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CAS No. : | 622-08-2 | MDL No. : | MFCD00002868 |
Formula : | C9H12O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CUZKCNWZBXLAJX-UHFFFAOYSA-N |
M.W : | 152.19 | Pubchem ID : | 12141 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.33 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 43.27 |
TPSA : | 29.46 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.44 cm/s |
Log Po/w (iLOGP) : | 1.92 |
Log Po/w (XLOGP3) : | 1.11 |
Log Po/w (WLOGP) : | 1.04 |
Log Po/w (MLOGP) : | 1.26 |
Log Po/w (SILICOS-IT) : | 1.87 |
Consensus Log Po/w : | 1.44 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.62 |
Solubility : | 3.63 mg/ml ; 0.0238 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.32 |
Solubility : | 7.26 mg/ml ; 0.0477 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.76 |
Solubility : | 0.264 mg/ml ; 0.00174 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.45 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P264-P270-P271-P280-P301+P312+P330-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.2% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -10 - 23℃; for 1 h; | Step 2: To a stirred solution of 2-(benzyloxy)ethanol (17.0 g, 1 1 1 .84 mmol) and PPh3 (35.0 g, 134.21 mmol) in DCM (170 mL) at -10 <C to -5 <C, NBS (23.88 g, 134.21 mmol) was added slowly in portions maintaining the temperature at -10 °C to -5 °C. After addition, the reaction mixture was allowed to stir at RT for 1 h until complete consumption starting material, as evidenced by TLC analysis. The reaction mixture was concentrated, the obtained crude compound was purified by CC using 5percent EtOAc in PE as eluent to afford ((2-bromoethoxy)methyl)benzene (13.5 g, 56.2percent) as pale yellow liquid (TLC solvent system: 30percent EtOAc in PE; Rf: 0.7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With pyridine; triphenylphosphine In methanol; dichloromethane; ethyl acetate | A. To an ice-cooled mechanically stirred solution of 2-benzyloxyethanol (25 mL, 0.18 mole), triphenylphosphine (115.2 g, 0.44 mole) and pyridine (56.9 mL, 0.70 mole) in methylene chloride (1000 mL) was added, dropwise, carbon tetrabromide (61.3 g, 0.18 mole). The mixture was stirred overnight at room temperature. Methanol (130 mL) was then added and, after further stirring for 1 hour, the solvents were evaporated. The residue was triturated with hexane and the hexane solution was concentrated to yield an oil which was set aside. The residue remaining after trituration was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution and brine and was concentrated to afford a brown oil. This was triturated with hexane. The resulting hexane solution was combined with the oil from the previous trituration and concentrated. The residue was chromatographed twice on silica gel eluding with hexane and then 5percent ethyl acetate/hexane to afford (2-bromoethoxymethyl)benzene as an oil (28.8 g, 76percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With sodium tetrahydroborate; zirconium(IV) chloride In tetrahydrofuran for 6h; Ambient temperature; | |
86% | With chloro-trimethyl-silane; zinc(II) tetrahydroborate In diethyl ether at 25℃; for 0.75h; | |
85% | Stage #1: 2-phenyl-1,3-dioxolane With 9-borabicyclo[3.3.1]nonane dimer In toluene for 18h; Inert atmosphere; Reflux; Stage #2: With ethanolamine In toluene; pentane at 20℃; for 1h; Inert atmosphere; |
82% | With diisobutylaluminium hydride In toluene for 4h; Ambient temperature; | |
With lithium aluminium tetrahydride; aluminium trichloride; diethyl ether | ||
With lithium aluminium tetrahydride; aluminium trichloride In diethyl ether | ||
With carbon monoxide; hydrogen at 210℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With pyridine; thionyl chloride at 65℃; for 4h; Inert atmosphere; | |
85.6% | With thionyl chloride; <i>N</i>,<i>N</i>-dimethyl-aniline at 20 - 50℃; | 5.5C Thionyl chloride (41.2 ml, 567.6 mmol) was slowly added to a mixture of Intermediate 5B (90 g, 80% purity, 473.1 mmol) and N,N-dimethyl aniline (76.5 ml, 597.5 mmol) while keeping the reaction temperature at 50° C. by ice-water cooling. After stirring at 50° C. for 1 h, further portions of N,N-dimethyl aniline (15.3 ml, 119.5 mmol) and thionyl chloride (8.2 ml, 113.5 mmol) were added, and the mixture was stirred at 50° C. for another 2 h and at room temperature overnight. The solution was then poured into a mixture of ice-water (200 ml) and conc. HCl (100 ml) and extracted three times with dichloromethane. The combined organic layers were washed twice with 10% HCl and twice with water, dried over Na2SO4, filtered and evaporated. The remaining residue was then distilled under vacuum (water pump) and the relevant fractions collected. Yield: 69.1 g (85.6%) of a colourless liquid. 1H-NMR (CDCl3): δ=3.69 (m, 4H), 4.59 (s, 2H), 7.35 (m, 5H). |
84% | With pyridine; thionyl chloride for 2h; Heating; |
84% | With pyridine; thionyl chloride In toluene at -5 - 105℃; for 3h; | Alkoxyethyl chlorides 7c-g (general procedure). General procedure: Thionylchloride (115 mmol) was added dropwise with stirring to a mixture of monoether 8a-e (100 mmol) and anhydrous pyridine (115 mmol) in anhydrous toluene (30 mL) at -5-0 °C. Then, the mixture was gradually heated for 1 h to 100 °C dissolving the precipitate, and gas evolution started. After stirring for 2 h at 100-105 °C, the mixture was diluted with water (60 mL). The organic layer was separated, washed consecutively with dilute HCl (1 : 2, 3×30 mL), a 10% aqueous solution of NaOH (2×30 mL), and water (3×30 mL), dried with Na2SO4, and evaporated in vacuo. The residue was distilled. The yields, physicochemical parameters, and microanalysis and 1H NMR spectral data are presented in Table 7. |
With thionyl chloride; chloroform; 2,3-Dimethylaniline dann unterhalb 55grad; | ||
With pyridine; thionyl chloride; chloroform dann unterhalb 55grad; | ||
With pyridine; thionyl chloride | ||
With thionyl chloride; <i>N</i>,<i>N</i>-dimethyl-aniline | ||
With N,N-dimethylphosphoroamidic dichloride In 1,2-dimethoxyethane | ||
With pyridine; thionyl chloride | ||
With pyridine; thionyl chloride In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane | P.189 PREPARATION EXAMPLE 189 PREPARATION EXAMPLE 189 To a solution of 2-benzyloxyethanol (11.7 g) and pyridine (6.08 g) in dichloromethane (50 ml) was added thionyl chloride (6.7 ml) under ice-cooling, and the resulting mixture was stirred at refluxing temperature for 2.5 hr. Ice-water was added to the reaction mixture, and the organic layer was washed with water and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform) to give 10.3 g of 2-benzyloxyethyl chloride. 1 H-NMR (CDCl3,ppm) δ: 3.62(2 H,t,J=6.3 Hz), 3.72(2 H,t,J=6.3 Hz), 4.57(2 H,s), 7.26-7.39(5 H,m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iron(III) perchlorate at 100℃; for 0.5h; neat (no solvent); | |
90% | for 3h; Heating; | |
85% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; hexane at 20℃; for 1h; Stage #2: benzyl chloride With sodium iodide for 12h; Heating; Further stages.; |
82% | With sodium at 100℃; for 12h; | |
66% | With sodium methylate at 155℃; | |
59% | With sodium hydroxide In water at 100℃; for 24h; | |
51% | With tetrabutylammomium bromide; potassium hydroxide In 1,4-dioxane at 100 - 105℃; | Ethylene glycol and diethylene glycol monoalkyl ethers 8a-e (general procedure). General procedure: Dioxane (15 mL), alkyl halide (25 mmol), and tetrabutylammonium bromide (0.4 g, 1.2 mmol) were added to a solution of KOH (1.6 g, 27.5 mmol) in glycol (75-125 mmol). After stirring at 100-105 °C for 5-10 h, the reaction mixture was diluted with CHCl3 (15 mL) and water (10 mL). The organic layer was separated, washed with water (3×20 mL), dried with Na2SO4, and evaporated in vacuo, and the residue was distilled using Vigreux column. For each particular case, the ratio of the starting reagents, yields, physicochemical parameters, and 1H NMR spectral data for monoalkyl ethers 8a-e are givenin Table 6. |
48.1% | With sodium hydroxide In water at 65 - 120℃; | 5.5B 2-(Benzyloxy)-1-ethanol Ethylene glycol (742.5 g, 11.96 mol) was added to a solution of sodium hydroxide pellets (475.2 g, 11.88 mol) in 450 ml of water kept at 80° C. Benzyl chloride (302.8 g, 2.39 mol) was then added at 65° C., and the resulting suspension was vigorously stirred at 120° C. overnight. After cooling to room temperature, the mixture was poured into ice-water and extracted five times with diethyl ether. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The remaining residue was then distilled under vacuum and the relevant fractions (bp. 95-125° C. at 0.1-1 mbar) collected. Yield: 175 g (48.1%) of a colourless liquid. 1H-NMR (CDCl3): δ=2.09 (tr, 1H), 3.60 (m, 2H), 3.77 (m, 2H); 4.56 (s, 2H) 7.35 (m, 5H). |
47% | With potassium hydroxide at 130℃; for 5h; | |
With potassium hydroxide at 90 - 130℃; | ||
(i) NaOH, (ii) /BRN= 471308/; Multistep reaction; | ||
(i) Na, (ii) /BRN= 471308/; Multistep reaction; | ||
With sodium hydride 1) THF, 30 min, r. t., 2) THF, 6 h, reflux; Yield given. Multistep reaction; | ||
With potassium <i>tert</i>-butylate 1) t-BuOH, 1.5 h; 2) dioxane, 55 deg C, 22 h; Yield given. Multistep reaction; | ||
Stage #1: ethylene glycol With sodium hydride In N,N-dimethyl-formamide at 50℃; for 10h; Stage #2: benzyl chloride In N,N-dimethyl-formamide at 20℃; | ||
With potassium hydroxide; dibenzo-18-crown-6 at 80℃; | ||
Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl chloride With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; mineral oil for 24h; Reflux; | ||
650 mg | Stage #1: ethylene glycol With potassium <i>tert</i>-butylate In dimethyl sulfoxide for 0.5h; Cooling with ice; Stage #2: benzyl chloride With tetra-(n-butyl)ammonium iodide In dimethyl sulfoxide at 20℃; for 3h; | 4.1 100mL single-necked flask, under ice water bath conditions, ethylene glycol (3 g, 48 mmo 1) was dissolved in dimethylsulfoxide (40 mL) potassium tert-butoxide (1460 mg, 13 mmol) was added, The reaction was continued for 0.5 h and tetrabutylammonium iodide (740 mg, 2 mmol) was added. To the above reaction solution was added dropwise water (1260 mg, 10mmol) of dimethyl sulfoxide (10 mL) was transferred to room temperature for 3 h. Was added to dichloromethane (50 mL) and washed successively with water (50 mL) and saturated brine (50 mL). The organic phase was dried, filtered, concentrated and the baby gel column (petroleum ether / ethyl acetate = 4/1) was purified to give 650 mg of product as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.1% | With dmap; potassium carbonate; In 1,2-dichloro-ethane; at 0 - 10℃; for 5h; | 30.44 g of 2-benzyloxyethanol (0.2 mol), 28.2 g of potassium carbonate (0.204 mol), 12.2 g of N,N-dimethylaminopyridine (0.1 mol), 23.37 g of methylsulfonyl chloride (0.204 mol) and 152 mL of 1,2 -Dichloroethane were sequentially added to a 500 mL four-necked flask, and the reaction was carried out at 0 C - 10 C for 5 h. The completion of the reaction was monitored by TLC. The reaction solution was washed with 0.1% aqueous solution of malic acid, washed with 0.1% aqueous sodium hydrogencarbonate, and washed with distilled water. The reaction solution was evaporated to dryness to give 45.2 g of yellow oil (0.196 mol); Yield 98.1%;The HPLC purity was 80.3%. 45.2 g of crude ethyl 2-benzyloxymethanesulfonate was added to 100 mL of a single-mouth bottle connected to a vacuum distillation apparatus, and fractions were collected at 0.1 Torr and 140 C - 150 C to obtain 37.5 g of a colorless transparent oil. Yield 83.1%, HPLC purity 99.3%, GC purity 99.9%. |
In tetrahydrofuran; at 0 - 10℃; for 3h; | 2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved in THF (500 ML) and methanesulfonyl chloride (76.8 g) was added dropwise at from 0 C. to 10 C. The mixture was stirred for 3 hr. 10% aqueous sodium bicarbonate (300 ML) was poured into the reaction mixture, the mixture was partitioned and combined with an extract of the aqueous layer with MTBE (300 ML), and the mixture was washed with 10% aqueous sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated to give 2-benzyloxyethyl methanesulfonate (124.0 g).The 2-benzyloxyethyl methanesulfonate (124.0 g) was dissolved in acetone (500 ML), and sodium iodide (130.0 g) was added.The mixture was stirred at from 50 C. to 60 C. for 3 hr.The reaction mixture was filtered and the solvent was evaporated.water (300 ML) was added, and the mixture was extracted twice with toluene (300 ML).The toluene layer was washed successively with aqueous sodium hydrogen sulfite solution, water and brine and dried over anhydrous magnesium sulfate.The solvent was evaporated to give the title compound (127.0 g). | |
With sodium chloride; triethylamine; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; | Referential Example 3 Synthesis of alpha-{2-[1-(alpha,alpha,alpha-trifluoro-4-tolyl)-2-imidazolidinon-3-yl]ethoxy]toluene To a solution of 2-(benzyloxy)ethanol in 320 ml of dichloromethane, 35 ml of triethylamine and 19.5 ml of methanesulfonyl chloride were added under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was added with ice water and then extracted with dichloromethane. After the extract was washed with a saturated solution of sodium chloride, the extract was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, whereby 49 g of 2-(benzyloxy)ethyl methanesulfonate were obtained (yield: stoichiometric). |
In pyridine; dichloromethane; | (a) 2-Benzyloxyethanol is reacted with methanesulfonyl chloride in pyridine/dichloromethane, in conventional manner, to give (2-benzyloxy)ethyl methanesulfonate. | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0℃; for 1h; | To a solution of 2-benzyloxyethanol (305 mg, 2.0 mmol) and DIPEA (0.69 mL, 4.0 mmol) in DCM (5 mL) cooled on an ice bath was added mesylchloride (0.19 mL, 2.5 mmol). The reaction mixture was stirred for 15 min before the ice bath was removed. After stirring for an additional 45 min the reaction mixture was washed with aqueous HCI (0.1 N, 5 mL). The aqueous phase was extracted with dichloromethane (2 x 5 mL) and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in acetonitrile (5 mL) before DIPEA (0.34 mL, 2.0 mmol) and 4- frans-methyl-cyclohexylamine (226 mg, 2.0 mmol) were added. The reaction mixture was refluxed for 18 hours before the volatiles were removed in vacuo. EPO <DP n="117"/>The residue was dissolved in tetrahydrofuran (2 ml_) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester (655 mg, 3.0 mmol), carbonyl diimidazole (487 mg, 3.0 mmol) and 4- (dimethylamino)pyridine (12 mg, 0.1 mmol) were added. The reaction mixture was stirred for 2 hours before the volatiles were removed in vacuo. The residue was dissolved in methanol (2.5 ml_) and NaOH (2N, 5 ml_,10 mmol) was added. The mixture was stirred for 2 hours before HCI (1 ml_, cone.) was added. The solvent was removed in vacuo before tetrahydrofuran, 5 ml_) was added and the mixture was filtered. The filtrate was purified on a preparative HPLC to give 230 mg {2-[3-(2-benzyloxy-ethyl)-3-(4- frans-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid. 1H NMR (400 MHz, DMSOd6) delta 7.41 (s, 1 H), 7.35-7.23 (m, 5H), 4.53 (s, 2H), 3.92 (m, 1 H), 3.57-3.44 (m, 6H), 1 .73-1.45 (m, 6H), 1.35-1 .25 (m, 1 H), 1 .10-0.95 (m, 1 H), 0.86 (d, 3H) HPLC-MS: m/z = 465 | |
With triethylamine; In dichloromethane; at 20℃; for 1h; | D. (Methoxy-dQethyl Methanesulfonate (27-d3).; D3CL //OMs O ^^27-d3; Step 1. (2-(Methoxy-d3)ethoxy)methyl)benzene (38-d3). To a solution of 2- benzyloxyethanol 37 (8.1O g, 53.2 mmol) in methylene chloride (80.0 mL) was added methanesulfonyl chloride 36 (6.60 mL, 79.7 mmol) and triethylamine (11.1 mL, 79.78 mmol) and the solution was stirred at room temperature for 1 hour. Water (25 mL) was added to the reaction mixture and the organic layer was separated, washed with satd. brine solution (15 mL), dried over Na2SO4 and concentrated in vacuo. The crude mesylate intermediate (3.73 mL, 92.0 mmol) was dissolved in DMF (100.0 mL) and combined with CD3O Na+ 39-d3 which was produced in situ by incubating CD3OD [99.8 atom % D, Aldrich] (3.73 mL, 92.0 mmol) in DMF (100.0 mL) with sodium hydride (3.70 g, 151.8 mmol, 55% dispersion in oil) and stirring at room temperature for 30 min. The mesylate/CD3O"Na+ solution was stirred at room temperature for 6 hours. Water (25 mL) was added to the reaction mixture and the solution was extracted with methyl £-butyl ether (2 x 15 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give 38-d3 (7.00 g, 95%). | |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | The product 2-10 (15.2 g, 0.1 mol) obtained in the previous step and Et3N (16.6 mL, 0.12 mol) were dissolved in 150 mL DCM, the mixture was cooled to 0 C., methanesulfonyl chloride (8.5 mL, 0.11 mol) was added dropwise slowly. The reaction mixture was warmed to room temperature and stirred for 2 hours. 50 mL water was added to quench the reaction, the organic phase was separated, washed with saturated brine for 3 times (50 mL×3), dried over anhydrous sodium sulfate, and concentrated to give 23 g crude product 3-10 as yellow oil, which was used directly for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In dichloromethane for 12h; Inert atmosphere; | |
95% | With potassium iodide; silver(I) oxide In dichloromethane at 40℃; | |
93% | With triethylamine for 18h; | 2-(benzyloxy)ethyl 4-methylbenzenesulfonate To a solution of 2-(benzyloxy)ethanol (1.47 g, 9.66 mmol, 1 equiv) and TEA (2.83 mL, 20.28 mmol, 2.1 equiv) was added TsCl (2.2 g, 11.59 mmol, 1.2 equiv). After stirring 18 h, the reaction was added to saturated aqueous NaHC03 and extracted with DCM (x2). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-50% EtOAc in hexane) to provide the product as a viscous colorless oil (2.75 g, 93%). 1H NMR (500 MHz, CDCl3) δ 7.89 - 7.78 (m, 2H), 7.41 - 7.23 (m, 7H), 4.51 (s, 2H), 4.27 - 4.20 (m, 2H), 3.76 - 3.62 (m, 2H), 2.46 (s, 3H). |
91% | With 4-dimethylaminopyridine; triethylamine In dichloromethane at 20℃; for 12h; | |
90.3% | With 4-dimethylaminopyridine; N-ethyl-N,N-diisopropylamine In chloroform at 20 - 30℃; for 5h; | 1-2; 4-5; 7-8 30.44 g of 2-benzyloxyethanol (0.2 mol), 26.37 g of N,N-diisopropylethylamine (0.204 mol), 1.22 g of N,N-dimethylaminopyridine (0.01 mol), 38.89 g of p-toluenesulfonyl chloride ( 0.204 mol) and 152 mL of chloroform were sequentially added to a 500 mL four-necked flask, and the reaction was carried out at 20 ° C to 30 ° C for 5 h. The completion of the reaction was monitored by TLC. The reaction solution was washed with 0.1% aqueous solution of malic acid, washed with 0.1% aqueous sodium hydrogencarbonate, and distilled water. After washing, the reaction mixture was evaporated to dryness to give 60.0 g of yellow semi-solid oil (0.196 mol). The yield was 98.0%; the HPLC purity was 85.2%. 60.0 g of 2-benzyloxy p-toluenesulfonate ethyl ester was added to 30mL of absolute ethanol, heated to dissolve, 60 mL of petroleum ether was added dropwise, stirred at 30-50 ° C for 0.5-1h, cooled down to 10 ° C, suction filtration was carried out, and the filter cake was washed with 10 mL of petroleum ether to obtain 54.2 g of white crystalline powder. The yield was 90.3%; HPLC purity was 98.6%. |
