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CAS No. : | 188975-30-6 | MDL No. : | MFCD09997709 |
Formula : | C6H7F3O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QXCAHEXKUMUTRF-UHFFFAOYSA-N |
M.W : | 232.18 | Pubchem ID : | 11356703 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 39.69 |
TPSA : | 60.98 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.84 cm/s |
Log Po/w (iLOGP) : | 1.52 |
Log Po/w (XLOGP3) : | 1.24 |
Log Po/w (WLOGP) : | 3.5 |
Log Po/w (MLOGP) : | 0.28 |
Log Po/w (SILICOS-IT) : | 0.89 |
Consensus Log Po/w : | 1.48 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.86 |
Solubility : | 3.19 mg/ml ; 0.0137 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.12 |
Solubility : | 1.77 mg/ml ; 0.00761 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.32 |
Solubility : | 11.1 mg/ml ; 0.048 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.14 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P264-P270-P271-P280-P303+P361+P353-P304+P340-P305+P351+P338-P310-P330-P331-P363-P403+P233-P501 | UN#: | 3265 |
Hazard Statements: | H302-H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
40% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -70℃; for 0.5 h; Stage #2: at -70 - 20℃; for 18 h; |
LDA/THF (31.5 ml of 1.92M solution) was slowly added to a stirred solution of tetrahydro-4H-pyran-4-one (5.5 g) in THF (30ml) at -70° C., under argon. The mixture was stirred for 30 minutes at -70° C. and then a solution of N-phenyl triflimide (21.6 g) in THF (30 mls) was added. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was evaporated and subjected to chromatography by MPLC on Alumina (ICN, N32-63, using as eluant a mixture of ethyl acetate (5percent) and iso-hexane). The product was distilled by Kugelruhr (100° C./10 mm). Remaining traces of the triflimide reagent were removed by a second MPLC (Silica, using as eluant a mixture of ethyl acetate (5percent) and iso-hexane) followed by a second Kugelruhr distillation, giving the title compound as a colourless oil in 40percent yield (5.1 g), which was stored at -20° C. NMR (300 MHz, CDCl3): δ: 2.24(m,2H), 3.90(m,2H), 4.25(m,2H), 5.82(m,1H). |
35.7% | Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Inert atmosphere Stage #2: at 15℃; for 16 h; Inert atmosphere |
Example 47A 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate To a solution of dihydro-2H-pyran-4(3H)-one (1.8 g, 18.0 mol) in THF (20 ml) was added LiHMDS (1 M, 21.6 ml, 21.6 mmol) at -78° C. under N2 atmosphere. After stirring for 1 h at -78° C., (CF3SO2)2NPh (6.4 g, 18.0 mmol) was added in portions. The mixture was stirred at 15° C. for 16 h and quenched with aq NH4Cl solution (20 mL). The aqueous layer was extracted with EtOAc (30 mL*2). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatograph to provide the title compound as a colorless oil (1.5 g, yield: 35.7percent). LCMS (ESI) m/z: 233 (M+1). |
15.1% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 0.166667 h; |
Under an atmosphere of nitrogen, to a solution of diisopropylamine (CAN 180-18-9, 2.42 g, 0.024 mol) in THF (40 mL) was added n-butyl lithium (10.4 mL, 2.5 M solution in hexane, 26 mmol) at -78° C. The reaction mixture was reacted for 30 min at -50° C. Then tetrahydropyran-4-one (CAN 29943-42-8, 2 g, 0.020 mol) in THF (10 mL) was added dropwise to the above solution at -78° C. The reaction mixture was reacted for 30 min at -78° C. Then trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (CAN 37595-74-7, 7.85 g, 0.022 mol) in THF (50 mL) was added dropwise to the above solution at -78° C. The reaction mixture was stirred for 10 min at room temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3.x.30 mL). The combined organic extracts were washed with citric acid (50 mL) and sodium hydroxide solution (1 N, 50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, 1percent ethyl acetate in petroleum ether) to yield the title compound (0.7 g, 3 mmol, 15.1percent) as yellow oil. 1H NMR (300 MHz, d6-DMSO): 6.05-6.03 (m, 1H), 4.17 (d, J=3 Hz, 2H), 3.78 (t, J=4.5 Hz, 2H), 2.38 (t, J=3 Hz, 2H). |
15.1% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Inert atmosphere Stage #2: at -78 - 20℃; for 0.166667 h; |
Under an atmosphere of nitrogen, to a solution of diisopropylamine (CAN 180-18-9, 2.42 g, 0.024 mol) in THF (40 mL) was added w-butyl lithium (10.4 mL, 2.5 M solution in hexane, 26 mmol) at -78°C. The reaction mixture was reacted for 30 min at -50°C. Then tetrahydropyran-4-one (CAN 29943-42-8, 2 g, 0.020 mol) in THF (10 mL) was added dropwise to the above solution at -78°C. The reaction mixture was reacted for 30 min at - 78°C. Then trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (CAN 37595-74-7, 7.85 g, 0.022 mol) in THF (50 mL) was added dropwise to the above solution at -78°C. The reaction mixture was stirred for 10 min at room temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with citric acid (50 mL) and sodium hydroxide solution (1 N, 50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography(silica gel, 10 g, 1percent ethyl acetate in petroleum ether) to yield the title compound (0.7 g, 3 mmol, 15.1percent) as yellow oil. 1H NMR (300 MHz , (f-DMSO): 6.05 - 6.03 (m, 1H), 4.17 (d, J = 3 Hz, 2H), 3.78 (t, J = 4.5 Hz, 2H), 2.38 (t, J = 3 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 2 h; Inert atmosphere Stage #2: at 0℃; for 3.25 h; Inert atmosphere |
In a 50 mL round-bottomed flask under nitrogen, a solution of n-butyllithium (1.45 M in hexanes, 1.90 mL, 2.76 mmol) was added dropwise to a solution of diisopropylamine (0.39 mL, 2.74 mmol) in THF (5 mL) at 0 °C and the resulting mixture was stirred for 15 min. The reaction mixture was then cooled to -78 °C and a solution of dihydro-2H-pyran-4(3H)-one (0.23 mL, 2.481 mmol) in THF (7.5 mL) was slowly added and the mixture was at -78 °C for another 2 h. To this mixture was added a solution of 2- (N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (1.082 g, 2.76 mmol) in THF (5 ml) over 15 min and the mixture was then allowed to warm to 0 °C and stirred for 3 h. The reaction was then quenched with water (15 mL) and the mixture was extracted with Et2O (x3). The combined organic extract was washed successively with 15percent aqueous NaOH and brine and then it was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was chromatographed on a silica gel column (22 mm x 80 mm) which was eluted with 0 to 20percent EtOAc in hexanes. This afforded 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 53percent) as a colorless oil which was used as such in the following step. 1H NMR (400 MHz, acetone-d6): δ ppm 6.01 (tt, J= 2.8, 1.5 Hz, 1 H) 4.25 (q, J= 3.0 Hz, 2 H) 3.88 (t, J= 5.5 Hz, 2 H) 2.48 (ttd, J= 5.5, 2.8, 1.4 Hz, 2 H). In a 25 mL round-bottomed flask, the obtained 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 1.322 mmol) and potassium fluoride (0.270 g, 4.65 mmol) were added to a solution of (3-(hydroxymethyl)phenyl)boronic acid (0.250 g, 1.645 mmol) in THF (7.5 ml) and the flask was evacuated and purged with nitrogen three times. Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.024 g, 0.029 mmol) was then added in one portion and the mixture was stirred at room temperature for 66 h. The resulting mixture was diluted with ethyl acetate, filtered through CELITE® and concentrated. The residue was purified on the ISCO using a REDISEP® Gold 24 g column (elution with hexanes-EtOAc) to give the title compound (0.131 g, 52percent) as yellowish oil. LC (Method B): 1.614 min. LCMS (APCI): calcd for C12H13O [M+H]+- H20 m/z 173.096, found 173.2. 1H NMR (400 MHz, acetone-d6): δ ppm 7.46 (s, 1H) 7.22-7.36 (m, 3H) 6.21 (tt, J= 3.0, 1.5 Hz, 1H) 4.64 (d, J= 5.9 Hz, 2H) 4.24 (q, J= 3.0 Hz, 2H) 4.17 (t, J= 5.7 Hz, 1H) 3.86 (t, J= 5.5 Hz, 2H) 2.49 (ttd, J= 5.4, 2.8, 1.6 Hz, 2H). |
800 mg | Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Stage #2: Cooling |
A solution of LiHMDS (1.0 M in THF, 11 mL, 11 mmol) was added dropwise to a cooled solution of 4-tetrahydropyranone (1 g, 10 mmol) in dry THF (5 mL) at -78° C. and the resulting reaction was maintained at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.93 g, 10 mmol) in dry THF (6 mL) was added dropwise and the reaction maintained overnight, allowing the cooling bath to expire. The reaction was quenched with water (10 mL) and partitioned with DCM. The layers were separated and the aqueous portion was extracted with DCM (2*). The combined organic portions were dried (Na2SO4) and evaporated. The crude residue was purified by flash chromatography (neutral alumina, 80:20 DCM-hexanes) to provide 800 mg of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.82-5.81 (m, 1H), 4.27-4.25 (m, 2H), 3.91-3.88 (m, 2H), 2.48-2.45 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium acetate In 1,4-dioxane at 80℃; | A 250 ml_ round bottom flask containing trifluoro-methanesulfonic acid 3, 6- dihydro-2H-pyran-4-yl ester (2.7 g, 11.6 mmol), PdCI2(dppf) (440 mg, 0.6 mmol) and potassium acetate (3g, 36 mmol) in dioxane (20 mL) was flushed with Ar three times. The reaction mixture was heated at 80 °C for overnight. After the reaction was cooled to room temperature, the reaction mixture was filter through a column packed with celite and the filtrate was concentrated. The residue was purified using column chromatography (10 percent hexane in dichloromethane) and product was obtained as white solid (2g, 81 percent yield). |
50.5% | With potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere | Under an atmosphere of nitrogen, a solution of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.7 g, 3.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (CAN 3183-34-3, 0.84 g, 3.3 mmol), 1,1'-bis(diphenylphosphino) ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 0.05 g, 0.06 mmol) and potassium acetate (0.89 g, 9.0 mmol) in DMSO (10 mL) was heated to 80° C. overnight. Water (50 mL) was added to the reaction mixture which then was extracted with ethyl acetate (3.x.30 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 9 g, 1percent ethyl acetate in petroleum ether) to yield the title compound (0.32 g, 2 mmol, 50.5percent) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 6.53 (s, 1H), 4.20 (t, J=3 Hz, 2H), 3.76 (t, J=6 Hz, 2H), 2.24 (dd, J1=6 Hz, J2=6 Hz, 2H), 1.28 (s, 12H). |
