Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 88738-78-7 | MDL No. : | MFCD00009901 |
Formula : | C7H9F6O5P | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PVSJXEDBEXYLML-UHFFFAOYSA-N |
M.W : | 318.11 | Pubchem ID : | 184894 |
Synonyms : |
|
Num. heavy atoms : | 19 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.86 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 11.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.26 |
TPSA : | 71.64 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.09 cm/s |
Log Po/w (iLOGP) : | 2.15 |
Log Po/w (XLOGP3) : | 1.62 |
Log Po/w (WLOGP) : | 5.03 |
Log Po/w (MLOGP) : | 1.13 |
Log Po/w (SILICOS-IT) : | 1.8 |
Consensus Log Po/w : | 2.35 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.24 |
Solubility : | 1.84 mg/ml ; 0.00577 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.74 |
Solubility : | 0.583 mg/ml ; 0.00183 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.42 |
Solubility : | 1.2 mg/ml ; 0.00378 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.45 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium hexamethylsilazane at -84℃; | |
88% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium carbonate In toluene at -13℃; for 0.25h; Inert atmosphere; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester In toluene at -13℃; Inert atmosphere; | |
With 18-crown-6 ether; potassium hydride; 1,1,1,3,3,3-hexamethyl-disilazane THF, -78 deg C; Multistep reaction; |
With 18-crown-6 ether; potassium hydride; 1,1,1,3,3,3-hexamethyl-disilazane 1.) THF, -78 deg C, 10 min, 2.) THF, -78 deg C, 30 min; Multistep reaction; | ||
96 % ee | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (4S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester With 18-crown-6 ether In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; enantioselective reaction; | 2 (S,Z)-tert-Butyl 4-(3-methoxy-3-oxoprop-1-enyl)-2,2-dimethyloxazolidine-3-carboxylate (S,Z)-2 General procedure: To an oily suspension of NaH 60% (2.1g, 52.5mmol) in THF (90mL), at 0°C, under nitrogen was added, dropwise, a solution of (CF3CH2O)2P(O)CH2CO2Me (10mL, 52.3mmol) in THF (60mL). The solution was stirred at 0°C for 30min and then cooled to -78°C. To this solution was added 18-Crown-6 (69g, 261mmol) in THF (150mL) and then (R)-Garner’s aldehyde 1 (9.2g, 40.2mmol) in THF (20mL). The reaction mixture was stirred at the same temperature for 2h and the reaction quenched with aqueous saturated NH4Cl solution. The reaction mixture was extracted with Et2O, dried over MgSO4, and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel, hexanes/Et2O:(1/4)) to give product (S,Z)-2 as white solid. Yield (9.39g, 82%). TLC (hexane/Et2O:1/1): Rf=0.71. HPLC (CH3CN/H2O:50/50, 0.7mL/min): tR=9.5min. 1H NMR (250MHz, CDCl3) δ (ppm) 6.22 (m, 1H, CH=CH-COOMe), 5.78 (d, 3JH-H=11.4Hz, 1H, CH=CH-COOMe), 5.34 (s, 1H, CH-α), 4.23 (t, 3JH-H=7.8Hz, 1 H, CH2aO), 3.71 (dd, 3JH-H=9.2 and 4JH-H=3.1Hz, 1H, CH2bO), 3.65 (s, 3H, COOCH3), 1.57 (s, 3H, C-CH3), 1.50-1.22 (m, 12H, C-CH3 and [C(CH3)3] Boc). 13C NMR (63MHz, CDCl3) δ (ppm) 166.25 (COOMe), 152.26 (CO Boc), 151.86/151.24 (rotamers, CH=CH-COOMe), 119.67/119.08 (rotamers, CH=CH-COOMe), 94.42/93.89 (rotamers, C-(CH3)2), 80.54/79.92 (rotamers, ([C(CH3)3]Boc), 69.03/68.80 (rotamers, CH2O), 56.61/55.58 (rotamers, CH-α), 51.38 (COOCH3), 28.34 ([C(CH3)3] Boc), 27.32/26.62 (rotamers, C-CH3), 24.92/23.75 (rotamers, C-CH3). The enantiomeric excess of (S,Z)-2 was determined by HPLC (Chiral OD-H column, i-PrOH/hexane:5/95), tR=7.8min for (R) enantiomer and tR=8.5min for (S) enantiomer in the HPLC chromatogram. The ee for (S,Z)-2 was 94% and its [α]25D[α]D25 -27.3 (c=0.91, CHCl3). For (R,Z)-2 enantiomer the ee=96% and the measured [α]25D[α]D25 +28.5 (c=1.03, CHCl3). LRMS-(ESI+), m/z: 286.2 [M+H]+, 308.1 [M+Na]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 18-crown-6 ether; sodium hydride at -78℃; | |
85% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With potassium hexamethylsilazane; 18-crown-6 complexed with acetonitrile In tetrahydrofuran; toluene at -78℃; for 0.25h; Inert atmosphere; Stage #2: (R)-3-tert-butoxycarbonyl-4-formyl-2,2-dimethyloxazolidine In tetrahydrofuran; toluene at -78 - 0℃; Inert atmosphere; | |
82% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (R)-3-tert-butoxycarbonyl-4-formyl-2,2-dimethyloxazolidine With 18-crown-6 ether In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; enantioselective reaction; | 2 (S,Z)-tert-Butyl 4-(3-methoxy-3-oxoprop-1-enyl)-2,2-dimethyloxazolidine-3-carboxylate (S,Z)-2 General procedure: To an oily suspension of NaH 60% (2.1g, 52.5mmol) in THF (90mL), at 0°C, under nitrogen was added, dropwise, a solution of (CF3CH2O)2P(O)CH2CO2Me (10mL, 52.3mmol) in THF (60mL). The solution was stirred at 0°C for 30min and then cooled to -78°C. To this solution was added 18-Crown-6 (69g, 261mmol) in THF (150mL) and then (R)-Garner’s aldehyde 1 (9.2g, 40.2mmol) in THF (20mL). The reaction mixture was stirred at the same temperature for 2h and the reaction quenched with aqueous saturated NH4Cl solution. The reaction mixture was extracted with Et2O, dried over MgSO4, and concentrated under vacuum. The crude residue was purified by column chromatography (silica gel, hexanes/Et2O:(1/4)) to give product (S,Z)-2 as white solid. Yield (9.39g, 82%). TLC (hexane/Et2O:1/1): Rf=0.71. HPLC (CH3CN/H2O:50/50, 0.7mL/min): tR=9.5min. 1H NMR (250MHz, CDCl3) δ (ppm) 6.22 (m, 1H, CH=CH-COOMe), 5.78 (d, 3JH-H=11.4Hz, 1H, CH=CH-COOMe), 5.34 (s, 1H, CH-α), 4.23 (t, 3JH-H=7.8Hz, 1 H, CH2aO), 3.71 (dd, 3JH-H=9.2 and 4JH-H=3.1Hz, 1H, CH2bO), 3.65 (s, 3H, COOCH3), 1.57 (s, 3H, C-CH3), 1.50-1.22 (m, 12H, C-CH3 and [C(CH3)3] Boc). 