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CAS No. : | 446-51-5 | MDL No. : | MFCD00004601 |
Formula : | C7H7FO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QEHXDOJPVIHUDO-UHFFFAOYSA-N |
M.W : | 126.13 | Pubchem ID : | 67969 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.53 |
TPSA : | 20.23 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.14 cm/s |
Log Po/w (iLOGP) : | 1.54 |
Log Po/w (XLOGP3) : | 1.31 |
Log Po/w (WLOGP) : | 1.59 |
Log Po/w (MLOGP) : | 1.97 |
Log Po/w (SILICOS-IT) : | 2.12 |
Consensus Log Po/w : | 1.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.87 |
Solubility : | 1.68 mg/ml ; 0.0133 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.34 |
Solubility : | 5.83 mg/ml ; 0.0462 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.46 |
Solubility : | 0.433 mg/ml ; 0.00344 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H227-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 |
---|---|---|
87% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; 6,8-di(tert-butyl)-3-[2-(1H-imidazol-4-yl)ethyl]-3,4-dihydro-2H-1,3-benzoxazine; oxygen; copper(I) triflate; In dichloromethane; at 25℃; for 7h; | General procedure: A 5-mL two-necked, round-bottom flask equipped with a magnetic stirrer and an oxygen balloon was charged in succession with 0.0106 g(0.05 mmol) of Cu(OTf), 0.0078 g (0.05 mmol) of TEMPO, 0.0136 g (0.04 mmol) of benzoxazine ligand L, and 1 mL of methylene chloride. The corresponding alcohol, 1 mmol, was then added at 25C under stirring, and oxygen from the balloon was introduced through a three-way valve. The progress of the reaction was monitored by GLC using a suitable column. |
87% | With [Cu(6-(2-carboxylatophenylcarbamoyl)picolinate)](4-dimethylaminopyridine)*3H2O; dihydrogen peroxide; In acetonitrile; at 45℃; | General procedure: To investigate the catalytic activity of complex (3), oxidation of primary alcohols into the corresponding carbonyl compounds was carried out [32]. Benzyl alcohol was selected as a model substratefor oxidation process. As an initial test, different amounts of complex from 0.01 to 0.05 g in acetonitrile solvent were mixed with 30 muL of hydrogen peroxide (30%) as an oxidant and benzyl alcohol(0.5 mmol, 0.05 g) was added to the mixture at room temperature. Also, the reaction was run in the absence of catalyst. Then, bychanging of parameters such as the amount of oxidant from 30to 65 lL and temperature from 20 to 70 C, optimized conditionsfor oxidation of benzyl alcohol to benzaldehyde was evaluated. After finding the optimized conditions for benzyl alcohol, oxidation of its derivatives and hexanol (0.5 mmol substrate) were studied inthe same way. The reaction progress was monitored by TLC in aregular alternative time. After completion of the reactions and removing of the solvent, the hemogeneous catalyst was separated from the reaction mixture by addition of water (5.0 mL). Then, the organic phase was separated by addition of chloroform (10.0 mL)and dried over Na2SO4. The product was purified by chromatographyon silica gel (ratio of eluent: hexane/ethyl acetate from 1:10 to1:5). Yields were obtained by weighting of isolated products. All products were known by MS and 1H NMR spectroscopy [9,24]. |
80% | With sym-collidinium chlorochromate; periodic acid; In acetonitrile; at 20℃; for 0.166667h; | General procedure: A solution of acetonitril (10 mL, 1mmol) and periodic acid was placed in flask and stir for the 15 min. Then, a mixture of alcohols (1mmol) and S-COCC (1%mmol) was added and the resulting mixture was stirred at room temperature for a suitable period (Table 3) and completion of the reaction investigated byTLC (n-hexane/EtOAc; 2:1) analysis. Then, EtOAc (20ml) was subjoined to the reaction mixture and after being washed with water/sodium solfite (1:1), the mixture was filtered off. The solvent was vaporized and produced pure products. |
58% | With potassium osmate; chloroamine-T; In water; tert-butyl alcohol; for 2h; | General procedure: Chloramine-T (0.5 equiv) was added to a solution of K2[OsO2 (OH)4] (3 mol%) in t-BuOH/H2O (1:1) followed by the addition of alcohol (1.0 mmol) and kept on stirring till completion (confirmed by TLC). The reaction was quenched by adding sodium sulphite(Na2SO3) and stirred for 30 min. The mixture after extraction with ethyl acetate (twice), usualworkup and purification over silica gel column using Hexane:EtOAc (95:5) afforded pure products. |
45% | With iron(III) sulfate; TEMPOL; oxygen; sodium nitrite; In water; acetonitrile; at 20℃; under 760.051 Torr; for 24h; | The oxidation of alcohols was carried out under O2 in a 50-mL two-necked, round-bottom flask equipped with a magnetic stirrer. Typically, Fe2(SO4)3 (0.25 mmol) and TMHPO (0.25 mmol) were added to the flask, followed by 15 mL of a CH3CN/H2O (1:2) solvent mixture. After stirring for 5 min, the alcohol (5 mmol) was added, followed by NaNO2 (0.25 mmol). The resulting mixture was stirred at room temperature and 1 atm pressure of oxygen. When the reactions were completed, the reaction mixture was transferred to a separating funnel and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4 and concentrated and further purified by flash chromatography to give the desired product. |
33% | With picoline; tert.-butylhydroperoxide; chlorophyllin coppered trisodium salt; In water; at 60℃; for 10h; | General procedure: A solution of benzyl alcohol (1 mmol), SCC (1 mol %), 70% TBHP (1 mmol or 3 mmol),and 4-methylpyridine (1.0 mmol) in H2O (2 mL) was stirred at 60 C (or 80 C) for 10 h (or 15 h).The reaction mixture was quenched with a saturated solution of sodium thiosulfate (5 mL) andextracted using dichloromethane (3 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtrated, and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel with petroleum ether/ethyl acetate as the eluent to obtain the desired product. |