50.5% | With potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere | Under an atmosphere of nitrogen, a solution of 3, 6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (0.7 g, 3.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2- dioxaborolane) (CAN 3183-34-3, 0.84 g, 3.3 mmol), 1,1*- bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 0.05 g, 0.06 mmol) and potassium acetate (0.89 g, 9.0 mmol) in DMSO (10 mL) was heated to 80°C overnight. Water (50 mL) was added to the reaction mixture which then was extracted with ethyl acetate (3><30 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 9 g, 1percent ethyl acetate in petroleum ether) to yield the title compound (0.32 g, 2 mmol, 50.5percent) as colorless oil. 1H NMR (300 MHz, CDCh): δ 6.53 (s, 1H), 4.20 (t, J= 3 Hz, 2H), 3.76 (t, J = 6 Hz, 2H), 2.24 (dd, J; = 6 Hz, J 2 = 6 Hz, 2H), 1.28 (s, 12H). |
150 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere | A mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (250 mg, 1.1 mmol), bis(pinacolato)diboron (410 mg, 1.6 mmol), and KOAc (323 mg, 3.3 mmol) dioxane (3 mL) was sparged with Ar for 5 min. Then PdCl2dppf.DCM (45 mg, 0.05 mmol) was added and reaction was sparged again with Ar for 5 min. The reaction was sealed and heated to and maintained at 80° C. for overnight. The reaction mixture was allowed to cool rt and was filtered through Celite, washing the filter cake with EtOAc. The combined filtrate was concentrated and the resulting residue was purified by flash chromatography (SiO2, 100:0-80:20 hexanes-EtOAc) to furnish 150 mg of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (m/z): 211.0 (MH+), tR=0.89 min; 1H NMR (400 MHz, CDCl3) δ 6.48 (br s, 1H); 4.15-4.14 (app dd, J=2.8, 5.6 Hz, 2H); 3.72-3.69 (app t, 5.2, 2H); 2.19-2.17 (m, 2H); 1.22 (s, 12H). |
300 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere | To a solution of 4.4,4',4',5.5,5',5'-octamethyl-2.2'-bi(1.3,2-dioxaborolane) (993 mg, 3.91 mmol) in DMSO (5 mL) under N2 was added KOAc (959.8 mg, 9.78 mmol) and Pd(dppf)CI2 (71.7 mg, 0.097 mmol). A solution of the triflate intermediate (750 mg) in DMSO (1 mL) was added and the reaction heated at 80 °C overnight. The mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with saturated NaHCC>3 (3 x 10 mL) and brine (3 x 10 mL), dried (Na2SO.t) and concentrated. The residue obtained was purified by silica gel chromatography (ethyl acetate /petroleum ether=1 /2) to give the title compound (300 mg) as a white solid which was used without further purification or analysis |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In ethanol; water; toluene for 16h; Heating / reflux; | 6.a To a stirred solution of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (10.7g) (prepared according to WO9709328) and tetrakis(triphenylphosphine)palladium (1.78g) in toluene (594ml) was added 3-cynophenylboronic acid (7.42g), dissolved a minimum amount of ethanol, followed by a 2M aqueous sodium carbonate solution (50.5ml). The resulting mixture was heated at reflux for 16 hours. After filtration, the mixture was concentrated to dryness in vacuo and the residue partitioned between dichloromethane and brine. The organics were dried over magnesium sulphate, filtered and concentrated to dryness. The residue was then purified by SiO2 chromotograhy, eluting with a zso-hexane to 15% ethyl acetate in iso-hexane gradient to yield 3-(3,6-dihydro-2H-pyran-4- yl)benzonitrile (5.9Ig). A solution of 3-(3,6-dihydro-2H-pyran-4-yl)benzonitrile (1.64g) in n-butanol (5ml) and 5M aqueous sodium hydroxide solution (5ml) was heated at reflux for 16 hours. The cooled reaction mixture was concentrated to dryness in vacuo and the residue taken up into water and acidified using a 2M aqueous hydrochloric acid solution. The mixture was then extracted into ethyl acetate (2x100ml) and the combined organics dried over magnesium sulphate, filtered and concentrated to dryness to give 3-(3,6- dihydro-2H-pyran-4-yl)benzoic acid (1.6Og). To a solution of 3-(3,6-dihydro-2H-pyran-4- yl)benzoic acid (6.3Ig) in ethanol (200ml) was added 10% palladium on carbon (0.4Og) and the mixture stirred under a balloon of hydrogen at room temperature for 72 hours. The reaction mixture was fltered through diatomaceous earth (Celite) and the filtrate concentrated to dryness in vacuo to afford 3-(tetrahydro-2H-ρyran-4-yl)benzoic acid (6.12g). NMR Spectrum: (DMSO-d6) 12.90 (s, 1η), 7.83 - 7.76 (m, 2η), 7.53 (d, J = 7.3 Hz, IH), 7.44 (t, J = 7.6 Hz, IH)3 3.99 - 3.91 (m, 2H), 3.44 (td, J = 11.2, 3.1 Hz, 2H), 2.91 - 2.79 (m, IH), 1.77 - 1.59 (m, 4H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
396 mg | Stage #1: (5R)-(-)-3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinecarboxamide With hexamethyldistannane In 1,4-dioxane at 90℃; for 2h; Stage #2: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran With triphenyl-arsane In 1-methyl-pyrrolidin-2-one at 20℃; for 120h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: 5R-acetamidomethyl-3-(4-trimethyltinphenyl)furan-(5H)-2-one; 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran With triphenyl-arsane; lithium chloride In 1-methyl-pyrrolidin-2-one; water at 40℃; for 37h; Stage #2: With potassium fluoride In 1-methyl-pyrrolidin-2-one; water for 0.333333h; | 6 EXAMPLE 6; 5R-acetamidomethyl-3-(4-[2,3-dihydro-6H-pyran-4-yl]phenyl)-furan-(5H)-2-one The triflate (Reference Example 8) (0.58 g, 2.50 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.144 g, 0.125 mmol), triphenyl arsine (0.153 g, 0.50 mmol) and lithium chloride (0.286 g, 6.75 mmol) were dissolved in degassed NMP (33 ml). The stannane (Reference Example 9) (0.89 g, 2.25 mmol) in NMP (9 ml) was added and the solution stirred at 40° C. for 17 hours. TLC indicated incomplete reaction and more triflate (0.155 g, 0.67 mmol) was added. After a further 20 hours, the solution was treated with aqueous potassium fluoride solution (2M) (6.50 ml, 12.50 mmol) and stirred for 20 minutes. The mixture was then drowned into water (150 ml) and extracted with ethyl acetate (3×80 ml). The organic extracts were washed with water (2×100 ml), dried (MgSO4) and evaporated to a residue. This was purified by MPLC (using as eluant a mixture of MeOH/CH2Cl2 increasing in polarity from 0% MeOH to 3% MeOH) to afford product which was triturated with diethyl ether to give the title product (0.301 g, 43%) as a powder. NMR (250 MHz, CDCl3): δ: 1.94 (s, 3H), 2.53 (bd s, 2H), 3.64 (dt, 1H), 3.76 (dt, 1H), 3.76 (dt, 1H), 3.94 (t, 2H), 4.34 (d, 2H), 5.19 (s, 1H), 6.06 (bd t, 1H), 6.20 (bd s, 1H), 7.43 (d, 2H), 7.55 (s, 1H), 7.80 (d, 2H). MS: ESP+(M+H)=314. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-bis-(diphenylphosphino)ferrocene; potassium hydroxide In 1,4-dioxane at 80℃; for 6h; | 342.1 Example 342; 342.1 To a stirred solution of (RS)-N- (4-Cyano-benzyl)-2- [2, 6-difluoro-4- (4, 4,5, 5-tetramethyl- [1, 3,2] DIOXABOROLAN-2-YL) -PHENYL] -2-ETHOXY-ACETAMIDE (350 MG, EXAMPLE 262.1) AT R. T. IN dioxane (3 ml) under an argon atmosphere were added TRIFLUORO-METHANESULFONIC acid 3,6- dihydro-2H-pyran-4-yl ester (196 mg, CAS 188975-30-6, solution in 2 ml dioxane), KOH (86 mg), PDCL2 (dppf) (31 mg) and 1, 1'-BIS (diphenylphosphino) ferrocene (21 mg). The mixture was then heated to 80°C for 6 hrs. The mixture was concentrated to leave a dark brown solid. The crude product was isolated by column chromatography (cyclohexane => cyclohexane/EtOAc 55: 45) to give (RS)- (4-CYANO-BENZYL)-2- [4- (3, 6-dihydro-2H-pyran-4- YL) -2, 6-DIFLUORO-PHENYL]-2-ETHOXY-ACETAMIDE (107 MG) AS LIGHT YELLOW GUM. MS 413.1 ( [M+H] +) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triphenyl-arsane In 1-methyl-pyrrolidin-2-one at 20℃; for 120h; | 443.2 [0714] Step 2: Preparation of (5R)-(-)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidine-carboxamide [0715] A mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonic acid ester (U.S. Pat. No. 5,968,962, Oct. 19, 1999, 682 mg, 2.94 mmol), tris(dibenzylidene-acetone)dipalladium(0) (54 mg, 0.0588 mmol) and triphenylarsine (144 mg, 0.470 mmol) in N-methyl-2-pyrrolidinone (14.7 mL) was degassed and stirred under nitrogen for 5 minutes. (5R)-3-[4-(trimethylstannyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide (Step 1, 1.14 g, 2.94 mmol) was then added, and the resulting mixture was stirred at ambient temperature for 5 days. The reaction mixture was then diluted with water (25 mL) and extracted with ethyl acetate (3×30 mL), and the combined organic phase was washed with water (3×30 mL) and saline (20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product mixture was chromatographed on a Flash 40M 90 g silica gel (32-63 μm) cartridge, eluting with a gradient of methanol/methylene chloride (1/99-2.5/97.5), and those fractions with an Rf=0.40 by TLC (methanol/chloroform, 2×5/95) are pooled and concentrated to give the title compound, mp 164-169° C.; MS (ESI-) for C15H15N2O4F m/z 305 (M-H)-; [α]25D=-23 (c 0.96, DMSO) | |
In 1-methyl-pyrrolidin-2-one at 20℃; for 120h; | 9.2 A mixture of 3, 6-dihydro-2H-pyran-4-yl trifluoromethanesulfonic acid ester (US 5,968, 962,19 October 1999,682 mg, 2.94 mmol), tris (dibenzylideneacetone) dipalladium (0) (54 mg, 0.0588 mmol) and triphenylarsine (144 mg, 0.470 mmol) in N-methyl-2-pyrrolidinone (14.7 mL) is degassed and stirred under nitrogen for 5 minutes. (5R)-3- [4- (Trimethylstannyl)-3-fluorophenyl]-2-oxo-5- oxazolidinecarboxamide (Step 1, 1.14 g, 2.94 mmol) is then added, and the resulting mixture is stirred at ambient temperature for 5 days. The reaction mixture is then diluted with water (25 mL) and extracted with ethyl acetate (3 x 30 mL), and the combined organic phase is washed with water (3 x 30 mL) and saline (20 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product mixture is chromatographed on a Flash 40M 90g silica gel (32-63 , tun) cartridge, eluting with a gradient of methanol/methylene chloride, (1/99- 2.5/97. 5), and those fractions with an Rf= 0.40 by TLC (methanol/chloroform, 2 x 5/95) are pooled and concentrated to give the title compound, mp 164-169°C ; MS (ESI-) for C15Hl5N204F m/z 305 (M-H)- ; [a] ZSD =-23 (c 0.96, DMSO). | |