85% | With 4-dimethylaminopyridine; triethylamine In acetonitrile at 0 - 20℃; for 3h; | 163.1 Step 1. Step 1. 2-(benzyloxy)ethyl 4-methylbenzenesulfonate (163-2) To a solution of 2-(benzyloxy)ethan-1-ol (163-1, 2.00 g, 13.1 mmol) in MeCN (10 mL) at 0° C. was added TEA (3.6 mL, 19 mmol), DMAP (48 mg, 0.39 mmol) and 4-methylbenzenesulfonyl chloride (3.75 g, 19.7 mmol) sequentially and the resulting mixture was stirred at rt for 3 h. The reaction mixture was filtered and the filtrate was concentrated to dryness. The obtained crude material was purified via silica gel chromatography eluting with 15% EtOAc in hexanes to afford 163-2 (3.41 g, 11.1 mmol, 85% yield) as a white solid. MS [M+H]+=307.3. |
84% | With pyridine for 18h; in the refrigerator; | |
82% | In pyridine at -10 - -5℃; for 2h; | |
81% | With pyridine; 4-dimethylaminopyridine for 3h; | |
80% | With pyridine; Zeolite A-3 at 0℃; for 3h; | |
78% | With pyridine 1.) 0 deg C, 1 h, 2.) 5 deg C, 3 h; | |
75% | With pyridine In chloroform at 20℃; for 24h; | |
74% | With potassium hydroxide In tetrahydrofuran at 25℃; for 1h; | 1 Step 1: Preparation of 2-(benzyloxy)ethyl 4-methylbenzenesulfonate To a solution of 2-benzyloxyethanol (50 g, 328.54 mmol, 46.73 mL, 1 eq) and potassium hydroxide (22.12 g, 394.24 mmol, 1.2 eq) in tetrahydrofuran (200 mL) was added toluenesulfonyl chloride (56.37 g, 295.68 mmol, 0.9 eq). The mixture was stirred at 25 °C for 1 hour. Ethyl acetate (1000 mL) was added, then the reaction was filtered, then the filtrate was washed by brine (200 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (Petroleum ether: Ethyl acetate =5:1 to 3:1). Compound 2-benzyloxyethyl 4-methylbenzenesulfonate (75 g, 243.82 mmol, 74% yield, 99% purity) was obtained as a yellow oil. 'H-NMR (400MHz, CDCb) d 7.85 - 7.79 (m, 2H), 7.38 - 7.31 (m, 4H), 7.30 - 7.26 (m, 2H), 7.31 (s, 1H), 4.51 (s, 2H), 4.26 - 4.19 (m, 2H), 3.73 - 3.65 (m, 2H), 2.50 - 2.40 (m, 3H). |
74% | With potassium hydroxide In tetrahydrofuran at 25℃; for 1h; | 1 [00270] Exemplary Synthesis of (2S,4R)-N-[[2-[2-[[1-[(2R)-2-[6-chloro-8-fluoro-7-(3-hydroxy-1-naphthyl)-4-(4-prop-2-enoylpiperazin-1-yl)quinazolin-2-yl]oxypropyl]-4-piperidyl]oxy]ethoxy]-4-(4-methylthiazol-5-yl)phenyl]methyl]-4-hydroxy-1-[(2R)-3-methyl-2-(3-methylisoxazol-5-yl)butanoyl]pyrrolidine-2-carboxamide Step 1: Preparation of 2-benzyloxyethyl 4-methylbenzenesulfonate To a solution of 2-benzyloxyethanol (50 g, 328.54 mmol, 46.73 mL, 1 eq) and KOH (22.12 g, 394.24 mmol, 1.2 eq) in THF (200 mL) was added toluenesulfonyl chloride (56.37 g, 295.68 mmol, 0.9 eq), and the reaction mixture was stirred at 25 °C for 1 hour. EtOAc (1 L) was added, the resulting mixture was filtered, and the filtrate was washed by brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography on SiO2 (15-25% EtOAc in petroleum ether) to afford 2-benzyloxyethyl 4-methylbenzenesulfonate (75 g, 243.82 mmol, 74% yield, 99% purity) as a yellow oil. 1H-NMR (400 MHz, CDCl3) δ 7.85 - 7.79 (m, 2H), 7.38 - 7.31 (m, 4H), 7.30 - 7.26 (m, 2H), 7.31 (s, 1H), 4.51 (s, 2H), 4.26 - 4.19 (m, 2H), 3.73 -3.65 (m, 2H), 2.50 - 2.40 (m, 3H). |
17.4% | With pyridine at 0 - 22℃; Inert atmosphere; | 4.4 Synthesis of 2-(phenylmethoxy)ethanol-1-(4-4.4 methylbenzenesulfonate)20 To a stirred solution of 2-(benzyloxy)ethanol (0.92g, 6.0mmol) in pyridine (9cm3) at 0°C was added p-toluenesulfonyl chloride (1.15g, 6.05mmol). The reaction mixture was stirred overnight at room temperature, diluted with water (20cm3) and extracted with diethyl ether (3×7cm3). The organic layers were combined, washed with saturated NaHCO3 solution (10cm3) and saturated NaCl solution (10cm3), dried (MgSO4) and concentrated under reduced pressure. The residue was then purified by flash column chromatography using gradient elution from 10/90 to 12/88 v/v EtOAc/petroleum ether to give the product (0.32g, 1.04mmol, 17.4%) as colourless oil; (found (EI): M++Na 329.0816. C16H18NaO4S requires M 329.0818); νmax/cm-1 (thin film) 2864 (CH2), 1353 and 1174 (SO2O), 1095 (C-O-C), 814 (p-substituted Ph), 722 and 698 (Ph); δH (300MHz, CDCl3) 7.79 (2H, d, J 8.4, ArH), 7.36-7.24 (7H, m, ArH), 4.48 (2H, s, OCH2Ph), 4.21-4.18 (2H, m, CH2OTs), 3.67-.64 (2H, m, CH2OCH2Ph), 2.43 (3H, s, CH3 of OTs); δC (75MHz, CDCl3) 144.74 (C), 137.50 (C), 132.95 (C), 129.77 (2× CH), 128.38 (2×CH), 127.94 (2×CH), 127.77 (CH), 127.62 (2×CH), 73.19 (CH2), 69.24 (CH2), 67.45 (CH2), 21.61 (CH3); ESI-MS m/z (CI) 329 (M++Na). |
With pyridine | ||
With pyridine at 0℃; | ||
In 1,2-dimethoxyethane | I EXAMPLE I EXAMPLE I To a slurry of sodium hydride (0.4 g,17 mmol) in 20 ml ethylene glycol dimethyl ether cooled with an ice bath under an atmosphere of nitrogen, a solution of 2-benzyloxyethanol (2.1 ml, 15 mmol) and p-toluene sulfonyl chloride (2.9 g, 15 mmol) in ethylene glycol dimethyl ether was added dropwise. When the addition was complete, the ice bath was removed and the solution stirred at room temperature for 18 hours. After dilution with diethyl ether, the resulting slurry was filtered through anhydrous magnesium sulfate and concentrated under vacuum to yield 3.6 g of crude 2-benzyloxyethyl p-toluenesulfonate. | |
With triethylamine | ||
In dichloromethane for 1h; Cooling with ice; | 3.31 (3-1) Synthesis of Tosyl Derivative (3b) Alcohol (3a; 45.7ml, 300 mmol) and para-toluenesulfonyl chloride (60.1 g, 315 mmol) were reacted in 120 ml of methylene chloride under ice-cooled condition for 1 hour. The reaction mixture was subjected to a separation procedure, and the organic layer was concentrated with an evaporator to obtain a tosyl ether (3b) as a crude yellow liquid. The product was directly used as raw material in the next step without being purified. 1HNMR (300 MHz, CDCl3) δ 2.4 (s, 3H), 3.6 (d, 2H), 4.2 (d, 2H), 4.4 (s, 2H), 7.1-7.4 (d x 3, s x 1,7H), 7.8 (d, 2H) |
|
With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0℃; for 4h; | ||
In 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran for 1h; Cooling with ice; | 1-1 Synthesis of (1-1) tosyl derivative (1b) of The alcohol (1a) (45.7ml, 300mmol) and p-toluenesulfonylchloride (60.1g, 315mmol) in 120ml of dichloromethaneReaction under ice-cooling for 1 hour. The reaction solutionfor liquid separation operation embodiment, the organic layer was concentratedby evaporation to give body tosyl ether as a yellow liquid crude product (.IB). Without purification, the product was used directly as the next rawmaterial processes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With carbon tetrabromide; triphenylphosphine In tetrahydrofuran at 0 - 20℃; | |
98% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; Inert atmosphere; Darkness; | |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 13h; |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; for 1h; | 1.ii ((2-bromoethoxy)methyl)benzene (Compound II) To a solution of NBS (17.7 g, 99.3 mol, 1 equiv.) in CH2CI2 (200 mL) was added dropwise a solution of PPfi3 (26.1 g, 99.3 mol, 1 equiv.) in CH2CI2 (140 mL) at -78 °C. The solution was stirred for 1 h, then a solution of 2-(benzyloxy)ethan-1-ol (14.4 g, 94.6 mmol, 1 equiv.) in ChhC OO mL) was added dropwise. The solution was allowed to return to rt and after one hour, the reaction was quenched using MeOH (10 mL) and PhMe (150 mL). The solution was evaporated, water was added and the aqeous phase was extracted three 24 times with EtOAc. The combined organics were washed with brine, dried over Na2S04 and evaporated. The residue was purified on silica gel column eluting with 10% EtOAc in cyclohexane to afford the desired product (18.1 g, 84.1 mol, 89%) as a light yellow oil.1H NMR (400 MHz, CDCh) d 7.41 - 7.28 (m, 5H), 4.60 (s, 2H), 3.80 (t, J = 6.2 Hz, 2H), 3.50 (t, J= 6.2 Hz, 2H); 13C NMR (101 MHz, CDCh) d 137.8, 128.5, 127.9, 127.8, 73.2, 70.0, 30.5; Rf : 0.85 (20% AcOEt in CyH) |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; for 1h; | |
89% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78 - 20℃; for 1h; | |
86% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane a) 1 h at r.t., b) 30 min at 35 deg C; | |
86% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane | |
77% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 12h; | |
56.2% | With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -10 - 23℃; for 1h; | A118.2
Step 2: To a stirred solution of 2-(benzyloxy)ethanol (17.0 g, 1 1 1 .84 mmol) and PPh3 (35.0 g, 134.21 mmol) in DCM (170 mL) at -10 |
47.4% | With pyridine; phosphorus tribromide In benzene for 48h; Ambient temperature; | |
With bromine; triphenylphosphine | ||
With N-Bromosuccinimide; PS-PPh3 In dichloromethane at 20℃; for 16h; | ||
With N-Bromosuccinimide; triphenylphosphine In dichloromethane at -78℃; | ||
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine; dmap / chloroform / 5 h / 20 - 30 °C 2: lithium bromide / acetonitrile / 2.5 h / 70 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 25℃; for 1h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil for 12h; Reflux; | 2- (Benzyloxy) ethanol To a mixture of NaH (3.4 g, 0.085 mol, 60% w/w in mineral oil) in THF (150 mL), ethylene glycol (1) (25.1 mL, 0.45 mol) was added and the mixture was stirred forh at 25°C. Then, benzyl bromide (8.9 g, 0.075 mol) was added and the reaction was refluxed for 12 h. After cooling down the mixture (0°C), a saturated aqueous solution of NH4C1 was added, the solvent was evaporated, and the mixture was extracted with EtOAc (3x). The combined organic layers were washed with a saturated aqueous solution of NH4C1 and brine, and dried (Na2SO4). The solvent was evaporated to afford 11.22 g (98% yield) of a colorless oil identified as 2-(benzyloxy)ethanol (2). The spectroscopic data were identical to those described in the literature. 1H-NMR (400 MHz, CDC13): ö 7.40-7.30 (m, 5H), 4.58 (s, 2H), 3.78 (t, J 5.0 Hz, 2H), 3.61 (t, J 4.9 Hz, 2H), 2.06 (br, 1H, OH) ppm. |
93% | Stage #1: ethylene glycol With di-n-butyltin(IV) oxide In methanol; toluene at 130℃; for 3h; Stage #2: benzyl bromide With tetrabutylammonium bromide In toluene at 130℃; for 1.5h; | |
93% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 0.5h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; for 12h; | 1.i 2-(benzyloxy)ethan-1-ol (Compound I). To a suspension of NaH (10.2 g, 0.25 mmol, 1.05 equiv) in dry THF (152 mL) ethylene glycol (250 g, 2.42 mol, 10 equiv) was added dropwise at 0 C. The reaction mixture was first stirred at rt for 30 min and afterwards benzylbromide (48 mL, 0.24 mol, 1.0 equiv) was added at 0 C. The mixture was stirred for 12 h at rt and afterwards quenched with saturated ammonium chloride (NH4CI) solution. The aqueous phase was extracted three times with diethyl ether (Et20). The combined organic layers were washed with H2O, brine, dried over sodium sulfate (Na2S04) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (20-100% EtOAc in petroleum ether (hereinafter referred to as PE) to afford the desired compound as a light yellow oil (56.7 g, 373 mmol, 93%).1H NMR (400 MHz, CDCh) d .39 - 7.27 (m, 5H), 4.56 (s, 2H), 3.79 - 3.69 (m, 2H), 3.61 - 3.54 (m, 2H), 2.61 - 2.50 (m, 1 H); 13C NMR (101 MHz, CDCh) d 138.0, 128.4, 127.8, 127.7, 73.2, 71.5, 61.8; Rf : 0.39 (40% AcOEt in PE). |
91% | With Fe(diisobutyrylmethane)<SUB>3</SUB>; potassium carbonate In acetonitrile at 80℃; regioselective reaction; | |
90% | With ferric(III) chloride; 2,2,6,6-tetramethylheptane-3,5-dione; tetrabutylammonium bromide; silver(I) oxide In acetonitrile at 40℃; for 3h; Green chemistry; | |
88% | With sodium hydride In tetrahydrofuran at 70℃; for 12h; | |
86% | Stage #1: ethylene glycol With sodium hydride In methanol; N,N-dimethyl-formamide for 10h; Stage #2: benzyl bromide In methanol; N,N-dimethyl-formamide for 10h; Further stages.; | |
85% | Stage #1: ethylene glycol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: benzyl bromide With N,N,N-tributyl-1-butanaminium iodide at 20℃; for 14h; | |
85% | Stage #1: ethylene glycol With natrium In tetrahydrofuran at 50℃; for 0.5h; Reflux; Stage #2: benzyl bromide In tetrahydrofuran Reflux; | 3.1 (1) Synthesis of Benzyloxyethanol 1 32.8 g (0.53 mol) of ethylene glycol was added to a tetrahydrofuran (100 mL) solution, and then 3.0 g(0.13 mol) ofsodium was addedand the temperature was controlled at 50°C.The resulting mixture was then stirred under reflux for 0.5 hours,17.1 g (0.1 mol) ofbenzyl bromide was added dropwise, and then the mixture was refluxed overnight.Then 100 mL of water was added, most of the solvent was removed on a rotary evaporator,80 mL of ethyl acetate was added, the organic phase was separated, and the aqueous layer was extracted three times with ethyl acetate.The combined organic layers werewashedwithbrine, dried over anhydrous sodium sulfate and concentrated, and purified by distillation. The 70°C (2 mmHg) fraction was collected to give 12.86 g of a productin a yield of 85%. |
84% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: benzyl bromide With N,N,N-tributyl-1-butanaminium iodide In tetrahydrofuran; dimethyl sulfoxide at 60℃; | |
84% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; dimethyl sulfoxide at 20℃; Stage #2: benzyl bromide With N,N,N-tributyl-1-butanaminium iodide In tetrahydrofuran; dimethyl sulfoxide at 60℃; | |
81% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran at 20℃; for 1.5h; Stage #2: benzyl bromide In tetrahydrofuran for 17h; Reflux; | |
81% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran at 20℃; for 1.5h; Stage #2: benzyl bromide In tetrahydrofuran for 17h; Reflux; | 5.1.2. 2-(Benzyloxy)ethanol (24) To a mixture of sodium hydride (5.10 g, 0.17 mol, 80%, w/w) in dried THF (300 mL) was added dry ethylene glycol (50.2 mL, 0.9 mol) at room temperature over 1 h, stirred another 0.5 h, then the mixture was refluxed and benzyl bromide (17.8 mL, 0.15 mol)was added over 2 h. The mixture was refluxed for 15 h, cooled to room temperature, quenched with saturated aqueous NH4Cl (5 mL) solution and evaporated THF under reduced pressure. The residue was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with saturated aqueous NH4Cl solution and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was distilled under reduced pressure to afford 24 (18.5 g, 81%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.35e7.29 (m, 5H), 4.57 (s, 2H), 3.78e3.74 (m,2H), 3.62e3.59 (m, 2H), 2.10 (br, 1H, OH) ppm. |
81% | With sodium hydride In tetrahydrofuran | |
81% | With sodium hydride In tetrahydrofuran at 20℃; for 12h; | |
80% | Stage #1: ethylene glycol With sodium hydride at 20℃; for 16h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran at 70℃; | |
79% | With sodium hydride In tetrahydrofuran for 3h; Heating; | |
76% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; n-Pentane at 20℃; for 0.5h; Stage #2: benzyl bromide In tetrahydrofuran; n-Pentane Heating / reflux; | |
72% | With potassium hydroxide at 90 - 110℃; | 10 Synthesis of compound 2-10 Compound 1-10 (37.2 g, 0.6 mol) was added to a 250 mL eggplant shaped bottle, KOH (11.2 g, 0.2 mol) was added while stirring. The suspension was heated to 90° C., and stirred till KOH was completely dissolved. BnBr (34 g, 23.6 mL, 0.2 mol) was added dropwise slowly. The reaction mixture was heated to 110° C. and stirred overnight. The reaction mixture was cooled to room temperature, 800 mL water was added, and the resultant mixture was extracted with EtOAc for 3 times (150 mL×3). The organic phases were combined, washed with water for 3 times (150 mL×3) and saturated brine (150 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (PE/EtOAc 10:1-3:1) to give 22 g product 2-10 as colorless oil, yield 72%. LCMS (ESI) m/z 153.1 (M+H)+ |
64% | With sodium hydride at 100℃; Inert atmosphere; | |
56% | With sodium hydride; potassium iodide for 48h; Inert atmosphere; | |
55% | Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide With potassium iodide In tetrahydrofuran; mineral oil at 20℃; for 48h; Inert atmosphere; Reflux; | |
53% | With potassium hydroxide at 20 - 127℃; for 2h; | |
51.2% | With silver(I) oxide In dichloromethane at 20℃; for 15h; | |
39.9% | Stage #1: ethylene glycol With sodium hydride In methanol; N,N-dimethyl-formamide; mineral oil at 20 - 22℃; for 17h; Inert atmosphere; Stage #2: benzyl bromide In methanol; N,N-dimethyl-formamide; mineral oil at 20 - 22℃; for 24h; Inert atmosphere; | 4.3 Synthesis of 2-(benzyloxy)ethanol19 To a stirred solution of ethylene glycol (11.13g, 179.3mmol) in a N,N-dimethylformamide: methanol solution (1:1 v/v, 10cm3) was added sodium hydride (1.04g, 26.0mmol, 60% in mineral oil) portionwise over a period of 20-25min. The resulting solution was stirred at 20-22°C for 17h, followed by the dropwise addition of benzyl bromide (3.07g, 18.0mmol). The reaction mixture was stirred at 20-22°C for 24h, quenched with 10% (v/v) HCl solution (11cm3) and extracted with ethyl acetate (3×20cm3). The organic layers were combined, washed with saturated NaCl solution (60cm3), dried (Na2SO4), filtered and concentrated under reduced pressure to give the product (1.09g, 7.16mmol, 39.9%) as colourless oil. This was used directly without further purification in the next step; (found (EI): M++Na 175.0732. C9H12NaO2 requires M 175.0730); νmax/cm-1 (thin film) 3394 (OH), 2927 and 2865 (CH2), 1719, 1453, 1115 (C-O-C), 1068, 1028, 892, 739 and 698 (Ph); δH (400MHz, CDCl3) 7.38-7.27 (5H, m, ArH), 4.56 (2H, s, OCH2Ph), 3.75 (2H, t, J 4.5, CH2O), 3.59 (2H, t, J 4.5, CH2OH), 2.25 (1H, br s, OH); δC (100MHz, CDCl3) 137.90 (C), 128.42 (2× CH), 127.76 (overlapping CH and 2× CH), 73.25 (CH2), 71.34 (CH2), 61.83 (CH2); ESI-MS m/z (CI) 175 (M++Na). The spectroscopic data were in agreement with the literature values. |
36% | With sodium hydroxide In tetrahydrofuran; lithium hydroxide monohydrate at 80℃; for 5h; | |
34% | With sodium hydride In tetrahydrofuran at 0 - 23℃; for 16h; | A118.1 Step 1 : To a solution of diethylengylcole (30 g, 483.87 mmol) in THF (300 mL) at 0 °C, a 60% suspension of NaH (9.67 g, 241 .93 mmol) was slowly added in portions which was followed by the addition of benzyl bromide (28.9 mL, 241 .93 mmol) after which the suspension was stirred at RT for 16h until complete consumption of starting material, as evidenced by TLC analysis. The reaction mixture was then diluted with ice cold water (100 mL), extracted with EtOAc (3x250 mL) and the combined EtOAc layers were washed with brine (50 mL), dried over anhydrous NaS04,filtered and concentrated. The obtained crude compound was purified by CC using 25% EtOAc in PE as eluent to afford 2-(benzyloxy)ethanol (25 g, 34%) as pale yellow liquid (TLC solvent system: 40% EtOAc in PE; Rf: 0.3). |