13C NMR (63MHz, CDCl3) δ (ppm) 166.25 (COOMe), 152.26 (CO Boc), 151.86/151.24 (rotamers, CH=CH-COOMe), 119.67/119.08 (rotamers, CH=CH-COOMe), 94.42/93.89 (rotamers, C-(CH3)2), 80.54/79.92 (rotamers, ([C(CH3)3]Boc), 69.03/68.80 (rotamers, CH2O), 56.61/55.58 (rotamers, CH-α), 51.38 (COOCH3), 28.34 ([C(CH3)3] Boc), 27.32/26.62 (rotamers, C-CH3), 24.92/23.75 (rotamers, C-CH3). The enantiomeric excess of (S,Z)-2 was determined by HPLC (Chiral OD-H column, i-PrOH/hexane:5/95), tR=7.8min for (R) enantiomer and tR=8.5min for (S) enantiomer in the HPLC chromatogram. The ee for (S,Z)-2 was 94% and its [α]25D[α]D25 -27.3 (c=0.91, CHCl3). For (R,Z)-2 enantiomer the ee=96% and the measured [α]25D[α]D25 +28.5 (c=1.03, CHCl3). LRMS-(ESI+), m/z: 286.2 [M+H]+, 308.1 [M+Na]+. |
81% | With 18-crown-6 ether; sodium hydride In tetrahydrofuran | |
72% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; Stage #2: (R)-3-tert-butoxycarbonyl-4-formyl-2,2-dimethyloxazolidine In tetrahydrofuran at -78℃; for 3h; | |
With 18-crown-6 ether; potassium hydride; 1,1,1,3,3,3-hexamethyl-disilazane THF, -78 deg C; Yield given. Multistep reaction; | ||
With 18-crown-6 ether; potassium hydride; 1,1,1,3,3,3-hexamethyl-disilazane 1.) THF, -78 deg C, 10 min, 2.) THF, -78 deg C, 30 min; Yield given. Multistep reaction; | ||
With sodium hydride 1.)THF, 0 deg C, 30 min 2.) THF, -78 deg C, 2 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at 40℃; for 2.25h; | 7 p-Chloro-cis-cinnamic acid EXAMPLE 7 p-Chloro-cis-cinnamic acid A solution of 18-crown-6 (5.0 g, 18.9 mmol) in THF (20 mL) was cooled to 40° C. and bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonate (0.85 mL, 4 mmol) followed by KHMDS (890 mg, 4 mmol) were added. After stirring for 15 min, p-chlorobenzaldehyde (560 mg, 3.78 mmol) was added and the solution was stirred for 2 h. Saturated aqueous ammonium chloride (50 mL) and ethyl ether (30 mL) were added and the organic phase was washed with 1 N HCl. After drying and evaporation, the residue was purified by chromatography (SiO2, H/E 4/1) to give p-chloro-cis-cinnamic acid methyl ester (610 mg, 82%). |
With 18-crown-6 ether; potassium bis-tetramethylsilylamide 1.) THF, -78 deg C; 2.) -78 deg C, 6 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; Inert atmosphere; Stage #2: benzaldehyde In tetrahydrofuran; toluene at -78℃; Inert atmosphere; | |
90% | With Tris(3,6-dioxaheptyl)amine; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 4h; | |
84% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; Inert atmosphere; Stage #2: benzaldehyde In tetrahydrofuran; toluene at -78℃; Inert atmosphere; |
81% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; Inert atmosphere; Stage #2: benzaldehyde In tetrahydrofuran; toluene at -78℃; Inert atmosphere; | |
With 18-crown-6 ether; potassium bis-tetramethylsilylamide 1.) THF, -78 deg C; 2.) -78 deg C, 6 h; Yield given. Multistep reaction; | ||
With 18-crown-6 ether; sodium hexamethyldisilazane In tetrahydrofuran | ||
With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; | 117 9.4 g of 18-crown-6 and 1.7 ml of methyl [bis(2,2,2-trifluoroethoxy)-phosphoryl]acetate are dissolved under argon in 120 ml of dry tetrahydro-furan and cooled to -78° C. 14.3 ml of a 0.5 molar solution of potassium bis(trimethylsilyl)amide in toluene are added to this mixture, followed by 0.85 ml of benzaldehyde. After stirring at -78° C. for thirty minutes, the reaction mixture is quenched by adding saturated ammonium chloride solution and extracted with five portions each of 50 ml of ethyl acetate. The combined organic phases are dried over MgSO4 and then the solvent is removed in vacuo. The residue is purified on silica gel with n-heptane:ethyl acetate=20:1 as eluent. 1.1 g of methyl (Z)-3-phenylacrylate are obtained as an oil. C10H10O2 (162.19), LCMS (ESI): 163.2 (M+H+). Rf (n-heptane:ethyl acetate=2:1)=0.62, | |
Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: benzaldehyde In tetrahydrofuran at -78℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 18-crown-6 ether; potassium hexamethylsilazane In toluene stereoselective reaction; | |
With 18-crown-6 ether; potassium bis-tetramethylsilylamide 1.) THF, -78 deg C; 2.) -78 deg C, 6 h; Yield given. Multistep reaction; | ||
Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran at -78℃; for 1h; | 46.1 Step 1: Z-3-(4-Bromo-phenyl)-acrylic acid methyl ester To a solution of [[BIS- (2,] 2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester [(L.] Oeq. ) and 18-C-6 [(5.] [0EQ.)] in THF (0.05M) at-78°C was added dropwise KN (TMS) 2 [(L.] Oeq. ). The mixture was stirred at-78°C for [15MIN] then 4- bromobenzaldehyde [(L.] Oeq. ) was added. The final mixture stirred for lh [AT-78°C,] poured in saturated aqueous [NH4CL] and extracted with [ET20] (3x). The combined organic extracts were washed with, brine, dried over [NA2SO4,] filtered and concentrated. Flash chromatography (Hex: EtOAc 10 to 25%) afforded a mixture of desired material and the starting aldehyde. Upon treatment in [CH2CI2] of the mixture with Amino-Merrifield resin for [10MIN,] the aldehyde was removed. Filtration and concentration afforded the title compound as an oil. |