Stage #1: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran With triphenyl-arsane In 1-methyl-pyrrolidin-2-one for 0.0833333h; Stage #2: (5R)-3-[4-(trimethylstannyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide In 1-methyl-pyrrolidin-2-one at 20℃; for 5h; | 9.2 Step 2: Preparation of (5R)-(-)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide Step 2: Preparation of (5R)-(-)-3-[4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide A mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonic acid ester (U.S. Pat. No. 5,968,962, 19 Oct. 1999, 682 mg, 2.94 mmol), tris(dibenzylideneacetone)dipalladium(0) (54 mg, 0.0588 mmol) and triphenylarsine (144 mg, 0.470 mmol) in N-methyl-2-pyrrolidinone (14.7 ML) is degassed and stirred under nitrogen for 5 minutes. (5R)-3-[4-(Trimethylstannyl)-3-fluorophenyl]-2-oxo-5-oxazolidinecarboxamide (Step 1, 1.14 g, 2.94 mmol) is then added, and the resulting mixture is stirred at ambient temperature for 5 days.The reaction mixture is then diluted with water (25 ML) and extracted with ethyl acetate (3*30 ML), and the combined organic phase is washed with water (3*30 ML) and saline (20 ML), dried over anhydrous magnesium sulfate and concentrated under reduced pressure.The crude product mixture is chromatographed on a Flash 40M 90 g silica gel (32-63 μm) cartridge, eluding with a gradient of methanol/methylene chloride (1/99-2.5/97.5), and those fractions with an Rf=0.40 by TLC (methanol/chloroform, 2*5/95) are pooled and concentrated to give the title compound, mp 164-169° C.; MS (ESI-) for C15H15N2O4F m/z 305 (M-H)-; [α]25D=-23 (c 0.96, DMSO). |
Yield | Reaction Conditions | Operation in experiment |
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66% | With sodium carbonate In ethanol; water; toluene at 85℃; for 0.75h; | 45 EXAMPLE 45; 2-(1H-Imidazol-2-yl)-4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazole 2.0 g Trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (8.6 mmol) and 2.89 g 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.3 mmol) were dissolved in a mixture of toluene (20 ml) and ethanol (50 ml) 0.35 g of dichloro (1,1'bis-(diphenylphosphine)ferrocene)palladium(II)dichloromethane (0.43 mmol) was added and heated to 85° C. Then aqueous sodium carbonate (2M) (10 ml) was added and the reaction kept at 85° C. for 45 min. After cooling to ambient temperature the reaction was extracted with ethyl acetate/water, the organic phase was dried over sodium sulfate and concentrated. Column chromatography on silica gel (n-heptane/ethyl acetate 4:1) yielded 1.33 g of 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (66%) as a yellow solid; M.p.: 117-120° C. |
60% | With sodium carbonate In ethanol; water; toluene at 80℃; for 0.333333h; | 14. b b) 4-(4-Methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (VIII) To a stirred solution of 4.36 g (15.6 mmol) 2-(4-methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (VII) and 3.30 g (14.2 mmol) trifluoromethanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester in 33 ml ethanol and 82 ml toluene was added 580 mg (0.71 mmol) dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloromethane adduct. The mixture was heated at 80o C. and 16.5 ml (33.0 mmol) 2 M aqueous sodium carbonate solution was added dropwise. The reaction mixture was stirred for 20 minutes at 80o C. and then cooled to room temperature, poured onto water, and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1 ethyl acetate/hexane) afforded 2.00 g (60%) 4-(4-methoxy-3-nitro-phenyl)-3,6-dihydro-2H-pyran (VIII) as a light yellow solid. ES-MS m/e (%): 253 (M+NH4+, 100), 236 (M+H+, 24). |
60% | With sodium carbonate In ethanol; water at 20 - 80℃; for 0.333333h; |
Yield | Reaction Conditions | Operation in experiment |
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With lithium chloride In water; ethyl acetate; acetonitrile | 10 N-((5S)-3-(4-(2,3-Dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide EXAMPLE 10 N-((5S)-3-(4-(2,3-Dihydro-6H-pyran-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide Triphenylarsine (61 mg), Pd2 (dba)3 (45.8 mg) and lithium chloride (128 mg) were added to a stirred solution of Reference Example 3 (278 mg) in NMP (5 ml) and the vessel was purged well with argon. After stirring for 5 minutes at ambient temperature, Reference Example 1 (397 mg) was added and the reaction mixture was stirred at 40° C. for 24 hours. TLC (ethyl acetate) indicated complete reaction. A 2.0M aqueous potassium fluoride solution (1 ml) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. Water was added and the product was extracted with ethyl acetate. with filtration of the two phase mixture. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and evaporated to a gum. The title compound was isolated by MPLC (Merck 9385 silica, using as eluant a mixture of acetonitrile (40%) and ethyl acetate), and was triturated with ether giving a crystalline powder (yield=104 mg, 33%). NMR (300 MHz, DMSO-D6): δ 1.83(t, 3H), 2.42(s, 2H), 3.40(m, 2H), 3.73(m, 1H), 3.80(t,2H), 4.10(t, 1H), 4.20(d, 2H), 4.70(m, 1H), 6.22(s, 1H), 7.47(AB, 4H), 8.23(t, 1H). MS: ESP+ (M+H)=317. |
Yield | Reaction Conditions | Operation in experiment |
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With diisopropylamine In tetrahydrofuran; ethyl acetate | R.3 5,6-Dihydro-4-trifluoromethylsulfonyloxy-2H-pyran REFERENCE EXAMPLE 3 5,6-Dihydro-4-trifluoromethylsulfonyloxy-2H-pyran LDA/THF (31.5 ml of 1.92M solution) was slowly added to a stirred solution of tetrahydro-4H-pyran-4-one (5.5 g) in THF (30 ml) at -70° C., under argon. The mixture was stirred for 30 minutes at -70° C. and then a solution of N-phenyl triflimide (21.6 g) in THF (30 mls) was added. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was evaporated and subjected to chromatography by MPLC on Alumina (ICN, N32-63, using as eluant a mixture of ethyl acetate (5%) and iso-hexane). The product was distilled by Kugelruhr (100° C./10 mm). Remaining traces of the triflimide reagent were removed by a second MPLC (Silica, using as eluant a mixture of ethyl acetate (5%) and iso-hexane) followed by a second Kugelruhr distillation, giving the title compound as a colourless oil in 40% yield (5.1 g), which was stored at -20° C. NMR (300 MHz, CDCl3): δ 2.24(m,2H), 3.90(m,2H), 4.25(m,2H), 5.82(m,1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; | |
68% | Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at 20℃; Inert atmosphere; | |
63% | Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; hexane at -78 - 20℃; for 18h; |
58% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 16h; Inert atmosphere; | |
52% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 16h; | |
40% | Stage #1: Tetrahydro-4H-pyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -70℃; for 0.5h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -70 - 20℃; for 18h; | |
40% | Stage #1: Tetrahydro-4H-pyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -70℃; for 0.5h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -70 - 20℃; for 18h; | 8 REFERENCE EXAMPLE 8; 2,3-Dihydro-4-trifluoromethylsulfonyloxy-(6H)-pyran LDA/THF (31.5 ml of 1.92M solution) was slowly added to a stirred solution of tetrahydro-4H-pyran-4-one (5.5 g) in THF (30ml) at -70° C., under argon. The mixture was stirred for 30 minutes at -70° C. and then a solution of N-phenyl triflimide (21.6 g) in THF (30 mls) was added. The mixture was allowed to warm to ambient temperature and stirred for 18 hours. The reaction mixture was evaporated and subjected to chromatography by MPLC on Alumina (ICN, N32-63, using as eluant a mixture of ethyl acetate (5%) and iso-hexane). The product was distilled by Kugelruhr (100° C./10 mm). Remaining traces of the triflimide reagent were removed by a second MPLC (Silica, using as eluant a mixture of ethyl acetate (5%) and iso-hexane) followed by a second Kugelruhr distillation, giving the title compound as a colourless oil in 40% yield (5.1 g), which was stored at -20° C. NMR (300 MHz, CDCl3): δ: 2.24(m,2H), 3.90(m,2H), 4.25(m,2H), 5.82(m,1H). |
38% | Stage #1: Tetrahydro-4H-pyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran; n-heptane; ethylbenzene at -78℃; for 0.75h; Inert atmosphere; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; n-heptane; ethylbenzene at -78 - 20℃; for 3h; Inert atmosphere; | |
35.7% | Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at 15℃; for 16h; Inert atmosphere; | 47A Example 47A 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate Example 47A 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate To a solution of dihydro-2H-pyran-4(3H)-one (1.8 g, 18.0 mol) in THF (20 ml) was added LiHMDS (1 M, 21.6 ml, 21.6 mmol) at -78° C. under N2 atmosphere. After stirring for 1 h at -78° C., (CF3SO2)2NPh (6.4 g, 18.0 mmol) was added in portions. The mixture was stirred at 15° C. for 16 h and quenched with aq NH4Cl solution (20 mL). The aqueous layer was extracted with EtOAc (30 mL*2). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatograph to provide the title compound as a colorless oil (1.5 g, yield: 35.7%). LCMS (ESI) m/z: 233 (M+1). |
15.1% | Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; hexane at -78 - 20℃; for 0.166667h; | 9.a Under an atmosphere of nitrogen, to a solution of diisopropylamine (CAN 180-18-9, 2.42 g, 0.024 mol) in THF (40 mL) was added n-butyl lithium (10.4 mL, 2.5 M solution in hexane, 26 mmol) at -78° C. The reaction mixture was reacted for 30 min at -50° C. Then tetrahydropyran-4-one (CAN 29943-42-8, 2 g, 0.020 mol) in THF (10 mL) was added dropwise to the above solution at -78° C. The reaction mixture was reacted for 30 min at -78° C. Then trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (CAN 37595-74-7, 7.85 g, 0.022 mol) in THF (50 mL) was added dropwise to the above solution at -78° C. The reaction mixture was stirred for 10 min at room temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with citric acid (50 mL) and sodium hydroxide solution (1 N, 50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 10 g, 1% ethyl acetate in petroleum ether) to yield the title compound (0.7 g, 3 mmol, 15.1%) as yellow oil. 1H NMR (300 MHz, d6-DMSO): 6.05-6.03 (m, 1H), 4.17 (d, J=3 Hz, 2H), 3.78 (t, J=4.5 Hz, 2H), 2.38 (t, J=3 Hz, 2H). |