45%Chromat. | With Graphite oxide; In toluene; at 80℃; for 1h;Sonication; | General procedure: To a solution of alcohol (0.1 g) in2 mL of solvent was added the appropriate amount of GO (as indicated in Table2). The resulting mixture was irradiated in an ultrasonic bath or with an ultrasonic probe (methods A to G) for the time indicated in Table 2 prior to GC/MS analysis. The mixture was filtered through a sintered funnel and evaporated under reduced pressure. Purification was achieved by column chromatography using hexane as the eluent. The spectroscopic data of the obtained aldehydes were compared with authentic samples.16 Other products were also known compounds10-12 and were characterized by 1H NMR, mass spectrometry, and FT-IR spectroscopy. |
45%Chromat. | With C28H27Br3N4O6V2; dihydrogen peroxide; In water; acetonitrile; at 60℃;Green chemistry; | General procedure: Oxidation reactions were carried out under aerial conditions using 2mL of solvent and aqueous H2O2 (30wt%) as oxidant. In a typical experiment, complex 1 (1.186mumol, 0.001g), the solvent (2mL) and the substrate (1mmol) were placed in a 25mL round bottomed glass flask. The mixture was heated to the desired temperature, and after addition of H2O2, the resulting solution was kept stable at the selected temperature to continue the reaction. At appropriate intervals, aliquots were taken and analyzed immediately by GC. The oxidation products were identified by comparison of their retention times with those of authentic samples |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With C55H44O2P4Ru; hydrogen; In toluene; at 80℃; under 38002.6 Torr; for 18h;Glovebox; Autoclave; | In an argon glove box,A 5 mL vial equipped with a magnetic stir bar was charged with the desired amount of catalyst 2 (0.005 mol%),3h (5 mmol) and toluene (1.5 mL), the mixture was transferred to a non-polluting autoclave,Then use the H2 (10atm) pressure / exhaust three cycles for ventilation.It was then pressurized with H2 (50 atm) and disconnected from the H2 source, the autoclave was placed in an oil bath preheated to 80 C,After the reaction was stirred for 18h, the autoclave was cooled in an ice bath and the hydrogen was slowly released.The yield of product over 4h on a silica gel column was 99%. |
95% | With [Ir(2,2':6',2'?-terpyridine)(1,10-phenanthroline)Cl](PF6)2; sodium formate; In ethanol; water; at 100℃; for 0.25h;Microwave irradiation; | General procedure: An aldehyde (1 mmol),sodium formate (4.5 eq), and catalyst (0.2 mol%) were taken in70% ethanol in water (4 mL) in a microwave vial and vortexed togenerate a homogenous solution. The mixture was heated in MWat 100 C using 150W of irradiation. Reaction progress was monitored by TLC. If complete conversion took place, the reaction colorturns to emerald green (color disappears after sometime) from paleyellow, and byproduct Na2CO3 precipitates. The Na2CO3 solid wasremoved by decanting the supernatant. The solid was washed withethyl acetate (20 mL). The combined decanted solution waswashed with water (5.0 mL), followed by brine solution (5.0 mL),dried over Na2SO4, filtered, and evaporated to dryness to affordthe desired alcohol as a pale-yellow liquid or off-white solid. |
92% | General procedure: To a 25 mL Schlenk tube containing a solution of 1 in 2 mL of THF was added an aldehyde (1.0 mmol) and (EtO)3 SiH (0.20 g, 1.2 mmol). The reaction mixture was stirred at 50-55 C until there was no aldehyde left (monitored by TLC and GC-MS). The reaction was then quenched byMeOH (2mL) and a 10% aqueous solution of NaOH (5 mL) with vigorous stirring at 60 C for about 24 h.The organic product was extracted with diethyl ether (10 mL × 3), dried over anhydrous MgSO4, and concentrated under vacuum. The alcohol product was further purified using flash column chromatography (elute with 5-10% ethyl acetate in petroleum ether). The 1H NMR and 13C NMR spectra of the alcohol products are providedin Supporting information. |
With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 20℃; | 2-fluorobenzaldehyde (25 g, 0.201 mol) was dissolved in THF (200 ml.) and sodium borohydride (3.8 g, 0.1 mol) was added to the reaction mixture. After that methanol (10 ml.) was added to it drop wise. The reaction mixture was stirred for 2 hours at ambient temperature. After total consumption of starting material the reaction mixture was washed with water (2 x 100 mL) and brine (100 ml_). The organic layer was dried over magnesium sulphate and concentrated under reduced pressure to afford the product (27 g). Step b: Step-a product (10 g, 0.079 mol) was dissolved in dichloromethane (75 ml_) and triethylamine (16.6 ml_, 0.119 mol) was added to it. The reaction mixture was then cooled to -15 0C and a solution of mesyl chloride (7.42 ml_, 0.095 mol) in dichloromethane (25 ml.) was added to it. The reaction mixture stirred for 30 minutes at same temperature. After total consumption of starting material the reaction mixture was diluted with dichloromethane (100 ml_) and washed with water (3 x 50 ml_). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford 12 g compound. | |
With hydrogen; In water; under 30003 Torr; for 1h;Autoclave; | For the hydrogenation of unsaturated compounds, Pt/xTS, Pt/ SBA-15, or Pt/TiO2 catalyst (0.1 g) was pretreated under hydrogen flow (40 mL min 1) at 673 K for 2 h before use. The catalyst was then mixed with solvent (20 mL) and substrate (21 mmol). The mixture was subsequently transferred to a 100-mL autoclave. The hydrogenation reaction began with stirring (1200 rpm) at a designated temperature after hydrogen (4.0 MPa) was introduced into the autoclave. The reaction was stopped after a proper time, and the products were analyzed by GC-FID (GC-2014, Shimadzu Co.) equipped with a capillary column (DM-WAX, 30 m 0.25 mm 0.25 lm). | |
98%Chromat. | With formic acid; iron(II) tetrafluoroborate hexahydrate; tris(2-diphenylphosphinoethyl)phosphine; In tetrahydrofuran; at 60℃; for 2h;Schlenk technique; Inert atmosphere; | General procedure: Fe(BF4)2·6H2O (0.7 mg; 0.002 mmol) and tris[2-(diphenyl-phosphino)-ethyl]phosphine [P(CH2CH2PPh2)3; tetraphos] (1.4 mg; 0.002 mmol) are placed in a Schlenk-tube under argon atmosphere. 1 mL dry tetrahydrofurane is added and the purple solution is stirred for 2 min. Cinnamaldehyde (63 muL; 0.5 mmol) and 100 muL n-hexadecane as an internal GC-standard are injected and a sample is taken for GC-analysis. The solution is heated to 60 C and the reaction starts by addition of 1.1 equiv formic acid (22 muL; 0.55 mmol). After 2 h, a second sample is taken for GC-analysis and conversion and yield are determined by comparison with authentic samples. For the isolation, the reaction is scaled up by a factor of 20. When the reaction is completed, the reaction solution is diluted with a mixture of n-hexane and ethyl acetate (3:1), filtered through a plug of silica and the solvent removed in vacuum. |
