compound as a colourless glass (1.57 g, 39%). LCMS (Method 3): Rt 3.67 min, m/z 417 [M+Na+]. |
39% | With caesium carbonate; In acetonitrile; at 60℃; for 3.5h; | A suspension of Intermediate 74b (2.72 g, 10.2 mmol) in acetonitrile (27 mL) was treated with caesium carbonate (5.0 g, 15.3 mmol) then 2-(2- bromoethoxy)tetrahydro-2H-pyran (1.70 mL, 11.2 mmol) and the mixture was stirred at 60 C for 3.5 h. The mixture was evaporated in vacuo and the residue was partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (2 x). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution and brine, dried (Na2S04), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-50% EtOAc in cyclohexane, isolating the lower running spot to give the title compound as a colourless glass (1.57 g, 39%). LCMS (Method 3): Rt 3.67 min, m/z 417 [M+Na+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | (S)-2-((Tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetic acid (2.67 g, 10.0 mmol) was dissolved in 70 mL of dimethylformamide and the solution was cooled in an ice bath. Sodium hydride (0.88 g, 60% in mineral oil, 22.0 mmol) was added in portions. The mixture was stirred for thirty minutes before 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.30 g, 1 1.0 mmol) in 30 mL of dimethylformamide was added portionally. The reaction mixture was stirred at room temperature for 17 hours. Sodium hydride (0.16 g) was added and reaction was continued for one hour and then diluted with ice/water. The mixture was extracted with ethyl acetate (100 mL chi 2). The aqueous layer was cooled in an ice bath and acidified using 1.5 M aqueous potassium hydrogen sulfate to pH 2-3. The resulting mixture was extracted with ethyl acetate (100 mL chi 2). The organic phase was washed with water, brine, and dried over sodium sulfate. The product (3.3 g) was obtained (yield: 84%). NMR (500 MHz, CDCI3): delta 7.32 (m, 2H), 6.92 (m, 2H), 5.55 (m, 0.5H), 5.28 (m, 0.5H), 4.74 (m, I H), 4.15 (m, 2H), 4.05 (m, IH), 3.90 (m, I H), 3.85 (m, I H), 3.55 (m, I H), 1 .85 (m, I H), 1.75 (m, I H), 1.60 (m, 5H), 1.45 (s, 5H), 1.28 (s, 4H); MS (EI) for C20H29NO7; 394 (MH"). | |
84% | Step 1 : Preparation of (2S)-2-((tert-butoxycarbonyl)amino)-2-(4-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)acetic acid. [00125] <strong>[69651-48-5](S)-2-((tert-butoxycarbonyl)amino)-2-(4-hydroxyphenyl)acetic acid</strong> (2.67 g, 10.0 mmol) was dissolved in 70 mL of dimethylformamide and the solution was cooled in an ice bath. Sodium hydride (0.88 g, 60% in mineral oil, 22.0 mmol) was added in portions. The mixture was stirred for thirty minutes before 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.30 g, 1 1.0 mmol) in 30 mL of dimethylformamide was added portionally. The reaction mixture was stirred at room temperature for 17 hours and then diluted with ice/water. The mixture was extracted with ethyl acetate (50 mL chi 2). The aqueous layer was cooled in an ice bath and acidified using 1.5 M aqueous potassium hydrogen sulfate to pH 2-3. The resulting mixture was extracted with ethyl acetate (100 mL chi 2). The organic phase was washed with water, brine, and then dried over sodium sulfate. The product (3.3 g) was obtained after removing the solvent and drying under high vacuum (yield: 84%). XH NMR (500 MHz, CDC13): delta 7.32 (m, 2H), 6.92 (m, 2H), 5.55 (m, 0.5H), 5.28 (m, 0.5H), 4.74 (m, 1H), 4.15 (m, 2H), 4.05 (m, 1H), 3.90 (m, 1H), 3.85 (m, 1H), 3.55 (m, 1H), 1.85 (m, 1H), 1.75 (m, 1H), 1.60 (m, 5H), 1.45 (s, 5H), 1.28 (s, 4H); MS (EI) for C20H29NO7; 394 (MH"). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | [0300] 2-(2-(2-FIuoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII: A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H- pyran (4.4 niL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C for 16h. The reaction was cooled to room temperature, diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H2O (5x's to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes - 1 : 1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII (1.5 g, 21%). |
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H2O (5*'s to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes-1:1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII. | |
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C for 16h. The reaction was cooled to room temperature, diluted with EtOAc and H20. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H20 (5x's to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes - 1: 1 hexanes:EtOAc to provide 2-(2-(2- fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII. |
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h; | A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C for 16h. The reaction was cooled to room temperature, diluted with EtOAc and H20. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H20 (5x's to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes - 1 : 1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5- nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[1076-22-8]3-methyl-1H-purine-2,6(3H,7H)-dione</strong> (166 mg, 1.0 mmol) in 10%NaOH (2 mL), MeOH (4 mL) was stirred at 70 C for 1 h. To the mixture was added 2-(2- bromoethoxy)tetrahydro-2H-pyran (230 mg, 1.1 mmol). After the addition the mixture was stirred at 70 C for 12 h. The mixture was cooled to room temperature and a white precipitate was formed. The solid was collected by filtration, washed with acetone and dried under vacuum. ESI: m/z 295.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In 250 mL round bottom flask, sodium hydride (5.0 g, 208.33 mmol, 4.00 equiv) was added to a solution of 1-benzylpiperidin-4-ol (9.0 g, 47.05 mmol, 1.50 equiv) in N, N-dimethylformamide (150 mL) at room temperature. The resulting mixture was stirred for 20 minutes at room temperature. Then 2-(2-bromoethoxy)oxane (6.5 g, 31.09 mmol, 1.00 equiv) was added and the reaction mixture was heated to 50 C. and stirred overnight. The reaction was then quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (100 mL*2) and the organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure and the residue was applied onto a silica gel column eluting with dichloromethane/methanol (v:v=10: 1). This resulted in 8.0 g (81%) of 1-benzyl-4-[2-(oxan-2-yloxy)ethoxy] piperidine as yellow oil. LC-MS (ES+): m/z 320.05 [M+H]+; tR=1.14 min (2.60 minute run). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With caesium carbonate; In acetonitrile; at 30℃; for 2h; | To a solution of <strong>[14521-80-3]3-bromo-1H-pyrazole</strong> (5.0 g, 34.0 mmol) in acetonitrile (100 mL) was added cesium carbonate (16.6 g, 51.0 mmol) and 2-(2-bromoethoxy)tetrahydro-2h-pyran (7.5 g, 35.7 mmol). The mixture was stirred at 30 C. for 2 h and quenched by the addition of water (80 mL). The resulting mixture was extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 3-bromo-1-(2-tetrahydropyran-2-yloxyethyl)pyrazole (5.5 g, 59%) as a yellow oil. 1HNMR (400 MHz, CDCl3) delta 7.40 (d, J=2.4 Hz, 1H), 6.24 (d, J=1.2 Hz, 1H), 4.55-4.29 (m, 1H), 4.30-4.22 (m, 2H), 4.06-4.02 (m, 1H), 3.75-3.68 (m, 1H), 3.65-3.60 (m, 1H), 3.46-3.45 (m, 1H), 1.76-1.49 (m, 6H). |
59% | With caesium carbonate; In acetonitrile; at 30℃; for 2h; | To a solution of <strong>[14521-80-3]3-bromo-1H-pyrazole</strong> (5.0 g, 34.0 mmol) in acetonitrile (100 mL) was added cesium carbonate (16.6 g, 51.0 mmol) and 2-(2-bromoethoxy)tetrahydro-2h-pyran (7.5 g, 35.7 mmol). The mixture was stirred at 30 C. for 2 h and quenched by the addition of water (80 mL). The resulting mixture was extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0 to 20% ethyl acetate in petroleum ether) to afford 3-bromo-1-(2-tetrahydropyran-2-yloxyethyl)pyrazole (5.5 g, 59%) as a yellow oil. 1HNMR (400 MHz, CDCl3) delta 7.40 (d, J=2.4 Hz, 1H), 6.24 (d, J=1.2 Hz, 1H), 4.55-4.29 (m, 1H), 4.30-4.22 (m, 2H), 4.06-4.02 (m, 1H), 3.75-3.68 (m, 1H), 3.65-3.60 (m, 1H), 3.46-3.45 (m, 1H), 1.76-1.49 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 16h; | To a solution of methyl3-nitro-1H-pyrazole-5-carboxylate (1.7 g, 10.0 mmol) in Nl'Vl:P(20 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.6 g, 13.0 mmol), followed byK2C03 (1. 7 g, 13.0 mmol). The resulting mixture was stirred at 80 C for 16 hrs. Then K~C03was filtered off. The filtrate was concentrated in vacuo to give a residue, which was purified bysilica gel column (PE;EA = 2/l) to afford methyl3-nitro-l-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazole-5-carboxylate (2.8 g, yield: 94%) as yellow oil.[00948] 1H NMR (400 lVlliz, CDCh): (5 = 7.39 (s, 1H), 4.92 (t, J = 7.2 Hz, 2H), 4.57 (s, 1H),4.11-4.07 (m, lH), 3.98 (overlap, lH), 3.96 (s, 3H), 3.84-3.80 (m, lH), 3.64-3.60 (m, IH), 3.49-3.46 (m, lH), 1.67-1.46 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | 2,2-Dimethyl-2,3,5,10-tetrahydro-[1,2]diazepine [3,4,5,6-def]indazole-6(1H)-one(100mg, 0.39mmol)Dissolved in dry DMF (8 mL) and added 2-(2-bromoethoxy)tetrahydro-2H-pyran (194 mg, 1.17 mmol)And potassium carbonate (215 mg, 1.6 mmol), the reaction mixture was heated to 70 C and stirred for 11.5 hours.Water (100 mL) was added, and extracted with ethyl acetate (50 mL×3).The mixture was washed with brine, dried over anhydrous sodium sulfateCrude to methanol (15 mL), <strong>[6192-52-5]p-toluenesulfonic acid monohydrate</strong> (100 mg, 0.52 mmol),The reaction mixture was stirred at room temperature for 1 hour.After adding water (100 mL), it was extracted with ethyl acetate (50 mL×3), and the organic phase was combined and washed sequentially with aqueous sodium hydrogen carbonate and brine.Dry over anhydrous sodium sulfate. Concentrated and the residue was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate)80mg (69% yield)10-(2-hydroxyethyl)-2,2-dimethyl-2,3,5,10-tetrahydro[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one,It is a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | To a solution of 2-phenoxyphenol (48; 383.3 mg, 2.06 mmol) indimethyl sulfoxide (3.0 mL) was added potassium hydroxide (231 mg,4.12 mmol) and the mixture was stirred at room temperature for 5 min.Then, bromoethyl tetrahydropyranyl ether (430 mg, 0.31 mL,2.06 mmol) was added dropwise. The reaction mixture was stirred atroom temperature for 20 h. The mixture was extracted with methylenechloride (2×25 mL) and the combined organic phases were washedwith brine (5×50 mL), dried (MgSO4) and the solvent was evaporated.The product was purified by column chromatography (silica gel) usinga mixture of hexane-EtOAc (24:1) as eluent to give 503.6 mg (78%yield) of 49 as a colorless oil: Rf=0.50 (hexane-toluene, 4:1); 1H NMR(300.18 MHz, CDCl3) delta 1.41-1.74 (m, 6H, H-2??, H-3??, H-4??), 3.44 (m,1H, H-6??a), 3.67 (ddd, J=11.2, 6.3, 4.8 Hz, 1H, H-6??b), 3.77 (ddd,J=11.3, 8.4, 3.0 Hz, 1H, H-1a), 3.91 (dt, J=11.3 Hz J=4.7 Hz, 1H,H-1b), 4.18 (m, 2H, H-1H-2), 4.55 (dist. t, J=3.3 Hz, 1H, H-1??),6.89-7.14 (m, 7H, aromatic protons), 7.26 (t, J=8.0 Hz, 2H, aromaticprotons); 13C NMR (75.48 MHz, CDCl3) delta 19.1 (C-3??), 25.4 (C-4??), 30.4(C-2??), 61.8 (C-1), 65.6 (C-5??), 68.6 (C-1), 98.8 (C-1??), 115.0 (C-6),116.7 (C-3?), 121.6 (C-2?), 121.9 (C-4?), 122.1 (C-4?), 125.0 (C-5?),129.3 (C-3?), 145.1 (C-2?), 151.0 (C-1?), 158.3 (C-1?). HRMS (ESI)calcd. for C19H22O4Na [M+Na]+ 337.1416; found 337.1425. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With caesium carbonate; sodium iodide; In acetone; at 50℃; for 16h; | Into a 100-mL round-bottom flask, was placed methyl 2-(3-hydroxy-1,2-oxazol-5-yl)-3-methylbutanoate (498 mg, 2.50 mmol, 1 equiv), 2-(2-bromoethoxy)oxane (627.3 mg, 3.00 mmol, 1.20 equiv), Cs2CO3 (1.63 g, 5.00 mmol, 2.00 equiv), and NaI (37.5 mg, 0.25 mmol, 0.10 equiv) in acetone (20 mL). The resulting mixture was stirred for 16 hours at 50 C. in an oil bath. The reaction mixture was cooled to room temperature and diluted with water (150 mL). The mixture was extracted with ethyl acetate (100 mL*2), and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column eluting with ethyl acetate/petroleum ether (1:9). This resulted in 570 mg (70%) of methyl 3-methyl-2-[3-[2-(oxan-2-yloxy)ethoxy]-1,2-oxazol-5-yl]butanoate as a light yellow oil. |
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h; | A mixture of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (Intermediate 3, 300mg, 1.51mmol), 2-(2-bromoethoxy) tetrahydro-2H-pyran (787 mg, 3.77 mmol) and K2C03 (623 mg, 4.52mmol) in DMF (3mL) was stirred at 50C for 1 hour. The reaction solution was portioned between ethyl acetate and water. Phases were separated. The organic phase was dried over anhydrous sodium sulfate and the concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0%-80% ethyl acetate/petroleum ether) to yield 299 mg (60%) of the title compound as a colorless oil. LCMS (ESI): RT (min) = 1.03, [M+H]+ = 328, method = I. |