With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 1h; | 8.1 Step 1: Methyl 2- (CIS)-3- (4-BROMOPHENYL) prop-2-enoate To a solution of bis (trifluoroethyl) (methoxycarbonylmethyl) phosphonate and 18-Crown-6 (5eq) in THF (0.05M) at-78°C was added KHMDS (LEQ, 0.5M, toluene) followed by 4- bromobenzaldehyde (LEQ). The reaction mixture was stirred at-78°C lh, quenched with a saturated ammonium chloride solution and diluted with ether. The combined organic extracts were washed with brine, dried over NA2S04, filtered and concentrated. Flash chromatography (Hexane: EtOAc; 9: 1 to 7: 3) afforded the title compound. | |
Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran 1.) -78 deg C, 5 min, 2.) -78 deg C, 50 min; | |
78% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: phenylacetaldehyde In tetrahydrofuran for 1.16667h; | General Procedure E for Compounds 16,17,22,23,26,29 General procedure: 1-(5-phenylpentyl)piperazine (16). 5-phenylpentanol (0.506 g, 3.08 mmol) was dissolved in DCM (15 mL). Et3N (0.86 mL, 6.2 mmol) was then added via syringe. The mixture was cooled to 0°C, and MsCl (0.406 mL, 5.2 mmol) was added dropwise. The yellow mixture was stirred at 0°C for 1 h, after which time it was washed with H2O (15 mL). Aqueous layer was discarded, and the organic solvents were filtered and removed to give crude mesylate as a yellow oil. Mesylate was redissolved in THF (15 mL) and piperazine (1.32 g) was added. The mixture was refluxed at 70°C for 16 h, after which time THF was removed and residue was redissolved in DCM. 2M HCl was added, and the organic layer was discarded. Aqueous layer was basified with solid NaOH to pH 14, and extracted with DCM. Combined organic extracts were dried with MgSO4, and solvents were filtered and removed to afford product as a colorless oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With Tris(3,6-dioxaheptyl)amine; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 4h; | |
53% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With Tris(3,6-dioxaheptyl)amine; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: 3-pyridinecarboxaldehyde In tetrahydrofuran at -78℃; for 4h; | 1 (Z)-methyl 3-(pyridin-3-yl)acrylate [00407] A solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (3.27 g, 10.28 mmol) and tris(2-(2-methoxyethoxy)ethyl)amine (3.32 g, 10.28 mmol) in dry tetrahydrofuran (30 ml) was cooled to -78 °C. Potassium hexamethyldisilazide (KHMDS) (2M in THF), 19.6 mL, 9.8 mmol) was added to the solution under nitrogen atmosphere. After stirring for 0.5 h, a solution of nicotinaldehyde (60) (1 g, 9.34 mmol) in dry tetrahydrofuran (5 mL) was added and the reaction mixture was maintained at -78 °C for 4 h. The mixture was quenched with aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers was dried over anhydrous Na2S0 , and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (33% EtO Ac/petroleum ether) to give (Z)-methyl 3-(pyridin-3- yl)acrylate (61) as a yellow solid. Yield (800 mg, 53%). LCMS: m/z 164.7 [M+H] ; = 1.45 min. |
With potassium hexamethylsilazane 1) THF, toluene, -70 deg C, 20 min, 2) THF, toluene, -70 deg C to -65 deg C, 45 min; Yield given; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With 18-crown-6 ether; potassium carbonate In toluene at -20 - 0℃; for 4h; | |
With 18-crown-6 ether In toluene at -20 - 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sodium hydroxide; bromine In water | |
85% | With sodium hydroxide; bromine In water at 0 - 10℃; for 0.0833333h; | |
47% | With sodium hydroxide; bromine at 0℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene; acetonitrile at -78℃; for 1h; Stage #2: methyl (2Z)-3-[4-(3-oxopropyl)-1,3-oxazol-2-yl]prop-2-enylcarbamate In tetrahydrofuran; toluene; acetonitrile at -78℃; for 0.166667h; Further stages.; | |
72% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; | |
62% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 3h; |
0.031 g | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.166667h; Stage #2: methyl (2Z)-3-[4-(3-oxopropyl)-1,3-oxazol-2-yl]prop-2-enylcarbamate In tetrahydrofuran at -78℃; for 4h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; Stage #2: (2R,3S,5R)-5,7-bis[(tert-butyldimethylsilyl)oxy]-2-methyl-3-[(triisopropyl-silyl)oxy]heptanal In tetrahydrofuran; toluene at -78 - 20℃; for 1h; Further stages.; | |
83% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium; 1,1,1,3,3,3-hexamethyl-disilazane In tetrahydrofuran; toluene at -78℃; for 15h; Stage #2: (2R,3S,5R)-5,7-bis[(tert-butyldimethylsilyl)oxy]-2-methyl-3-[(triisopropyl-silyl)oxy]heptanal In tetrahydrofuran; toluene at -78℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; | |
2.05 g | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.583333h; Stage #2: (2R,3S,4S,7S,8R,9R)-9-(tert-Butyl-diphenyl-silanyloxy)-3,7-bis-methoxymethoxy-2,4,8-trimethyl-undec-10-ynal In tetrahydrofuran; toluene at -78℃; for 4.33333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PLE Enzymatic reaction; | ||
With porcine liver esterase In phosphate buffer; acetone | ||
2.32 g | With sodium hydrogencarbonate In tetrahydrofuran; water at -75℃; for 18h; Inert atmosphere; | 1-5 Example 5 Methyl [bis(2,2,2-trifluoroethoxy)phosphinyl]acetate (6.22 g, 0.01 mol) was dissolved in tetrahydrofuran (40 times) under nitrogen.Cool down to -75 ° C, slowly add sodium bicarbonate (0.77 g, 0.9 mol,Tetrahydrofuran/water (1:1) dripped in about 8 hours, after the addition is completed,The reaction was continued at this temperature for 18 hours, and after the reaction was completed, the acid was adjusted.The aqueous phase was extracted three times with ethyl acetate, and the organic solvent was evaporated under reduced pressure.The column was purified to give a white solid [bis(2,2,2-trifluoroethoxy)phosphinyl]acetic acid (2.32 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; | |
59% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; | 121.A EXAMPLE 121 (Z)-(S)-4-(3-Biphenyl-4-yl-ureido)-5-phenyl-pent-2-enoic acid (2-pyrrolidin-1-yl- ethyl)-amide. A. ()- (S)-4-tert-Butoxvcarbonvlamino-5-phenyl-pent-2-enoic acid methyl ester. To a solution of bis (2,2, 2-trifluoroethyl) (methoxycarbonylmethyl)- phosphonate (0.32 g, 1.0 mmol) in THF (10 mL) was added 18-crown-6 (0.265 g, 1.0 mmol), and the resulting solution was cooled (-78 °C). The solution was treated with potassium bis (trimethylsilyl) amide (0.2 g, 1.0 mmol) and ((S)-1- benzyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (0.25 g, 1.0 mmol), and stirred (-78 °C, 0.5 h). The reaction mixture was quenched with saturated aqueous NH4CI (50 mL) and extracted with EtOAc (2 X 50 mL). The organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography using 0-40% (EtOAc/hexanes) to provide the desired product as a white solid (0.185 g, 59%): MS (electrospray) : mass calculated for C17H23NO4, 305.37 ; rrvz found, 328.1 [M+Na] +.'H NMR (CDC13, 400 MHz): 7.31-7. 38 (m, 2H), 7.20-7. 26 (m, 3H), 6.23 (br s, 1 H), 5.86 (dd, J = 11.6, 1.0 Hz, 1 H), 5.36 (br s, 1 H), 4.79 (br s, 1 H), 3.75 (s, 3H), 2.99-3. 04 (m, 1 H), 2.91 (br s, 1 H), 1.39 (s, 9H). |
With 18-crown-6 ether; potassium hexamethylsilazane at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran | ||
0.104 g | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; Stage #2: (2E,8Z,21Z)-(4R,5S,7S,10S,11R,12S,14S,17R,18R,19S,20S)-5,7,11,17-Tetrakis-(tert-butyl-dimethyl-silanyloxy)-19-(4-methoxy-benzyloxy)-4,10,12,14,18,20-hexamethyl-tetracosa-2,8,21,23-tetraenal In tetrahydrofuran; toluene at -78℃; for 4h; Further stages.; | |
With potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 4h; | 4.e.ii The alcohol 45 (127 mg, 0.117 µmol) in CH2C12 (4 mL) was treated with Dess-Martin periodinane (75 mg, 0.18 µmol). After 1 h, the mixture was quenched with saturated aqueous NaHC03 (5 mL) and Na2S203 (5 mL). The aqueous layer was extracted with Et20 (2 x 10 mL) and the combined extracts were dried over anhydrous MgS04. Filtration and concentration followed by short flash column chromatography (hexane/EtOAc 9: 1) provided the crude aldehyde as a colorless oil, which was used for the next reaction without further purification. KHMDS (0.28 mL, 0.14 µmol, 0.5M solution in toluene) was added dropwise to a stirred solution of bis(2,2,2- trifluoroethyl)-(methoxycarbonylmethyl) phosphate (0.030 mL, 0.14 µmol) and 18-crown-6 (0.15 g, 0.57 mmol) in THF (2.3 mL) at-78 °C. Thereafter, the aldehyde in THF (0.5 mL) was added and the solution was stirred for 4 h at-78 °C. The reaction mixture was quenched by addition of a saturated aqueous NH4Cl (5 mL) and diluted with Et20 (20 mL). The organic phase was washed with brine (30 mL), dried with MgS04, filtered and concentrated. The residue was purified by flash chromatography (EtOAc/hexane 1:19) yielding (E,2(at)-doubly unsaturated ester 46 (0.12 g, 86% for 2 steps) as a colorless oil: IR (CHC13) 2955,2929, 2856, 1722, 1514, 1471, 1462, 1250, 1174, 1085, 1041, 836, 773 cm-1 ; 'H NMR (300 MHz, CDCl3) (at) 7.39 (dd, J = 15.4, 11.3 Hz, 1H), 7.29 (m, 2H), 6.88 (m, 2H), 6.59 (ddd, J = 16.9, 10.8,10.6 Hz, 1 H), 6.55 (t, J = 11.3 Hz, 1 H), 6.01 (t, J = 11.0 Hz, 1H), 6.00 (dd, J = 15 . 7, 7. 0 Hz, 1H), 5.60 (d, J = 11.3 Hz, 1H), 5.59 (t, J = 10.4 Hz, 1H), 5.39 (t, J= 10.4 Hz, 1H), 5.27 (dd, J= 11.0,8.3 Hz, 1H), 5.18 (d, J= 16.8 Hz, 1H), 5.11 (d, J= 10.3 Hz, 1H), 4.54 (m, 3H), 3.96 (m, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.63 (m, 1H), 3.34 (m, 2H), 3.00 (m, 1H), 2.57 (m, 2H), 1.64 (m, 3H), 1.55 (m, 1H), 1.46 (t, J= 5.9 Hz, 2H), 1.26 (m, 5H), 1.11 (d, J= 6.8 Hz, 3H), 1.05 (d, J= 6.7 Hz, 3H), 0.97 (d, J= 6.9 Hz, 3H), 0.96 (d, J= 7.1 Hz, 3H), 0.94 (s, 9H), 0.92 (s, 9H), 0.91 (s, 9H), 0.87 (s, 9H), 0.83 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.0 Hz, 3H), 0.13 (s, 3H), 0.11 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H), 0.06 (s, 3H), 0.05 (s, 6H), 0.04 (s, 3H); i3C NMR (75 MHz, CDC13) (at) 166.8, 159.0, 147.3, 145.5, 134.6, 132.9, 132.8, 132.4, 131.4, 129.0,128.9, 126.9, 117.1, 115.5, 113.7, 84.4,80.0, 75.0,72.9, 72.1,66.5, 55.2,50.9, 43.5, 42.5, 41.8, 40.5,36.0, 35.3, 34.5,32.5, 31.6, 30.5,26.3, 25.99, 25.96, 25.91, 20.2, 19.2, 18.8, 18.5,18.2, 18.1, 15.0,13.4, 9.2, -3.0, -3.2, -3.3, -3.6, -3.7, -4.1, -4.4,-4.5; LRMS (ESI) 1163.9 [M+Na]+, 1009.8, 684.3, 610.2, 513.4; HRMS (ESI) calcd for C65HI2008Si4Na 1163.7958 [M+Na]+, found 1163.7985; [oc]ZOD -9.3 (c 1.2, CHC13). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With 18-crown-6 ether; potassium hexamethylsilazane; acetonitrile In tetrahydrofuran; toluene at 0℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.32 g | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; Stage #2: C62H116O7Si4 In tetrahydrofuran; toluene at -78℃; for 4h; Further stages.; | |
With potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 4h; | 7.a.ii The alcohol 95 (0.34 g, 0.31 µmol) in CH2C12 (20 mL) was treated with Dess-Martin periodinane (0.20 g, 0.47 (at)mol). After 1 h, the mixture was quenched with saturated NaHC03 (5 mL) and Na2S203 (5 mL). The aqueous layer was extracted with ethyl ether (10 mL x 2) and the combined extracts were dried over anhydrous MgS04. Filtration and concentration followed by short flash column chromatography (hexane/EtOAc 9: 1) to remove the Dess-Martin residue provided the crude aldehyde as a colorless oil, which was used for the next reaction without further purification. To a stirred solution of bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl) phosphate (0.080 mL, 0.37 µmol), 18-crown-6 (0.41 g, 1.55 mmol) in THF (6 mL) cooled to -78 °C was added dropwise potassium bis (trimethylsilyl)amide mL, 0.37 µmol, 0.5M solution in toluene). Thereafter the above aldehyde in THF (1 mL) was added and the solution was stirred for 4 h at -78 °C. The reaction mixture was quenched by addition of a sat'd NH4Cl solution (5 mL) and diluted with diethyl ether (20 mL). The layers were separated and organic phase was washed with brine (30 mL) and dried with MgS04, filtered, and concentrated. The residue was purified by flash chromatography (EtOAc/hexane 5: 95) to obtain (E,Z)-doubly unsaturated ester 96 (0.32 g, 90 % for 2 steps) as a colorless oil: IR (CHC13) 2956,2929, 2885, 1722, 1641, 1514, 1471, 1250, 1174, 1075, 836, 773 cm-¹, ¹H NMR (300 MHz, CDC13) No. 7.34 (dd, J= 15.5, 11.2 Hz, 1H), 7.29-7.26 (m, 2H), 6.87-6.84 (m, 2H), 6.56 (ddd, J= 17.0, 10.6, 10.5 Hz, 1H), 6.52 (t, J = 11.4 Hz, 1 H), 6.19 (dd, J= 15.5, 6.4 Hz, 1 H), 5.99 (t, J =11.0 Hz, 1H), 5.57 (t, J = 10.5 Hz, 1H), 5.54 (d, J = 11.3 Hz, 1H), 5.42 (m, 1H), 5.30 (m, 1H), 5.15 (d, J = 16.8 Hz, 1H), 5 .07 (d, J = 10.1 Hz, 1H), 4.51 (m, 3H), 3 .92 (m, 1 H), 3.78 (s, 3H), 3.70 (s, 3H), 3.61 (m, 1H), 3.32 (dd, J= 7.9, 2.8 Hz, 1H), 3.20 (m, 1H), 2.97 (m, 2H), 2.57 (m, 2H), 1.65 (m, 1H), 1.56-1.39 (m, 3H), 1.29-1.16 (m, 3H), 1.10 (d, J= 6.8 Hz, 3H), 1.03 (d, J= 6.9 Hz, 3H), 0.98 (d, J= 7.0 Hz, 3H), 0.94 (d, J= 6.9 Hz, 3H), 0.93-0.83 (m, 39H), 0.77 (m, 1H), 0.91 (s, 9H), 0.87 (s, 9H), 0.83 (d, J = 6.4 Hz, 3H), 0.82 (d, J = 6.0 Hz, 3H), 0.13 (s, 3H), 0.76 (d, J= 6.6 Hz, 3H), 0.71 (d, J= 5.9 Hz, 3H), 0.10-0.02 (m, 24H) ; ¹3C NMR (75 MHz, CDC13) No. 166.8,159.0, 147.2,145.6, 134.5,133.1, 132.4,131.5, 131.4,129.0, 128.9,126.4, 117.1, 115.1, 113.7, 84.4,81.3, 75.0,72.8, 72.7,66.4, 55.2,50.9, 42.9,42.6, 40.5,40.2, 35.3,35.2, 33.8,32.6, 30.5,26.3, 26.0,25.9, 19.6,18.9, 18.8,18.4, 18.2, 18.1, 16.7,14.5, 9.2,-2.8, -3.4,-3.5, -3.6, -4.07, -4.14, -4.24, -4.49; LRMS (ESI) 1163.8 [M+Na] +, 1107.9,782.5; HRMS (ESI) calcd for C65H12008S14Na 1163.7958 [M+Na] +, found 1163.8004; [(X]20D -27.3 (c 5.0, CHC13). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78 - 23℃; for 24.5h; | 29 2-Methylsulfanyl-4,8-diphenyl-8H -pyrido[2,3-d]pyrimidin-7-one A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (81 μL, 0.38 mmol, 1.2 eq) in anhydrous THF (20 mL) was cooled to -78°. To this solution was added potassium bis(trimethylsilyl)amide (0.96 mL, 0.48 mmol, 1.5 eq) as a 0.5 mol solution in toluene. This solution was stirred for additional 30 min at -78° and 2-methylsulfanyl-4-phenyl-6-phenylamino-pyrimidine-5-carbaldehyde (102 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The reaction mixture was then stirred for 8 h at -78° and warmed to 23° and stirred 16 h. Sat'd aq. NH4Cl (5 mL), followed by diethyl ether (20 mL), was added. The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was then purified by flash chromatography to afford 100 mg (91% yield) of pure 2-methylsulfanyl-4,8-diphenyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 2.19 (s, 3H), 6.70 (d, 1H, J=9.9 Hz), 7.26 (m, 2H), 7.42-7.83 (m, 8H), 7.88 (d, 1H, J=9.9 Hz), LC MS (m/e)=346 (MH+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 8.5h; | 107 4-(2-Fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one 4-(2-Fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (81 UL, 0.38 mmol, 1.2 eq) in anhyd THF (20 ML) was cooled to -78°, potassium bis(trimethylsilyl)amide (0.96 ML, 0.48 mmol, 1.5 eq) as a 0.5 mol solution in toluene was added.This solution was stirred for additional 30 min at -78° and 4-amino-6-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde (85 mg, 0.32 mmol) in dry THF (1 ML) was added dropwise.The reaction mixture was then stirred for 8 h at -78° and warmed to 23°, and stirred 16 h.Saturated aq NH4Cl (5 ML), followed by Et2O (20 ML), was added.The layers were separated.The organic layer was washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated.The yellow residue was purified by Flash chromatography to afford 100 mg (91% yield) of 4-(2-fluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 2.62 (s, 3H), 6.55 (d, 1H, J=9.9 Hz), 7.26 (m, 3H), 7.52 (m, 2H), 8.99 (br s, 1H). LC MS (m/e)=288 (MH+). Rt=1.75 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 8.5h; | 111 8-(2-Chloro-phenyl)-2-methylsulfanyl4-phenoxy-8H-pyrido[2,3-d]pyrimidin-7-one A solution of 18-crown-6 (422 mg, 1.6 mmol, 5 eq) and bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (81 μL, 0.38 mmol, 1.2 eq) in anhyd THF (20 mL) was cooled to -78°. To this solution was added potassium bis(trimethylsilyl)amide (0.96 mL, 0.48 mmol, 1.5 eq) as a 0.5 mol solution in toluene. This solution was stirred for additional 30 min at -78° and 4-(2-chloro-phenylamino)-2-methylsulfanyl-6-phenoxy-pyrimidine-5-carbaldehyde (119 mg, 0.32 mmol) in dry THF (1 mL) was added dropwise. The reaction mixture was