General procedure: To a solution of benzaldehyde (3.18 g, 30.0 mmol) inmethanol (20 mL) was added sodium borohydride (1.37g, 36.0 mmol) in portions inice-water bath. The mixture was stirred at room temperature, and after 2.0 hquenched with diluted HCl (1M). The resulting aqueous solution was then extracted with CH2Cl2 (10 mL×3).The organic phase was combined, dried over anhydrous MgSO4, filteredand concentrated reduced pressure by a rotary evaporator to provide the crude product. The crude product was purified by column chromatography on silica gelusing EtOAc-petroleumether (1:20, v/v) as eluentto give the corresponding phenylmethanol | ||
86.4%Chromat. | With hydrogen; In ethanol; water; at 20℃; under 30003 Torr; for 1h;Autoclave;Catalytic behavior; | General procedure: 0.05 g 5 wt.% Pt catalyst was pretreated in a hydrogen flow at 673 K for 2 h before use. The catalyst was then mixed with 20 mL solvent and transferred to a 100 mL autoclave. The hydrogenation reaction began at a designated temperature after 4.0 MPa hydrogen was introduced into the autoclave. The reaction was stopped after an allotted period and the products were analyzed by GC-FID (GC-2014, Shimadzu Co.) equipped with a capillary column (DM-WAX, 30 m × 0.32 mm × 0.25 mum). |
With [{RuCl2(sodium 3-diphenylphosphinobenzenesulfonate)2}2]; water; sodium formate; sodium 3-(diphenylphosphanyl)benzenesulfonate; In propan-1-ol; at 30℃; for 1h;Inert atmosphere; | General procedure: In a typical reaction, 408mg (6mmol) sodiumformate and 126 L (1mmol) cinnamaldehyde were added to a mixture of 4.0mL water and 3.5m L2-propanolat T=30C. 5mg (0.005mmol) [{RuCl2(mtppms)2}2] and 16mg(0.04mmol) mtppms weredis-solved in the deoxygenated solution and the mixture was stirred vigorously. Samples(0.2mL) were withdrawn periodically and diluted with 1mL of water before extraction by chlorobenzene.The organic layers were filtered through short silica plugs and analyzed by gas chromatography. | |
99%Chromat. | With formic acid; sodium hydroxide; In water; at 100℃; for 18h;Inert atmosphere; Schlenk technique; Sealed tube; | General procedure: The transfer hydrogenation reactions were carried out under argon atmosphere using standard Schlenk technique unless otherwise stated. Benzyl aldehyde (1 mmol), formic acid (3.5 eqiv.), and water (3.5 mL) were injected into a sealed tube with the catalyst (0.048 g Ir(at)CN) and sodium hydroxide (2 eqiv.) under Ar. Then the mixture was stirred under 100 C (with an oil bath) for the given time. After cooled, the reaction mixture was diluted with 3 9 5 mL of ether, and then the catalyst Ir(at)CN was filtered. The conversions and yields were determined by GC using n-hexadecane as an internal standard. |
With hydrogen; In water; at 24.84℃; under 30003 Torr; for 1h;Autoclave;Catalytic behavior; | General procedure: liquid-phase hydrogenation with the Pt/MIL-101 catalyst, 0.04 g or 0.05 g catalyst was pretreated under a hydrogen flow(40 mL/min) at 503 K for 2 h before use; while for the Pt/35AS catalyst involved hydrogenation, 0.05 g catalyst was used after pre-treated under the similar conditions at 673 K for 2 h. The catalyst was then transferred to a 100 mL autoclave and mixed with sol-vent and substrate. The reaction began when hydrogen (4.0 MPa) was introduced with stirring at 298 K. The reaction was stopped after a proper time and products were analyzed by GC-FID (GC-2014, Shimadzu) equipped with a capillary column (DM-WAX,30 m × 0.25 mm × 0.25 m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; at 25℃; for 2h; | Example 79; According to the same manner as that of Example 78 except that 0.13 g of 3-fluorobenzyl alcohol was used in place of <strong>[446-51-5]2-fluorobenzyl alcohol</strong>, 203 mg of a compound represented by the formula (79) :(hereinafter, referred to as present compound (79) ) was obtained. 1H-NMR (CDCl3, TMS) delta (ppm) : 7.38 (IH, td) , 7.22 (IH, d) ,7.16 (IH, dt) , 7.08 (IH, td) , 5.53 (2H, s), 3.06 (6H, br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In acetonitrile; at 20 - 70℃; for 17h; | 3. N-(4-tert-Butyl-phenyl)-6-(2-fluoro-benzyloxy)-[1,3,5]triazine-2,4-diamine Suspend N- (4-TEI-T-BUTYL-PHENYL)-6-CHLORO- [1, 3,5] triazine-2,4-diamine (0.035 g, 0.126 mmol) in acetonitrile (1 mL) and add (2-FLUORO-PHENYL)-METHANOL (50 mg). Add NaH (35 mg, 60% dispersion in mineral oil) and stir for 1 hour at room temperature, and then at 70C for 16 hours. Concentrate under reduced pressure and partition between ethyl acetate and brine. Dry the organic layer (NA2S04) and concentrate under reduced pressure. Chromatograph on silica gel using preparative plate TLC (1: 1 ethyl acetate/hexanes eluent) to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at -15℃; for 0.5h; | Step-a product (10 g, 0.079 mol) was dissolved in dichloromethane (75 ml_) and triethylamine (16.6 ml_, 0.119 mol) was added to it. The reaction mixture was then cooled to -15 0C and a solution of mesyl chloride (7.42 ml_, 0.095 mol) in dichloromethane (25 ml.) was added to it. The reaction mixture stirred for 30 minutes at same temperature. After total consumption of starting material the reaction mixture was diluted with dichloromethane (100 ml_) and washed with water (3 x 50 ml_). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford 12 g compound. | |
With triethylamine; In dichloromethane; at 0℃; for 3h;Inert atmosphere; | Step A: Preparation of 2-Fluorobenzyl methanesulfonate To a solution of <strong>[446-51-5]2-Fluorobenzyl alcohol</strong> (10 g, 79.28 mmol) in dry dichloromethane (200 ml) was added triethylamine (12.03 g, 118.9 mmol) under argon at room temperature. Methanesulfonyl chloride (10.71 g, 93.5 mmol) was added to the above reaction mixture at 0 C., and stifling was continued for another 3 hours. Water (100 ml) was added to the reaction mixture and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine. The reaction mixture was dried over Na2SO4, filtered and concentrated to give the title compound as an yellow oil which was used without further purification. 1H NMR (270 MHz, CDCl3): 1.3 (t, 3H); 2.4-2.6 (m, 4H); 5.25 (s, 2H); 6.9-7.5 (m, 4H). | |