33% | With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide | |
28% | Stage #1: ethylene glycol With sodium hydride In methanol; N,N-dimethyl-formamide at 20 - 21℃; Inert atmosphere; Stage #2: benzyl bromide In methanol; N,N-dimethyl-formamide at 21 - 22℃; Inert atmosphere; | |
With sodium hydride | ||
(i) nBuLi, (ii) /BRN= 385801/; Multistep reaction; | ||
With sodium hydride 1. THF, 1.5h, r.t., 2. 45 deg C, 3h; Yield given. Multistep reaction; | ||
With potassium carbonate; potassium iodide In propan-2-one Heating; | ||
With sodium hydride In tetrahydrofuran | ||
With thallium(I) ethanolate 1) MeCN, r.t., 2) MeCN, 20 deg C, 24 h; Yield given. Multistep reaction; | ||
With sodium hydride 1.) THF 2.) reflux, 16 h; Yield given. Multistep reaction; | ||
With sodium hydride 1.) THF, DMF, RT, 3 h, 2.) THF, DMF, RT, 12 h; Yield given. Multistep reaction; | ||
Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran at 20℃; for 1h; Stage #2: benzyl bromide In tetrahydrofuran at 60℃; for 16h; | ||
Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Reflux; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil for 12h; Reflux; | 70 Synthesis of monobenzyloxy carbinols (24, Step 1): To a stirred suspension of NaH (3. 5 g, 1.04eq) in dry THF (50mL) was added diol (23) (3eq) over 0.5 h at 0°C. After the addition was complete, the mixture was brought to reflux and benzyl bromide (10 mL, 0.084 mol, leq) was added dropwise. The reaction mixture was stirred at reflux for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC). After the reaction was complete, the mixture was allowed to cool to room temperature, and diluted with ether. The combined extracts were dried over MgS04, filtered, and concentrated under reduced pressure. The residue was passed through a short silica gel column using a gradient of hexane and ethyl acetate as eluents to get the pure monobenzyloxycarbinol (24) as a colorless oil in moderate yields. | |
Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran at 0 - 20℃; for 12h; Inert atmosphere; | ||
With sodium hydride In tetrahydrofuran at 20℃; | ||
2.5g | Stage #1: ethylene glycol With N,N,N-tributyl-1-butanaminium iodide; sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.16667h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil at 0 - 25℃; | 1 Step 1. 2-(benzyloxy)ethan-1-ol To a stirred solution of NaH (1.93 g, 80.645 mmol, 1.0 eq.) in THF (50 mL) at 0°C was added Ethylene glycol (5 g, 80.645 mmol, 1.0 eq.), followed by catalytic amount of TBAI (100 mg). The reaction mixture was stirred for 10 min at 0 °C and then stirred at RT for lh. Benzyl bromide (13.7 mL, 80.645 mmol, 1.0 eq.) was then added drop wise to the reaction mixture at 0°C. Then the reaction was left to stir at 25 °C. The reaction mixture was quenched with cold water (250 mL) and extracted with EtOAc (3 X 250 mL). The combined organic layer was dried over anhydrous Na2SCO4 and concentrated under vacuum. The obtained crude product (9 g) was purified via silica gel chromatography using gradient elution with 30% EtOAc/Hexane, giving the title compound as a pale-yellow oil (2.5 g). 1H NMR (CDCl3): d 7.38-7.30 (m, 5H), 4.56 (s, 2H), 3.78-3.74 (m, 2H), 3.61-3.59 (m, 2H), 2.06 (t, J= 6.4 Hz, 1H). |
Stage #1: ethylene glycol With natrium In tetrahydrofuran for 0.5h; Stage #2: benzyl bromide In tetrahydrofuran at 40 - 60℃; | 2 Example 2. Method for synthesizing benzyloxy alcohol General procedure: 2 mol of Dihydroxyalkane (R = 2~9) was diluted with THF, reacted with 1 mol of sodium (Na) for 30 minutes, and then 1 mol of benzyl bromide was added dropwise.After all the dropping was completed, the reaction was carried out by refluxing at a temperature of 40 to 60 degrees for 4 to 12 hours.After completion of the reaction by adding water to the reaction mixture, extraction was performed three times with diethyl ether, and the ether extract was washed with water and washed with water.Then, it was dried over magnesium sulfide. From the crude extract, pure benzyloxy alcohol was isolated by column chromatography. | |
Stage #1: ethylene glycol With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 1h; Stage #2: benzyl bromide In tetrahydrofuran; mineral oil at 0 - 20℃; | ||
With sodium hydride In tetrahydrofuran at 20℃; for 12.5h; | 13.1 Step 1: Synthesis of 2-(benzyloxy)ethanol (Compound 12a-1) Add 15.001g of ethylene glycol to the flask,45ml of tetrahydrofuran, add 2.320g of sodium hydrogen (60% content) under stirring, add 9.920g of benzyl bromide after 30 minutes of stirring at room temperature. The reaction was stirred at room temperature for 15 hours. After the reaction was completed, the tetrahydrofuran was evaporated under reduced pressure, and 100 ml of water was added to the residue.Extract with 30ml petroleum ether to remove residual benzyl bromide, extract the aqueous phase with 100ml ethyl acetate, separate the aqueous layer, wash the organic layer twice with water, 50ml each time; wash once with 50ml saturated sodium chloride aqueous solution, and then use After drying with sodium sulfate and filtering, the filtrate was evaporated under reduced pressure to remove the solvent to obtain 6.302 g of compound 12a-1. | |
2.5 g | Stage #1: ethylene glycol With N,N,N-tributyl-1-butanaminium iodide; sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.16667h; Stage #2: benzyl bromide In tetrahydrofuran at 0 - 25℃; for 18h; | 2.1 Step 1. 2-(benzyloxy)ethan-l-ol To a stirred solution of NaH (1.93 g, 80.645 mmol, 1.0 eq.) in THF (50 mL) at 0°C was added ethylene glycol (5 g, 80.645 mmol, 1.0 eq.) and catalytic amount of TBAI (100 mg). The reaction was stirred for 10 minutes at 0°C and then warmed to RT over 1 hour. After 1 hour, benzyl bromide (13.7mL, 80.645 mmol, 1.0 eq.) was added drop wise to the reaction mixture at 0°C. The reaction was stirred at 25 °C for 18 hours and monitored by TLC. The reaction mixture was quenched with cold water (250 mL) and extracted with EtOAc (3 x 250 mL). The total organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude, which was purified by silica gel chromatography (60-120 mesh) using gradient elution with 30% EtOAc/Hexane to afford 2-(benzyloxy)ethan- 1 -ol (2.5 g) as a pale- yellow oil. 1H NMR (CDCb): δ 7.38-7.30 (m, 5H), 4.56 (s, 2H), 3.78-3.74 (m, 2H), 3.61-3.59 (m, 2H), 2.06 (t, J= 6.4 Hz, 1H). |
2.5 g | Stage #1: ethylene glycol With N,N,N-tributyl-1-butanaminium iodide; sodium hydride In tetrahydrofuran at 0 - 20℃; for 1.16667h; Stage #2: benzyl bromide In tetrahydrofuran at 0 - 25℃; for 18h; | 2.1 Step 1. 2-(benzyloxy)ethan-l-ol To a stirred solution of NaH (1.93 g, 80.645 mmol, 1.0 eq.) in THF (50 mL) at 0°C was added ethylene glycol (5 g, 80.645 mmol, 1.0 eq.) and catalytic amount of TBAI (100 mg). The reaction was stirred for 10 minutes at 0°C and then warmed to RT over 1 hour. After 1 hour, benzyl bromide (13.7mL, 80.645 mmol, 1.0 eq.) was added drop wise to the reaction mixture at 0°C. The reaction was stirred at 25 °C for 18 hours and monitored by TLC. The reaction mixture was quenched with cold water (250 mL) and extracted with EtOAc (3 x 250 mL). The total organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain crude, which was purified by silica gel chromatography (60-120 mesh) using gradient elution with 30% EtOAc/Hexane to afford 2-(benzyloxy)ethan- 1 -ol (2.5 g) as a pale- yellow oil. 1H NMR (CDCb): δ 7.38-7.30 (m, 5H), 4.56 (s, 2H), 3.78-3.74 (m, 2H), 3.61-3.59 (m, 2H), 2.06 (t, J= 6.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With boron trifluoride diethyl etherate; In dichloromethane; at 0℃; for 0.166667h; | [0418] To a mixture of 3-09-1 (5.0 g, 25 mmol) and 2-(benzyloxy)ethan-l-ol (4.92 g, 32.3 mmol) in dichloromethane (70 mL) was added a solution of boron trifluoride diethyl ether complex (375 mg, 1.24 mmol) in dichloromethane (10 mL) drop wise at 0C. The mixture was stirred at 0C for 10 minutes. The reaction mixture was poured into saturated aqueous sodium carbonate (200 mL) and extracted with dichloromethane (200 mL*3). The combined organic phase was washed with brine (200 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified chromatography column (petroleum ether: ethyl acetate = 30: 1 - 10: 1) to afford compound 3-09-2 (3.8 g, 43% yield) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 0℃; for 2h; | 3 Example 3; N-hydroxy-2-(1-methyl-3-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxo-3-pyrrolidinyl)acetamide To a solution of 2-(benzyloxy)ethanol (75.0 g, 493 mmol), triphenylphosphine (142.1 g, 542 mmol), and imidazole (36.9 g, 542 mmol) in methylene chloride (1.5 L) at 0° C. was added iodine (143.9 g, 567 mmol). The mixture was stirred at 0° C. for 2 h. The solvent was removed in vacuo and the remaining residue was filtered through a pad of silica gel eluting with 10% ethyl acetate/hexanes. The filtrate was then washed with a 1: 1 solution of 10% sodium sulfite/saturated sodium bicarbonate (2×), saturated sodium bicarbonate (1×), and brine. The organic layer was dried and concentrated to give the desired iodide (123.6 g, 96%), which was used without further purification or characterization. |
94% | With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran at 20℃; for 1h; | |
93% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 23℃; for 18h; Inert atmosphere; |
92% | With 1H-imidazole; iodine; triphenylphosphine In benzene at 0℃; | |
90% | With 1H-imidazole; iodine; triphenylphosphine In benzene for 4h; | |
87% | Stage #1: 2-Benzyloxyethanol With methanesulfonyl chloride; triethylamine In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: With sodium iodide In dichloromethane; acetone at 20℃; | |
81% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 20℃; for 12h; | |
66% | With 1H-imidazole; iodine; triphenylphosphine In benzene at 0℃; for 2h; | |
66% | With 1H-imidazole; iodine; triphenylphosphine In benzene at 0℃; for 2h; | |
62% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane for 24h; | |
52% | Stage #1: 2-Benzyloxyethanol With methanesulfonyl chloride; triethylamine In dichloromethane at 0℃; for 3h; Stage #2: With sodium iodide In acetone at 20℃; for 50h; | 44-1 To a solution of 3.00 g (20.0 mmol) of 2-benzyloxy ethanol and 2.30 g (22.0 mmol) of triethylamine in 30 ml of dichloromethane was added 2.50 g (22.0 mmol) of mesyl chloride, followed by stirring at 0°CFor 3 hours. The precipitated solid was removed by filtration, and then the filtrate was concentrated under reduced pressure. To the obtained residue was added 30 ml of acetone, and the precipitated solid was removed by filtration. To the filtrate was added 4.50 g (30.0 mmol) of sodium iodide, followed by stirring at room temperature for 50 hours, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=7:1) to prepare 2.70 g (yield 52%) of a target compound. 1H-NMR (CDCl3, ppm) δ 3.29 (2H, t, J=6.8 Hz), 3.74 (2H, t, J=6.8 Hz), 4.58 (2H, s), 7.29-7.37 (5H, m). |
With 1H-imidazole; iodine; triphenylphosphine In toluene | ||
Multi-step reaction with 2 steps 1: triethylamine / CH2Cl2 / 0.5 h / 20 °C 2: NaI / CH2Cl2; acetone / 20 °C | ||
Multi-step reaction with 2 steps 1: pyridine / CH2Cl2 / 3 h / 20 °C 2: NaI / acetone / 5 h / Heating | ||
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 / 2.5 h / 5 - 20 °C 2: NaI / acetone / 18 h / Heating | ||
Multi-step reaction with 2 steps 1: 100 percent / Et3N / tetrahydrofuran 2: 88.7 percent / NaI / acetonitrile / 6 h / Heating | ||
Multi-step reaction with 2 steps 1: SOCl2, Py 2: NaI / acetone | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 - 20 °C 2: sodium iodide / acetone / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.5% | Stage #1: 2-Benzyloxyethanol With 4-ethanoyloxy-2,2,6,6-tetramethyl-piperidinyloxy; Sodium hydrogenocarbonate In water monomer; 4-methyl-2-pentanone at 0 - 5℃; Stage #2: With sodium chlorine monoxide In water monomer at 20℃; for 2.5h; Stage #3: With Na2S2O3 In water monomer for 0.0833333h; | |
79% | With tert.-butylhydroperoxide; vanadium(IV) oxide sulphate pentahydrate In water monomer; acetonitrile at 20℃; for 5h; Green chemistry; | General procedure for oxidation of alcohol: General procedure: In a typical experiment, 1 mmol 1-phenyl ethanol and 10 mol % (25.30 mg) VOSO4.5H2O (purchased from Loba Chemie, molecular weight 253.08) in 2 ml CH3CN/H2O (1:1) in a round bottomed flask. To this mixture 2 equiv 70% TBHP (aqueous) was added and stirred at room temperature for the time specified in Table 1. The progress of the reaction was monitored by TLC. After the completion of the reaction, the mixture was extracted with ethyl acetate (3 x 20 mL) three times. The ethyl acetate layer was dried with anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography using ethyl acetate-hexane as the eluent. Formation of the product was confirmed by comparing FTIR spectra, 1H NMR spectra, 13C NMR spectra, melting point measurement and GC-MS with authentic compounds. |
77% | Stage #1: 2-Benzyloxyethanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.75h; Inert atmosphere; Stage #2: With triethylamine at -78 - 20℃; for 0.666667h; Inert atmosphere; |
75% | Stage #1: 2-Benzyloxyethanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60 - -50℃; for 0.25h; Stage #2: With triethylamine In dichloromethane at -60 - -50℃; for 1h; | 3.2 (2) Synthesis of Benzaldehyde Oxyacetaldehyde 2 2.72 g (0.023 mol) of oxalyl chloride was dissolved in 50 mL of dichloromethane, cooled to -50 to -60C, and then a mixture of 10 mL ofdichloromethane and 2.5 g of dimethyl sulfoxide (0.05 mol) wasadded dropwise.After 30 minutes, 3.5 g (0.023 mol) of benzyloxyethanol 1 was added dropwise and thetemperature was maintained at -50--60°C.After 15 minutes triethylamine 14g (0.138 mol) was added while maintaining the temperature at -50~-60°C.ContinueAfter stirring for 1h 70mL of water was added, separated and the aqueous layer extracted twice with dichloromethane.The combined organic layers were washed with 3% hydrochloric acid and brine, dried over anhydrous sodium sulfate and concentrated, and purified by distillation. The 80°C (2 mmHg) fraction was collected to give 2.57 g of productin 75% yield. |
75% | With dihydrogen peroxide In acetonitrile at 80℃; for 3h; | |
71.4% | Stage #1: 2-Benzyloxyethanol With Potassium phosphate, dibasic; 4-ethanoyloxy-2,2,6,6-tetramethyl-piperidinyloxy In dichloromethane; water monomer at 0 - 5℃; Stage #2: With sodium chlorine monoxide In water monomer at 20℃; for 2.5h; Stage #3: With Na2S2O3 In water monomer for 0.0833333h; | |
70% | With Dess-Martin periodane In dichloromethane | |
70% | With pyridinium chlorochromate In dichloromethane at 20℃; for 10h; | |
66.8% | Stage #1: 2-Benzyloxyethanol With 4-ethanoyloxy-2,2,6,6-tetramethyl-piperidinyloxy; Sodium hydrogenocarbonate In dichloromethane; water monomer at 0 - 5℃; Stage #2: With sodium chlorine monoxide In water monomer at 20℃; for 2.5h; Stage #3: With Na2S2O3 In water monomer for 0.0833333h; | |
66.2% | Stage #1: 2-Benzyloxyethanol With 4-ethanoyloxy-2,2,6,6-tetramethyl-piperidinyloxy; Sodium hydrogenocarbonate In water monomer; toluene at 0 - 5℃; Stage #2: With sodium chlorine monoxide In water monomer at 20℃; for 2.5h; Stage #3: With Na2S2O3 In water monomer for 0.0833333h; | |
56% | With dicyclohexyl-carbodiimide In dimethyl sulfoxide | |
53% | Stage #1: 2-Benzyloxyethanol With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -78℃; for 0.0833333h; Inert atmosphere; Stage #2: With triethylamine In ethanol; dichloromethane; dimethyl sulfoxide at -78℃; for 0.5h; Inert atmosphere; | |
46% | With sodium bismuthate | |
27% | Stage #1: 2-Benzyloxyethanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78 - -70℃; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at -78 - 21℃; Inert atmosphere; | |
19.7% | Stage #1: 2-Benzyloxyethanol With oxalyl dichloride In dichloromethane; dimethyl sulfoxide at -78℃; for 1h; Stage #2: With triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; | 124.2 Step 2: 2-(benzyloxy)acetaldehyde In 40mL vial, DCM (3.0 mL) was added followed by oxalyl chloride (0.2 mL, 2.29 mmol) then cooled to -78 °C. DMSO (0.4 mL, 5.64 mmol) in DCM (3.0 mL) was added dropwise and the reaction mixture continue to stir at -78 °C for 30 mins.2-(benzyloxy)ethan-1-ol 181 (293 mg, 1.925 mmol) in DCM (6 mL) was added dropwise and the reaction mixture continued to stir at -78 °C for 1 hr. Triethylamine (1.3 mL, 9.33 mmol) was added and the reaction warmed to r.t. overnight. The reaction was quenched with saturated aqueous ammonium chloride and extracted with DCM three times. The organic layers were combined, passed through a phase separated and concentrated in-vacuo. The crude material was purified by silica gel chromatography (0-100% EtOAc in heptane) to afford 2-(benzyloxy)acetaldehyde INT-182 (57.0 mg, 0.380 mmol, 19.7 % yield) as a yellow liquid.1H NMR (400 MHz, CD2Cl2) δ 9.71 (s, 1H), 3.28 (s, 3H), 2.13 (s, 6H). |
With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5h; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) hexane, CH2Cl2, -78 deg C, 10 min, 2.) -78 deg C to room temperature; Multistep reaction; | ||
With diphosphorus pentoxide; dimethyl sulfoxide; triethylamine 1.) CH2Cl2, 3 h, 2.) 2 h; Yield given. Multistep reaction; | ||
With pyridinium chlorochromate | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) CH2Cl2, -78 deg C, 30 min, 2.) CH2Cl2, a) 0 deg C, 30 min, b) RT, 1 h; Multistep reaction; | ||
78 % Chromat. | With N-tert-butylbenzenesulfinimidoyl chloride; zinc oxide In dichloromethane at 0℃; for 1h; | |
78 % Chromat. | With N-tert-butylbenzenesulfinimidoyl chloride; zinc oxide In dichloromethane at 0℃; for 1h; | |
With pyridine; Dess-Martin periodane In dichloromethane at 15℃; for 2h; | ||
With pyridine; phthalic acid dimethyl ester In dichloromethane at 15℃; for 2h; | ||
With pyridine; phthalic acid dimethyl ester In dichloromethane at 15℃; for 2h; | ||
With pyridine; Dess-Martin periodane In dichloromethane at 0 - 15℃; for 2h; | ||
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In ethyl acetate Reflux; | ||
Stage #1: 2-Benzyloxyethanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.666667h; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at -78℃; for 0.333333h; Inert atmosphere; | ||
71 %Spectr. | With sodium chlorine monoxide; 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; sulfuric acid; Sodium hydrogenocarbonate; sodium bromide In dichloromethane; water monomer at -10℃; for 0.05h; | |
Stage #1: 2-Benzyloxyethanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.25h; Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 1h; | ||
150 mg | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 90℃; for 0.166667h; | 1 Step 1: 2-(benzyloxy)acetaldehyde [0469] To a solution of 2-(benzyloxy)ethan-1-ol (1.0 g, 6.6 mmol) in MeCN (30 mL) was added IBX (8.4 g, 19.7 mmol). The mixture was stirred at 90 °C for 10 min. The reaction was diluted with EtOAc (30 mL) and was washed with water (2 x 10 mL) then saturated brine (1 x 10 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude was then purified by silica gel chromatography (EA : PE = 1 : 5) to give 2-(benzyloxy)acetaldehyde (150 mg, 1.00 mmol). LCMS calc'd for C9H11O2 [M+H]+: 151.1; Found: 151.1. |