then stirred for 8 h at -78° and warmed to 23° and stirred 16 h. Saturated aq NH4Cl (5 mL), followed by Et2O (20 mL), was added. The layers were separated. The organic layer was washed with satd aq NaCl, dried (MgSO4) filtered and solvent was removed in vacuo. The yellow residue was then purified by Flash chromatography to give 100 mg (91% yield) of pure 8-(2-chloro-phenyl)-2-methylsulfanyl-4-phenoxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR δ 1.89 (s, 3H), 6.55 (d, 1H, J=9.9 Hz), 7.18 (m, 4H), 7.28 (m, 4), 7.44 (m, 1H), 7.98 (d, 1H, J=9.9 Hz). LC MS (m/e)=396 (MH+). Rt=2.68 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; | T.1 Methyl bis (trifluoroethyl) phosphonoacetate (4.77 g, 15 [MMOL)] and 23.7g (90 [MMOL)] of 18-crown-6 were dissolved in 80 mL of anhydrous THF and cooled to-78 ° C. To this soution was added 30 mL (15 [MMOL)] of potassium bis (trimethylsilyl) amide, followed by 5. [1G] (14.7 [MMOL)] of N, N-diBoc glutamic aldehyde methyl ester from Example U-3 (see Example [U] infra). After stirring for 30 minutes at-78 ° C, the reacion was quenched with aqueous [KHS04.] Extraction of the reaction mixture with EtOAc and concentration afforded 2.95g (49%) of the desired compound. Mass spectra M + H = 402. |
49% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate; methyl (S)-2-N,N-di(tert-butoxycarbonyl)amino-5-oxopentanoate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: With potassium hydrogensulfate; water In tetrahydrofuran | T.Ex-T-1 Methyl bis (trifluoroethyl) phosphonoacetate (4.77 g, 15 mmol) and 23.7g (90 mmol) of 18- crown-6 were dissolved in 80 mL of anhydrous THF and cooled to-78°C. To this soution was added 30 mL (15 mmol) of potassium bis (trimethylsilyl) amide, followed by 5. lg (14.7 mmol) OF N, N-diBoc glutamic aldehyde methyl ester from Ex-U-3 (see Example U, infra). After stirring for 30 min at-78°C, the reacion was quenched with aqueous KHS04 . Extraction of the reaction mixture with EtOAc and concentration afforded 2.95g (49%) of the desired compound. Mass spectra M + H = 402. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78 - 20℃; for 32h; | 34 Methyl (2Z)-3-(2,4-difluorophenyl)acrylate Preparation 34 Methyl (2Z)-3-(2,4-difluorophenyl)acrylate To a solution of 18-crown-6 (30 g, 110 mmol), bis(2,2,2-trifluororethyl) (methoxycarbonylmethyl)phosphonate (6 mL, 28 mmol) in tetrahydrofuran at -78° C. was added potassium hexamethyldisilazide (0.5 M in toluene) (50 mL, 25 mmol) followed by 2,4-difluorobenzaldehyde (4 g, 28 mmol). The reaction mixture was stirred at this temperature for 8 hours and slowly warmed to room temperature over 24 hours. The reaction mixture was then poured into a saturated solution of ammonium chloride (200 mL). The phases were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude residue. Purification of the residue by column chromatography using pentane:ethyl acetate (99:1-98:2) as eluent afforded the desired product as a colourless oil, 5.1 g (91%). 1H NMR (400 MHz, CDCl3) [13.70 (s, 3H), 6.05 (d, 1H), 6.80 (m, 1H), 6.86 (m, 1H), 6.97 (d, 1H), 7.69 (q, 1H). LRMS (APCI) 199 [MH+] |
With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 2.33h; | 1.D Part D. (Z)-isopropyl 2-(3-methoxy-3-oxoprop-1-enyl)-6-(trifluoromethyl)benzoate; To a solution of 18-crown-6 (9.1 g, 34.6 mmol) in 100 mL of THF at -78° C. was added bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (4.13 g, 12.98 mmol). Potassium bis(trimethylsilyl)amide (19.6 mL of a 15 wt % solution in toluene, 12.98 mmol) was added dropwise over 20 min and the mixture was stirred an additional 1 h at -78° C. Then there was added isopropyl 2-formyl-6-(trifluoromethyl)benzoate (1.5 g, 5.74 mmol) in 10 mL of THF and the resulting cloudy mixture was stirred at -78° C. for 1 h. The reaction was quenched with sat'd aq NH4Cl, diluted with EtOAc, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 6:1 hexane/ethyl acetate) to afford 2.58 g (94%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.66-7.62 (m, 2H), 7.51 (t, 1H, J=7.7 Hz), 7.11 (d, 1H, J=12.1 Hz), 6.11 (d, 1H, J=12.1 Hz), 5.26 (septet, 1H), 3.63 (s, 3H), 1.32 (d, 6H, J=6.0 Hz). LRMS (ESI): 339.19 (M+H+Na)+. |
94% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Example 1; 4-Chloro-2-methylsulfanyl-8-(4-trifluoromethyl-phenyl)-8H- A solution of 4,<5-dichloro-2-methylsulfanyl-pyrimidine-5~ carbaldehyde (LOg, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TEtaF (25mL) was mixed with 4~trifluoromethylaniline (0.62mL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)- EPO <DP n="62"/>phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 12 hours, the mixture was diluted with dichloromethane (5OmL) and washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was further purified by washing with a mixture of THF / Hexane (1 : 3, 2 x 1OmL) to provide the title compound (1.17g, 70%): MS (ES) m/z 372 (M+H)+; 1H-NMR(CDCl3) delta 2.18 (s, 3H), 6.79 (d, J= 9.8 Hz, IH), 7.40(d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 9.8 Hz, IH). | |