With triethylamine; In dichloromethane; water; | Step A Preparation of 2-Fluorobenzyl methanesulfonate: To a solution of <strong>[446-51-5]2-Fluorobenzyl alcohol</strong> (10 g, 79.28 mmol) in dry dichloromethane (200 ml) was added triethylamine (12.03 g, 118.9 mmol) under argon at room temperature. Methanesulfonyl chloride (10.71 g, 93.5 mmol) was added to the above reaction mixture at 0C, and stirring was continued for another 3 hours. Water (100 ml) was added to the reaction mixture and the mixture was extracted twice with dichloromethane. The combined organic layers were washed with water and brine. The reaction mixture was dried over Na2SO4, filtered and concentrated to give the title compound as an yellow oil which was used without further purification. 1NMR (270 MHz, CDCl3): 1.3 (t, 3H); 2.4-2.6 (m, 4H); 5.25 (s, 2H); 6.9-7.5 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.5 g (58%) | Step 2 Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for 20 hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, IH), 9.40 (s, 1H). | |
13.5 g (58%) | Step 2 Preparation of Dibutyl 4-fluorobenzyl Alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C. was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C. for 20 hours. To the cooled solution at -40 C. was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, 1H), 9.40 (s, 1H). | |
13.5 g (58%) | Step 2 Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for 20 hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1 H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, 1H), 9.40 (s, 1H). |
13.5 g (58%) | Step 2 Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C. was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C. for 20 hours. To the cooled solution at -40 C. was added sufficient amount of ethyl acetate to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1 H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, 1H), 9.40 (s, 1H). | |
13.5 g (58%) | Step 2 Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C. was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C. for 20 hours. To the cooled solution at -40 C. was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, 1H), 9.40 (s, 1H). | |
13.5 g (58%) | Step 2 Preparation of dibutyl 4-fluorobenzyl alcohol To a solution of 22.6 g (69.8 mmol) of the dialdehyde obtained from Step 1 in 650 mL of THF at -60 C was added 69.8 mL (69.8 mmol) of DIBAL (1M in THF) via a syringe. The reaction mixture was stirred at -40 C for 20 hours. To the cooled solution at -40 C was added sufficient amount of ethyl acetae to quench the excess of DIBAL, followed by 3 N HCl. The mixture was extracted with ethyl acetate, washed with water, dried (MgSO4), and concentrated in vacuo. Silica gel chromatographic purification of the crude product gave 13.5 g (58%) of recovered starting material, and 8.1 g (36%) of the desired fluorobenzyl alcohol as a colorless oil: 1H NMR (CDCl3) d 0.88 (t, J=7.05 Hz, 6H), 1.0-1.4 (m, 8H), 1.5-1.72 (m, 4H), 1.94 (br s, 1H), 3.03 (s, 2H), 4.79 (s, 2H), 6.96 (dt, J=8.46, 3.02 Hz, 1H), 7.20 (dd, J=9.47, 2.82 Hz, 1H), 7.42 (dd, J=8.67, 5.64, 1H), 9.40 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In water; N,N-dimethyl-formamide; | to a stirred suspension of sodium hydride (60%, 0.63 g) in DMF (10 ml) at 0 C. was added portionwise over 10 min 6-chloronicotinic acid (1.0 g). The mixture was stirred for 30 min then a solution of <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (0.84 g) in DMF (5 ml) was added dropwise over 10 min. The mixture was warmed to room temperature, stirred for 1 h then heated to 100 C. and stirred for a further 18 h then cooled to room temperature. To the mixture were added dropwise water (10 ml) and hydrochloric acid (2M, 10 ml). The emerging precipitate was washed with water and dried to give the product as an off-white solid (1.34 g); 1H-NMR (400 MHz, CDCl3) deltaH 8.75 (1H, dd, J 2.5, 1 Hz), 8.17 (1H, dd, J 8.5, 2.5 Hz), 7.56 (1H, dt, J 7.5, 1.5 Hz), 7.43 (1H, m), 7.27 (1H, dd, J 8.5, 1 Hz), 7.22 (1H, dd, J 7.5, 1 Hz), 6.97 (1H, dd, J 8.5, 1 Hz) and 5.48 (2H, s); [XTERRA; methanol-10 mM aqueous NH4OAc (50:50); 2 mL/min; 220 nm] 98%, 0.80 min. 2-(2-Fluorobenzyloxy)-5-pyridylmethanol: |
Yield | Reaction Conditions | Operation in experiment |
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With pyridine; hydrogenchloride; triethylamine; In 1,4-dioxane; methanol; dichloromethane; | Example 50 cis-2,6-Dimethylpiperazine-1-carboxylic acid 2-fluorobenzyl ester <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (2 eq), triethylamine (3 eq) and pyridine (1 eq) was added to a solution of cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester in dichloromethane (30 vol.) and the mixture was shaken at 25 C. for 6 days. The mixture was evaporated, and the resultant crude material purified by preparative HPLC [C18, 10 mM aqueous NH4OAc solution:MeOH] to afford the intermediate product, which was used immediately in the next step. A solution of HCl in dioxane (4 M, 10 eq) was added to a solution of the above intermediate in methanol (50 volumes) and the mixture was shaken for 16 h. Evaporation to dryness afforded the desired product. HPLC: [XTERRA; methanol-10 mM aqueous NH4OAc (60:40); 2 mL/min; 210 nm] 96.8% (0.88 min); MS (ISP): 267 MH+. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; | Example 100 2-[(2-Fluorobenzyl)Oxy]-6-(1-Piperazinyl)Pyrazine, Maleate. The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(2-fluorobenzyl)oxy]pyrazine (3.68 g, 15.4 mmol; obtained according to the procedure of example 50, step 1, starting from <strong>[446-51-5]2-fluorobenzyl alcohol</strong>), piperazine (4.06 g, 47.1 mmol) and K2CO3 (2.24 g, 16.2 mmol) with the exception that the final filtration through alumina was omitted. The yield of the free base of the title compound was 3.28 g (74%) which was obtained as an oil. The free base was converted into its maleate salt. Purity 100% (HPLC). MS m/z 288 (M)+. HRMS m/z calcd for C15H17FN4O(M)+288.1386, found 288.1378. |