150 mg | With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In acetonitrile at 90℃; for 0.166667h; | 1 Step 1: 2-(benzyloxy)acetaldehyde [0469] To a solution of 2-(benzyloxy)ethan-1-ol (1.0 g, 6.6 mmol) in MeCN (30 mL) was added IBX (8.4 g, 19.7 mmol). The mixture was stirred at 90 °C for 10 min. The reaction was diluted with EtOAc (30 mL) and was washed with water (2 x 10 mL) then saturated brine (1 x 10 mL). The organic layer was dried over MgSO4, filtered and concentrated to dryness. The crude was then purified by silica gel chromatography (EA : PE = 1 : 5) to give 2-(benzyloxy)acetaldehyde (150 mg, 1.00 mmol). LCMS calc'd for C9H11O2 [M+H]+: 151.1; Found: 151.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With zirconium(IV) tetraisopropoxide 2-propanol; 4 Angstroem MS; 1,1'-bi-2-naphthol In isopropyl alcohol; toluene at 20℃; for 9h; | |
95% | With zirconium(IV) tetraisopropoxide 2-propanol; 1,1'-bi-2-naphthol In toluene at 20℃; for 1h; | |
84% | With lithium aluminium tetrahydride In diethyl ether |
75% | With alpha-D-glucopyranose; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; sodium acetate In 1,2-dichloro-ethane at 120℃; for 24h; | |
With sodium tetrahydroborate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-Benzyloxyethanol With sodium hydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: bromoacetic acid methyl ester In tetrahydrofuran at 0 - 20℃; for 16h; Inert atmosphere; | |
78.9% | With tetra-(n-butyl)ammonium iodide; sodium hydroxide In dichloromethane at 30℃; for 72h; | 21.1 Step 1: Preparation of methyl 2-(2-benzyloxyethoxy)acetate To a mixture of NaOH (10M, 300.0 mL), methyl 2 -bromo acetate (23.5 g, 155.6 mmol) and tetrabutylammonium iodide (8.8 g, 24.06 mmol) in DCM (300 mL) was added 2- benzyloxyethanol (12.99 mL, 123.32 mmol) at 30 °C and the mixture was stirred at 30 °C for 72 hours. After the reaction was completed, the organic phase was separated out and the aquatic phase was extracted with DCM (150 mL) twice. The combined organic layer was washed with brine, dried over MgSCL and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with PE: EtOAc = 3:1) to give methyl 2-(2- benzyloxyethoxy)acetate (21.3g, 78.9% yield) as a colorless liquid. MS obsd. (ESI+) [(M+Na)+]: 225.2. |
55% | In tetrahydrofuran at 0 - 25℃; for 12h; |
24% | Stage #1: 2-Benzyloxyethanol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 25℃; for 2.33333h; Inert atmosphere; Ice bath; Stage #2: bromoacetic acid methyl ester In N,N-dimethyl-formamide; mineral oil at 20 - 25℃; Inert atmosphere; | A13 A13. Methyl [2-(benzyloxy)ethoxy]acetateSodium hydride (60% suspension in mineral oil, 2.07 g) is suspended in dimethylformamide (30 ml) under nitrogen atmosphere and the suspension is cooled to O0C (ice bath). A solution of 2- (benzyloxy)ethanol (7.5 g) in dimethylformamide (10 ml) is added drop by drop within 20 min. The mixture is stirred for 2 h at room temperature, until gas evolution ceases. A solution of methyl bromoacetate (8.2 g) in dimethylformamide (10 ml) is added drop by drop. The mixture is stirred for 3 h at room temperature. After that, saturated ammonium chloride solution (10 ml), water (50 ml) and dichloromethane (50 ml) are added, the aqueous phase is extracted with dichloromethane (2 x 50 ml), the combined organic extracts are washed with saturated sodium chloride solution (1 x 100 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by flash chromatography (silica gel, eluting with petroleum ether / ethyl acetate 9:1 (v/v)) to yield 2.61 g (24%) of the title compound as a yellow oil.1H-NMR (300 MHz, CDCI3); δ = 3.63-3.70 (m, 2H), 3.74 (s, 3H), 3.74-3.80 (m, 2H), 4.18 (s, 2H), 4.57 (s, 2H), 7.24-7.39 (m, 5H). MS (MH+ found) = 440.1 |
With sodium hydride 1.) dioxane, reflux, 2.) dioxane; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With silver(l) oxide In benzene | |
84% | Stage #1: 2-Benzyloxyethanol With silver(l) oxide In dichloromethane at 20℃; for 0.25 - 0.5h; Stage #2: 1-bromomethyl-4-nitro-benzene In dichloromethane at 20℃; for 72h; | 163 EXAMPLE 163 N-(4-Chlorobenzyl)-4-hydroxy-6-[(2-hydroxyethoxy)methyl]-3-quinolinecarboxamide [] To a suspension of Ag2O (4.50 g) in 37 mL distilled CH2Cl2 is added 2-benzyloxyethanol (2.62 mL). The mixture is stirred at room temperature for 15-30 min. 4-Nitrobenzyl bromide (3.98 g) is added and the reaction is stirred at room temperature for 3 days. The reaction mixture is filtered over celite to remove the Ag2O. The filtrate is condensed to obtain a yellow residue. The residue is chromatographed eluting with 7% EtOAc in hexanes. TLC plates are stained in polymolybdic acid to visualize the product. Fractions homogenous by TLC are combined and condensed to afford 4.46g (84%) of 1-[2-(benzyloxy)ethoxy]methyl}-4-nitrobenzene as a yellow residue. To a suspension of 1-[2-(benzyloxy)ethoxy]-methyl}-4-nitrobenzene (-240 mg) in 11 mL EtOAc is added PtO2 (48 mg). The reaction mixture is placed under the Parr hydrogenator at 21 psi H2 and monitored by TLC for complete reduction of the nitro group. The reaction is complete in 25 min. The reaction mixture is filtered over celite to remove the catalyst. The filtrate is condensed to afford 4-((2-(benzyloxy)ethoxy)methyl)aniline as an orange residue contaminated with residual EtOAc. In a 3-necked roundbottom connected to a Dean-Stark trap, a suspension of 4-[2-(benzyloxy)methyl}aniline (∼0.384 g) and diethyl ethoxymethylenemalonate (0.32 mL) is refluxed for 2 hrs. The reaction is cooled to room temperature. Diphenyl ether (2.5 mL) is added and the reaction mixture is heated at 230 °C for 2 hrs. The reaction mixture is cooled to room temperature and diluted with a minimal amount of CH2Cl2 (-1 mL). The slurry is directly loaded onto a silica column and chromatographed eluting with 100% CH2Cl2, followed by 2% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 123.9 mg (21%) of ethyl 6-((2-(benzyloxy)ethoxy)methyl)-4-hydroxy-3-quinolinecarboxylate as a creme solid. A mixture of ethyl 6-[2-(benzyloxy)ethoxy]methyl}-4-hydroxy-3-quinolinecarboxylate (250 mg) and Pd/C (10%, 50 mg) is dissolved in 20 mL 3:1 CH2Cl2:MeOH. The reaction mixture is placed under the Parr hydrogenator at 20 psi H2 and monitored by mass spectroscopy for complete conversion to desired product. The old palladium catalyst is replaced with fresh palladium catalyst each time the reaction was taken off the Parr. In this case, the reaction is taken off the Parr once. The reaction is complete in 18 1/2 hrs. The reaction mixture is filtered over celite to remove the palladium. The filtrate is condensed to yield a solid. The crude product is adsorbed onto silica and chromatographed eluting with 5% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to afford 116.2 mg (61%) of ethyl 4-hydroxy-6-[(2-hydroxyethoxy)methyl]-3-quinolinecarboxylate as a white solid. Ethyl 4-hydroxy-6-[(2-hydroxyethoxy)methyl]-3-quinolinecarboxylate (134.2 mg) and p-chlorobenzylamine (0.84 mL) are heated neat at 180 °C for 1 hr. The reaction is cooled to room temperature and partitioned between CH2Cl2 and H2O. The aqueous layer is extracted with CH2Cl2 (2X). The organic layers are combined, dried over Na2SO4, and condensed to afford a yellow residue. The residue is chromatographed eluting with 4% MeOH in CH2Cl2. Fractions homogenous by TLC are combined and condensed to yield 133.6 mg (75%) of the title compound as a white solid. Physical characteristics are as follows: Mp 180-182 °C.1H NMR (300 MHz, DMSO) 12.68, 10.47, 8.76, 8.20, 7.71, 7.39, 4.66, 4.63, 4.56, 3.53.IR (drift) 3248, 3176, 3086, 3053, 2933, 1646, 1610, 1568, 1531, 1490, 1360, 1108, 1090, 816, 797 cm -1.MS (ESI) 387.1 (M+H)+, 385.2 (M-H)-.Anal. Found: C, 61.89; H, 4.94; N, 7.27. |
84% | With silver(l) oxide In dichloromethane for 120h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1) Sixty % sodium hydride in oil (6.80 g) is suspended in N,N-dimethylacetamide (80 ml) and a solution of 2-(benzyloxy)ethanol (12.9 g) in N,N-dimethylacetamide (50 ml) is added dropwise to the mixture over 10 minutes under ice-cooling. After stirring at room temperature for 15 minutes, the reaction solution is cooled with ice, and thereto is added chloroacetic acid (8.13 g) in small portions. The mixture is then stirred at room temperature for 11 hours. The reaction solution is concentrated under reduced pressure, and to the resulting residue is added aqueous sodium hydrogen carbonate solution and the mixture is washed with diethyl ether. The aqueous layer is acidified with conc. hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove solvent under reduced pressure to give [2-(benzyloxy)ethoxy]acetic acid (18.24 g). ESI-MS M/Z:209[M-H]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With sodium hydroxide In water at 20℃; for 5h; | 1 A mixture of 31.4 g (206.3 mmol) of 2-benzyloxyethanol, 99.8 ml of 1 ,6-dibromohexane, 78.3 ml of 50 % w/v NaOH and 1.3 g of tetrabutylammonium bromide is vigorously stirred for 5 hr at room temperature. Excess of water and hexane are added and the organic phase is washed thoroughly with water, dried over magnesium sulphate and concentrated. The residue is distilled at 0.2 mm Hg giving a first fraction, b.p.: 50-700C consisting mainly of dibromohexane, and a second one, b.p.: 125-14O0C, consisting in the title compound (50.4 g; 78%). |
63% | With tetrabutylammomium bromide; sodium hydroxide In water for 72h; | |
600 mg | With tetrabutylammomium bromide; sodium hydroxide In water at 20℃; for 16h; | 4.2 100 mL of a one-necked flask at room temperature to the compound 4 - 1 (610 mg, 4 mmol) of 1,6-dibromohexane(1.94 g, 8 mmol) added in the solution tetrabutyl ammonium bromide (260 mg, 0.8 mmol) and 50% sodium hydroxide solution (1.6 g, 40 mmol), the reaction 16 h. Add dichloromethane (50 ml), it with water (50 ml) and saturated salt water (50 ml) . The organic phase drying, filtering, concentrated. Silica gel column (petroleum ether/ethyl acetate=10/1) to obtain the pale yellow oily product 600 mg. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With ammonium bromide; sodium hydroxide at 20℃; for 25h; | 1 Step 1-((2-((5-bromopentyl)oxy)ethoxy)methyl)benzene A solution of 2-(benzyloxy) ethan-1-ol (1.67 g, 10.96 mmol), 1,5-dibromopentane (10.0 g, 43.0 mmol), and ammonium bromide (0.5 g) in 8N NaOH (20 mL) was stirred at room temperature for 25 h. The reaction mixture was then transferred into ice water mixture, the pH was adjusted to 6-7, and resulting mixture was extracted using n-hexane (3×100 mL). The combined organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated under vacuum to give ((2-((5-bromopentyl)oxy)ethoxy)methyl)benzene as colorless liquid (23 g, 95%). LC-MS (ESI+) m/z 303 (M+H)+2. |
74.5% | With sodium hydroxide In lithium hydroxide monohydrate at 20℃; for 17h; | 89 A mixture of 2-(benzyloxy)etanol (10.0 g, 0.0657 mol), 1 ,5-dibromopentane (33.3 ml, 0.2447 mol), tetrabutylammonium bromide (1.3 g, 0.0040 mol) and 50 ml (0.40 mol) of aqueous 8N NaOH solution, was vigorously stirred at room temperature for 17 hours. The reaction mixture was partitioned between water and hexane. The hexane phase was separated and washed with water, methanol (small volume), water and brine, dried (MgSO4), and concentrated. The excess of 1,5-dibromopentane was eliminated by distillation under reduced pressure. The title compound was obtained as a colourless oil (14.74 g, 74.5%). |
51% | With sodium hydroxide In tetrahydrofuran for 16h; Reflux; | 2.1 1. Synthesis of compound 2-2 Compound 2-1 (30.0 g, 197 mmol) and 1,5-dibromopentane (44.9 g, 197 mmol) were dissolved in tetrahydrofuran solution (700 mL), sodium hydroxide (23.6 g, 591 mmol) was added in batches, refluxed The reaction was carried out for 16 hours. The reaction solution was cooled, slowly poured into ice water, extracted with ethyl acetate, the extract was washed with saturated brine solution, concentrated and evaporated to dryness, and purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate=80:1) to obtain pale 30.1 g of yellow oily liquid product, yield 51%. |
With ammonium bromide; sodium hydroxide In lithium hydroxide monohydrate at 20℃; for 25h; | 6 ((2-((5-bromopentyl)oxy)ethoxy)methyl)benzene: A mixture of 2- (benzyloxy)ethan-l-ol (5.0 g, 22 mmol), 1,5-dibromopentane (0.49 mL, 5.4 mmol), ammonium bromide (0.25 g, 2.5 mmol) and 8 N aq. NaOH (10 mL) was stirred at room temperature for 25 h. Ice-cold water was added, then the pH was adjusted to 6-7 with IN aq. HC1. The mixture was extracted with hexanes, and the combined organic layers were concentrated in vacuo to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In tetrahydrofuran; | Reference Example 1 Synthesis of 2-benzyloxyethyl iodide 2-Benzyloxyethanol (85.0 g) and triethylamine (73.5 g) were dissolved in THF (500 mL) and methanesulfonyl chloride (76.8 g) was added dropwise at from 0 C. to 10 C. The mixture was stirred for 3 hr. 10% Aqueous sodium bicarbonate (300 mL) was poured into the reaction mixture, the mixture was partitioned and combined with an extract of the aqueous layer with MTBE (300 mL), and the mixture was washed with 10% aqueous sodium bicarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-benzyloxyethyl methanesulfonate (124.0 g). |
Yield | Reaction Conditions | Operation in experiment |
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71% | With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 0 - 20℃; for 4.33333h; | B.6 To a solution of (2S)-2-(4-ter^butylphenoxy)-3-(4-hydroxyphenyl)propionic acid ethyl ester (26.5 g, 77.48 mmol) in dry dichloromethane (300 ml) was added 2- benzyloxyethanol (12.94 g, 85.11 mmol) and triphenyl phosphine (24.33 g, 92.84 mmol) at room temperature. The reaction mixture was cooled to 0 0C and to this was added a solution of diethylazadicarboxylate (16.15 g, 14.18 ml, 92.84 mmol) in dry dichloromethane (50 ml) in a dropwise manner over a period of 20 min. The resulting reaction mixture was stirred at room temperature for 4 h. After completion of reaction, reaction mixture was diluted with dichloromethane (300 ml) washed with water (1x50 ml), brine (1x50 ml), dried over sodium sulphate and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 80% dichloromethane- hexanes as an eluent to afford the title compound (26.0 g 71%). MS: m/z 499 (M+23) 1HNMR (CDCl3, 200 MHz): δ 1.23 (t, J= 7.2 Hz, 3H), 1.30 (s, 9H), 3.18-3.22 (m, 2H), 3.84 (t, J= 5.2 Hz, 2H), 4.13-4.26 (m, 4H), 4.66 (s, 2H), 4.73 (t, J= 6.0 Hz5 IH), 6.79 (d, J= 8.6 Hz, 2H), 6.88 (d, J= 8.6 Hz, 2H), 7.22-7.70 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
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80% | With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 0℃; for 4.33333h; | B.5 To a solution of (2S)-2-ethoxy-3-(4-hydroxyphenyl)propionic acid ethyl ester (8.0 g,0.034 mol) in dry dichloromethane (88 ml) was added 2-benzyloxyethanol (6.13 g, 0.040 mol) and triphenyl phosphine (10.49 g, 0.040 mol) at room temperature. The reaction mixture was cooled to 0 0C and to this was added a solution of diethylazadicarboxylate (6.3 ml, 0.040 mol) in dry dichloromethane (10 ml) in a drop wise manner over a period of 20 min. The resulting reaction mixture was stirred at same temperature for 4,h. After completion of reaction, reaction mixture was diluted with dichloromethane (150 ml) washed with water (2x25 ml), brine (1x25 ml), dried over Na2SO4 and concentrated under reduced pressure to yield crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 30% ethyl acetate-hexanes as an eluent to afford the title compound (10.0 g, 80.0%). ,- MS: m/* 390 (M+18)1HNMR (CDCl3, 400 MHz): δ 1.13 (t, J= 6.8 Hz, 3H), 1.19 (t, J= 7.2 Hz, 3H), 2.92 (d, J = 6.8 Hz, 2H), 3.31-3.37 (m, IH), 3.54-3.65 (m, IH), 3.80 (t, J= 4.4 Hz, 2H), 3.93 (t, J= 6.8 Hz, IH), 4.10-4.18 (m, 4H), 4.62 (s, 2H), 6.82 (d, J= 8.4 Hz, 2H), 7.12 (d, J= 8.4 Hz5 2H), 7.25-7.35 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triphenylphosphine; | a) From <strong>[2042-14-0]4-methyl-3-nitrophenol</strong> (9.48 g, 61.90 mmol), triphenylphosphine (19.60 g, 74.73 mmol), and 2-benzyloxyethanol (9.83 g, 64.59 mmol) in tetrahydofuran (130 ml) with DEAD (12.4 ml, 95%, 74.81 mmol) was obtained 2-methyl-1-nitro-4-[2-(phenylmethoxy)ethoxy]benzene (14.06 g, 79%) as a yellow oil. 1 H NMR (CDCl3) 8.04 (1H, d, J=9.77), 7.35-7.25 (5H, m), 6.80-6.77 (2H, m), 4.59 (2H, s), 4.17 (2H, m), 3.82 (2H, m), 2.58 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; | Preparation 1 A mixture of chlorodiphenylacetyl chloride (20 g), <strong>[13220-33-2]1-methyl-3-pyrrolidinol</strong> (7.6 g), and pyridine (35 g) is kept at room temperature for two hours. After adding 45 g of 2-benzyloxyethanol, the mixture is refluxed gently for 18 hours. Excess pyridine and benzyloxyethanol are distilled off under reduced pressure, the residue is dissolved in ether and washed twice with water. The organic phase is dried over magnesium sulfate (MgSO4), filtered and the filtrate evaporated to dryness. Chromatography of the residue on the silica gel with ethyl acetate-hexane-triethylamine (50:50:1) as eluent affords 18 g of 1-methyl-3-[2,2-diphenyl-2-(2-benzyloxyethoxy)acetoxy]pyrrolidine as an oil. |
Yield | Reaction Conditions | Operation in experiment |