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 1h; | A mixture of methyl 2-(3-hydroxyisoxazol-5-yl)-3-methyl-butanoate (intermediate 3, 300mg, 1.51mmol), 2-(2-bromoethoxy) tetrahydro-2H-pyran (787 mg, 3.77 mmol) and K2C03 (623 mg, 4.52mmol) in DMF (3mL) was stirred at 50C for 1 hour. The reaction solution was portioned between ethyl acetate and water. Phases were separated. The organic phase was dried over anhydrous sodium sulfate and the concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0%-80% ethyl acetate/petroleum ether) to yield 299 mg (60%) of the title compound as a colorless oil. LCMS (ESI): RT (min) = 1.03, [M+H]+ = 328, method = I. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | A solution of compound 14 (50 mg, 0.14 mmol) and K2CO3 (39 mg,0.27 mmol) in anhydrous DMF (5 mL) was treated with a solution of compound 18 (57 mg, 0.27 mmol)in DMF (1 mL), and the resulting mixture was stirred at rt overnight. The reaction mixture wasquenched with H2O and extracted with EtOAc (3). The combined organic layers were washed withH2O (3), and brine (3), dried over anhydrous MgSO4, filtered, and concentrated under reducedpressure. The crude product obtained was purified by column chromatography (SiO2 gel, pure CH2Cl2to CH2Cl2:MeOH/19:1; Rf 0.21 in CH2Cl2:MeOH/19:1) to yield compound 19 (63 mg, 93%) as a yellowoil: 1H NMR (400 MHz, CDCl3, Figure S62) delta 7.35-7.22 (m, 5H, aromatic), 7.21 (s, 1H, aromatic), 6.82(s, 1H, aromatic), 4.70 (t, J = 3.6 Hz, 2H), 4.21 (t, J = 4.8 Hz, 2H), 4.05 (m, 1H), 3.91 (s, 3H, OCH3),3.87-3.82 (m, 2H), 3.49 (m, 2H, NCH2Ph), 3.20 (dd, J1 = 17.6 Hz, J2 = 8.4 Hz, 1H), 2.88 (m, 2H), 2.66(dt, J1 = 14.4 Hz, J2 = 3.6 Hz, 2H), 2.00-1.76 (m, 4H), 1.75-1.48 (m, 8H), 1.38-1.23 (m, 3H); 13C NMR(100 MHz, CDCl3, Figure S63) delta 207.6, 155.9, 148.8, 148.7, 129.5 (2 carbons), 129.1 (2 carbons), 128.2 (2carbons), 127.3, 107.6, 106.3, 98.9, 68.5, 65.42, 65.41, 63.1, 62.1, 56.12, 56.10, 53.5, 45.3, 38.6, 34.1, 33.4,31.4, 30.4, 25.4, 19.2; m/z calcd for C30H39NO5 493.3; found 494.2 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | To a stirred solution of <strong>[100058-61-5]3-(benzyloxy)cyclobutan-1-ol</strong> (10.0 g, 56.1 mmol) in DMF (75.0 mL) was added NaH (5.61 g, 140 mmol, 60% dispersion in mineral oil) in portions at 0 C under nitrogen atmosphere. The mixture was stirred for 30 min at 0 C. Then 2-(2- bromoethoxy)oxane (17.6 g, 84.2 mmol) was added. The mixture was stirred for 2 h at room temperature. Upon completion, the reaction was quenched by the addition of water (100 mL) at 0 C. The resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50.0 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EtOAc:Petroleum ether (v:v = 1: 3) to afford 2-[2-[3- (benzyloxy)cyclobutoxy]ethoxy]oxane (16.0 g, 93%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) d 7.44-7.15 (m, 5H), 4.60- 4.54 (m, 1H), 4.36 (s, 2H), 3.78-3.57 (m, 4H), 3.50-3.37 (m, 4H), 2.62-2.56 (m, 2H), 1.81-1.57 (m, 4H), 1.51-1.37 (m, 4H). LC/MS (ESI, m/z): [(M + 18)]+ = 324.15 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.58 g | With tetrabutylammomium bromide; potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | <strong>[14339-33-4]3-chloro-1H-pyrazole</strong> 1.75 g (0.017 mol), 2-(2-bromoethoxy)tetrahydro-2H-pyran 4.1g (0.02mol), potassium carbonate 5g (0.036mol),Tetrabutylammonium bromide 0.9g (2.8mmol), DMF 40ml, react overnight at room temperature, add water, EA extraction, wash, crude column chromatography to obtain 3.58g. |
Tags: 17739-45-6 synthesis path| 17739-45-6 SDS| 17739-45-6 COA| 17739-45-6 purity| 17739-45-6 application| 17739-45-6 NMR| 17739-45-6 COA| 17739-45-6 structure
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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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