Yield | Reaction Conditions | Operation in experiment |
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79% | With pyridine; hydrogenchloride; dmap; triethylamine; In 1,4-dioxane; methanol; dichloromethane; | Example 58 (R)-2-Fluorobenzyl 2-methylpiperazine-1-carboxylate hydrochloride To a stirred solution of (R)1-tert-butoxycarbonyl-4-chlorocarbonyl-2-methylpiperazine (348 mg, 1.32 mmol), triethylamine (550 uL, 3 eq) and <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (420 uL, 2 eq) in dichloromethane (8 mL) were added pyridine (110 uL, 1 eq) and DMAP (cat.). The resultant mixture was stirred at ambient temperature for 5 days. Purification by flash column chromatography [SiO2; ethyl acetate-heptane (1:3)] afforded a colourless oil (692 mg). This material was dissolved in MeOH (12 mL) and treated with a solution of HCl in dioxane (4 M; 3.3 mL, ~10 equiv.), with overnight stirring. Purification by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide (90:8:2)] afforded a colourless oil. Dissolution in dichloromethane (4 mL) and treatment with HCl in dioxane (4 M; 1 mL) afforded, after evaporation the desired product (368 mg, 79%) as a white solid: deltaH(400 MHz; d6-DMSO) 1.26 (3H, d, J 7.0 Hz), 2.81-2.94 (1H, m), 3.01-3.27 (4H, m), 3.90-3.98 (1H, m), 4.31-4.40 (1H, m), 5.13 (1H, d, J 12.5 Hz), 5.17 (1H, d, J 12.5 Hz), 7.20-7.26 (2H, m), 7.38-7.50 (2H, m), 9.13 (1H, br s) and 9.59 (1H, br s); LC (XTERRA, 30/70, 210 nm) 99.6% (2.01 min). |
Yield | Reaction Conditions | Operation in experiment |
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81% | With triphenylphosphine; In tetrahydrofuran; | Preparation 10 Synthesis of 6-(2-fluorobenzyloxy)-2-naphthylaldehyde 6-hydroxy-2-naphthylaldehyde (520 mg) and triphenylphosphine (0.87 g) was dissolved in THF (20 ml), and then <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (0.49 ml) was added thereto. The reaction mixture was stirred, and diethyl azodicarboxylate (0.57 ml) was slowly added. The mixture was stirred at room temperature for 36 hours. After reaction, the solvent was distilled off, and the residue was subjected to column chromatography on silica gel (50 g) eluding with hexane/ethyl acetate. The combined solutions were concentrated, and dried to obtain the objective title compound (654 mg, yield=81%). The NMR spectrum is as follows. 1 H NMR (CDCl3); 5.41 (s, 2H), 7.22 (d, 1H, J=2.5 Hz), 7.32 (dd, 1H, J=9.0 Hz 2.5 Hz), 7.44 (t, 1H, J=7.8 Hz), 7.58 (t, 1H, J=8.3 Hz), 7.72 (d, 2H, J=8.5 Hz), 7.78 (d, 1H, J=8.5 Hz), 7.8-8.0 (m, 2H), 8.26 (s, 1H), 10.09 (s, 1H), |
Yield | Reaction Conditions | Operation in experiment |
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In diethyl ether; | 2-(2,4-dichlorophenyl)-2-(2-fluorobenzyloxy)-pentan-1-ol A mixture of 11.6 g (92 mmoles) of <strong>[446-51-5]2-fluorobenzyl alcohol</strong> and 21.9 g (92 mmoles) of 2-(2,4-dichlorophenyl)-1,2-epoxypentane is added dropwise at 0-2 C. to a solution of 2.0 ml (16.5 mmoles) of boron trifluoride ethyl etherate in 10 ml of diethyl ether. The solution is allowed to react further overnight at +7 C. and is worked up as in Example I by extraction and column chromatography. 2.95 g of the pure product are obtained in the form of a colourless oil. 100 MHz-1 H-NMR (CDCl3): delta=6.8-7.7 ppm (m, 7H aromatic); 4.5 ppm (s, 2H, STR27 3.9-4.4 ppm (m, 2H, --CH2 OH); 1.7-2.3 ppm (m, 3H, --CH2 CH2 CH3 and OH); 0.7-1.4 ppm (m, 5H, --CH2 CH3). |
Yield | Reaction Conditions | Operation in experiment |
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72% | In tetrahydrofuran; water; | EXAMPLE 1 Preparation of O-(2-Fluorobenzyl) S-t-butylethylphosphonodithioate (Compound 43 herein, Method A) To a slurry of 0.35 grams (g) (0.0146 mole) of oil-free sodium hydride in 15 milliliters (ml) of tetrahydrofuran under nitrogen and at room temperature was added dropwise 1.75 g (0.0138 mole) of <strong>[446-51-5]2-fluorobenzyl alcohol</strong>. After stirring for 45 minutes, the mixture was cooled to 0 and a solution of 3.0 g (0.0138 mole) of S-t-butyl ethylphosphonodithioic chloride in 5 ml of tetrahydrofuran was added dropwise and the mixture quenched with 10 ml of water and extracted with ether (3*10 ml). The etheral layers were combined and washed with 20 ml of water and 20 ml of saturated sodium chloride, dried with magnesium sulfate, and evaporated to produce 4.15 g of an oil. Purification with a preparative, centrifugally-accelerated, thin-layer chromatograph (4 mm thick silica gel with 98:2 hexane-acetone as eluent) afforded 3.03 g (72% of theoreticl yield) of the title compound, a clear, mobile oil. The structure was confirmed by nuclear magnetic resonance, infrared and mass spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
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In toluene; | A. diethyl 2-(2-fluorobenzyloxy)-2-methylmalonate To a suspension of 20.2 g of sodium hydride in 1200 ml of anhydrous toluene, in a 2-liter flask equipped with stirring bar, thermometer, dropping funnel and condenser with drying tube, was added 88.4 g of <strong>[446-51-5]2-fluorobenzyl alcohol</strong>. Addition was carried out at 25-30 C during 45 minutes. The reaction mixture was heated at 90 C for 11/2 hours. After the mixture was cooled, 177.1 g of diethyl 2-bromo-2-methylmalonate was added during 11/4 hours at 30-50 C. The reaction mixture was heated at 90-95 C for 2 hours. After remaining at room temperature overnight, the reaction mixture and 500 ml of ether were added to a vessel containing 1 liter of saturated sodium bicarbonate solution and 1 kg of crushed ice. After the ice had melted, the aqueous phase was separated and extracted with three 500-ml portions of ether. Ethereal solutions were combined, washed with three 500-ml portions of water and dried by filtration through sodium sulfate. Removal of ether and residual toluene (at reduced pressure) gave 176.2 g of diethyl 2-(2-fluorobenzyloxy)-2-methylmalonate, the identity of which was confirmed by its ir spectrum. |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid; sodium sulfate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; toluene; | A. preparation