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73% | With sodium hydride In tetrahydrofuran at 20℃; for 3h; Heating / reflux; | 27.1 STEP 1: PREPARATION OF 4-BENZYLOXYETHOXY-6,7-DIHYDRO-5H-CYCLOPENTAPYRIMIDIN-2-YLAMINE To stirred suspension of NaH (60% 552 mg) in THF 2-benzyloxyethanol (3.38 g, 20 mmol) was slowly added at room temperature. After the addition, 3.28 grams (19.4 mmol) of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml THF and added to it and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. The product was extracted with chloroform; washed well with water and dried over anhydrous MgSO4. It was filtered and concentrated. Low melting solid; Yield: 4.2 gram (73%); (M+H) 286.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 3h; | Example II-i01 Synthesis of ethyl 2-[2-(benzyloxy)ethoxy]isonicotinate (Intermediate ii-01) (Preparation method id-1) A solution of <strong>[89978-52-9]ethyl 2-bromoisonicotinate</strong> (575 mg, MATRIX) in THF (25 ml) was added with ethylene glycol monobenzyl ether (710 mul, TCI), cooled to 0 C., and added with potassium t-butoxide (420 mg, TCI), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added with purified water (15 ml), and extracted with ethyl acetate (30 ml*2). The organic layers were combined, washed with saturated brine, and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Flash, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate ii-01). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With pyridine In dichloromethane at 20℃; for 12h; | 14.A EXAMPLE 14 2-[(di-tert-butoxyphosphoryl)oxy]ethyl 4-[([(1R)-5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate EXAMPLE 14A Carbonic acid 2-benzyloxy-ethyl ester 4-nitro-phenyl ester; To a 250 ml round bottom flask was added 2-benzyloxyethanol (7.54 g, 49.60 mmol) (Aldrich), 4-nitrophenyl chloroformate (10 g, 49.60 mmol) (Aldrich), dichloromethane (100 ml) followed by the addition of pyridine (5.89 g, 79.10 mmol) and the reaction was stirred at room temperature for 12 hours. The reaction was diluted with 200 ml of dichloromethane was washed with 1N HCl (100 ml), sat NaHCO3 (100 ml), dried (Na2SO4) and concentrated in vacuo. The reaction was purified on SiO2 and eluted with hexane/ethyl acetate 4/1 to provide a yellow solid (11.20 g) in 71% yield. 1H NMR (CDCl3, 300 MHz); δ ppm 3.70-3.80 (m, 2H), 4.30-4.57 (m, 2H), 4.61 (s, 2H), 7.26-7.40 (m, 7H), 8.26 (d, J=8.82 Hz, 2H); DCI/NH3 m/z 318.00. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium <i>tert</i>-butylate; 1,3-bis[2,6-diisopropylphenyl]imidazolium chloride In 1,4-dioxane at 100℃; for 4h; | 1 N-[6-(2-Benzyloxy-ethoxy)-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide A mixture of 0.10 g (0.19 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.03 ml (0.02 mmol) 2-(benzyloxy)ethanol and 2 ml dioxane was degassed by two freeze-thaw cycles. After addition of 7 mg (0.008 mmol) tris(dibenzylideneacetone)dipalladium(0), 7.0 mg (0.016 mmol) 1,3-bis-(2,6-diisopropyl-phenyl)-3H-imidazol-1-ium chloride and 32 mg (0.29 mmol) potassium tert-butylate the reaction mixture was heated under argon at 100° C. for 2 h. The mixture was cooled to room temperature, followed by addition of 10 mg (0.089 mmol) potassium tert-butylate, 7 mg (0.008 mmol) tris(dibenzylideneacetone)dipalladium(0) and 7.0 mg (0.016 mmol) 1,3-bis-(2,6-diisopropyl-phenyl)-3H-imidazol-1-ium chloride. After heating at 100° C. for another 2 h the reaction mixture was cooled to room temperature, diluted with tert-butyl methyl ether and washed with two portions of water. The combined aqueous layers were extracted with two portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 60 mg (49%) of the title compound as light yellow, viscous oil. MS m/e (%): 651 (M+H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 2-Benzyloxyethanol With sodium hydride In tetrahydrofuran at 20℃; for 0.25h; Stage #2: 2-chloro-4-nitropyridine In tetrahydrofuran at 20℃; | 20 Reference Example 20: 4-(2-Benzyloxy-ethoxy)-2-chIoro-pyridine. Sodium hydride (50 % in mineral oil; 0.54 g, 11.35 mmol) was added portionwise to a solution of 2-benzyloxylethanol (1.72 g, 11.4 mmol) in THF (15 mL) at r.t. under nitrogen. After 15 min. 2-chloro-4-nitro-pyridine (1.20 g, 7.57 mmol) was added and the reaction mixture stirred at r.t. overnight. The reaction mixture was quenched by slowly pouring onto ice and concentrated to remove the organic solvent. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate, filtered and concentrated. The crude material was subjected to column chromatography over silica gel (60-120 mesh) using 5%-25% ethyl acetate in petroleum ether as eluent to afford 4- (2-benzyloxy-ethoxy)-2-chloro-pyridine (1.91 g, 96 %) as an oily liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (trimethyl-lambda5-phosphanyliden)acetonitrile; In toluene; at 20 - 110℃; for 12h; | 18.1 ethyl 5-fluoro-1-(2-benzyloxyethyl)-1H-indole-2-carboxylate 94 mul (0.657 mmol) of 2-benzyloxyethanol and 50.4 mg (0.438 mmol) of (cyanomethylene)trimethylphosphorane (Tet. Lett., 1996, 37, 2459-2462) are added to a solution of 68 mg (0.329 mmol) of <strong>[348-36-7]ethyl 5-fluoro-1H-indole-2-carboxylate</strong> in 2 ml of toluene, stirred at 20° C. The reaction mixture is heated at 110° C. for 12 hours and then concentrated under reduced pressure, taken up in 20 ml of ethyl ether, filtered over a celite buffer and concentrated under reduced pressure. The residue obtained is purified by preparative HPLC, elution being carried out with a mixture of water, acetonitrile and trifluoroacetic acid. 99 mg of a yellow oil are thus isolated. 1H NMR (DMSO D6), delta (ppm): 1.3 (t, 3H); 3.72 (t, 2H); 4.28 (q, 2H); 4.38 (s, 2H); 4.81 (t, 2H); 7.28-7.07 (m, 7H); 7.45 (dxd, 1H); 7.68 (dxd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 2-Benzyloxyethanol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 35℃; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran; toluene; mineral oil at 0 - 20℃; Inert atmosphere; | |
97% | Stage #1: 2-Benzyloxyethanol With sodium hydride In 2-methyltetrahydrofuran; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: propargyl bromide In 2-methyltetrahydrofuran; toluene; mineral oil at 0 - 85℃; for 16h; | A18b Preparation of intermediate 61 b: In a 500 mL triple-neck flask under N2, NaH (95%) (7.91 g, 313 mmol) was suspended at0 °C in dry Me-THF (200 mL). 2-benzyloxyethanol (31.75 g, 209 mmol) was addeddropwise at 0-5 °C over 30 mm, and the mixture was stirred at rt for 30 mm. Propargyl bromide (80% in toluene) (45.35 mL, 417 mmol) was then added dropwise at 0-5 °C over 30 mm and the mixture was allowed to reached rt, then refluxed (oil bath temperature: 85°C) for 16 h and cooled down to rt. A 10% aqueous solution of NH4C1 (1OO mL) was added dropwise to the reaction mixture at 0-5 °C over 30 mm under stirring, and theresulting mixture was extracted with EtOAc (5 x 200 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was then suspended in 500 mL of a mixture heptane/EtOAc (9:1). Irregular silica was added and the suspension was stirred for 30 mm, then filtered. The plug of silica was washed with heptane/EtOAc (9:1, 3 x 500 mL). The solvent was evaporated to give 38.6 g of intermediate 61b (97% yield, clear yellow oil). |
70% | Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.333333h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | 1.1 Step 1: ( (2- (prop-2-yn-1-yloxy) ethoxy) methyl) benzene A mixture of 2- (benzyloxy) ethan-1-ol (10 g, 65.8 mmol) and t-BuOK (3.9 g, 34.87 mmol) in dry THF (100 mL) was stirred in a round bottom flask at RT for 20 min under the atmosphere of Ar. Then, 3-bromoprop-1-yne (8.08 g, 69.1 mmol) was added dropwise. The mixture was stirred at R.T. for 12 h under the atmosphere of Ar. The reaction was monitored with TLC (stained by KMnO4) . When the reaction was completed, solvent was evaporated in vacuum and saturated aqueous NaCl was added to quench the reaction. The mixture was acidified with 1M HCl to pH = 35, then extracted with DCM. The organic layer was dried over anhydrous Na2SO4, and evaporated in vacuum to afford the crude product, which was further purified with silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to give the product (8 g, 70%) . |
Stage #1: 2-Benzyloxyethanol With sodium hydride In toluene; mineral oil at 10 - 20℃; for 1.75h; Inert atmosphere; Stage #2: propargyl bromide In toluene; mineral oil at 20 - 25℃; for 2h; Inert atmosphere; | ||
Stage #1: 2-Benzyloxyethanol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: propargyl bromide In tetrahydrofuran at 0℃; Reflux; | ||
240 mg | Stage #1: 2-Benzyloxyethanol With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: 2-Benzyloxyethanol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: 7-fluoro-5-methoxy-2-(2-methoxymethoxymethylbenzofuran-5-yl)-3H-quinazolin-4-one In N,N-dimethyl-formamide at 80℃; for 16h; Stage #3: With acetic acid In water | 24 Example 24. Preparation of 7-(2-benzyloxy-ethoxy)-2-(2-hydroxymethyl-benzofuran-5-yl)-5-methoxy-3H-quinazolin-4-one [0251] To a stirred solution of 2-hydroxymethyl-benzofuran-5-carbaldehyde (2.00 g, 11.4 mmol) in anhydrous CH2CI2 (25 ml_) were added N, N- diisopropylethyl amine (5.17 g, 40.0 mmol) and chloromethyl methyl ether (2.76 g, 34.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours under nitrogen. Phosphate buffer (pH 7, 100 mL) was added and the mixture was extracted with dichloromethane (100 mL). The organic phase was separated, washed with brine, and dried over anhydrous Na2SO4. Removal of solvent gave 2-methoxymethoxymethyl-benzofuran-5-carbaldehyde as an orange oil. Yield 2.41 g (96%).[0252] To a solution of 2-methoxymethoxymethyl-benzofuran-5- carbaldehyde (2.31 g, 10.5 mmol) and 2-amino-4,6-difluoro-benzamide (1.20 g, 7.00 mmol) in N,N-dimethyl acetamide (15 mL) were added sodium hydrogen sulfite (58.5 wt%; 1.54 g, 8.40 mmol) and p-toluenesulfonic acid monohydrate (0.26 g, 1.40 mmol). The reaction mixture was stirred at 1200C for 4 hours under nitrogen, then cooled to room temperature. Solvent was evaporated under reduced pressure and water (100 mL) was added. The separated solid was filtered, washed with water (50 mL), and dried under vacuum, to give 5,7-difluoro-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one as a white solid. Yield 0.96 g (37%).[0253] To a suspension of 5,7-difluoro-2-(2-methoxymethoxymethyl- benzofuran-5-yl)-3H-quinazolin-4-one (0.95 g, 2.56 mmol) in anhydrous DMF (5 mL) was added a solution of sodium methoxide (25 wt%) in methanol at 00C under nitrogen. Then, the reaction mixture was stirred at 00C for 6 hours. Water (20 mL) was added, the mixture was acidified to pH approximately 6 with glacial acetic acid. The separated solid was filtered, washed with water (20 mL), and dried under vacuum to give 7-fluoro-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one as a white solid. Yield 0.94 g (95%). [0254] Sodium hydride (60% suspension in mineral oil; 0.48 g, 12.0 mmol) was taken in anhydrous DMF (5 mL). 2-Benzyloxyethanol (3.65 g, 24.0 mmol) was added dropwise at room temperature under nitrogen. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. Then, 7-fluoro-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one (0.46 g, 1.2 mmol) was added and the reaction mixture was stirred at 800C for 16 hours. The reaction mixture was then cooled to room temperature. Water (50 mL) was added, the mixture was acidified to pH approximately 6 with glacial acetic acid and extracted with CH2CI2 (2 x 100 ml_). The organic phase was washed with brine (100 ml_) and then dried over anhydrous Na2SO4. Removal of solvent, followed by purification, by the Simpliflash system (0-2% methanol in CH2CI2 as eluent) gave 7-(2-benzyloxy-ethoxy)-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one as a white solid. Yield 0.28 g (45%).[0255] To a solution of 7-(2-benzyloxy-ethoxy)-5-methoxy-2-(2-methoxymethoxymethyl-benzo-furan-5-yl)-3H-quinazolin-4-one (0.27 g, 0.53 mmol) in 50% aqueous acetic acid (15 mL), cone. H2SO4 (0.3 ml_) was added. The reaction mixture was stirred at 75°C for 2 hours, then cooled to room temperature. Water (50 mL) was added, and the mixture was neutralized to pH approximatley 7 with 4 N aqueous NaOH solution. The separated solid was filtered, washed with water (20 mL), and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230-400 mesh; 2:20:78 methanol / ethyl acetate / CH2CI2 as eluent) to give the title compound as a white solid. Yield 0.13 g (52%).1H NMR (400 MHz, DMSO-d6): δ 12.03 (bs, 1 H), 8.43 (s, 1H), 8.09 (dd, J = 8.58 and 1.95 Hz, 1 H), 7.65 (d, J = 8.58 Hz1 1 H), 7.37-7.29 (m, 5H), 6.88 (s, 1 H), 6.77 (d, J = 1.95 Hz, 1 H), 6.55 (d, J = 1.56 Hz, 1 H), 5.51 (s, 1 H), 4.60 (t, J = 4.68 Hz, 4H), 4.31 (s, 2H), 3.90-3.83 (m, 5H). MS (ES+) m/z 473.48 (100%). |
45% | Stage #1: 2-Benzyloxyethanol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: 7-fluoro-5-methoxy-2-(2-methoxymethoxymethylbenzofuran-5-yl)-3H-quinazolin-4-one In N,N-dimethyl-formamide; mineral oil at 80℃; for 16h; | 21 Sodium hydride (60% suspension in mineral oil 0.48 g, 12.0 mmol) was taken in anhydrous DMF (5 mL). 2-Benzyloxyethanol (3.65 g, 24.0 mmol) was added dropwise at room temperature under nitrogen. After the addition, the reaction mixture was stirred at room temperature for 30 minutes. Then, 7-fluoro-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one (0.46 g, 1.2 mmol) was added and the reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was then cooled to room temperature. Water (50 mL) was added, the mixture was acidified to pH approximately 6 with glacial acetic acid and extracted with CH2Cl2 (2*100 mL). The organic phase was washed with brine (100 mL) and then dried over anhydrous Na2SO4. Removal of solvent, followed by purification, by the Simpliflash system (0-2% methanol in CH2Cl2 as eluent) gave 7-(2-benzyloxy-ethoxy)-5-methoxy-2-(2-methoxymethoxymethyl-benzofuran-5-yl)-3H-quinazolin-4-one as a white solid. Yield 0.28 g (45%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With di-(p-nitrobenzyl) azodicarboxylate; triphenylphosphine In dichloromethane at 0 - 20℃; for 2.5h; Inert atmosphere; | 4.6. General procedure for the Mitsunobu reactions General procedure: An alcohol (1.0 equiv) was added to a solution of acidic pronucleophile (1.1 equiv) and phosphine reagent (1.1 equiv) in anhydrous CH2Cl2 or THF under a N2 atmosphere at 0 °C. The resulting suspension/solution was treated with azo-reagent (1.1 equiv) and the reaction mixture was continued stirring at room temperature up to completion of the reaction, indicated by TLC monitoring (The reaction mixture was filtered to recover the reduced azodicarboxylate 2 if DNAD was used as the azo-reagent.). The solvent was evaporated and the residue dissolved in cyclohexane. The triphenylphosphane oxide precipitated and was filtered off and then the filtrate evaporated under reduced pressure. The product was purified by column chromatography on silica gel to afford the pure products. |
89% | With triphenylphosphine; diethylazodicarboxylate In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With tetrabutyl-ammonium chloride; sodium hydroxide In dichloromethane at 20℃; for 4h; | 1 Step 1: Preparation of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate Into a 1000-mL round-bottom flask, was placed 2-(benzyloxy)ethan-1-ol (10.0 g, 65.71 mmol, 1.00 equiv), tert-butyl 2-bromoacetate (19.2 g, 98.43 mmol, 1.50 equiv), 37% sodium hydroxide (150 mL), Tetrabutylammonium chloride (18.3 g, 65.83 mmol, 1.00 equiv) in dichloromethane (150 mL). The resulting solution was stirred for 4 h at room temperature in a water/ice bath. The resulting solution was extracted with dichloromethane (100 mL x 3) and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/15). This resulted in 15.0 g (86%) of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate as yellow oil. |
59% | Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 2.5h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 20℃; | 2 fert-butyl [2-{benzyloxy)ethoxy]acetate 9. To a stirred solution of 2-BnO(benzyloxy)ethanol 8 (1.7 g, 1 1 .17 mmol) in f-BuOH (25 ml) was added at room temperature f-BuOK (1.38 g, 12.29 mmol). Mixture was stirred at room temperature for 2.5 hrs. f- butyl bromoacetate (2.7 ml, 20.1 1 mmol) was then added while mixture was cooled with a water bath. Mixture was stirred overnight at room temperature and concentrated. Water was added and aqueous layer was extracted with dichloromethane. Combined organic layers were dried over MgS04, filtered and concentrated. Flash chromatography on silica gel (EtOAc/pentane 1/4) afforded ester 9 as an oil (1.749 g, 59%). |
49% | Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 0.5h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 10 - 20℃; for 16h; |
49% | Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 0.5h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 10 - 20℃; for 16h; | 22.1 Step 1: Synthesis of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate Potassium tert-butoxide (2.24 g, 20 mmol) was added to a solution of compound 49 (3.00 g, 20 mmol) in anhydrous tert-butanol (24 mL), and stirred at room temperature for 30 minutes.At 10°C, tert-butyl bromoacetate (3.90 g, 20 mmol) was added by injection and stirred at room temperature for 16 hours.Extract with ethyl acetate and H2O.The organic layer was separated, washed with brine, and dried over Na2SO4.After spin-drying the solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=6:1) to obtain colorless oil 51 (2.60 g, 9.76 mmol, 49%): |
40% | With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 16.5h; | 7.4 Step 4: preparation of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (7) To a solution of compound 5 (10.0 g) in fBuOH (100 mL) was added fBuOK (8.1 g) at rt. The mixture was stirred at rt for 0.5 h, and then compound 6 (12.8 g) was added. The mixture was stirred at rt for 16 h. Compound 7 (7.0 g, yield 40%) was obtained after standard work up procedure. |
38% | Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 0.5h; Inert atmosphere; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 20℃; for 16h; Inert atmosphere; | |
9% | Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 2h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol at 20℃; | KOtBu (3.24 g, 29 mmol) was added to a stirred solution of 2 -(benzyloxy) ethanol (commercially available from for example Aldrich) (4 g, 26 mmol) in tBuOH (30 mL) and the mixture was stirred at room temperature for 2 hours. Tert-butyl 2-bromoacetate (commercially available from for example Aldrich) (7 mL, 47 mmol) was then added, and the mixture was stirred at room temperature overnight. The mixture was diluted with DCM (50 mL) and washed with water (2 x 50 mL) and then brine (2 x 50 mL). The organic extract was dried using a hydrophobic frit and concentrated under reduced pressure. The crude product was purified by chromatography on silica (330g cartridge) using a gradient elution from 0 % to 100 % methyl tert-butyl ether in cyclohexane to afford the title compound (724 mg, 2.3 mmol, 9% yield). LCMS RT= 1.10 min, ES+ve m/z 267 A [M+H]+ |
9% | With tetrabutyl-ammonium chloride; sodium hydroxide In dichloromethane at 20℃; | 76.1 1. Step- Synthesis of Tert-butyl 2-(2-(benzyloxy)ethoxy)acetate To a solution of 2-(benzyloxy)ethanol (10.0 g, 0.07 mol) in DCM ( 150 mL) were added tert-butyl 2-bromoacetate (51.0 g, 0.26 mol), TBACl (18.4 g, 0.07 mol) and 37% NaOH (15 mL) subsequently. The resulting solution was stirred at r.t. overnight. After the reaction was quenched with water (200 mL), the mixture was extracted with DCM (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography (DCM : MeOH=20 : 1) to afford the desired product tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (1.5 g, 5.60 mmol, 9%) as colorless oil. (2035) [00700] Chemical Formula: C15H22O4; Molecular Weight: 266.33 |
Stage #1: 2-Benzyloxyethanol With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 20℃; for 2.5h; Stage #2: bromoacetic acid <i>tert</i>-butyl ester In <i>tert</i>-butyl alcohol | 1; 2 tert-butyl [2-(benzyloxy)ethoxy]acetate 9. To a stirred solution of 2- (benzyloxy)ethanol 8 (1.7 g, 11.17 mmol) in t-BuOH (25 ml) was added at room temperature t-BuOK (1.38 g, 12.29 mmol). Mixture was stirred at room temperature for 2.5 hrs. t-butyl bromoacetate (2.7 ml, 20.11 mmol) was then added while mixture was cooled with a water bath. Mixture was stirred overnight at room temperature and concentrated. Water was added and aqueous layer was extracted with dichloromethane. Combined organic layers were dried over MgSO4 filtered and concentrated. Flash chromatography on silica gel (EtOAc/pentane 1/4) afforded ester 9 as an oil (1.749 g, 59%). | |