15.1% | Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; hexane at -78 - 20℃; for 0.166667h; | 9.a Under an atmosphere of nitrogen, to a solution of diisopropylamine (CAN 180-18-9, 2.42 g, 0.024 mol) in THF (40 mL) was added w-butyl lithium (10.4 mL, 2.5 M solution in hexane, 26 mmol) at -78°C. The reaction mixture was reacted for 30 min at -50°C. Then tetrahydropyran-4-one (CAN 29943-42-8, 2 g, 0.020 mol) in THF (10 mL) was added dropwise to the above solution at -78°C. The reaction mixture was reacted for 30 min at - 78°C. Then trifluoro-N-phenyl-N-(trifluoromethylsulfonyl) methanesulfonamide (CAN 37595-74-7, 7.85 g, 0.022 mol) in THF (50 mL) was added dropwise to the above solution at -78°C. The reaction mixture was stirred for 10 min at room temperature. The reaction mixture was quenched with a saturated solution of sodium bicarbonate (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with citric acid (50 mL) and sodium hydroxide solution (1 N, 50 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography(silica gel, 10 g, 1% ethyl acetate in petroleum ether) to yield the title compound (0.7 g, 3 mmol, 15.1%) as yellow oil. 1H NMR (300 MHz , (f-DMSO): 6.05 - 6.03 (m, 1H), 4.17 (d, J = 3 Hz, 2H), 3.78 (t, J = 4.5 Hz, 2H), 2.38 (t, J = 3 Hz, 2H). |
Stage #1: Tetrahydro-4H-pyran-4-one; N,N-phenylbistrifluoromethane-sulfonimide With lithium hexamethyldisilazane In tetrahydrofuran at -78 - -5℃; for 17h; Stage #2: With water monomer; ammonia hydrochloride In tetrahydrofuran | 63.1 Step 1. Preparation of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (Intermediate 63A). Dihydro-2H-pyran-4(3H)-one (0.3 g, 3.30 mmol) was dissolved in THF and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (1.18 g, 3.30 mmol) was added. The resulting mixture was cooled to -78° C. and lithium bis(trimethylsilyl)amide (1M in THF, 3.30 mL) was added dropwise and the reaction mixture was stirred at -78° C. for 2 hours. The mixture was then allowed to warm to -5° C. over a period of 15 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by regular phase chromatography eluding with 10% ethyl acetate/hexanes. The resulting crude oil 63A (200 mg) was used in the next step without purification. | |
Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran at -78 - -72℃; for 1h; Inert atmosphere; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -60 - 20℃; | Intermediate (1a): 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate; Under argon, diisopropylamine (66.8 g (92.5 mL), 0.66 mol) was dissolved in THF (1 L) and cooled to -5° C. in an ice/methanol bath. Over 30 minutes, n-butyllithium (2.34M, 290 mL, 0.66 mol) was added while maintaining the temperature below 1° C. The mixture was stirred at about 0° C. to about -5° C. for 15 minutes and cooled to -72° C. with an acetone and dry ice bath. Dihydro-2H-pyran-4(3H)-one was added slowly over 15 minutes while maintaining the temperature at -78° C. for 1 hour. N-phenyl-bis-(trifluoromethyl sulfonamide) was suspended in THF (500 mL) and added slowly to the mixture while maintaining a temperature below -60° C. The mixture was left stirring in the cooling bath, warming to room temperature overnight. The mixture was concentrated under reduced pressure. The residue were slurried in hexane at 50° C. (1 L and 250 mL), the liquors were concentrated under reduced pressure to afford Intermediate (1a). 1H NMR (CDCl3, 300 MHz) δ 5.74 (1H), 4.19 (2H), 3.80 (2H), 2.39 (2H). | |
With 1,1,1,3,3,3-hexamethyldisilazane potassium In tetrahydrofuran at -78℃; for 0.5h; | 215.A 3,6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonate KHMDS (6.66 mL, 3.33 mmol) was added to the THF (7 mL) solution of dihydro-2H-pyran-4(3H)-one (0.2224 g, 2.221 mmol) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.952 g, 2.67 mmol) at -78 °C. The reaction was stirred for 30 min. The reaction was diluted with diethyl ether and washed with water (3x). The diethyl ether layer was separated, dried (Na2SO4), filtered and concentrated. The crude material was carried on without further purification. | |
With 1,1,1,3,3,3-hexamethyldisilazane potassium In tetrahydrofuran at -78℃; for 0.5h; | 215.A Part A: 3, 6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonate KHMDS (6.66 niL, 3.33 mmol) was added to the THF (7 niL) solution of dihydro-2H-pyran-4(3H)-one (0.2224 g, 2.221 mmol) and 1,1,1-trifluoro-N-phenyl- N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.952 g, 2.67 mmol) at -78 °C. The reaction was stirred for 30 min. The reaction was diluted with diethyl ether and washed with water (3x). The diethyl ether layer was separated, dried (Na2S04), filtered and concentrated. The crude material was carried on without further purification. | |
With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃; for 1.75h; Cooling with acetone-dry ice; | ||
Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; N,N-diisopropylamine In tetrahydrofuran; hexanes at -78 - -10℃; for 2.5h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran; hexanes at -78 - 23℃; for 3.5h; | 26.i (i) 3,6-Dihydro-2H-pyran-4-yl trifluoromethanesulfonate. A solution of di-isopropylamine (2663 μl, 18425 μmol) in TηF (55 mL) in an oven- dried round bottomed flask was cooled to -10°C under nitrogen and treated with butyllithium (2.5 M solution in hexanes, 7049 μL, 17624 μmol) in a dropwise fashion. The reaction mixture was stirred at -10°C for 20 minutes, cooled to - 78°C, and treated with a solution of 4-oxacyclohexanone (1480 μL, 16021 μmol) in TηF (10 mL) in a dropwise fashion over 10 minutes. The stirring was continued at -78°C for 2 hours and N-phenyltrifluoromethanesulfonimide (6868 mg, 19226 μmol) was added in one portion. The reaction mixture was stirred at - 78°C for 30 minutes, and at 0°C for 3 hours. The reaction mixture was warmed to 23°C, diluted with EtOAc (250 mL), washed with water (2 x 100 mL) and brine (100 mL), dried over MgSOφ and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (gradient: 5-10 % EtOAc/hexanes) to give the title compound as a light-yellow oil. 1H νMR (400 MHz, CDCl3) δppm: 5.82 (dq, J= 2.9, 1.4 Hz, 1 H), 4.27 (q, J= 2.9 Hz, 2 H), 3.89 (t, J= 5.5 Hz, 2 H), 2.44-2.49 (m, 2 H). | |
Stage #1: Tetrahydro-4H-pyran-4-one With lithium dipropan-2-ylazanide In tetrahydrofuran at -78℃; for 3.33333h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 20h; | 435.1 Stepl: 3, 6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate To a solution of dihydro-2H-pyran-4 (3H)-one (1 g, 0.01 mol) in THF was added LDA (Prepared: To a solution of diisopropylamine (1.54 ml, 0.011 mol) in dry THF (10ml) was added n-BuLi (4.39 ml, 2.5 Min hexane) drop-wised in ice-salt bath during 10 min under N2, the mixture was stirred at this temperature for 30 min) drop- wised during 20 min at -78°C, the mixture was stirred for 3h at this temperature, then a solution of 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl)methanesulfonamide (3.75 g, 0.105 mol) in THF was added drop-wised, the resulting mixture was stirred at - 78 °C for 2h, then allowed to warm to rt and stirred for 18r, removed the solvent to left the residue which was partitioned between EA and water, EA layer was washed with water, 2M NaOH solution and brine, dried over Na2SC>4, removal the solvent to left the crude 3, 6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (1.1 g, 70% yield), which can be used directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 23h; | 26.j (j) tørt-Butyl 2-(6-(3,6-dihydro-2H-pyran-4-yl)-4-hydroxy-1- methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamido)acetate. To a suspension of tert-buty 2-(4-hydroxy-1-methyl-2-oxo-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- 1 ,2-dihydro- 1 ,8-naphthyridine-3-carboxamido)acetate (350 mg, 762 μmol), 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (239 mg, 1029 μmol), potassium carbonate (316 mg, 2286 μmol) and DMF (5 mL) in a pressure vial under argon atmosphere, was added dichloro[l,l'-bis(diphenyl- phosphino)ferrocene]palladium(II) DCM adduct (55.8 mg, 76.2 μmol). The vial was sealed, and the mixture was heated to 80°C for 23 hours. The reaction mixture was cooled to 23°C, diluted with EtOAc (50 mL), washed with water (50 mL) and brine (50 mL), dried over MgSOφ and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (gradient: 24-36% EtOAc/hexanes) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 416 (M+l). 1H NMR (400 MHz, CDCl3) δ ppm: 10.70 (t, J= 5.2 Hz, 1 H), 8.79 (d, J= 2.5 Hz, 1 H), 8.39 (d, J= 2.5 Hz, 1 H), 6.20-6.37 (m, 1 H), 4.37 (d, J= 2.9 Hz, 2 H), 4.13 (d, J= 5.3 Hz, 2 H), 3.99 (t, J= 5.4 Hz, 2 H), 3.81 (s, 3 H), 2.46-2.69 (m, 2 H), 1.51 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium acetate In 1,4-dioxane at 80℃; | 63.2 A 250 ml_ round bottom flask containing trifluoro-methanesulfonic acid 3, 6- dihydro-2H-pyran-4-yl ester (2.7 g, 11.6 mmol), PdCI2(dppf) (440 mg, 0.6 mmol) and potassium acetate (3g, 36 mmol) in dioxane (20 mL) was flushed with Ar three times. The reaction mixture was heated at 80 °C for overnight. After the reaction was cooled to room temperature, the reaction mixture was filter through a column packed with celite and the filtrate was concentrated. The residue was purified using column chromatography (10 % hexane in dichloromethane) and product was obtained as white solid (2g, 81 % yield). |
50.5% | With potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere; | 9.b Under an atmosphere of nitrogen, a solution of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.7 g, 3.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (CAN 3183-34-3, 0.84 g, 3.3 mmol), 1,1'-bis(diphenylphosphino) ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 0.05 g, 0.06 mmol) and potassium acetate (0.89 g, 9.0 mmol) in DMSO (10 mL) was heated to 80° C. overnight. Water (50 mL) was added to the reaction mixture which then was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 9 g, 1% ethyl acetate in petroleum ether) to yield the title compound (0.32 g, 2 mmol, 50.5%) as colorless oil. 1H NMR (300 MHz, CDCl3): δ 6.53 (s, 1H), 4.20 (t, J=3 Hz, 2H), 3.76 (t, J=6 Hz, 2H), 2.24 (dd, J1=6 Hz, J2=6 Hz, 2H), 1.28 (s, 12H). |