of 2-(2-Fluorobenzyloxy)-2-methyl-1,3-propanediol In a two-liter flask equipped with stirring bar, thermometer, dropping funnel, and condenser with drying tube 88.4 g of <strong>[446-51-5]2-fluorobenzyl alcohol</strong> was added dropwise over a period of 45 minutes to a stirred suspension of 20.2 g of sodium hydride in 1200 ml of anhydrous toluene. After the addition was carried out at 25-30 C, the reaction mixture was heated at 90 C for 11/2 hours, then cooled, and 177.1 g of diethyl 2-bromo-2-methylmalonate was added over 11/4 hours at 30-50 C. The reaction mixture was heated at 90-95 C for 2 hours and then allowed to cool and remain at room temperature overnight. The reaction mixture and 500 ml of ether were poured into a flask containing 1 liter of saturated sodium bicarbonate solution and 1 kg of crushed ice. After the ice had melted, the aqueous phase was separated and extracted with three 500-ml portions of ether. The ethereal solutions were combined, washed with three 500-ml portions of water, and dried by filtration through sodium sulfate. Removal of ether and residual toluene under reduced pressure gave 176.2 g of diethyl 2-(2-fluorobenzyloxy)-2-methylmalonate, identity confirmed by ir spectrum. A suspension of 25.8 g of lithium aluminum hydride in 1000 ml of anhydrous ether was prepared in a 2-liter flask equipped with stirrer, dropping funnel, and condenser with drying tube. Diethyl 2-(2-fluorobenzyloxy)-2-methylmalonate (101.6 g) was added to the stirred suspension at a rate sufficient to maintain refluxing. When the addition was complete, the dropping funnel was rinsed with 100 ml of ether, and the reaction mixture was refluxed for 4 more hours. The mixture was cooled and kept in an ice bath while excess reducing agent was decomposed by dropwise addition of saturated sodium sulfate solution. Ice-water (250 ml) and 1150 ml of 10% sulfuric acid were then added to the stirred reaction mixture. The aqueous phase was separated from the ether solution, saturated with sodium chloride, and extracted with two 500-ml portions of ether. The ether solutions were combined, dried over sodium sulfate, and concentrated to an oil. Distillation at 0.01 mm Hg removed volatile impurities, leaving a residue which was recrystallized from petroleum ether-chloroform to give 27.5 g of 2-(2-fluorobenzyloxy)-2-methyl-1,3-propanediol, m.p. 74.5-75 C. The ir and nmr spectra were consistent with the assigned structure. Analysis: Calc'd for C11 H14 FO3: C 61.66; H 7.06, Found: C 61.44; H 6.95. |
Yield | Reaction Conditions | Operation in experiment |
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With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In toluene; at 100℃; for 15h; | Compound 16: 3-(2-fluorobenzyloxy)-5-(2-methoxyphenyl)-1H-pyrazole Referring to Scheme 2, Compound 14 (4.4 g) was reacted with hydrazine monohydrate (1.0 ml) in ethanol (20 ml) for 15 hours at room temperature. The reaction mixture was diluted with water and the precipitate was collected by filtration to give Compound 15. A solution of Compound 15 (285 mg), <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (189 mg), ADDP (378 mg) and tri-n-butylphosphine (303 mg) was heated in toluene (5 ml) at 100 C. for 15 hours. The reaction mixture was diluted with ethyl acetate and the precipitate was removed by filtration. The filtrate was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, and concentrated in vacuo. Purification by HPLC afforded the title Compound 16 as a pale pink solid (80 mg). 1H NMR (400 MHz, DMSO-d6) delta 3.87 (s, 3H) 5.24 (s, 2H) 6.19 (s, 1H) 7.01 (t, J=7.45 Hz, 1H) 7.12 (d, J=8.08 Hz, 1H) 7.19-7.28 (m, 2H) 7.29-7.37 (m, 1H) 7.37-7.45 (m, 1H) 7.53-7.60 (m, 1H) 7.64 (dd, J=7.58, 1.52 Hz, 1H) 12.07 (s, 1H). [M+H] calc'd for C17H15FN2O2, 299; found, 299. |
Yield | Reaction Conditions | Operation in experiment |
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0.64 g (44%) | 2-Fluorobenzyl 5-amino-4-oxopentanoate Hydrochloride [Compound 17] From <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (5.7 g; 45 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 27 h at 100 C. The yield was 0.64 g (44%). Mp 91-94 C. (dec.) 1H NMR (200 MHz; DMSO-d6): delta 2.63 (2H, t, J=6.0 Hz), 2.88 (2H, t, J=6.0 Hz), 3.98 (2H, br s), 5.16 (2H, s), 7.2-7.6 (4H, m), 8.56 (3H, br s). 13C NMR (50 MHz; DMSO-d6): delta 27.0, 34.3, 46.4, 59.7, 59.8, 115.1, 115.5, 122.7, 123.0, 124.5, 130.4, 130.6, 130.7, 130.8, 157.8, 162.7, 171.8, 202.4. |
Yield | Reaction Conditions | Operation in experiment |
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82% | Example 96; 5-(2-Fluorobenzyloxy)-quinazoline-2,4-diamine; [00291] Step 1; A solution of <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (0.7 ml; 6.5 mmol) in dimethylformamide was added to a cooled (0 C) slurry of sodium hydride (260 mg; 6.5 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, and stirred for 45 minutes. In another vessel, a solution of 2,6-difluorobenzonitrile (900 mg, 6.5 mmol) in dimethylfomamide was chilled to 0 C, and activiated anion was added over 20 minutes. Mixture was then stirred 2 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 1.3 g of solid (82% yield) of 2-fluoro-6-(2-fluorobenzyloxy)-benzonitrile. |
Yield | Reaction Conditions | Operation in experiment |
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14% | Example 22: Synthesis of [2-ethoxy-3-(2-fluoro-beiizyIoxy)-phenyI]-(lH-pyrrolo[2,3-b]pyridin-3- yl)-methanone P-2127 and related compounds.[0211] [2-Ethoxy-3 -(2 -fluoro-benzyloxy) -phenyl]-( 1 H-pyrrolo [2,3 -b]py?din-3-yl)-methanone P-2127 was synthesized in one step from (2-ethoxy-3-hydroxy-phenyl)-(l-t?isopropylsilanyl-lH- pyrrolo[2,3-bJpy?din-3-yl)-methanone 99 as shown in Scheme 44Scheme 44Step 1 - Preparation [2-ethoxy-3-(2-fluoro-benzyloxv)-phenyl]-(lH-pyrrolo[2 3-b]pynchn-3-yI)- methanone (P-2127)[0212] In a 4 mL vial, (2-ethoxy-3-hydroxy-phenyl)-(l-tnisopropylsilanyl-lH-pyrrolo[2 3-b]py?din- 3-yl)-methanone (99, 10 mg, 0 022 mmol) was combined with (2-fluoro-phenyl)-methanol (134, 3 5 mg 0 027 mmol) The solids were dissolved in dry tetrahydrofuran (200mul) and t?phenylphosphine (7 0 mg, 0 022 mmol) was added Once the solution was homogeneous, the mixture was cooled to below 0 0C in a liquid nitrogen bath and dnsopropyl azodicarboxylate solution (20mg in lOOmul tetrahydrofuran) was added The reaction mixture was allowed to warm to room temperature and the reaction was continued for 2 hours The solvents w ere removed under reduced atmosphere The resultant residue w as diluted with 200mul dimethyl sulfoxide and potassium fluonde (10 mg) was added The solution was allowed to react overnight to remove the TiPS group The supernatant was purified by reverse phase HPLC using a Phenomenex C-18 column (50mm x 10mm ID), and eluting with water with 0 1% t?fluoroacetic acid and a gradient of 20%- 100% acetomt?le with 0 1% tnfluoroacetic acid over 16 minutes and a flow rate ol 6 niL/mmute to provide P-2127 (1 2 mg, 14 %) MS(ESI) [M+H+]+ = 391 1 |