With potassium carbonate In acetonitrile at 20 - 80℃; for 16h; | 182.1 Step 1 : Synthesis of tert-butyl 2-[2-(benzyloxy)ethoxy] acetate Step 1 : Synthesis of tert-butyl 2-[2-(benzyloxy)ethoxy] acetate:[0801] To a stirred solution of 2-(benzyloxy)ethanol (5.0 g, 32.8 mmol) and tert-butyl 2- bromoacetate (7.02 g, 36.0 mmol) in acetonitrile (10.0 mL) was added potassium carbonate (6.78 g, 49.1 mmol) at rt. The reaction mixture then stirred at 80 °C for 16 h. The reaction was monitored by TLC analysis, which indicated completion of reaction. The reaction mixture was diluted with water (10.0 mL) and extracted with EtOAc (20.0 mL). The organic layer was washed with water (5.0 mL), brine (5.0 mL), dried over Na2S04, filtered, and concentrated under reduced pressure to give titled product (yield: 100% based on crude) as a yellow oil. This crude material was used in next step reaction without any further purification. | |
15 g | With tetrabutyl-ammonium chloride; sodium hydroxide In dichloromethane at 20℃; for 4h; | 6 Step 6: Preparation of tert-butyl 2-[2-(benzyloxy)ethoxy]acetate Into a 1000-mL round-bottom flask, was placed 2-(benzyloxy)ethan- l-ol (10.0 g, 65.71 mmol, 1.00 equiv), tert-butyl 2-bromoacetate (19.2 g, 98.43 mmol, 1.50 equiv), dichloromethane (150 mL), 37% sodium hydroxide (150 mL), and tetrabutylammonium chloride (18.3 g, 65.83 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at room temperature in a water/ice bath. The resulting solution was extracted with dichloromethane (100 mL x 3) and the organic layers were combined and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1/15). This resulted in 15.0 g (86%) of tert-butyl 2- [2-(benzyloxy)ethoxy] acetate as yellow oil. |
With water; tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In toluene at 20℃; for 2h; Inert atmosphere; | 94 tert-butyl 2-(2-benzyloxyethoxy)acetate A mixture of 2-benzyloxyethanol (10.0 g, 65.7 mmol), tert-butyl 2-bromoacetate (19.2 g, 98.6 mmol), tetrabutylammonium hydrogen sulfate (1.1 g, 3.3 mmol), and water (5 mL) in toluene (200 mL) was added NaOH (39.4 g, 985.6 mmol) in water (60 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched by ice-water (90 mL) and then extracted with MTBE (3 x 90 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. | |
With tetrabutyl-ammonium chloride; sodium hydroxide In dichloromethane; water at 20℃; | ||
8.998 g | With tetrabutylammomium bromide; sodium hydroxide In dichloromethane at 20℃; for 18.5h; Cooling with ice; | 13.2 Step 2:Synthesis of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (Compound 12a-2) Add 5.931g of compound 12a-1, 15.131g of tert-butyl bromoacetate, 18ml of dichloromethane, 0.303g of tetrabutylammonium bromide to the flask, add 18ml of 35% sodium hydroxide aqueous solution under ice bath,After stirring for 30 minutes, the mixture was transferred to room temperature and stirred for 18 hours. After the reaction was completed, 30ml of dichloromethane was added to separate the layers, and the organic layer was washed twice with water.20ml each time; then dried with anhydrous sodium sulfate, filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluted with petroleum ether: ethyl acetate (V/V) = 5:1) Obtain 8.998 g of compound 12a-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide;tetrabutylammomium bromide; at 70℃; | Intermediate 15.13,13,14,14-Tetramethyl-1-phenyl-2,5,12-trioxa-13-silapentadecane.To a mixture of 2-(benxyloxy)ethanol (1.8 mL, 0.01 mol), (6-bromohexyloxy)(tert- butyl)dimethylsilane (7.18 mL, 0.02 mol) and tetrabutylammonium bromide (0.23 g, 0.71 mmol) was added dropwise sodium hydroxide (32% p/v, 9.6 mL, 0.07 mol). The mixture was stirred vigorously overnight at 70C. Water (200 mL) was added into the mixture and the crude was extracted with hexane (2 x 100 mL), the combined organic layers were washed with water and brine, dried, filtered and evaporated to dryness. The crude oil obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 50:1 to 5:1 ) to give the title compound as colourless oil (85%).LRMS (m/z): 367(M+1)+. |
85% | With tetrabutylammomium bromide; sodium hydroxide; In water; at 70℃; | 13,13,14,14-Tetramethyl-1-phenyl-2,5,12-trioxa-13-silapentadecane. To a mixture of 2-(benxyloxy)ethanol (1.8 mL, 0.01 mol), (6-bromohexyloxy)(tert-butyl)dimethylsilane (7.18 mL, 0.02 mol) and tetrabutylammonium bromide (0.23 g, 0.71 mmol) was added dropwise sodium hydroxide (32% p/v, 9.6 mL, 0.07 mol). The mixture was stirred vigorously overnight at 70C. Water (200 mL) was added into the mixture and the crude was extracted with hexane (2 * 100 mL), the combined organic layers were washed with water and brine, dried, filtered and evaporated to dryness. The crude oil obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 50:1 to 5:1) to give the title compound as colourless oil (85%). LRMS (m/z): 367(M+1)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | boron trifluoride diethyl etherate; In dichloromethane; at 20℃; for 3h; | (18a)Trans-4-[2-(benzyloxy)ethoxy]tetrahydrofuran-3-olInto dichloromethane (5.0 mL), 2-benzyloxyethanol (7.07 g, 46.5 mmol) and <strong>[285-69-8]3,4-epoxytetrahydrofuran</strong> (1.0 g, 11.6 mmol) were dissolved, to which a boron trifluoride-diethyl ether complex (0.08 g, 0.58 mmol) was added at room temperature, followed by stirring for three hours.To the resulting reaction liquid, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with dichloromethane.The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The residue thus obtained was purified by silica gel column chromatography (hexane : ethyl acetate, 100 : 0 - 0 : 100, V/V) to give the desired title compound (2.28 g, yield 82percent).1H-NMR (CDCl3) delta: 3.61-3.65 (2H, m), 3.69-3.77 (4H, m), 3.93-3.96 (1H, m),3.97 (1H, dd, J = 10.1, 4.6 Hz), 4.07 (1H, dd, J = 10.1, 4.6 Hz), 4.30-4.34 (1H, m), 4.57 (2H, s), 7.27-7.38 (5H, m).MS (EI+) m/z: 239 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 2-Benzyloxyethanol; cis-4-(2-chloro-5-nitropyridin-4-ylamino)cyclohexanecarboxylic acid With 18-crown-6 ether; caesium carbonate In toluene at 75℃; Inert atmosphere; Stage #2: ethanol With thionyl chloride In toluene at 20℃; for 16h; | 77.A Step A: cis-Ethyl 4-(2-(2-(benzyloxy)ethoxy)-5-nitropyridin-4- ylamino)cyclohexanecarboxylate. To a suspension of cis-4-(2-chloro-5-nitropyridin-4- ylamino)cyclohexanecarboxylic acid (5 g, 16.68 mmol) in toluene (111 mL) was added 2- (benzyloxy)ethanol (7.62 g, 50.0 mmol), cesium carbonate (16.31 g, 50.0 mmol), and 18- crown-6 (6.61 g, 25.02 mmol). The resulting mixture was purged with argon and stirred at 75 °C overnight. The mixture was allowed to cool to RT and diluted with EtOAc to about 150 mL total volume and washed sequentially with brine (2-150 mL), aqueous NH4C1 (2-150 mL) and water (150 mL). The organic phase was collected, dried over sodium sulfate and concentrated under reduced pressure. The residue was suspended in EtOH (111 mL) and thionyl chloride (36.5 mL, 500 mmol) was added dropwise via syringe. The reaction mixture was stirred at RT for 16 hours. The mixture was concentrated to 1/3 volume and diluted with DCM (150 mL). The organic portion was washed with aqueous NaHC03 (100 mL), dried over sodium sulfate and concentrated. The residue was purified by silica gel chormatography (10-50% EtOAc/Hexanes) to afford cis-ethyl 4-(2-(2-(benzyloxy)ethoxy)-5-nitropyridin-4- ylamino)cyclohexanecarboxylate (5.6 g, 76 % yield). MS m/z = 444.2 [M+H]. Calc'd |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; N,N-diisopropylimidazolium bromide | |
81% | With 3-methyl-butan-2-one; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; caesium carbonate; 1,4-di(diphenylphosphino)-butane In <i>tert</i>-butyl alcohol at 125℃; for 24h; Schlenk technique; Inert atmosphere; | Representative Procedure for Formation of Amides from Alcohols General procedure: To an oven-dried, nitrogen purged Schlenk tube containing [Ru(p-cymene)Cl2]2(46.9 mg, 0.075 mmol), dppb (64.0 mg, 0.15 mmol) and Cs2CO3(97.7 mg, 0.30 mmol) was added alcohol (3 mmol), amine (0.33 mmol),3-methyl-2-butanone (0.8 ml, 7.5 mmol) and tBuOH(3 ml) and the reaction heated at reflux for 24 h. On completion, the reaction was allowed to cool to room temperature before the solvent was removed invacuo. The crude product was purified by column chromatography (diethyl ether/petroleum ether (b.p. 40-60 °C) as eluent) before recyrstallization from(dichloromethane/hexane), to afford the corresponding amide in good yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 27h; | 4.1.37 Ethyl 3-[2-(benzyloxy)ethoxy]-4-iodobenzoate (39) Diisopropyl azodicarboxylate (DIAD) (590 μL, 3.00 mmol) was added dropwise to a stirred solution of 38 (436 mg, 1.49 mmol), 2-(benzyloxy)ethanol (456 mg, 3.00 mmol) and PPh3 (1.11 g, 1.81 mmol) in THF (15.0 mL). The reaction mixture was stirred for 27 h at rt, then concentrated, quenched with H2O, and extracted with AcOEt. The organic layer was dried over MgSO4, and concentrated. The resulting residue was purified by silica gel chromatography (hexane/AcOEt = 4/1) to afford 39 (591 mg, 1.39 mmol, 93%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Reflux; | 123.1 Step 1: 2-chlbro-5-nitropyridine (1.51 g, 9.55 mmol, 1 eqiiiv.) and 2-(benzyloxy)ethanol (1.53 g, 10.0 mmol, 1.05 equiv.) were dissolved in DMF (9 ml.) and cooled to 0 °C. Sodium hydride (60% w/w in mineral oil, 392 mg, 9.84 mmol, 1.03 equiv.) was added in portions and the mixture was allowed to warm to room temperature overnight. After the reaction was complete (TLC), acetic acid (1 mL) was added and the solvent was evaporated. The residue was suspended in Et20 (20 mL) and filtered. The filter cake was washed with dichloromethane (2 x 2 mL), the filtrate was evaporated and purified by column chromatography (silica gel, ethyl acetate/n-hexane 1/4, v/v as eluent) to yield 2-(2- (benzyloxy)ethoxy)-5-nitropyridine (2.09 g, 80 %) as a yellow solid. |
80% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 23℃; | 133.1 Step 1: 2-Chloro-5-nitropyridine (1.51 g, 9.55 mmol, 1 eq) and 2-(benzyloxy)ethanol (1.53 g, 10.0 mmol, 1.05 eq) were dissolved in dimethylformamide (9 mL) and cooled to 0 °C. Sodium hydride (60% w/w in mineral oil, 392 mg, 9.84 mmol, 1.03 eq) was added in portions and the mixture was allowed to warm to room temperature overnight. After the reaction was complete (TLC), acetic acid (1 mL) was added and the solvent was evaporated. The residue was suspended in diethyl ether (20 mL) and filtered. The filter cake was washed with dichloromethane (2 x 2 mL), the filtrate was evaporated and purified by column chromatography (silica gel, ethyl acetate/n-hexane 1/4, v/v as eluent) to yield 2-(2- (benzyloxy)ethoxy)-5-nitropyridine (2.09 g, 80 %) as a yellow solid. |
80% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | 123.1 Step 1: 2-chloro-5-nitropyridine (1.51 g, 9.55 mmol, 1 equiv.) and 2-(benzyloxy)ethanol (1.53 g, 10.0 mmol, 1.05 equiv.) were dissolved in DMF (9 mL) and cooled to 0° C. Sodium hydride (60% w/w in mineral oil, 392 mg, 9.84 mmol, 1.03 equiv.) was added in portions and the mixture was allowed to warm to room temperature overnight. After the reaction was complete (TLC), acetic acid (1 mL) was added and the solvent was evaporated. The residue was suspended in Et2O (20 mL) and filtered. The filter cake was washed with dichloromethane (2*2 mL), the filtrate was evaporated and purified by column chromatography (silica gel, ethyl acetate/n-hexane 1/4, v/v as eluent) to yield 2-(2-(benzyloxy)ethoxy)-5-nitropyridine (2.09 g, 80%) as a yellow solid. |
80% | With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; | 133.1 Step 1 2-Chloro-5-nitropyridine (1.51 g, 9.55 mmol, 1 eq) and 2-(benzyloxy)ethanol (1.53 g, 10.0 mmol, 1.05 eq) were dissolved in dimethylformamide (9 mL) and cooled to 0° C. Sodium hydride (60% w/w in mineral oil, 392 mg, 9.84 mmol, 1.03 eq) was added in portions and the mixture was allowed to warm to room temperature overnight. After the reaction was complete (TLC), acetic acid (1 mL) was added and the solvent was evaporated. The residue was suspended in diethyl ether (20 mL) and filtered. The filter cake was washed with dichloromethane (2*2 mL), the filtrate was evaporated and purified by column chromatography (silica gel, ethyl acetate/n-hexane 1/4, v/v as eluent) to yield 2-(2-(benzyloxy)ethoxy)-5-nitropyridine (2.09 g, 80%) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane at 20℃; Molecular sieve; Inert atmosphere; | 1-O-(2-Benzyloxyethyl)-2-deoxy-3,4-di-O-benzoyl-2-trifluoroacetylamino-6-O-triisopropylsilyl-β-D-glucopyranose (8) To the solution of 7 (6.07 g, 8.30 mmol) in CH2Cl2 (15 mL) was added molecule sieves 4Å (2 g), N-iodosuccinimide(4.70 mL, 20.8 mmol) and trifluoromethanesulfonic acid (150 μL) and the mixture was stirred at room temperature for 15 min. After completion of the reaction, the molecule sieves 4Å was filtered with celite and the filtrate was extracted with CHCl3. The extract was washed with saturated Na2S2O3 aqueous solution, saturated NaHCO3 aqueous solution. The organic layer was wash with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/EtOAc,3:1) to give 8 as a pale yellow oil (5.01 g, 78%); 1H NMR (400MHz, CDCl3) δ 7.91-7.88 (m, 4H),7.55-7.47 (m, 2H), 7.38-7.27 (m, 9H), 5.68-5.63 (m, 1H), 5.57-5.52 (m, 1H), 4.87 (d, J = 8.4 Hz), 4.59-4.48 (m, 2H), 4.28-4.20 (m, 1H), 4.03-3.98 (m, 1H), 3.94-3.76 (m, 4H), 3.70-3.59 (m, 2H), 1.01-1.00 (m, 21H); 13C NMR (100 MHz, CDCl3) δ 166.9, 165.0, 157.4 (q,J = 37.2 Hz), 137.9, 133.6, 133.3, 129.9,129.6, 129.1, 129.0, 128.4, 128.4, 127.8, 127.7, 125.4, 115.6 (q, J = 287 Hz), 100.7, 75.5, 73.2, 72.9,69.3, 69.1, 68.8, 62.7, 55.1, 17.8, 11.9; MS (DRAT) m/z 774 [M+H]+, HRMS (DART) Calcd for C40H51F3NO9Si [M+H]+:774.3285. Found: 774.3252; Anal. Calcd for C40H51F3NO9Si:C, 62.08; H, 6.51; N, 1.81. Found: C, 61.91; H, 6.37; N, 1.68. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium <i>tert</i>-butylate In 1,4-dioxane at 80℃; for 16h; | 162.2 Potassium tert-butoxide (458 mg, 4.08 mmol) was added to 2-(benzyloxy)ethanol (0.726 ml, 5.10 mmol) in 15.0 mL of dioxane in a microwave vial and stirred at room temperature for 15 mm. Subsequently, 2-chloro-6-(ethylamino)nicotinonitrile (370.7 mg, 2.041 mmol) in 15.0 mL of dioxane was added to the reaction mixture and it was stirred at 80 °0 for 16 h. Reaction mixture was cooled to room temperature and diluted with water (50 mL) and extracted with ethyl acetate (2 X 50 mL). The organic layer was washed with water (50 mL), 1 M hydrochloric acid (25 mL), sat. sodium bicarbonate solution (25 mL), sat. NaCI (25 mL) and dried with anhydrous sodium sulfate. The crude compound was purified by column chromatography over silica gel (100-200 mesh) using a solvent gradient of 50% ethyl acetate in cyclohexane as eluant to afford 228mg (75%) of 2-(2-(benzyloxy)ethoxy)- 6-(ethylamino)nicotinonitrile 162-2. ESI-LC/MS: m/z299.7 [(M+2)+H]; R = 1.13 mm. [Agilent UHPLC 1290 coupled with API 3200; Acquity UPLC BEH 018 column, 1.7 pm, 2.1 X 50 mm; gradient of 98:2 H20 (0.1% H000H):CH3CN to 2:98 H20 (0.1% H000H):CH3CN for 2 mm run time with 1.0 mL/min flow rate]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h; | To a mixture of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol) in DMF (50 mL) was added K2CO3 (6.61 g, 47.8 mmol) and 2-(benzyloxy)ethanol (4.00 g, 26.3 mmol) at rt. The mixture was stirred at 110° C. for 12 h. LCMS and TLC (PE/EA=5:1, Rf=0.4) showed the reaction was finished. The mixture was filtrated, and the filtrate was concentrated to give crude product, which was purified by silica gel column to obtain 1-(2-(benzyloxy)ethoxy)-4-nitro-2-(trifluoromethyl)benzene (7.1 g, 18.18 mmol, 76.0percent yield): 1H NMR (400 MHz, CDCl3) 8.49 (d, J=2.4 Hz, 1H), 8.38 (d, J=9.2 Hz, 1H), 7.54-7.28 (m, 5H), 7.13 (d, J=8.4 Hz, 1H), 4.56 (s, 2H), 4.36 (t, J=4.8 Hz, 2H), 3.89 (t, J=3.6 Hz, 2H); ES-LCMS m/z 342(M+H). |
76% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 12h; | To a mixture of l-fluoro-4-nitro-2-(trifluoromethyl)benzene (5 g, 23.91 mmol) in DMF (50 mL) was added K2CO3 (6.61 g, 47.8 mmol) and 2-(benzyloxy)ethanol (4.00 g, 26.3 mmol) at rt. The mixture was stirred at 110 °C for 12 h. LCMS and TLC (PE/EA = 5: 1, Rf = 0.4) showed the reaction was finished. The mixture was filtrated, and the filtrate was concentrated to give crude product, which was purified by silica gel column to obtain l-(2-(benzyloxy)ethoxy)-4-nitro-2- (trifluoromethyl) benzene (7.1 g, 18.18 mmol, 76.0percent yield): lH NMR (400 MHz, CDC13) 8.49 (d, J= 2.4 Hz, 1H), 8.38 (d, J= 9.2 Hz, 1H), 7.54-7.28 (m, 5H), 7.13 (d, J= 8.4 Hz, 1H), 4.56 (s, 2H), 4.36 (t, J= 4.8 Hz, 2H), 3.89 (t, J= 3.6 Hz, 2H); ES-LCMS m/z 342(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 0.3h; | 3,4,6-Tri-acetyl-2-O-(2,4,6-tri-O-acetyl-3-O-carbamoyl-a-D- mannopyranosyl)-a-L-gulopyranosyl 2-(benzyloxy)ethane (167). To a solution of 63 mg (0.07 mmol) of 84 and 9.2 tL (0.06 mmol) of 2-(benzyloxy)ethanol (166) in 1.8 mL of anhydrous CH2C12 was added 24 tL (29 mg, 0.13 mmol) of TMSOTf at 0 °C. The reaction mixture was stirred at 0 °C for 18 mm, at which time it was poured into a two-phase solution of EtOAc (30 mL) and satd aq NaHCO3 (15 mL). The organic layer was washed with two 15 mL portions of brine, dried (Na2504), filtered and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel colunm (1.5 x 25 cm). Elution with 1:1 - 1:3 hexanes-ethyl acetate afforded compound 167 as a colorless oil: yield 34 mg (68%); silica gel TLC Rf 0.41 (1:3 hexanes-ethyl acetate). ‘H NMR (CDC13) ö 1.98-2.14 (m, 18H), 3.69 (m, 3H), 3.81 (m, 2H), 4.19 (m, 4H), 4.26 (m, 2H), 4.57 (m, 3H), 4.75 (m, 1H), 4.91 (m, 2H), 5.35 (m, 3H), 7.27-7.3 1 (m, 5H); mass spectrum (APCI), m/z 772.2665 (M +H) (C34H46N09, requires m/z 772.2664). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 0.333333h; | 3,4,6-Tri-acetyl-2-O-(2,3,4,6-tri-O-acetyl-a-D-mannopyranosyl)-a-L- gulopyranosyl 2-(benzyloxy)ethane (172). To a solution of 108 mg (0.12 mmol) of 171 and 16 tL (0.12 mmol) of 2-(benzyloxy)ethanol (166) in 3.5 mL of anhydrous CH2C12 was added 40 tL (0.22 mmol) of TMSOTf at 0 °C. The reaction mixture was stirred at 0 °C for 20 mm, at which time it was poured into a twophase solution of EtOAc (30 mL) and satd aq NaHCO3 (15 mL). The organic layer was washed with two 15 mL portions of brine, dried (Na2SO4), filtered and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (2.5 x 25 cm). Elution with 3:1 - 1:1 hexanes-ethyl acetate afforded compound 172 as a colorless oil: yield 60 mg (69%); silica gel TLC Rf 0.51 (1:1 hexanes-ethyl acetate). ‘H NMR (CDC13) ö1.97-2.15 (m, 21H), 3.67 (m, 3H), 3.84 (m, 2H), 4.09 (m, 4H), 4.25 (m, 2H), 4.55(m, 3H), 4.76 (m, 1H), 4.95 (m, 2H), 5.32 (m, 3H), 7.33 (m, 5H); ‘3C NMR(CDC13) ö 20.77, 20.83, 20.90, 20.92, 20.99, 21.11, 62.55, 66.17, 66.43, 67.49,67.99, 68.54, 68.88, 69.00, 69.30, 69.44, 70.18, 70.20, 71.51, 73.36, 73.40, 97.76,127.61, 127.81, 127.84, 128.59, 138.19, 155.34, 169.79, 170.11, 170.80. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 25℃; for 6h; | 11231] To a solution of 643-1 (1.5 g, 6.9 mmol) in DMF (20 mL) was added 2- benzyloxyl ethanol (6.3 g, 41 mmol) at 25 °C. The solution wras stirred for 6 h and then poured into 0 (20 mL). The mixture was extracted with EA (2 x 40 mL). The combined organic phase was washed with brine, dried over anhydrous Na^SC^ and concentrated under reduced pressure. The residue was purified by column chromatography using 5-10percent EA in PE as the eluent to give a mixture of 643-2 and 643-2 A ( 1 .50 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11231] To a solution of 643-1 (1.5 g, 6.9 mmol) in DMF (20 mL) was added 2- benzyloxyl ethanol (6.3 g, 41 mmol) at 25 °C. The solution wras stirred for 6 h and then poured into 0 (20 mL). The mixture was extracted with EA (2 x 40 mL). The combined organic phase was washed with brine, dried over anhydrous Na^SC^ and concentrated under reduced pressure. The residue was purified by column chromatography using 5-10percent EA in PE as the eluent to give a mixture of 643-2 and 643-2 A ( 1 .50 g). [1232] To a solution of 643-2A and 643-2 A (1.50 g. crude mixture) in EtOI I/I I20 (20/1 OmL) were added Fe ( 1 .5 g. 26.7 mmol) and NH4C1 (1 .5 g, 28 mmol) at 25 °C. The solution was heated to 80 °C and stirred for 2 h. The mixture was filtered, and the filtrate was concentrated to give a mixture of 643-3 and 643-3A ( 1.20 g, crude). The products were used for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11231] To a solution of 643-1 (1.5 g, 6.9 mmol) in DMF (20 mL) was added 2- benzyloxyl ethanol (6.3 g, 41 mmol) at 25 °C. The solution wras stirred for 6 h and then poured into 0 (20 mL). The mixture was extracted with EA (2 x 40 mL). The combined organic phase was washed with brine, dried over anhydrous Na^SC^ and concentrated under reduced pressure. The residue was purified by column chromatography using 5-10percent EA in PE as the eluent to give a mixture of 643-2 and 643-2 A ( 1 .50 g). [1232] To a solution of 643-2A and 643-2 A (1.50 g. crude mixture) in EtOI I/I I20 (20/1 OmL) were added Fe ( 1 .5 g. 26.7 mmol) and NH4C1 (1 .5 g, 28 mmol) at 25 °C. The solution was heated to 80 °C and stirred for 2 h. The mixture was filtered, and the filtrate was concentrated to give a mixture of 643-3 and 643-3A ( 1.20 g, crude). The products were used for the next step without further purification.[1233] A mixture of 643-3 and 643-3A (1.2 g, crude) in H2S04/H20 (1 : 1 ) (l OmL) was cooled to -5 °C. NaN02 (376 mg, 5.45 mmol) was added in portions at -5 °C. The solution wras stirred at -5 °C for 0.5 h. The solution was heated to 120 °C. After stirring 0.5 h at 120 °C, the solution was poured into ice water (20 mL) and extracted with EA (2 x 20 mL). The organic phase was concentrated at low pressure. The residue was purified by chromatography to give 643-4 (0.3 g, crude). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-Benzyloxyethanol With sodium hydride In dimethyl sulfoxide at 20℃; for 3h; Inert atmosphere; Stage #2: 2,6 difluorobenzonitrile In dimethyl sulfoxide at 20 - 110℃; for 10h; Inert atmosphere; | 2-(2-Benzyloxyethoxy)-6-fluorobenzonitrile (36). To a solution of 2-benzyloxyethanol (0.96 g) in dimethyl sulfoxide (DMSO, 5 mL), was added 60% sodium hydride (0.156 g) and the mixture was stirred in an atmosphere of nitrogen at room temperature for 3 h. To the mixture 2,6-difluorobenzonitrile (35, 0.47 g) was added and then the temperature was increased to 110 °C. The reaction mixture was stirred for 10 h and, after cooling, poured into 100 mL water, and extracted with dichloromethane (DCM, 40mL) three times. The organic layers were combined, dried with anhydrous sodium sulfate, and then concentrated to dryness. The residue was purified by flash column chromatography on silica gel, eluted with a mixture of ethyl acetate (EA)/PE (1:5, v/v), to afford 36(0.77 g, 84%) as a white solid: |
With sodium hydride In dimethyl sulfoxide; mineral oil at 20 - 130℃; for 10h; Inert atmosphere; | 31 Example 31 Synthesis of 2-fluoro-6-(β-(benzyloxy)ethoxy)benzonitrile (compound of formula 15) 0.96 g ethylene glycol monobenzyl ether (0.9 ml) was dissolved in 5 ml of dimethylsulfoxide was added 0.156 g of 60% sodium hydride,Was stirred under nitrogen at room temperature until no bubbles produced, the reaction solution was added 0.47 g of 2,6-difluorobenzonitrile, rapid heating to 130 After stirring for 10 hours. Cooling to room temperature, the reaction mixture was added to a large amount of water, extracted three times with methylene chloride, acetate layer were combined, dried, concentrated, and the residue was purified by silica gel column chromatography to give a white solid of 2-fluoro-6-(β-(benzyloxy)ethoxy)benzonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 2-Benzyloxyethanol With sodium hydride In dimethyl sulfoxide at 20℃; for 3h; Inert atmosphere; Stage #2: 2,6 difluorobenzonitrile In dimethyl sulfoxide at 20 - 120℃; for 10h; Inert atmosphere; | 2,6-Bis-(2-benzyloxyethoxy)-benzonitrile (41). To a solution of 2-benzyloxyethanol (1.7 g) in DMSO (5 mL), was added 60% sodium hydride (0.45 g) and the mixture was stirred in an atmosphere of nitrogen at room temperature for 3 h. To the mixture, 2,6-difluorobenzonitrile (35, 0.47 g) was added and then the temperature was increased to 110 °C. The reaction mixture was stirred for 10 h and, after cooling it was poured into water (100 mL), and extracted with DCM (40 mL) three times. The organic layers were combined, dried with anhydrous sodium sulfate, then concentrated to dryness. The residue was purified by flash column chromatography on silica gel, eluted with a mixture of EA/PE (1:5, v/v), to afford 41 (1.1 g, 81%) as a white solid: |
With sodium hydride In dimethyl sulfoxide; mineral oil at 130℃; for 10h; Inert atmosphere; | 29 Example 29 Synthesis of 2,6-di-(β-(benzyloxy)ethoxy)benzonitrile (a compound of formula 10) The 1.698 g of ethylene glycol monobenzyl ether (1.6 ml) was dissolved in 5 ml of dimethyl sulfoxide was added 0.446 g of 60% sodium hydride under nitrogen atmosphere was stirred at room temperature until no bubbles produced, the reaction solution was added 0.47 g of 2,6-difluorobenzonitrile, fast After the temperature was raised to 130°C stirring for 10 hours. Cooled to room temperature, the reaction mixture was added a lot of water, and extracted with dichloromethane threeCi acetate layer were combined, dried, concentrated, and the residue was purified by silica gel column chromatography to give a white solid 2,6-di-(β-(benzyloxy)ethoxy)benzonitrile |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; for 16.5h; | 2.6 4.2.6. 2-Benzyloxyethyl 2,3,4,6-tetra-O-acetyl-α-Dmannopyranoside(17) The trichloroacetimidate 1628 (13.0 g, 26.4 mmol, 1.0 eq) and2-benzyloxyethanol (4.51 mL, 31.7 mmol, 1.2 eq) were dissolved indry CH2Cl2 (180 mL). Then, BF3·etherate (5.27 mL, 42.2 mmol, 1.6 eq)was added dropwise at 0 °C and the solution was stirred for 30 minat this temperature. After stirring for 16 h at room temperature, thesolution was diluted with CH2Cl2 and the organic phase was washedwith satd. aq. NaHCO3 solution until no further gas formation wasobserved. The organic phase was dried over MgSO4 and filtered, andthe filtrate was concentrated under reduced pressure. Purificationof the crude mixture by column chromatography (toluene/EtOAc,4:1 to 3:1) gave product 17 (10.3 g, 21.3 mmol, 81%) as a colourlesssyrup: [α]25D +29.0 (c 1.0, CH2Cl2); Rf = 0.50 (toluene/EtOAc, 1:1); 1HNMR (500 MHz, CDCl3): δ 7.37-7.27 (m, 5H, Ar-H), 5.38 (dd,J2,3 = 3.4 Hz, J3,4 = 10.1 Hz, 1H, H-3), 5.30-5.26 (m, 2H, H-2, H-4), 4.88(d, J1,2 = 1.6 Hz, 1H, H-1), 4.58 (d, JOCHPh,OCH′Ph = 12.1 Hz, 1H, OCH′HPh),4.55 (d, JOCHPh,OCH′Ph = 12.1 Hz, 1H, OCH′HPh), 4.23 (dd, J5,6a = 5.1 Hz,J6a,6b = 12.4 Hz, 1H, H-6a), 4.09-4.04 (m, 2H, H-5, H-6b), 3.86-3.82(m, 1H, OCH′HCH2OBn), 3.72-3.65 (m, 3H, OCH′HCH2OBn,OCH2CH2OBn), 2.15, 2.08, 2.03, 2.00 (each s, each 3H, 4 OAc); 13CNMR (125 MHz, CDCl3): δ 170.8, 170.2, 170.0, 169.9 (4 C = O), 138.2(Ar-Cquart), 128.6, 127.9, 127.8 (3 Ar-C), 97.8 (C-1), 73.4 (OCH2Ph), 69.7(C-2), 69.3 (C-3), 69.0 (OCH2CH2OBn), 68.5 (C-5), 67.5 (OCH2CH2OBn),66.3 (C-4), 62.5 (C-6), 21.0, 20.9, 20.8 (4 COCH3); IR (ATR) υ: 3373,3250, 2930, 2866, 1745, 1738, 1694, 1369, 1244, 1214, 1044, 976,745 cm-1; ESI-MS (m/z): [M + Na]+ calcd for C23H30O11, 505.168, found,505.171. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 2h; | 7 4-(2-(Benzyloxy)ethoxy)-l-(4-fluorophenyl)pyridin-2(lH)-one (W) 4-(2-(Benzyloxy)ethoxy)-l-(4-fluorophenyl)pyridin-2(lH)-one (W): To a solution of compound D (200 mg, 0.975 mmol, 1.0 eq.) and 2-benzyloxyethanol (V) (166 μ^, 1.17 mmol, 1.2 eq.) in THF (4.9 mL) cooled to 0 °C was added triphenylphosphine (562 mg, 2.14 mmol, 2.2 eq.) and DlBAD (359 mg, 1.56 mmol, 1.6 eq.). The reaction was concentrated to dryness after two hours of stirring. Purification by flash chromatography on silica gel using 0-60% hexanes/ethyl acetate afforded 250 mg (76%) of the title compound. 1H MR (400 MHz, OMSO-d6) δ 7.56 (d, J= 7.64 Hz, 1H), 7.43-7.3 (m, 9H), 6.08 (q, J= 7.64, 2.7 Hz, 1H), 5.9 (d, J = 2.7, 1H), 4.56 (s, 2H), 4.18 (m, 2H), 3.77 (m, 2H). ES-MS [M+l]+: 340.2. |
76% | With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.1% | With pyridine In dichloromethane at -78 - 20℃; for 0.5h; | 1.11; 1.12 Synthesis of 2-benzyloxy triflate: To a solution of glydicol (0.545 g, 3.582 mmol) in dry DCM (5 mL) was added pyridine (0.38 mL, 1.3 eq.) at RT. The solution was cooled to -78° C. and Tf2O (2.97 mL, 1.2 eq.) was added dropwise. After the addition, the reaction was stirred at RT for 30 min. The mixture was washed with 0.5M HCl, sated. NaHCO3, dried over anhydrous MgSO4 and evaporated on a rotary evaporator to give 0.989 g (97.1%) as a slightly tan oil, slowly turned to brown color on standing on a bench. The triflate product was stored at -18° C. 1H NMR (300 MHz, CDCl3): δ 7.35-7.49 (m, 5H), 4.68 (dd, J=0.6, 4.5 Hz, 2H), 4.63 (s, 2H), 3.81 (dd, J=0.6, 4.5 Hz, 2H) |
With 2,6-dimethylpyridine In dichloromethane at -30 - 0℃; for 1h; | 73.1 Step 1: Preparation of 2-benzyloxy ethyl trifluoromethanesulfonate To a solution of 2-benzyloxyethanol (2.0 g, 13.4 mmol) and 2,6-dimethylpyridine (2.8 g, 26.8 mmol) in dichloro methane (40 mL) was added trifluoromethanesulfonic anhydride (7.4 g, 26.8 mmol) at -30°C and the mixture was then stirred at 0 °C for 1 hour. The mixture was then washed with 1 N HC1 (20 mL) twice, water (20 mL) twice, brine (20 mL), dried over anhydrous Na2S04 and concentrated in vacuo to give the crude of 2-benzyloxyethyl trifluoromethanesulfonate (4.0 g, 100% yield), which was used in the next step directly without further purification. MS obsd. (ESI+) [(M+H)+]: 307.3. | |
With 2,6-dimethylpyridine In dichloromethane at -30℃; for 1h; | 1 Step 1: preparation of cis-tert- butyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate To a solution of trifluoromethanesulfonic anhydride (27.8 g, 98.56 mmol) and 2,6-lutidine (11.48 mL, 98.56 mmol) in DCM (100 mL) cooled at -30 °C was added 2-(benzyloxy)ethanol (10.0 g, 65.71 mmol) and the reaction mixture was stirred at -30 °C for 1 hr. The reaction mixture was washed with brine (30ml) twice and the organic layer was concentrated in vacuo to give the crude 2-(benzyloxy)ethyltrifluoromethanesulfonate (18.7 g) as a yellow oil. To a solution of cis-tert-butyl 3-hydroxycyclobutanecarboxylate (CAS : 939768-64-6, Cat.: B253665, from BePharm Ltd., 11.3g, 65.71 mmol) in THF (150 mL) cooled at 0 °C was added NaH (3.95g, 98.56 mmol) and the mixture was stirred at room temperature for 1 hr. To the resulting solution was added 2-(benzyloxy)ethyltrifluoromethanesulfonate (18.7 g, previously prepared) and the mixture was stirred at room temperature for 2 hrs. The reaction was then quenched with ice water (100 mL) and extracted with EtOAc (200 mL) twice. The combined organic layer was dried over NaiSQr and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (eluting with PE:EtOAc 100:1 to 2: 1) to give cis-tert- butyl 3-(2- benzyloxyethoxy)cyclobutanecarboxylate (10.0 g, 49.67% yield) as a yellow oil. |
With 2,6-dimethylpyridine In dichloromethane at -30℃; for 1h; | 21.1 To a solution of trifluoromethanesulfonic anhydride (27.8 g, 98.56 mmol) and 2,6-lutidine (11.48 mL, 98.56 mmol) in DCM (100 mL) cooled at -30 °C was added 2-(benzyloxy)ethanol (10.0 g, 65.71 mmol) and the reaction mixture was stirred at -30 °C for 1 hour. The reaction mixture was washed with brine (30 mL) twice and the organic layer was concentrated in vacuo to give the crude 2-(benzyloxy)ethyl trifluoromethanesulfonate (18.7 g, 65.7 mmol) as yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Under nitrogen, sodium hydride (1 eq)And 2- (benzyloxy) ethanol (1 eq)Is added to the anhydride THF and stirred for 1 hour in an ice bath.Then, 4,6-dichloro-2-methanesulfonyl-pyrimidine (1.5 eq) is dissolved in THF and stirred overnight.After completion of the reaction, the solvent was dried with a rotary evaporator, and the EA layer was separated from the separatory funnel by using NaHCO 3 solution / EA and dried by drying with MgSO 4.Filter solution was removed by rotary evaporator and column.Yield: white oil 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | Step 1: 5-(2-(benzyloxy)ethoxy)-3-chloropyridazine To a stirred solution of 2-(benzyloxy)ethanol (440 mg, 2.895 mmol) and <strong>[1837-55-4]3,5-dichloropyridazine</strong> (428 mg, 2.895 mmol) in 1-methyl-2-pyrrolidinone (5 ml) was added sodium hydride (60% in oil) (347 mg, 8.68 mmol) at 0 C. Then the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous ammonium chloride solution (15 ml) at 0 C., and extracted with ethyl acetate (20 ml*3). The organic layer was with brine (20 ml*2), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 15% ethyl acetate in hexane) to give 5-(2-(benzyloxy)ethoxy)-3-chloropyridazine (680 mg, 89% yield) as light brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 6h; | 87 General procedure F (Mitsunobu reaction): General procedure: To a solution of nucleophile (1.0eq), PPh3 (1.5-3.0eq) in THF was added ROH (2.0-5.0eq) and DIAD (1.5-3.0eq) dropwise at 0°C. Then the mixture was allowed to warm to room temperature and stirred for 0.5-24h. The mixture was diluted with EtOAc, washed with H2O. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.4% | With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Molecular sieve; | C.1.71a General procedure D for the preparation of compounds 71a to 71g To a solution of oxazoline 69 (1,0 eq.) in dry DCE (200 ml/50,0 mmol) and the alcohol 70a- 70g (1,10 eq.) were added moleculare sieves 4A (20,0 g). At room temperature, TMSOTf (0,5 eq.) was added dropwise and the solution was stirred until complete conversion was achieved. The reaction was quenched by adding a solution of NaHC03 (2,0 eq.) in 400 ml H20. The organic phase was separated and the aqueous layer was extracted with 2 x 100 ml DCM. The combined organic extracts were dried with Na2S04 and concentrated i. vac. The crude products were purified by silicagel chromatography to yield the glycosides 71a to 70g. |
8.64 g | With trimethylsilyl trifluoromethanesulfonate In 1,2-dichloro-ethane for 3.5h; Inert atmosphere; Cooling with ice; | 13 00516] Compound (107): Compound 101 (5.0g, 15.19mmol) and 2-(Benzyloxy)ethanol (2.80ml, 19.75mmol) was dissolved with dry dichloroethane (DCE) (60ml). The reaction flash was evacuated, purged with argon and cooled in ice bath. Trimethylsilyl trifluoromethanesulfonate (0.550ml, 3.04mmol) was added via syringe. Reaction was checked after 3.5 hours by TLC (5%MeOH DCM) and developed using Hanessian stain. Reaction was complete. Sodium bicarbonate (383mg, 4.56mmol) was dissolved in lOOmL and cooled in ice bath. The reaction mixture was added dropwise to the stirring sodium bicarbonate solution. The reaction was left to stir for 20 minutes to completely neutralize. The mixture was added to separation funnel and organic layer was separated and aqueous layer was washed with dichloromethane. The organic layers were combined and washed with a brine solution. The organic layer was separated and dried with sodium sulfate. The solid was filtered off and the mother liquor was concentrated and put on hi vacuum to yield (8.64g) of 107. NMR (400 MHz, DMSO-d6) δ 7.38 - 7.22 (m, 4H), 5.21 (d, J = 3.4 Hz, 1H), 4.97 (dd, J = 11.2, 3.4 Hz, 1H), 4.56 (d, J = 8.5 Hz, 1H), 4.47 (d, J = 1.4 Hz, 2H), 4.09 - 3.95 (m, 2H), 3.89 (s, 1H), 3.84 (ddd, J = 14.7, 7.5, 3.4 Hz, 1H), 3.63 (ddd, J = 10.8, 6.4, 3.6 Hz, 1H), 3.54 (dq, J = 10.7, 5.2 Hz, 2H), 3.44 (t, J = 5.1 Hz, 1H), 2.09 (d, J = 4.4 Hz, 2H), 1.98 (s, 2H), 1.88 (s, 2H), 1.73 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: 2-Benzyloxyethanol With methanesulfonyl chloride; triethylamine In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran at 0 - 25℃; for 3h; Inert atmosphere; Stage #2: N-(4-((7-hydroxy-6-methoxyquinazolin-4-yl)oxy )phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 6h; | 8 Preparation of N-( 4-( (7 -(2-(Benzyloxy )ethoxy )-6-methoxyquinazolin-4-yl)oxy )phenyl)-2-20 ( 4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide To a solution of 2-(benzyloxy)ethan-1-ol (0.19 mL, 1.3 mmol) in DCM (5 mL) was addedtriethylamine (0.55 mL, 3.9 mmol) and methanesulfonyl chloride (0.12 mL, 1.6 mmol) at 0°C.The reaction was stirred at ambient temperature for 3 hours, then evaporated to dryness. Theresidue was dissolved in DMF (3 mL) and 1.7 mL of this solution was added to a suspension25 of potassium carbonate (153 mg, 1.1 mmol) and N-(4-((7-hydroxy-6-methoxyquinazolin-4-yl)oxy)phenyl)-2-(4-isopropyl-1H-1,2,3-triazol-1-yl)acetamide (160 mg, 0.4 mmol) in DMF(2.3 mL) and the reaction was heated at 90°C for 6 hours. The reaction mixture was dilutedwith ethyl acetate (50 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried, filtered and concentrated under vacuum to afford the title compound (0.21 g,100%) as a yellow liquid, which was used without further purification. m/z: ES+ [M+H]+ 569. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.05% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | 201.1 Step 1: methyl l-(2-(benzyloxy)ethyl -lH-pyrazole-5-carboxylate To a stirred solution of methyl lH-pyrazole-5-carboxylate (10 g, 79.29 mol, 1 equiv.) and 2-(benzyloxy)ethan-l-ol (14.5 g, 95.28 mol, 1.2 equiv.) in THF (lOOmL) was added DIAD (24.1 g, 119.18 mmol, 1.5 equiv.) and PPH3 (41.6 g, 158.61 mmol, 2 equiv.) in portions at 0-10°C under nitrogen atmosphere. The resulting mixture was stirred ovemight at room temperature under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (10/1) to afford the title compound as a yellow oil in 61.05% yield. |