50.5% | With potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere; | 9.b Under an atmosphere of nitrogen, a solution of 3, 6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (0.7 g, 3.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(l,3,2- dioxaborolane) (CAN 3183-34-3, 0.84 g, 3.3 mmol), 1,1*- bis(diphenylphosphino)ferrocene-palladium(II)dichloride methylene chloride complex (CAN 95464-05-4, 0.05 g, 0.06 mmol) and potassium acetate (0.89 g, 9.0 mmol) in DMSO (10 mL) was heated to 80°C overnight. Water (50 mL) was added to the reaction mixture which then was extracted with ethyl acetate (3><30 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silica gel, 9 g, 1% ethyl acetate in petroleum ether) to yield the title compound (0.32 g, 2 mmol, 50.5%) as colorless oil. 1H NMR (300 MHz, CDCh): δ 6.53 (s, 1H), 4.20 (t, J= 3 Hz, 2H), 3.76 (t, J = 6 Hz, 2H), 2.24 (dd, J; = 6 Hz, J 2 = 6 Hz, 2H), 1.28 (s, 12H). |
38% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 90℃; for 19h; Inert atmosphere; | |
With potassium acetate In 1,4-dioxane at 80℃; | 63.2 Step 2. Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate 63B). Intermediate 63A (0.20 g 0.86 mmol) was dissolved in dioxane and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.32 g, 1.29 mmol) was added followed by KOAc (0.25 g, 1.29 mmol). The resulting mixture was degassed with nitrogen and PdCl2(dppf) (0.050 g, 0.069 mmol) was added. The resulting mixture was heated at 80° C. overnight. The mixture was concentrated, and the oily residue was extracted with ethyl acetate. The organic extracts were concentrated and the residue was purified by regular phase chromatography eluding with 10% ethylacetate/hexanes to give a title compound 63B as a clear oil which was used in the next step without purification. | |
With potassium acetate In 1,4-dioxane at 90℃; for 19h; Inert atmosphere; | 112 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran A mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (commercially available from J&W Pharmlab) (0.54 g, 2.338 mmol), bis(pinacolato)diboron (0.74 g, 2.92 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloride adduct (0.19 g, 0.23 mmol), and potassium acetate (0.92 g, 9.38 mmol) in dry 1,4-dioxane (10.0 mL) was degassed by nitrogen. The mixture was heated to 90° C. After 19 h, the reaction was cooled to rt then filtered. After concentration, the residue was purified on silica gel using 0-5% EtOAc in hexanes to yield a white solid as 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran. 1H NMR (400 MHz, CDCl3) δ ppm 6.49 (1H, t, J=2.0 Hz), 4.15 (2H, q, J=2.7 Hz), 3.72 (2H, t, J=5.4 Hz), 2.19 (2H, tq, J=5.1, 2.7 Hz), 1.23 (12H, s). | |
150 mg | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere; | 10.2 Step 2. Preparation of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane A mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (250 mg, 1.1 mmol), bis(pinacolato)diboron (410 mg, 1.6 mmol), and KOAc (323 mg, 3.3 mmol) dioxane (3 mL) was sparged with Ar for 5 min. Then PdCl2dppf.DCM (45 mg, 0.05 mmol) was added and reaction was sparged again with Ar for 5 min. The reaction was sealed and heated to and maintained at 80° C. for overnight. The reaction mixture was allowed to cool rt and was filtered through Celite, washing the filter cake with EtOAc. The combined filtrate was concentrated and the resulting residue was purified by flash chromatography (SiO2, 100:0-80:20 hexanes-EtOAc) to furnish 150 mg of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (m/z): 211.0 (MH+), tR=0.89 min; 1H NMR (400 MHz, CDCl3) δ 6.48 (br s, 1H); 4.15-4.14 (app dd, J=2.8, 5.6 Hz, 2H); 3.72-3.69 (app t, 5.2, 2H); 2.19-2.17 (m, 2H); 1.22 (s, 12H). |
300 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; Inert atmosphere; | xxviii 2-(3,6-Dihvdro-2H-pyran-4-vl)-4.4.5.5-tetramethvl-1 ,3,2-dioxaborolane 171 To a solution of 4.4,4',4',5.5,5',5'-octamethyl-2.2'-bi(1.3,2-dioxaborolane) (993 mg, 3.91 mmol) in DMSO (5 mL) under N2 was added KOAc (959.8 mg, 9.78 mmol) and Pd(dppf)CI2 (71.7 mg, 0.097 mmol). A solution of the triflate intermediate (750 mg) in DMSO (1 mL) was added and the reaction heated at 80 °C overnight. The mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were washed with saturated NaHCC>3 (3 x 10 mL) and brine (3 x 10 mL), dried (Na2SO.t) and concentrated. The residue obtained was purified by silica gel chromatography (ethyl acetate /petroleum ether=1 /2) to give the title compound (300 mg) as a white solid which was used without further purification or analysis |
With potassium acetate In 1,4-dioxane at 80℃; Inert atmosphere; | 10.2 A mixture of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (250 mg, 1.1 mmol), bis(pinacolato)diboron (410 mg, 1.6 mmol), and KOAc(323 mg, 3.3 mmol) dioxane (3 mL) was sparged with Ar for 5 min. Then PdCl2dppfDCM (45 mg, 0.05 mmol) was added and reaction was sparged again with Ar for 5 min. The reaction was sealed and heated to and maintained at 80 0C for overnight. The reaction mixture was allowed to cool rt and was filtered through Celite, washing the filter cake with EtOAc. The combined filtrate was concentrated and the resulting residue was purified purified by flash chromatography (SiO2, 100 : 0 - 80 : 20 hexanes-EtOAc) to furnish 150 mg of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane:. LCMS (m/z): 211.0 (MH+), R = 0.89 min; 1H NMR (400 MHz, CDCl3) δ 6.48 (br s, 1 H); 4.15-4.14 (app dd, J = 2.8, 5.6 Hz, 2 H); 3.72-3.69 (app t, 5.2, 2 H); 2.19-2.17 (m, 2 H); 1.22 (s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Stage #1: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran With triphenyl-arsane; lithium chloride In 1-methyl-pyrrolidin-2-one at 20℃; for 0.0833333h; Stage #2: (S)-(-)-N-[[3-[4-(trimethylstannyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide In 1-methyl-pyrrolidin-2-one at 40℃; for 24h; Stage #3: With potassium fluoride In 1-methyl-pyrrolidin-2-one; water at 20℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 0℃; for 2h; Inert atmosphere; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran; hexane at 0℃; for 3.25h; Inert atmosphere; | In a 50 mL round-bottomed flask under nitrogen, a solution of n-butyllithium (1.45 M in hexanes, 1.90 mL, 2.76 mmol) was added dropwise to a solution of diisopropylamine (0.39 mL, 2.74 mmol) in THF (5 mL) at 0 °C and the resulting mixture was stirred for 15 min. The reaction mixture was then cooled to -78 °C and a solution of dihydro-2H-pyran-4(3H)-one (0.23 mL, 2.481 mmol) in THF (7.5 mL) was slowly added and the mixture was at -78 °C for another 2 h. To this mixture was added a solution of 2- (N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (1.082 g, 2.76 mmol) in THF (5 ml) over 15 min and the mixture was then allowed to warm to 0 °C and stirred for 3 h. The reaction was then quenched with water (15 mL) and the mixture was extracted with Et2O (x3). The combined organic extract was washed successively with 15% aqueous NaOH and brine and then it was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was chromatographed on a silica gel column (22 mm x 80 mm) which was eluted with 0 to 20% EtOAc in hexanes. This afforded 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 53%) as a colorless oil which was used as such in the following step. 1H NMR (400 MHz, acetone-d6): δ ppm 6.01 (tt, J= 2.8, 1.5 Hz, 1 H) 4.25 (q, J= 3.0 Hz, 2 H) 3.88 (t, J= 5.5 Hz, 2 H) 2.48 (ttd, J= 5.5, 2.8, 1.4 Hz, 2 H). In a 25 mL round-bottomed flask, the obtained 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 1.322 mmol) and potassium fluoride (0.270 g, 4.65 mmol) were added to a solution of (3-(hydroxymethyl)phenyl)boronic acid (0.250 g, 1.645 mmol) in THF (7.5 ml) and the flask was evacuated and purged with nitrogen three times. Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.024 g, 0.029 mmol) was then added in one portion and the mixture was stirred at room temperature for 66 h. The resulting mixture was diluted with ethyl acetate, filtered through CELITE and concentrated. The residue was purified on the ISCO using a REDISEP Gold 24 g column (elution with hexanes-EtOAc) to give the title compound (0.131 g, 52%) as yellowish oil. LC (Method B): 1.614 min. LCMS (APCI): calcd for C12H13O [M+H]+- H20 m/z 173.096, found 173.2. 1H NMR (400 MHz, acetone-d6): δ ppm 7.46 (s, 1H) 7.22-7.36 (m, 3H) 6.21 (tt, J= 3.0, 1.5 Hz, 1H) 4.64 (d, J= 5.9 Hz, 2H) 4.24 (q, J= 3.0 Hz, 2H) 4.17 (t, J= 5.7 Hz, 1H) 3.86 (t, J= 5.5 Hz, 2H) 2.49 (ttd, J= 5.4, 2.8, 1.6 Hz, 2H). |
800 mg | Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran Cooling; | 10.1 Step 1. Preparation of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate A solution of LiHMDS (1.0 M in THF, 11 mL, 11 mmol) was added dropwise to a cooled solution of 4-tetrahydropyranone (1 g, 10 mmol) in dry THF (5 mL) at -78° C. and the resulting reaction was maintained at -78° C. for 1 h. A solution of 2-[N,N-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (3.93 g, 10 mmol) in dry THF (6 mL) was added dropwise and the reaction maintained overnight, allowing the cooling bath to expire. The reaction was quenched with water (10 mL) and partitioned with DCM. The layers were separated and the aqueous portion was extracted with DCM (2*). The combined organic portions were dried (Na2SO4) and evaporated. The crude residue was purified by flash chromatography (neutral alumina, 80:20 DCM-hexanes) to provide 800 mg of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.82-5.81 (m, 1H), 4.27-4.25 (m, 2H), 3.91-3.88 (m, 2H), 2.48-2.45 (m, 2H). |
Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 20℃; for 1h; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran at -78 - 20℃; | 63.1 To a solution of 4-tetrahydropyranone (2g, 0.02 mol) in THF (10 ml_) at -78 °C, LiHMDS (1 M, 11 ml) was added dropwise through a syringe. The formed solution was then stirred at -78 °C for about 1 hour. The reaction was warmed up to room temperature briefly and was cooled back to -78 °C. Then 2-[N, N- bis(trifluoromethylsulfonyl)amino]-5-chloropyhne (7.85 g, 0.02 mol) was added in four portions. The resulted reaction mixture was gradually warmed up to room temperature and was stirred for overnight. After removal of solvent, the residue was purified using chromatography (eluted with DCM/Hexane = 80/20) to give product as a colorless oil(3g). |