Yield | Reaction Conditions | Operation in experiment |
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With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene; at 20℃; | Example 26 To a solution of 4-(3-hydroxybenzoyl)-N-pyridin-3-ylpiperazine-1-carboxamide (300 mg), <strong>[446-51-5]2-fluorobenzyl alcohol</strong> (0.10 ml) and PPh3 (362 mg) in THF (10 ml) was added dropwise DEAD (0.63 ml, 40% Tol solution), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (eluent; chloroform:methanol=20:1) to obtain a colorless and oily 4-{3-[(2-fluorobenzyl)oxy]benzoyl}-N-pyridin-3-ylpiperazine-1-carboxamide (298 mg). The obtained compound was dissolved in ethanol (10 ml), and oxalic acid (186 mg) was added thereto, followed by stirring at room temperature for 30 minutes. The precipitated solid was collected by filtration, washed with ethanol, and dried under heating to obtain 4-{3-[(2-fluorobenzyl)oxy]benzoyl}-N-pyridin-3-ylpiperazine-1-carboxamide oxalate (140 mg) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
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A 250 ml round-bottomed flask is filled with magnesium (2.67 g, 0.1 1 mol) and iodine (0.1 g) is sublimated to the magnesium, then diethyl ether (60 ml) is added and under boiling a solution of 2-fluor benzyl chloride (11.9 ml, 0.1 mol) and diethyl ether (20 ml) is added to the reaction mixture. The mixture is boiled for two hours, then cooled to - 70 0C and a solution of cyclopropanecarbonyl chloride (8.36 g, 80 mmol 1) and tetrahydrofuran (50 ml) are added, and the reaction mixture is left to warm to room temperature.A sample was taken from the reaction mixture and it was washed with aqueous ammonium chloride and examined with GC/MS measurements. The content of the reaction mixture was the following:11.5 % cyclopropanecarboxylic acid <n="16"/>10.8 % 2-fluorobenzyl alcohol,25.2 % 2-fluorotoluene,4.8 % compound of formula (III) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A 250 ml round-bottomed flask is filled with magnesium (2.67 g, 0.11 mol) and iodine (0.1 g) is sublimated to the magnesium, then diethyl ether (60 ml) is added and under boiling a solution of 2-fluor benzyl chloride (11.9 ml, 0.1 mol) and diethyl ether (20 ml) is added to the reaction mixture. The mixture is boiled for two hours, then cooled to - 50 C and a solution of cyclopropanecarbonitrile (5.4 g, 80 mmol) and tetrahydrofuran (50 ml) are added, and the reaction mixture is warmed to boiling point and boiled for half an hour.A sample is taken from the reaction mixture and it is washed with aqueous hydrochloric acid and examined with GC/MS measurements. The content of the reaction mixture was the following:14.6 % 2-fluorotoluene,24.4 % 2-fluorobenzyl alcohol,16.5 % compound of formula (III). |
Yield | Reaction Conditions | Operation in experiment |
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54.2% | EXAMPLE 3 Preparation of 3methyl-1-(2-fluoro phenyl)butyllalcohol (12) [0037] In a 3 necked round bottom flask (100 ml), equipped with a dropping funnel reflux condenser and thermometer pocket, placed magnesium turnings (1.45 gm 0.0604 mole) and flame dried the apparatus. Dry diethyl ether (15 ml.) was added to Mg. Turning, Isobutyl bromide (6.57 ml, 8.28 gm, 0.0645 mole) was taken in 5 ml of dry ether and added drop wise to the Mg turnings. As soon as ether starts boiling (in a few minutes) the reaction was cooled using ice-salt and continued the addition of isobutyl bromide. After complete addition of isobutyl bromide continued for another 20 minutes. o-Fluro benzaldehyde (4.25 ml, 5.0 gm, 0.0403 mole) in 10 ml of ether was added drop wise at -10 C. (around ½ hr). After the completion of addition of fluoro benzaldehyde continued the stirring for 1 hr and the reaction was quenched with ice-cooled saturated ammonium chloride solution (30 ml), the solid separated is filtered off, the filtrate is extracted with ethyl acetate (20×1, 10×2 ml) dried over sodium sulphate and concentrated to yield 6.54 gm of crude product (GC showed area of 85% purity). The crude product on vacuum distillation gave 3.93 gm (54.2%) of pure 3-methyl-1-(2-fluoro phenyl)butyllalcohol (12) and impure product 2.87 gm contaiing 3-methyl-1-(2-fluoro phenyl)butylalcohol (12) 60% and byproduct (o-fluoro benzylalcohol) 40%. 1HNMR CDCl3 (spectrum 11): 0.96(d, 6H), 1.55(m, 1H), 1.75(m, 2H), 1.95 (bs, 1H), 5.05(m, 1H), 7.0(m, 1H), 7,20(m, 2H), 7.45(m, 1H) [0038] GC Conditions [0039] Column: HP1 [0040] Temperature: 100 C. [0041] o-Fluorobenzaldehyde: 0.61 RT [0042] o-Fluorobenzylalcohol: 0.89 RT [0043] 3-methyl-1-(2-fluoro phenyl)butylalcohol (12): 4.07 RT |
Yield | Reaction Conditions | Operation in experiment |
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86% | With 18-crown-6 ether; potassium hydroxide; In toluene; | General procedure: To a solution of 2-chloro-3-nitropyridine (200 mg, 0.63 mmol) in toluene (10 mL) was added different phenylmethanol (1.89 mmol, including phenylmethanol, (2-chlorophenyl) methanol, (3-chlorophenyl) methanol, (4-chlorophenyl) methanol, (2-fluorophenyl) methanol, (4-fluorophenyl) methanol, 1,1'-biphenyl-4-ylmethanol, pyridin-2-ylmethanol, (1-(4-chlorophenyl)-1H-pyrazol-3-yl) methanol and (5-(2,5-dichlorophenyl)furan-2-yl) methanol). Then 18-crown-6 (33 mg, 0.13 mmol) and KOH (142 mg, 2.52 mmol) were added. The reaction was stirred until the consumption of 2-chloro-3-nitropyridine was complete. The reaction mixture was partitioned between EtOAc (100 mL) and brine (40 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel provided the desired compounds. The physical data in detail can be found in the Supporting Information. |