61.05% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 10℃; Inert atmosphere; | 201.1 Step 1: methyl l-(2-(benzyloxy)ethyl)-lH-pyrazole-5-carboxylate To a stirred solution of methyl lH-pyrazole-5-carboxylate (10 g, 79.29 mol, 1 equiv.) and 2-(benzyloxy)ethan-l-ol (14.5 g, 95.28 mol, 1.2 equiv.) in THF (lOOmL) was added DIAD (24.1 g, 119.18 mmol, 1.5 equiv.) and PP (41.6 g, 158.61 mmol, 2 equiv.) in portions at 0- l0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room (2159) temperature under nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography by eluting with PE/EtOAc (10/1) to afford the title compound as a yellow oil in 61.05% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.37% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 3h; | 172.1 Step 1: ethyl l-[2-(benzyloxy)ethyl -lH-pyrazole-5-carboxylate Into a 100-mL 3-necked round-bottom flask, was placed ethyl lH-pyrazole-5- carboxylate (5.0 g, 35.68 mmol, 1 equiv.), THF (50 mL), 2-(benzyloxy)ethan-l-ol (5.97 g, 39.25 mmol, 1.1 equiv.), DIAD (10.82 g, 53.52 mmol, 1.5 equiv.), PPh3 (18.7 g, 71.36 mmol, 2 equiv.). The resulting solution was stirred for 3 h at room temperature and then (1705) concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/50) to give the title compound as a yellow liquid in 64.37% yield. |
64.37% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 3h; | 172.1 Step 1: ethyl l-[2-(benzyloxy)ethyl]-lH-pyrazole-5-carboxylate Into a lOO-mL 3-necked round-bottom flask, was placed ethyl lH-pyrazole-5- carboxylate (5.0 g, 35.68 mmol, 1 equiv.), THF (50 mL), 2-(benzyloxy)ethan-l-ol (5.97 g, 39.25 mmol, 1.1 equiv.), DIAL) (10.82 g, 53.52 mmol, 1.5 equiv.), PPh3 (l8.7 g, 71.36 mmol, 2 equiv.). The resulting solution was stirred for 3 h at room temperature and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl (1889) acetate/petroleum ether (1/50) to give the title compound as a yellow liquid in 64.37% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 25℃; for 16h; Inert atmosphere; | 109.5 3-(2-(2-(benzyloxy)ethyl)-2H-tetrazol-5-yl)-N-methyl-4-((4-(trifluoromethyl)phenyl)amino)benzenesulfonamide To a stirring solution of compound 116-5 (65 mg, 0.16 mmol, 1.0 eq), compound (1403) 116-5a (30 mg, 0.20 mmol, 1.2 eq) and PPh3 (128 mg, 0.490 mmol, 3.0 eq) in THF (2 mL) was added DIAD (99 mg, 0.49 mmol, 3.0 eq) slowly at 0 °C under N2. The reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The mixture was diluted with water (10 mL) and the resultant mixture was extracted with EA (30 mL * 3). The combined organic layers were dried over Na2SC>4, filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography over silica gel to afford compound 116-6 (70 mg, 78% yield). LCMS (ESI): RT = 0.865 min, mass calcd. for C24H23F3N603S 532.15, m/z found 533.1 [M+H]+, lH NMR (400MHz, CDC13) δ 9.67 (s, 1H), 8.70 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 2.4, 8.9 Hz, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.32 - 7.26 (m, 3H), 7.25 - 7.21 (m, 2H), 4.91 (t, J = 5.4 Hz, 2H), 4.55 (s, 2H), 4.30 (q, J = 5.4 Hz, 1H), 4.09 (t, J = 5.3 Hz, 2H), 2.71 (d, J = 5.5 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: ((3S,4aS,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-((benzyloxy)carbonyl)-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,14,14a,14b-icosahydropicene-3-carbonyl)glycine With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20 - 55℃; for 2h; Stage #2: 2-Benzyloxyethanol In dichloromethane at 55℃; | 25 Example 25 (25,4a5,6a5,6bR, 8a5, 1OS,1 2a5, 1 2bR, 1 4bR)- 1 0-((2-(2-Hydroxyethoxy)-2- oxoethyl)carbamoyl)-2,4a,6a,6b,9,9, 1 2a-heptamethyl- 13 -oxo- 1,2,3 ,4,4a, 5,6,6a,6b,7, 8,8a, 9,10,11,12, 12a, 12b, 13, 14b-icosahydropicene-2-carboxylic acid (45-2) Synthesis of Benzyl (25,4a5,6a5,6bR,8a5, 1OS,1 2a5, 1 2bR, 1 4bR)- 1 0-((2-(2-(benzyloxy)ethoxy)-2-oxoethyl)carbamoyl)-2,4a,6a,6b,9,9, 1 2a-heptamethyl- 13 -oxo- 1,2,3 ,4,4a, 5,6,6a,6b,7,8, 8a, 9,10,11,12,1 2a, 1 2b, 13,1 4b-icosahydropicene-2-carboxylate (45-1). Into a 1 00-mL round-bottom flask, was placed EDCI (44 mg, 0.23 mmol, 1.50 equiv.), DCM (15 mL), DMAP (95 mg, 0.78 mmol, 5.00 equiv.). The resulting solution was stirred for 1 h at room temperature. 30-2 (100 mg, 0.15 mmol, 1.00 equiv.) was added. The resulting solution was allowed to react, with stirring, for an additional 1 h at 55 °C. 2-(benzyloxy)ethan-1-ol (0.088 mL, 4.00 equiv.) was added. The resulting solution was allowed to react, with stirring, for an additional overnight at 55 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (9:1). This resulted in 95 mg (79%) of 45-1 as an off-whitesolid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In water at 70℃; for 4h; | Intermediate 9a: 2-((5-(2-(Benzyloxy)ethoxy)pentyl)oxy)tetrahydro-2H-pyran Intermediate 9a: 2-((5-(2-(Benzyloxy)ethoxy)pentyl)oxy)tetrahydro-2H-pyran Tetrabutylammonium hydrogen sulfate (0.214 g, 0.63 mmol) was added in one portion to 2-(benzyloxy)ethan-1-ol (0.598 mL, 4.20 mmol) and 2-((5-bromopentyl)oxy)tetrahydro-2H-pyran (1.16 g, 4.62 mmol) in 50% aq. NaOH solution (2.5 mL) at 20° C. The resulting mixture was stirred at 70° C. for 4 hours. The cooled reaction mixture was diluted with water (10 mL) and extracted with Et2O (20 mL) and EtOAc (20 mL). The combined extracts were washed with water (10 mL), saturated brine solution (10 mL), dried (MgSO4), filtered and evaporated to afford crude product as a colourless oil. The crude product was purified by flash column chromatography, elution gradient 0 to 10% EtOAc in heptane to afford the title compound (0.900 g, 67%) as a colourless oil; 1H NMR (400 MHz, CDCl3) 1.38-1.47 (2H, m), 1.48-1.75 (9H, m), 1.82 (1H, m), 3.39 (1H, m), 3.48 (3H, q), 3.57-3.65 (4H, m), 3.74 (1H, m), 3.86 (1H, m), 4.57 (3H, s), 7.27-7.3 (1H, m), 7.3-7.37 (4H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide; In water; at 70℃; for 4h; | Intermediate 24a: 2-(4-(2-(Benzyloxy)ethoxy)butoxy)tetrahydro-2H-pyran Tetrabutylammonium hydrogen sulfate (0.895 g, 2.64 mmol) was added in one portion to 2-(benzyloxy)ethan-1-ol (2.5 mL, 17.6 mmol) and 2-(4-bromobutoxy)tetrahydro-2H-pyran (5.0 g, 21.1 mmol) in 50% aq. NaOH solution (11.6 mL) at 20 C. The resulting mixture was stirred at 70 C. for 4 hours. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3*25 mL). The combined organic extracts were washed with water (20 mL), saturated brine solution (20 mL), dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash column chromatography, elution gradient 0 to 10% EtOAc in heptane to afford the title compound (4.54 g, 84%) as a colourless oil; 1H NMR (400 MHz, CDCl3) 1.47-1.62 (4H, m), 1.62-1.75 (5H, m), 1.82 (1H, m), 3.41 (1H, m), 3.45-3.54 (3H, m), 3.62 (4H, s), 3.75 (1H, m), 3.86 (1H, m), 4.57 (3H, s), 7.24-7.38 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In water at 70℃; for 4h; | Intermediate 25a: 2-(3-(2-(Benzyloxy)ethoxy)propoxy)tetrahydro-2H-pyran Intermediate 25a: 2-(3-(2-(Benzyloxy)ethoxy)propoxy)tetrahydro-2H-pyran Tetrabutylammonium hydrogen sulfate (0.951 g, 2.80 mmol) was added in one portion to 2-(benzyloxy)ethan-1-ol (2.66 mL, 18.7 mmol) and 2-(3-bromopropoxy)tetrahydro-2H-pyran (5.0 g, 22.4 mmol) in 50% aq. NaOH solution (12.3 mL) at 20° C. The resulting mixture was stirred at 70° C. for 4 hours. The cooled reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3*25 mL). The combined organic extracts were washed with water (20 mL), saturated brine solution (20 mL), dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash column chromatography, elution gradient 0 to 10% EtOAc in heptane to afford the title compound (4.31 g, 78%) as a colourless oil; 1H NMR (400 MHz, CDCl3) 1.47-1.6 (4H, m), 1.65-1.74 (1H, m), 1.80 (1H, m), 1.89 (2H, p), 3.45-3.53 (2H, m), 3.54-3.65 (6H, m), 3.83 (2H, m), 4.57 (3H, s), 7.23-7.37 (5H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | With sodium hydroxide; In toluene; at 20℃; for 16h; | A mixture of fert-butyl 4-bromobutanoate (22.0 g, 98.6 mmol), 2- (benzyloxy)ethanol (6.00 g, 39.4 mmol) and sodium hydroxide (3.23 g, 78.9 mmol) in toluene (75.0 mL) was stirred at room temperature for 16 hours. The resulting solution was partitioned between water and EtOAc. Phases were separated. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (gradient: 0%-20% ethyl acetate/petroleum ether) to yield 530 mg (5%) of the title compound as a colorless oil. LCMS (ESI): RT (min) = 1.45, [M+Na]+ = 317, method =A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.9% | With triethylamine In dichloromethane at 0 - 25℃; for 16h; | 12.5 Step 5: Preparation of 2-benzyloxyethoxy(trimethyl)silane To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in dichloro methane (200 mL) cooled at 0 °C was added trimethylsilyl chloride (17.1 g, 157.7 mmol) and the mixture was then stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution with PE:EtOAc=50:l to 10:1) to give the 2- benzyloxyethoxy(trimethyl)silane (25.0 g, 84.9%) as a colorless oil. |
84.9% | With triethylamine In dichloromethane at 0 - 25℃; for 16h; | 1 Step 1: Preparation of 2-benzyloxyethoxy(trimethyl)silane To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in DCM (200 mL) was added trimethylsilyl chloride (17.1 g, 157.7 mmol) at 0 °C and theresulting mixture was then stuffed at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution with PE:EtOAc=50: 1 to 10:1) to give the 2-benzyloxyethoxy(trimethyl)silane (25.0 g, 84.9%) as a colorless oil. |
84.9% | With triethylamine In dichloromethane at 0 - 25℃; for 16h; | 1 Step 1: Preparation of 2-benzyloxyethoxy(trimethyl)silane To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in dichloro methane (200 mL) cooled at 0 °C was added trimethylsilyl chloride (17.1 g, 157.7 mmol) and the mixture was then stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elution with PE:EtOAc=50:l to 10:1) to give the 2- benzyloxyethoxy(trimethyl)silane (25.0 g, 84.9%) as a colorless oil. |
84.9% | With TEA In dichloromethane at 0 - 25℃; for 16h; | 20.1 Step 1: Preparation of 2-benzyloxyethoxy(trimethyl)silane To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in dichloro methane (200 mL) cooled at 0°C was added trimethyls ilyl chloride (17.1 g, 157.7 mmol) and the mixture was then stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc=50:l to 10:1) to give the 2- benzyloxyethoxy(trimethyl)silane (25.0 g, 84.9%) as a colorless oil. |
84.9% | With triethylamine In dichloromethane at 0 - 25℃; for 16h; | 1 Step 1: Preparation of 2-benzyloxyethoxy(trimethyl)silane To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in dichloromethane (200 mL) cooled at 0 °C was added trimethylsilyl chloride (17.1 g, 157.7 mmol) and the mixture was then stirred at 25 °C for 16 hrs. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with PE:EtOAc=50:l to 10:1) to give the 2-benzyloxyethoxy(trimethyl)silane (25.0 g, 84.9%, compound AO-1) as a colorless oil. |
84.9% | With triethylamine In dichloromethane at 25℃; for 16h; | 15.1 Step 1: Preparation of 2-benzyloxyethoxy(trimethyl)silane To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in DCM (200 mL) at 0 °C was added trimethylsilyl chloride (17.1 g, 157.7 mmol) and the mixture was then stirred at 25 °C for 16 hrs. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel using gradient elution with PE-EtOAc from 50:1 to 10:2 (v/v) to give the 2- benzyloxyethoxy(trimethyl)silane (compound 15a, 25.0 g, 84.9%) as a colorless oil. |
84.9% | With triethylamine In dichloromethane at 0 - 25℃; for 16h; | 19.1 Step 1: Preparation of 2-benzyloxyethoxy(trimethyl)silane To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in dichloromethane (200 mL) cooled at 0°C was added trimethylsilyl chloride (17.1 g, 157.7 mmol) and the mixture was then stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc=50:l to 10:1) to give the 2- benzyloxyethoxy(trimethyl)silane (25.0 g, 84.9% yield) as colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.74% | With caesium carbonate; copper dichloride; at 130℃;Inert atmosphere; | To a stirred mixture of 4-bromo-l-methyl-lH-pyrazole-5-carboxylic acid (60 g, 292.67 mmol, 1 equiv) in 2-(benzyloxy)ethan-l-ol (300 mL) were added CS2CO3 (286.1 g, 878.00 mmol, 3.00 equiv) and CuCh (3.9 g, 29.27 mmol, 0.10 equiv). The resulting mixture was stirred for overnight at 130 C under nitrogen atmosphere. The reaction was quenched with water and extracted with EtOAc. The aqueous phase was acidified to pH 2 with cone. HC1 and the resulting mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by reverse flashchromatography under the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water, 0% to 35% gradient in 25 min; detector, UV 254 nm to give (19.2 g, 23.74%) of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]+277. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.2% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; | 2.4; 7.1; 13.1 Step 4: Synthesis of ethyl l-(2-(benzyloxy)ethyl)-4-methyl-lH-pyrazole-5-carboxylate Into a 50-mL 3-necked round-bottom flask purged under nitrogen atmosphere, was placed ethyl 4-methyl- lH-pyrazole-5-carboxylate (2 g, 12.97 mmol, 1 equiv), 2- (benzyloxy)ethan-l-ol (2.0 g, 13.14 mmol, 1.01 equiv), DIAD (3.9 g, 19.46 mmol, 1.5 equiv), and PPh3 (5.1 g, 19.46 mmol, 1.5 equiv) in THF (20 mL). The resulting solution was stirred for overnight at room temperature. After concentrating the reaction mixture under vacuum, the residue was applied onto a sdica gel column and eluted with ethylacetate/petroleum ether (1/50) to give (3 g, 80.20%) of the title compound as colorless oil. LC-MS: (ES, m/z): [M+H]+288 |
80.2% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; Inert atmosphere; | 2.4; 7.1; 13.1 Step 4: Synthesis of ethyl l-(2-(benzyloxy)ethyl)-4-methyl-lH-pyrazole-5-carboxylate Into a 50-mL 3-necked round-bottom flask purged under nitrogen atmosphere, was placed ethyl 4-methyl- lH-pyrazole-5-carboxylate (2 g, 12.97 mmol, 1 equiv), 2- (benzyloxy)ethan-l-ol (2.0 g, 13.14 mmol, 1.01 equiv), DIAD (3.9 g, 19.46 mmol, 1.5 equiv), and PPh3 (5.1 g, 19.46 mmol, 1.5 equiv) in THF (20 mL). The resulting solution was stirred for overnight at room temperature. After concentrating the reaction mixture under vacuum, the residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/50) to give (3 g, 80.20%) of the title compound as colorless oil. LC-MS: (ES, m/z): [M+H]+ 288. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.55% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 25℃; for 12h; Inert atmosphere; | 64.1 Step 1: Synthesis of methyl l-(2-(benzyloxy)ethyl)-4-bromo-lH-pyrazole-5-carboxylate Into a 500-mL 3-necked round-bottom flask under N2 atmosphere, were placed methyl 4-bromo-lH-pyrazole-5-carboxylate (20 g, 97.556 mmol, 1 equiv), 2- (benzyloxy)ethan-l-ol (29.69 g, 195.111 mmol, 2 equiv), DIAD (39.45 g, 195.111 mmol, 2 equiv), and THF (200 mL, 2468.598 mmol, 25.30 equiv), and PPh3 (51.17 g, 195.111 mmol, 2 equiv) was added at 0 °C. The resulting solution was stirred for 12 h at 25 °C and then concentrated. The residue was applied onto a silica gel column and eluted withdichloromethane/petroleum ether (1: 10) to give the title compound (25 g, 75.55%) as a yellow liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With potassium carbonate; copper(ll) bromide; at 100℃;Inert atmosphere; | To a stirred solution of <strong>[64224-60-8]5-bromopyrimidine-4-carboxylic acid</strong> (4.3 g, 21.183 mmol, 1 equiv) and 2-(benzyloxy)ethan-l-ol (25 mL) were added K2CO3 (8.78 g, 63.548 mmol, 3 equiv) and CuBr2 (0.95 g, 4.237 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 100 C under nitrogen atmosphere. The mixture was acidified to pH 5 with HC1 (aq.) and extracted with EA. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10: 1) to afford PH-IDE-0637-1 (1.0 g, 17 %) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | To a stirred solution of <strong>[53636-56-9]methyl 3-bromopyridine-2-carboxylate</strong> (9.4 g, 43.512 mmol, 1 equiv) in 2-(benzyloxy)ethan-l-ol (50 mL) was added t-BuOLi (17.42 g, 217.558 mmol, 5 equiv) and Cu(OAc)2 (1.58 g, 8.702 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 130 C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and then extracted with EtOAc. The aqueous layer was collected and acidified to pH 4 with HC1 (aq.) and extracted with EtOAc. The organic layer was collected and concentrated and the residue was purified by silica gel column chromatography by eluting with CH2CI2 /MeOH (20: 1) to afford the title compound (5 g, 42%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 2-Benzyloxyethanol With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Inert atmosphere; Sealed tube; Stage #2: 2-chloro-N-ethylacetanilide In tetrahydrofuran at 20℃; for 1h; | 5.1 RRN 37(1) Synthesis of N-ethyl-2-(2-benzyloxyethoxy)-N-phenylacetamide (Compound 19 Compound 18 was synthesized according to the method of the article (Lorella Pasquinucci et al., “Evaluation of N-substitution in 6,7-benzomorphan compounds” Bioorg. Med. Chem., 2010, 18, pp. 4975-4982). 2-Benzyloxyethanol (4 g, 26.2 mmol) was weighed out into a dried 100 mL round-bottomed two-necked flask and dissolved in 20 mL of distilled THF. The inside of the container was then replaced with an argon atmosphere using a three-way cock fitted with a balloon filled with argon, and the container was sealed using a rubber septum. A quantity of 1.19 g of NaH (60% dispersion in mineral oil) was added to this solution, stirred for 30 minutes at room temperature in an argon atmosphere, and a solution of sodium 2-benzyloxyethoxide was prepared. Three milliliters of compound 17 was weighed out into a separately prepared round-bottomed flask and dissolved in distilled THF. The sodium 2-benzyloxyethoxide solution prepared above was added using a syringe and stirred for one hour at room temperature. Fifty milliliters of ice water was added gradually to stop the reaction, and the mixed solution was extracted three times using 30 mL of AcOEt. After washing with saturated saline, the extract was dried using anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated residue was purified by column chromatography using silica gel as the carrier, and 7.04 g of compound 19 was obtained as a colorless liquid at a yield of 94%. 1H-NMR (300 MHz, CD2Cl2): δ 1.10 (t, J=7.3 Hz, 3H); 3.58 (s, 4H); 3.71 (q, J=7.3 Hz, 2H); 3.82 (s, 2H); 4.49 (s, 2H); 7.15-7.18 (m,2H); 7.27-7.41 (m, 8H). 13C-NMR (75 MHz, CD2Cl2): δ 13.1, 44.3, 69.8, 70.1, 70.9, 73.4, 127.8, 128.0, 128.5, 128.6, 128.7 .130.0, 138.9, 141.3, 168.6. HRMS (ESI+): m/z calcd for C19H23NNaO3, [M+Na]+, 336.15756; found 336.15517 (-2.39 mmu). |
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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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