Stage #1: Tetrahydro-4H-pyran-4-one With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; Stage #2: N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-[(trifluoromethyl)sulphonyl]methanesulphonamide In tetrahydrofuran | 10.1 A solution of LiηMDS (1.0 M in TηF, 11 mL, 11 mmol) was added dropwise to a cooled solution of 4- tetrahydropyranone (Ig, 10 mmol) in dry TηF (5 mL) at -78 0C and the resulting reaction was maintained at -78 0C. for 1 h. A solution of 2-[N, N-bis(trifiuoromethanesulfonyl) amino]-5- chloropyridine (3.93 g, 10 mmol) in dry TηF (6 mL) was added dropwise and the reaction maintained overnight, allowing the cooling bath to expire. The reaction was quenched with water (10 mL) and partitioned with DCM. The layers were separated and the aqueous portion was extracted with DCM (2 X). The combined organic portions were dried (Na2SC^) and evaporated. The crude residue was purified by flash chromatography (neutral alumina, 80 : 20 DCM-hexanes) to provide 800 mg of 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate as a colorless oil: η NMR (400 MHz, CDCl3) δ 5.82-5.81 (m, 1 H), 4.27-4.25 (m, 2 H), 3.91-3.88 (m, 2 H), 2.48-2.45 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51 %Chromat. | With pyridine; 1,2-bis(di-1-adamantylphosphinomethyl)benzene; hydrogen; palladium diacetate In diethylene glycol dimethyl ether; N,N-dimethyl-formamide at 80℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; zinc In N,N-dimethyl-formamide at 20 - 50℃; for 0.420833h; Inert atmosphere; Stage #2: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran In N,N-dimethyl-formamide at 50℃; Inert atmosphere; | 38 Intermediate: (f?)-methyl 2-(te/t-butoxycarbonyl)-3-(3,6-dihydro-2/-/-pyran-4- yl)propanoate (38b).(38b)In rigorously anaerobic conditions, zinc dust (72.7 g, 1.11 mol) was suspended in anhydrous DMF (100 ml_), and to the stirred solution, trimethylsilyl chloride (23 ml_ 0.18 mol) was added (exotherm to 55°C). The mixture was stirred for 20 minutes, during which time the supernatant became brown in color. The mixture was allowed to settle, and the supernatant decanted off using vacuum. The activated zinc powder was washed with DMF (4 x 50 ml_), until the supernatant solvent became colorless. (f?)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (85 g, 0.26 mol) was dissolved in DMF under argon, added in one portion to the activated zinc powder and stirred briskly. After approximately 5 minutes, the mixture self heated rapidly (21 -300C over about 15 seconds). The stirring was stopped and the cooling bath immediately applied, allowing the exothermic reaction to be ceased at 500C. As the temperature subsided, the cooling bath was removed and the mixture stirred at ambient temperature for 20 minutes and allowed to settle. The supernatant was syringed into a pre-prepared solution of Intermediate (38a) (60 g, 0.26 mol) and PdCI2(PPh3^ (5.44 g, 7.75 mmol). The metallic solids were washed with DMF (30 ml_) and the washings added to the thflate/catalyst mixture, which was stirred at 50°C overnight. The solution was concentrated under reduced pressure and the crude product slurried in water (500 ml_) and 20% ethyl acetate in hexane (500 ml_). The mixture was filtered and partitioned, and the aqueous layer re-extracted with 20% ethyl acetate in hexane (500 ml_). The combined organic phases were washed with brine (500 ml_), dried over MgSO4, and concentrated under reduced pressure. The semi-crude product was obtained as a free running red-brown oil (81 g), which was purified twice by dry-flash chromatography (SiO2, ethyl acetate and hexanes, 0 to 100%) followed by carbon treatment in 10% ethyl acetate/hexane to afford (38b): 1H NMR (CDCI3, 300 MHz): δ 5.50 (1 H), 4.95 (1 H), 4.40 (1 H), 4.10 (2H), 3.77 (2H), 3.73 ( 3H), 2.50 (1 H), 2.31 (1 H), 2.07 (2H), 1.43 (9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 2,3-dihydro-4H-pyran-4-one With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - -72℃; for 1.25h; Inert atmosphere; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -60 - 20℃; Inert atmosphere; | 38 Intermediate: 3,6-dihydro-2/-/-pyran-4-yl trifluoromethanesulfonate (38a).(38a)Under argon, diisopropylamine (66.8 g (92.5ml_), 0.66 mol) was dissolved in THF (1 L) and cooled to -5°C in an ice/methanol bath. Over 30 minutes, n-butyllithium (2.34 M, 290 mL, 0.66 mol) was added while maintaining the temperature below 1 °C. The mixture was stirred at about 00C to about -5°C for 15 minutes and cooled to -72°C with an acetone and dry ice bath. Dihydro-2H-pyran-4(3H)-one was added slowly over 15 minutes while maintaining the temperature at -78°C for 1 hour. N-phenyl-bis- (trifluoromethyl sulfonimide) was suspended in THF (500 mL) and added slowly to the mixture while maintaining a temperature below -600C. The mixture was left stirring in the cooling bath, warming to room temperature overnight. The mixture was concentrated under reduced pressure. The residues were slurried in hexane at 500C (1 L and 250 ml_), the liquors were concentrated under reduced pressure to afford (38a). 1H NMR (CDCI3, 300 MHz) δ 5.74 (1 H); 4.19 (2H); 3.80 (2H); 2.39 (2H). | |
Stage #1: 2,3-dihydro-4H-pyran-4-one With n-butyllithium; diisopropylamine In tetrahydrofuran at -78 - -72℃; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; | Under argon, diisopropylamine (66.8 g (92.5 ml_), 0.66 mol) was dissolved in THF (1 L) and cooled to -5°C in an ice/methanol bath. Over 30 minutes, n-butyl-lithium (2.34 M, 290 ml_, 0.66 mol) was added while maintaining the temperature below 1 °C. The mixture was stirred at about 00C to about -5°C for 15 minutes and cooled to -72°C with an acetone and dry ice bath. Dihydro-2/-/-pyran-4(3H)-one (Aldrich Chemical Company, Inc., Milwaukee, Wl) was added slowly over 15 minutes while maintaining the temperature at -78°C for 1 hour. Λ/-phenyl-bis-(trifluoromethyl sulfonimide; Aldrich Chemical Company, Inc., Milwaukee, Wl) was suspended in THF (500 ml_) and added slowly to the mixture while maintaining a temperature below -600C. The mixture was left stirring in the cooling bath, warming to room temperature overnight. The mixture was concentrated under reduced pressure. The residues were slurried in hexane at 500C (1 L and 250 ml_), the liquors were concentrated under reduced pressure to afford (l-10a). 1H NMR (CDCI3, 300 MHz) δ 5.74 (1 H), 4.19 (2H), 3.80 (2H), 2.39 (2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; N,N-dimethyl-formamide; zinc at 20 - 30℃; Inert atmosphere; Stage #2: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran With bis-triphenylphosphine-palladium(II) chloride In N,N-dimethyl-formamide | In rigorously anaerobic conditions, zinc dust (72.7 g, 1.11 mol) was suspended in anhydrous Λ/,Λ/-dimethylformamide (100 ml_), and to the stirred solution, trimethylsilyl chloride (23 ml_ 0.18 mol) was added (exotherm to 55°C). The mixture was stirred for 20 minutes, during which time the supernatant became brown in color. The mixture was allowed to settle, and the supernatant decanted off using vacuum. The activated zinc powder was washed with /V,/V-dimethylfornnannide (4 x 5OmL), until the supernatant solvent became colorless.(R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (Oakwood Products, West Columbia, SC) (85 g, 0.26 mol) was dissolved in Λ/,Λ/-dimethylformamide under argon, added in one portion to the activated zinc powder and stirred briskly. After approximately 5 minutes, the mixture self heated rapidly (21-300C over about 15 seconds). The stirring was stopped and the cooling bath immediately applied, allowing the exothermic reaction to be ceased at 500C. As the temperature subsided, the cooling bath was removed and the mixture stirred at ambient temperature for 20 minutes and allowed to settle. The supernatant was syringed into a pre-prepared solution of (l-10a) (60 g, 0.26 mol) and PdCI2(PPh3^ (5.44 g, 7.75 mmol). The metallic solids were washed with Λ/,Λ/-dimethylformamide (30 ml_) and the washings added to the triflate/catalyst mixture, which was stirred at 50°C overnight. The solution was concentrated under reduced pressure and the crude product slurried in water (500 ml_) and 20% ethyl acetate in hexane (500 ml_). The mixture was filtered and partitioned, and the aqueous layer re-extracted with 20% ethyl acetate in hexane (500 ml_). The combined organic phases were washed with brine (500 ml_), dried over MgSO4, and concentrated under reduced pressure. The semi-crude product was obtained as a free running red-brown oil (81 g), which was purified twice by dry-flash chromatography (SiO2, ethyl acetate and Hexanes, 2 to 20%) followed by carbon treatment in 10% ethyl acetate/hexane to afford (l-10b): 1H NMR (CDCI3, 300 MHz): δ 5.50 (1 H), 4.95 (1 H), 4.40 (1 H), 4.10 (2H), 3.77 (2H), 3.73 ( 3H), 2.50 (1 H), 2.31 (1 H), 2.07 (2H), 1.43 (9H). | |