70% | A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5- carbaldehyde (1.Og, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TetaF (25mL) was mixed with 4-trifluoromethylaniline (0.62mL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2- trifluoroethyl)(methoxycarbonylmethyl)-phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 12 hours, the mixture was diluted with dichloromethane (5OmL) and washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was further purified by washing with a mixture of THF / Hexane (1 : 3, 2 x 1OmL) to provide the title compound (1.17g, 70%): MS (ES) m/z 372 (M+H)+; 1H-NMR(CDCl3) delta 2.18 (s, 3H), 6.79 (d, J= 9.8 Hz, IH),7.40 (d, J= 8.4 Hz, 2H), 7.83 (d, J= 8.4 Hz, 2H), 8.03 (d, J= 9.8 Hz, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Example 2; 4-Chloro-2-methylsulfanyl-8-('2,4-difluoro-rhohenylV8H"-rJyridor2.3-6? pyrimidin-7-oneA solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5- carbaldehyde (1.Og, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TEtaF(25mL) was mixed with 2,4-difluoroaniline (0.5OmL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2-trifluoroethyl) (methoxycarbonyl-methyl)phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 48 hours, the mixture was diluted with dichloromethane (5OmL) and then washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was applied to flash chromatography (EtOAc / Hexane, 1 : 5) to provide the title compound (0.79g, 52%): MS (ES) m/z 340 (M+H)+; 1H-NMR(CDCl3) delta 2.24(s, 3H), 6.79 (d, J= 9.8 Hz, IH), 7.06 (m, 2H), 7.29 (m, IH), 8.03 (d, J= 9.8 Hz, IH). | |
52% | A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5- carbaldehyde (1.Og, 4.5mmol) and Et3N (1.26mL, 9.0mmol) in TetaF (25mL) was mixed with 2,4-difluoroaniline (0.5OmL, 4.9mmol). The resultant mixture was stirred at room temperature for 2 hours before bis(2,2,2- trifluoroethyl) (methoxycarbonyl-methyl)phosphonate (0.95mL, 4.5mmol) was added. After stirring at room temperature for additional 48 hours, the mixture was diluted with dichloromethane (5OmL) and then washed with H2O (2 x 25mL). The organic layer was dried over Na2SO4, filtered and concentrated. This crude product was applied to flash chromatography (EtOAc / Hexane, 1 : 5) to provide the title compound (0.79g, 52%): MS (ES) m/z 340 (M+H)+; 1H-NMR(CDCl3) delta 2.24 (s, 3H), 6.79 (d, J= 9.8 Hz, IH), 7.06 (m, 2H),7.29 (m, IH), 8.03 (d, J= 9.8 Hz, IH). | |
40% | Example 96; 3-(8-(2,4-difluorophenylV2-(r2-hvdroxy-l-(Tivdroxymethyl)ethyllamino>-7-oxo- 7,8-dihydropyrido[2,3-d]pyrimidin-4-yl)benzoic acid96a) 4-chloro-8-(2,4-difluorophenylV2-rmethylthio)pyridof2.3-(/1Pyrimidin-7(8/D- oneTo a solution of <strong>[33097-11-9]4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde</strong> (4.2g, 18.95mmol) and triethylamine (5.3ml, 38mmol) in THF (100ml) was added 2,4-difluoroaniline (2.ImI5 20.58mmol). The mixture was stirred for 2h, and methyl {bis[(2,2,2-trifluoroethyl)oxy]phosrhohoryl} acetate (6.Og, 18.95mmol) was added. The mixture was stirred for 18h, diluted with DCM (200ml) and washed with water EPO <DP n="196"/>(2 x 100ml). The dried (Na2SO4) organic phase was filtered and evaporated. Flash chromatography (EtOAc/ Hexane, 1 :5) provided the title compound as a cream solid (2.5g5 40%): LC-MS m/z 340 (M+H)+ retention 3.24min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.5% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78 - 20℃; | 47; 54 Example No.47: Preparation of (Z)-methyl 3-(4-(3-(3-chIoro-4-isopropoxyphenyl)-l,2,4- oxadiazol-5-yl)phenyl)acrylate; A two-neck round bottom flask was charged with methyl 2-(bis(2,2,2- trifluoroethoxy)phosphoryl)acetate (0.235 ml, 1.109 mmol), 18-crown-6 (1465 mg, 5.54 mmol) and THF (15 ml). The mixture was then cooled to -78°C under an atmosphere of nitrogen. Potassium bis(trimethylsilyl)amide (221 mg, 1.109 mmol) was added and the mixture stirred for a few minutes. 4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5- yl)benzaldehyde (380 mg, 1.109 mmol) was added and the mixture stirred at -78°C for 90 minutes and then left to warm to room temperature overnight. Reaction was quenched by the addition of saturated NH Cl (aqueous). The mixture was separated and the aqueous layer was extracted with ether (3 x 1OmL). The combined organics were dried over MgSO and concentrated to give an off-white solid. Thesolid was triturated with MeOH and collected by vacuum filtration and washed with MeOH (3 x 10 mL). Collected solid was dried overnight in a vacuum oven to give (Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol- 5-yl)phenyl)acrylate (325 mg, 73.5%).LCMS (Table 1, Method c) Rt = 3.22 min, m/z 399.16 (M+H)+. 1H NMR (400 MHz, DMSO) δ ppm 8.18 (d, 2H), 8.06 (d, IH), 8.01 (dd, IH), 7.79 (d, 2H), 7.40 (d, IH), 7.18 (d, IH), 6.84 (d, IH), 6.20 (d, IH), 4.83 (sept, IH), 3.67 (s, 3H), 1.35 (d, 6H). |
73.5% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: 4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)benzaldehyde In tetrahydrofuran at -78 - 20℃; Inert atmosphere; | 33 Preparation No.33: Preparation of (Z)-methyl 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4- oxadiazol-5-yl)phenyl)acrylate; A two-neck round bottom flask was charged with methyl 2-(bis(2,2,2- trifluoroethoxy)phosphoryl)acetate (0.235 mL, 1.109 mmol), 18-crown-6 (1465 mg, 5.54 mmol) and THF (15 mL). The mixture was then cooled to about -78°C under an atmosphere of nitrogen. Potassium bis(trimethylsilyl)amide (221 mg, 1.109 mmol) was added and the mixture stirred for a few min. 4-(3-(3-chloro-4-isopropoxyphenyl)-l,2,4-oxadiazol-5- yl)benzaldehyde (380 mg, 1.109 mmol) was added and the mixture stirred at about -78°C for about 90 min and then left to warm to RT overnight. Reaction was quenched by the addition of saturated NH CI (aqueous). The mixture was separated and the aqueous layer was extracted with ether (3 x 10 