Yield | Reaction Conditions | Operation in experiment |
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41% | With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 20℃; | General procedure: To a solution of 4-hydroxy-1-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}pyridin-2(1H)-one (19, 30 mg, 0.10 mmol), PBu3 (0.075 mL, 0.30 mmol), 2-(4-fluorophenyl)ethanol (0.025 mL, 0.20 mmol) in THF (1 mL) was added 1,1'-(azodicarbonyl)dipiperidine (76 mg, 0.30 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (MeOH/CHCl3) to give compound 5e (24 mg, 57%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-oxo-2-ethoxy-4,5-benzo-1,3,2-dioxaphospholane; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃;Cooling with ice; | General procedure: A cooled mixture of 12 (6.7 g, 20.0 mmol), 2-hydroxybenxyl alcohol (2.6 g, 20.0 mmol) and diisopropylethylamine (10.2 mL, 58.6 mmol) in CH2Cl2 (50 mL) was added ethyl o-phenylenephosphate (EPPA) (4.8 mL) in an ice bath. The mixture was stirred at room temperature for 60 min, and poured into EtOAc. The solution was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized from diethyl ether to give 13a (6.9 g, 85%) as crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 100℃; for 8h;Microwave irradiation; Inert atmosphere; | General procedure: Into a flame-dried microwave vial, containing a magnetic stirring bar was weighed corresponding benzyl alcohol (2 mmol, 1 equiv) under Ar. Triethylphosphane hydrochloride (2 mmol, 1 equiv) was added to the vial. The vial was septa-sealed and stirred at 100 C for 8 h. The septum was removed and water (800 muL) was added to make a 2.5 M solution. Powdered lithium hydroxide (8 mmol, 4 equiv) was added to the vial which was subsequently magnetically stirred for 3 min prior to the addition of 4-hydroxymethylbenzaldehyde (LI) (2 mmol, 1 equiv). The reaction was stirred vigorously at 80 C for 3 hours The oil bath was removed and the flask was left to attain room temperature. 6 mL water was added to the reaction mixture and the flask was stirred for 10 min. The slurry was vacuum filtered and dried to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro bis(acetonitrile) palladium(II); C46H45FeN2P2(1+)*I(1-); caesium carbonate; In acetonitrile; at 20℃; for 4h;Inert atmosphere; | General procedure: Chiral ferrocene ligand (25.6 lmol) and Pd(CH3CN)2Cl2 (6.4 mg, 25.6 lmol) were dissolved in dry solvent (1 mL) in a dried Schlenk flask under argon and then stirred at room temperature for 1 h. The solvent was removed under vacuum, then 1a or 1b (0.512 mmol), Cs2CO3 or another salt (1.536 mmol), three times the equivalent of the nucleophile (1.536 mmol), and 2 mL of an appropriate solvent were added, and the mixture was stirred for an additional 20 min. The reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with CH2Cl2 (10 mL). The organic phase was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate 30:1) to give the product. | |
With bis(eta3-allyl-mu-chloropalladium(II)); (R)-(2-(tert-butylsulfinyl)phenyl)di-p-tolylphosphine; caesium carbonate; In acetonitrile; at 10℃; for 24h;Inert atmosphere; | General procedure: Under an argon atmosphere, to a dried Schlenk flask, ligand L5 (3.5 mg, 4.4 mol %), [Pd(eta3-C3H5)Cl]2 (1.4 mg, 2.0 mol %), and cesium carbonate (200 mg, 0.6 mmol) were added, followed by addition of CH3CN (1.0 mL). The mixture was stirred at room temperature for 30 min, and then rac-1,3-diphenyl-2-propenyl acetate (50 mg, 0.2 mmol) was added to the reaction system via a syringe. The nucleophile (63 muL, 0.6 mmol) was then added to the mixture. Conversion was monitored by TLC; the reaction was diluted with Et2O, washed with saturated NH4Cl (aq), saturated NaHCO3 (aq), and brine. The combined aqueous solutions were extracted with CH2Cl2. The combined organic phase was dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (petroleum ether/ethyl acetate = 200:1, V/V). | |
With bis(eta3-allyl-mu-chloropalladium(II)); (R)-(2-(tert-butylsulfinyl)phenyl)di-o-tolylphosphine; caesium carbonate; In acetonitrile; at 10℃; for 24h;Inert atmosphere; | General procedure: Under an argon atmosphere, to a dried Schlenk flask, ligand L5 (3.5 mg, 4.4 mol %), [Pd(eta3-C3H5)Cl]2 (1.4 mg, 2.0 mol %), and cesium carbonate (200 mg, 0.6 mmol) were added, followed by addition of CH3CN (1.0 mL). The mixture was stirred at room temperature for 30 min, and then rac-1,3-diphenyl-2-propenyl acetate (50 mg, 0.2 mmol) was added to the reaction system via a syringe. The nucleophile (63 muL, 0.6 mmol) was then added to the mixture. Conversion was monitored by TLC; the reaction was diluted with Et2O, washed with saturated NH4Cl (aq), saturated NaHCO3 (aq), and brine. The combined aqueous solutions were extracted with CH2Cl2. The combined organic phase was dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (petroleum ether/ethyl acetate = 200:1, V/V). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro bis(acetonitrile) palladium(II); C46H45FeN2P2(1+)*I(1-); caesium carbonate; In acetonitrile; at 20℃; for 4h;Inert atmosphere; | General procedure: Chiral ferrocene ligand (25.6 lmol) and Pd(CH3CN)2Cl2 (6.4 mg, 25.6 lmol) were dissolved in dry solvent (1 mL) in a dried Schlenk flask under argon and then stirred at room temperature for 1 h. The solvent was removed under vacuum, then 1a or 1b (0.512 mmol), Cs2CO3 or another salt (1.536 mmol), three times the equivalent of the nucleophile (1.536 mmol), and 2 mL of an appropriate solvent were added, and the mixture was stirred for an additional 20 min. The reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with CH2Cl2 (10 mL). The organic phase was dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether/ethyl acetate 30:1) to give the product. |
Tags: 446-51-5 synthesis path| 446-51-5 SDS| 446-51-5 COA| 446-51-5 purity| 446-51-5 application| 446-51-5 NMR| 446-51-5 COA| 446-51-5 structure
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