Stage #1: N-(tert-butoxycarbonyl)-L-3-iodoalanine methyl ester With chloro-trimethyl-silane; zinc In N,N-dimethyl-formamide at 20 - 50℃; Stage #2: 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran In N,N-dimethyl-formamide at 50℃; | Intermediate (1b): (R)-methyl 2-(tert-butoxycarbonyl)-3-(3,6-dihydro-2H-pyran-4-yl)propanoate; In rigorously anaerobic conditions, zinc dust (72.7 g, 1.11 mol) was suspended in anhydrous N,N-dimethylformamide (100 mL), and to the stirred solution, trimethylsilyl chloride (23 mL 0.18 mol) was added (exotherm to 55° C.). The mixture was stirred for 20 minutes, during which time the supernatant became brown in color. The mixture was allowed to settle, and the supernatant decanted off using vacuum. The activated zinc powder was washed with N,N-dimethylformamide (4×50 mL), until the supernatant solvent became colorless.(R)-methyl 2-(tert-butoxycarbonylamino)-3-iodopropanoate (85 g, 0.26 mol) (Sigma-Aldrich, Milwaukee, Wis.) was dissolved in N,N-dimethylformamide under argon, added in one portion to the activated zinc powder and stirred briskly. After approximately 5 minutes, the mixture self heated rapidly (21-30° C. over about 15 seconds). The stirring was stopped and the cooling bath immediately applied, allowing the exothermic reaction to be ceased at 50° C. As the temperature subsided, the cooling bath was removed and the mixture stirred at ambient temperature for 20 minutes and allowed to settle. The supernatant was syringed into a pre-prepared solution of Intermediate (1a) (60 g, 0.26 mol) and PdCl2(PPh3)2 (5.44 g, 7.75 mmol). The metallic solids were washed with N,N-dimethylformamide (30 mL) and the washings added to the triflate/catalyst mixture, which was stirred at 50° C. overnight. The solution was concentrated under reduced pressure and the crude product slurried in water (500 mL) and 20% ethyl acetate in hexane (500 mL). The mixture was filtered and partitioned, and the aqueous layer re-extracted with 20% ethyl acetate in hexane (500 mL). The combined organic phases were washed with brine (500 mL), dried over MgSO4, and concentrated under reduced pressure. The semi-crude product was obtained as a free running red-brown oil (81 g), which was purified twice by dry-flash chromatography (SiO2, ethyl acetate and hexanes, 0 to 100%) followed by carbon treatment in 10% ethyl acetate/hexane to afford Intermediate (1b): 1H NMR (CDCl3, 300 MHz): δ 5.50 (1H), 4.95 (1H), 4.40 (1H), 4.10 (2H), 3.77 (2H), 3.73 (3H), 2.50 (1H), 2.31 (1H), 2.07 (2H), 1.43 (9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: Tetrahydro-4H-pyran-4-one With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 2h; Inert atmosphere; Stage #2: 2-<N,N-bis(trifluoromethylsulfonyl)amino>-5-chloro-pyridine In tetrahydrofuran; hexane at 0℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate; triethylamine In toluene at 80℃; for 16h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate; <i>N</i>,<i>N</i>-dimethyl-aniline In toluene at 25℃; for 16h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
With (R)-1-[2-(2'-diphenylphosphinophenyl)ferrocenyl]ethyldiphenylphosphine; palladium diacetate; <i>N</i>,<i>N</i>-dimethyl-aniline In 1,4-dioxane at 25℃; for 16h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With trifluorormethanesulfonic acid; (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate; diisopropylamine In toluene at 80℃; for 12h; Inert atmosphere; | |
With catalyst: Pd(OCOCH3)2 and TANIAPHOS; N(C2H5)3 or (CH(CH3)2)CH3N(C(CH3)3) In toluene toluene, 5 mol% Pd(OCOCH3)2, 10 mol% TANIAPHOS, N(C2H5)3 or isopropyl(tert-butyl)methylamine as base, 80°C, 16 h; 49-56% ee, detected by NMR spectra and chiral HPLC; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methoxy-N,N-dimethylanilne; (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate In toluene at 25℃; for 16h; Inert atmosphere; | ||
With 4-methoxy-N,N-dimethylanilne; (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate In 1,4-dioxane at 25℃; for 4h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; | ||
0% | With catalyst: Pd(OCOCH3)2 and TANIAPHOS; 4-FC6H4N(CH3)2 In toluene toluene, 5 mol% Pd(OCOCH3)2, 10 mol% TANIAPHOS, 4-FC6H4N(CH3)2 as base, 80°C, 16 h; detected by NMR spectra and chiral HPLC; |
With catalyst: Pd(OCOCH3)2 and TANIAPHOS; C6H5N(CH3)2 In 1,4-dioxane dioxane, 5 mol% Pd(OCOCH3)2, 10 mol% TANIAPHOS, C6H5N(CH3)2 as base, 25°C, 16 h; 91% ee, detected by NMR spectra and chiral HPLC; | ||
With catalyst: Pd(OCOCH3)2 and TANIAPHOS; DTBMP or s-collidine or proton sponge In toluene toluene, 5 mol% Pd(OCOCH3)2, 10 mol% TANIAPHOS, DTBMP or s-collidine or proton sponge as base, 80°C, 16 h; 53-84% ee, detected by NMR spectra and chiral HPLC; | ||
With catalyst: Pd(OCOCH3)2 and TANIAPHOS; aromatic amines In toluene toluene, 5 mol% Pd(OCOCH3)2, 10 mol% TANIAPHOS, aromatic amines as base,25-80°C, 16 h; 78-92% ee, detected by NMR spectra and chiral HPLC; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methoxy-N,N-dimethylanilne; (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate In toluene at 80℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate; triethylamine / toluene / 16 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; trifluorormethanesulfonic acid; palladium diacetate; diisopropylamine / toluene / 12 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: (R)-1-[2-(2'-diphenylphosphinophenyl)ferrocenyl]ethyldiphenylphosphine; palladium diacetate; <i>N</i>,<i>N</i>-dimethyl-aniline / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Multi-step reaction with 3 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; 4-methoxy-N,N-dimethylanilne; palladium diacetate / 1,4-dioxane / 4 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate; triethylamine / toluene / 16 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; trifluorormethanesulfonic acid; palladium diacetate; diisopropylamine / toluene / 12 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: (R)-1-[2-(2'-diphenylphosphinophenyl)ferrocenyl]ethyldiphenylphosphine; palladium diacetate; <i>N</i>,<i>N</i>-dimethyl-aniline / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; 4-methoxy-N,N-dimethylanilne; palladium diacetate / 1,4-dioxane / 4 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate; triethylamine / toluene / 16 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; trifluorormethanesulfonic acid; palladium diacetate; diisopropylamine / toluene / 12 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: (R)-1-[2-(2'-diphenylphosphinophenyl)ferrocenyl]ethyldiphenylphosphine; palladium diacetate; <i>N</i>,<i>N</i>-dimethyl-aniline / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; 4-methoxy-N,N-dimethylanilne; palladium diacetate / 1,4-dioxane / 4 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; palladium diacetate; triethylamine / toluene / 16 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; trifluorormethanesulfonic acid; palladium diacetate; diisopropylamine / toluene / 12 h / 80 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: (R)-1-[2-(2'-diphenylphosphinophenyl)ferrocenyl]ethyldiphenylphosphine; palladium diacetate; <i>N</i>,<i>N</i>-dimethyl-aniline / 1,4-dioxane / 16 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Multi-step reaction with 2 steps 1: (S)-(-)-[(S)-2-diphenylphosphinoferrocenyl](N,N-dimethylamino)(2-diphenylphosphinophenyl)methane; 4-methoxy-N,N-dimethylanilne; palladium diacetate / 1,4-dioxane / 4 h / 25 °C / Inert atmosphere 2: 12 h / 80 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In 1,4-dioxane; water at 100℃; for 24h; Inert atmosphere; | 38.A Example 38: N-fl-ffls.,4s)-4-ftetrahv(iro-2H-pyran-4-yl)cvclohexyl)azeti(iin-3-yl)-2-ff6- ftrifluoromethyl) uinazolin-4-yl)amino)acetamide-( 3, 6-dihydro-2H-pyran-4-yl)-l, 4-dioxaspiro[ 4.5] dec- 7-ene; 8-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,4-dioxa-spiro[4.5]dec-7-ene(prepared as described in PCT Int. Appl. WO2006064189, 1.57 g, 5.90 mmol), commercially available 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (5.23 mmol), and tetrakis (triphenylphosphino)palladium(O) (302 mg, 0.262 mmol) were dissolved in 1,4-dioxane (20 mL), treated with 2M aqueous Na2C03 (14 mL, 28 mmol), bubbled with argon for a few minutes, and heated to 100 °C under reflux condenser for 24 h. After cooling to ambient temperature, the reaction was diluted with water (30 mL), extracted thrice with dichloromethane, aqueous layer acidified to ca. pH 7, extracted twice more with dichloromethane, and the combined organic layers washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give an orange oil. This was purified by flash chromatography (silica gel, EtOAc) to give the title compound as a colorless crystalline solid.1H NMR (CHLOROFORM-d) δ: 5.75 (br. s., 1H), 5.68 - 5.73 (m, 1H), 4.26 (br. s., 2H), 4.01 (s, 3H), 3.79 - 3.90 (m, 2H), 2.38 - 2.50 (m, 3H), 2.25 - 2.34 (m, 2H), 1.86 (t, J = 6.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium carbonate In methanol; water; toluene for 3h; Reflux; | 34.i (i) 4-(3,6-Dihydro-2H-pyran-4-yl)benzonitrile 2.2 g (15.1 mmol) of (4-cyanophenyl)boronic acid, 2.5 g (10.8 mmol) of 3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate, 373 mg (0.32 mmol) of tetrakis(triphenylphosphine)palladium(0) and 1.59 g (15.1 mmol) of sodium carbonate were heated under reflux in a mixed solvent comprising 4 mL of H2O, 57 mL of toluene, and 17 mL of methanol for 3 hours. After the completion of the reaction, the organic solvent was distilled off under reduced pressure, H2O was added to the residue, and ethyl acetate extraction was performed. Subsequently, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 1.27 g of 4-(3,6-dihydro-2H-pyran-4-yl)benzonitrile (yield: 64%). 1H-NMR (CDCl3) δ: 2.46-2.57 (2H, m), 3.95 (2H, t, J=5.4 Hz), 4.35 (2H, m), 6.25-6.32 (1H, m), 7.44-7.52 (2H, m), 7.59-7.67 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With cobalt(III) acetylacetonate In tetrahydrofuran at 40℃; Inert atmosphere; | |
71% | With cobalt(III) acetylacetonate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.131 g | With potassium fluoride; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In tetrahydrofuran at 20℃; for 66h; Inert atmosphere; | 92.92A (3-(3,6-Dihydro-2H-pyran-4-yl)phenyl)methanol In a 50 mL round-bottomed flask under nitrogen, a solution of n-butyllithium (1.45 M in hexanes, 1.90 mL, 2.76 mmol) was added dropwise to a solution of diisopropylamine (0.39 mL, 2.74 mmol) in THF (5 mL) at 0 °C and the resulting mixture was stirred for 15 min. The reaction mixture was then cooled to -78 °C and a solution of dihydro-2H-pyran-4(3H)-one (0.23 mL, 2.481 mmol) in THF (7.5 mL) was slowly added and the mixture was at -78 °C for another 2 h. To this mixture was added a solution of 2- (N,N-bis(trifluoromethylsulfonyl)amino)-5-chloropyridine (1.082 g, 2.76 mmol) in THF (5 ml) over 15 min and the mixture was then allowed to warm to 0 °C and stirred for 3 h. The reaction was then quenched with water (15 mL) and the mixture was extracted with Et2O (x3). The combined organic extract was washed successively with 15% aqueous NaOH and brine and then it was dried over anhydrous Na2SO4, filtered and concentrated. The crude product was chromatographed on a silica gel column (22 mm x 80 mm) which was eluted with 0 to 20% EtOAc in hexanes. This afforded 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 53%) as a colorless oil which was used as such in the following step. 1H NMR (400 MHz, acetone-d6): δ ppm 6.01 (tt, J= 2.8, 1.5 Hz, 1 H) 4.25 (q, J= 3.0 Hz, 2 H) 3.88 (t, J= 5.5 Hz, 2 H) 2.48 (ttd, J= 5.5, 2.8, 1.4 Hz, 2 H). In a 25 mL round-bottomed flask, the obtained 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (0.307 g, 1.322 mmol) and potassium fluoride (0.270 g, 4.65 mmol) were added to a solution of (3-(hydroxymethyl)phenyl)boronic acid (0.250 g, 1.645 mmol) in THF (7.5 ml) and the flask was evacuated and purged with nitrogen three times. Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.024 g, 0.029 mmol) was then added in one portion and the mixture was stirred at room temperature for 66 h. The resulting mixture was diluted with ethyl acetate, filtered through CELITE and concentrated. The residue was purified on the ISCO using a REDISEP Gold 24 g column (elution with hexanes-EtOAc) to give the title compound (0.131 g, 52%) as yellowish oil. LC (Method B): 1.614 min. LCMS (APCI): calcd for C12H13O [M+H]+- H20 m/z 173.096, found 173.2. 1H NMR (400 MHz, acetone-d6): δ ppm 7.46 (s, 1H) 7.22-7.36 (m, 3H) 6.21 (tt, J= 3.0, 1.5 Hz, 1H) 4.64 (d, J= 5.9 Hz, 2H) 4.24 (q, J= 3.0 Hz, 2H) 4.17 (t, J= 5.7 Hz, 1H) 3.86 (t, J= 5.5 Hz, 2H) 2.49 (ttd, J= 5.4, 2.8, 1.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis-triphenylphosphine-palladium(II) chloride; sodium hydrogencarbonate In tetrahydrofuran; water at 80℃; for 1.5h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane at 120℃; for 5h; | 215.C A mixture of 2N sodium carbonate solution (0.106 mL, 0.212 mmol), 1,1'-bis(diphenylphosphine)ferrocene-palladium(II)dichloride dichloromethane complex (6.06 mg, 7.42 μmol), 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (98 mg, 0.424 mmol) and (S)-tert-butyl (2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (53.1 mg, 0.106 mmol) in dioxane (2 mL) (degassed) was heated at 120 °C for 5 h. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was diluted with DCM (3 mL) and TFA (2 mL, 26.0 mmol) was added at room temperature. The reaction was stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase Prep HPLC to give (S)-1-(4-(3 ,6-dihydro-2H-pyran-4-yl)-2- (trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine (2.7 mg, 0.213 mmol, 7% yield over three steps). 1H NMR (500MHz, DMSO-d6) δ 7.69 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.24 (m, 1H), 4.21 (d, J=2.6 Hz, 2H), 3.83 - 3.79 (m, 4H), 2.42 (br. s., 2H), 1.80 - 1.72 (m, 1H), 1.42 - 1.37 (m, 2H), 1.12 (s, 3H), 0.89 (m, 6H), two exchangeable protons not observed; LCMS (ESI) m/e 358.3 [(M+H)+, calcd C19H27F3NO2, 358.2]; LC/MS retention time (method B): tR = 1.99 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of diisopropylamine (1 .41 g, 13.98 mmol) in THF (10 mL) at -20 C under N2 was added dropwise n-BuLi (5.82 mL, 13.98 mmol). The mixture was stirred for 30 minutes at -20 C then cooled to -70 C and a solution of dihydro-2H-pyran-4(3H)-one (2.0 g, 9.99 mmol) in THF (5 mL) was added. The reaction was then stirred at -70 C for 30 minutes. A solution of 1 , 1.1 -trifluoro-A/-phenylmethanesulfonamide (3.57 g, 9.99 mmol) in THF (5mL) was added dropwise, the resulting mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue obtained diluted with water (20 mL). The mixture was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers dried (Na2SO.t), filtered and concentrated. The residue obtained was purified by silica gel chromatography (ethyl acetate /petroleum ether=1/20) to give the triflate intermediate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
36% | With 2,6-di-tert-butyl-4-methylpyridine In dichloromethane at 0 - 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | Stage #1: (S)-tert-butyl (2,4-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate; 5,6-dihydro-4-trifluoromethylsulfonyloxy-2H-pyran With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,4-dioxane at 120℃; for 5h; Inert atmosphere; Stage #2: With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h; | 215.C Part C: (S)-l-(4-(3, 6-dihydro-2H-pyran-4-yl)-2-(trifluoromethyl)phenoxy)-2, 4- dimethylpentan-2-amine A mixture of 2N sodium carbonate solution (0.106 mL, 0.212 mmol), 1,1'- bis(diphenylphosphine)ferrocene-palladium(II)dichloride dichloromethane complex (6.06 mg, 7.42 μιηο), 3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate (98 mg, 0.424 mmol) and (S)-tert-buty (2,4-dimethyl-l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-2-(trifluoromethyl)phenoxy)pentan-2-yl)carbamate (53.1 mg, 0.106 mmol) in dioxane (2 mL) (degassed) was heated at 120 °C for 5 h. The reaction was diluted with ethyl acetate and washed with water three times. The ethyl acetate layer was dried (Na2S04), filtered and concentrated under reduced pressure. The residue was diluted with DCM (3 mL) and TFA (2 mL, 26.0 mmol) was added at room temperature. The reaction was stirred at room temperature for 0.5 h. The solvent was removed under reduced pressure and the residue was purified by reverse phase Prep HPLC to give (5)-l-(4-(3,6-dihydro-2H-pyran-4-yl)-2- (trifluoromethyl)phenoxy)-2,4-dimethylpentan-2-amine (2.7 mg, 0.213 mmol, 7% yield over three steps). NMR (500MHz, DMSO-de) δ 7.69 (d, J=8.4 Hz, 1H), 7.61 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 6.24 (m, 1H), 4.21 (d, J=2.6 Hz, 2H), 3.83 - 3.79 (m, 4H), 2.42 (br. s., 2H), 1.80 - 1.72 (m, 1H), 1.42 - 1.37 (m, 2H), 1.12 (s, 3H), 0.89 (m, 6H), two exchangeable protons not observed; LCMS (ESI) m/e 358.3 [(M+H)+, calcd C19H27F3NO2, 358.2]; LC/MS retention time (method B): fe. = 1.99 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 1,3-bis-(diphenylphosphino)propane; NiBr2•diglyme; 5,5′-bis(trifluoromethyl)-2,2′-bipyridine; palladium dichloride; zinc In N,N-dimethyl-formamide at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With manganese; 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; 4,4',4-tri-tert-butyl-2,2':6',2-terpyridine In N,N-dimethyl acetamide; toluene at 70℃; for 15h; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With pyridine N-oxide; potassium fluoride; 1,10-Phenanthroline; lithium chloride; nickel dichloride; zinc In N,N-dimethyl acetamide at 0℃; for 72h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With nickel(II) iodide; manganese; (S)-4-(tert-butyl)-2-(5-(trifluoromethyl)pyridine-2-yl)-4,5-dihydrooxazole In N,N-dimethyl-formamide at 25℃; for 24h; Inert atmosphere; Sealed tube; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With nickel(II) iodide; 2,2':6,2''-terpyridine; manganese In N,N-dimethyl acetamide at 100℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium hexafluorophosphate; p-phenylpyridine; nickel dichloride In tetrahydrofuran at 80℃; for 15h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium hexafluorophosphate; p-phenylpyridine; nickel dichloride In tetrahydrofuran at 80℃; for 15h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium hexafluorophosphate; p-phenylpyridine; nickel dichloride In tetrahydrofuran at 80℃; for 15h; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In methanol at 20℃; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With [2,2]bipyridinyl; manganese; [1,1'-bis(diphenylphosphino)ferrocene]nickel(II) chloride In N,N-dimethyl-formamide at 30℃; for 24h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With 1,2-bis(diphenylphosphino)ethane nickel(II) chloride; tetra-(n-butyl)ammonium iodide; 4,4'-di-tert-butyl-2,2'-bipyridine; magnesium chloride; zinc In N,N-dimethyl-formamide at 20℃; for 12h; Inert atmosphere; | Standard method General procedure: To a flame-dried Schlenk tube was charged with NiCl2(dppe) (7.9 mg, 0.015 mmol, 0.1 equiv ), Zn (19.5 mg, 0.3 mmol, 2.0 equiv), MgCl2 (35.6 mg, 0.375 mmol, 2.5 equiv), TBAI (11.08 mg, 0.03 mmol, 0.2 equiv), and dtbpy (4.0 mg, 0.015 mmol, 0.1 equiv). The tube was capped with a rubber septum. After evacuated and backfilled with nitrogen three times, vinyl triflates (0.225 mmol, 1.5 equiv), oxalate (0.15 mmol, 1.0 equiv) and DMF (1 mL) were added via syringes. The reaction mixture was allowed to stir for 12 h under N2 atmosphere at room temperature. After which point, the mixture was added ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered, and evaporated under vacuum. The residue was purified by column chromatography to give the target product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrakis(triphenylphosphine) palladium(0); triethylamine In tetrahydrofuran; water at 70℃; for 2h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With nickel(II) bromide dimethoxyethane; 5-Chloro-8-hydroxyquinoline; lithium tert-butoxide In tetrahydrofuran at 80℃; for 6h; Inert atmosphere; Glovebox; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With nickel(II) bromide dimethoxyethane; 5-Chloro-8-hydroxyquinoline; lithium tert-butoxide In acetonitrile at 60℃; for 6h; Inert atmosphere; Glovebox; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With [nickel(II)(pyridine)4(chloride)2]; tetra-(n-butyl)ammonium iodide; 4,4'-di-tert-butyl-2,2'-bipyridine; magnesium chloride; zinc In N,N-dimethyl acetamide at 40℃; for 12h; Inert atmosphere; Sealed tube; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With copper(l) iodide; triethylamine; triphenylphosphine; palladium dichloride In tetrahydrofuran at 50℃; for 10h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With chromium(II) chloride; diludine; bathophenanthroline; nickel(II) bromide In acetonitrile at 20℃; Inert atmosphere; Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With nickel trifluoromethanesulfonate; [2,2]bipyridinyl; manganese powder In N,N-dimethyl acetamide at 35℃; for 24h; Inert atmosphere; Sealed tube; |
Tags: 188975-30-6 synthesis path| 188975-30-6 SDS| 188975-30-6 COA| 188975-30-6 purity| 188975-30-6 application| 188975-30-6 NMR| 188975-30-6 COA| 188975-30-6 structure
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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