mL). The combined organics were dried over MgS04 and concentrated to give an off-white solid. The solid was triturated with MeOH and collected by vacuum filtration and washed with MeOH (3 x 10 mL). The collected solid was dried overnight in a vacuum oven to give (Z)-methyl 3-(4-(3-(3-chioro-4-isopropoxyphenyi)-l,2,4- oxadiazol-5-yl)phenyl)acrylate (325 mg, 73.5%).LC/MS (Table 1, Method c) Rt = 3.22 min, m/z 399.16 (M+H)+. .H NMR (400 MHz, DMSO) δ ppm 8.18 (d, 2H), 8.06 (d, 1H), 8.01 (dd, 1H), 7.79 (d, 2H), 7.40 (d, 1H), 7.18 (d, 1H), 6.84 (d, 1H), 6.20 (d, 1H), 4.83 (sept, 1H), 3.67 (s, 3H), 1.35 (d, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; | 12.3 A solution of potassium bis(trimethylsilyl)amide (414 mg, 1.973 mmol) in tetrahydrofuran (3 ml) was added dropwise at a slow speed to a mixture of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (627 mg, 1.973 mmol), 18-crown-6 (2.048 g, 7.750 mmol) and tetrahydrofuran (20 ml) at -78° C. under argon atmosphere. A solution of 4-fluoro-4'-(trifluoromethoxy)biphenyl-3-carbaldehyde (584 mg, 1.409 mmol) in tetrahydrofuran (3 ml) was added dropwise at a slow speed to the mixture at -78° C. under argon atmosphere, and the mixture was stirred at -78° C. for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture. The residue obtained by evaporation of the solvent under reduced pressure was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (597 mg, 90.1%) as a pale yellow oil.1H-NMR (CDCl3) δ: 1.32 (9H, s), 3.71 (3H, s), 6.04 (1H, d, J=12.6 Hz), 6.90-6.98 (3H, m), 7.20-7.31 (3H, m), 7.36 (2H, d, J=9.6 Hz), 7.44 (1H, dd, J=2.4, 8.4 Hz), 7.59 (2H, d, J=8.7 Hz), 7.95 (1H, d, J=2.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With potassium hexamethylsilazane In tetrahydrofuran; toluene at -78 - -40℃; for 1h; Stage #2: 2R, [3R,] [5R]-8-(TERT-BUTYLDIPHENYLSILANYLOXY)-5, 7-BIS-(4-methoxybenzyloxy)-4-methyl oct-2-enal In tetrahydrofuran; toluene at -78℃; for 3h; | [4R, 5R, [7R]-10- (TERT-BUTYLDIPHENYSILANYLOXY)-7,] 9-bis (4-methoxybenzyloxy)- 6-methyldeca-2,4-dienoicacid methyl ester. [4R, 5R, [7R]-10- (TERT-BUTYLDIPHENYSILANYLOXY)-7,] 9-bis (4-methoxybenzyloxy)- 6-methyldeca-2,4-dienoicacid methyl ester. To a stirred solution of [[BIS- (2,] 2,2- trifluoroethoxy) phosphoryl] acetic acid methyl ester (210 mg, 0.65 mmol) in THF (12 mL) at - 78°C under argon was added dropwise [KHMDS] in toluene (1.4 mL, 0.5 M). The reaction mixture was warmed to-40 °C for [1] h then cooled to-78°C and the intermediate aldehyde (400 mg, 0.59 mmol) in THF (0.5 mL) was added dropwise. After 3 h [AT-78 °C,] the solution was warmed to [0 °C] and quenched by addition of a saturated solution [OF NH4C1] (5 mL) and diluted with Et2O (5 mL). The aqueous layer was separated and extracted with diethyl ether [(5 X 3] mL). The combined organic phases were washed with brine (5 mL), dried over [MGS04,] filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (10% to 30% EtOAc in hexanes), yielding 220 mg (65% 2 steps) of conjugated ester, a clear oil [: IH] NMR (300 MHz, [CDC13)] [5] 7.69-7. 65 [(M,] 4H), 7.39-7. 37 [(M,] 7H), 7.20-7. 16 [(M,] 4H), 6. [85-6.] 79 [(M,] 4H), 6.64 (t, [J= 11.] 2 Hz, 1H), 6.22 (ddd, J=15. 4,6. 8 Hz, [1H),] 5.87 (d, [J=] 11.2 Hz, 1H), 5.04-4. 99 (m, 2H), 4.64 (d, [J=] 11.2 Hz, [1H),] 4.49 (d, [J=] 11.1 Hz, 1H), 4.30 (d, [J= 11.] 2 Hz, 1H), 4.18 (d, [J= 11.] 1 Hz, 1H), 3.78 (s, 6H), 3.81-3. 52 [(M,] 4H), 2.60-2. 56 [(M,] 1H), 1.57-1. 51 (m, 2H), 1.05 (s, 9H), 1.00 (d, J= 6.9 Hz, 3H) [; 13C] NMR (75 MHz, [CDC13)] [5 166.] 9,147. 3,145. 4,135. 6,133. 5 (2C), 130.3, 129.6, 126.7, 115.5, 113.5, 78. 4,75. 9,71. 7,71. 8,64. 1,55. 0,51. 1,39. 7,34. 1,26. 8,19. 2,14. 1; IR (CH2Cl2) 3048,2987, 2931,2875, 2822,1715, 15251,1423, 1250,1110 cm-1; HRMS [(EI)] cald for 722.3642, found 722. 3640m/z. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (R)-3-((tert-butyldimethylsilyl)oxy)pent-4-enal In tetrahydrofuran at -78℃; Inert atmosphere; | |
0.24 g | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at -78 - 0℃; Inert atmosphere; Stage #2: (R)-3-((tert-butyldimethylsilyl)oxy)pent-4-enal In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; stereoselective reaction; | Methyl (Z,R)-5-(tert-Butyldimethylsiloxy)hepta-2,6-dienoate (20) To a stirred solution of alcohol 10 (0.24 g, 1.11 mmol) in dry CH2Cl2 (4 mL) was added Dess-Martin periodinane (0.710 g, 1.66 mmol) at 0 °C, and the mixture was stirred for 1 h at r.t. The mixture was quenched with sat. Na2S2O3 and NaHCO3 solns (1:1 mixture, 5 mL) and extracted with CH2Cl2 (2 × 5 mL). The combined organic layers were washed with H2O (10.0 mL) and brine (10.0 mL), dried (Na2SO4), and concentrated to furnish the corresponding aldehyde as a yellow liquid, which was directly used in the next reaction. To a stirred solution of (CF3CH2O)2POCH2CO2Me (0.5 mL, 2.21 mmol) in anhyd THF (3 mL) was added NaH (66 mg, 1.66 mmol) at -78 °C.The temperature was raised to 0 °C and the mixture was stirred for0.5 h. To the mixture, the aldehyde (0.237 g, 1.11 mmol) dissolved inTHF (3 mL) was added at -78 °C. The mixture was stirred for 1 h, quenched with sat. NH4Cl solution (5 mL), and extracted with EtOAc (2 × 8 mL). The combined organic layers were washed with brine (10mL), dried (Na2SO4), concentrated, and purified by column chromatography (silica gel, 5% EtOAc-hexane) to give 20 (0.24 g, 80% over 2 steps) as a yellow syrup; [α]D25 -9.6 (c 1.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 6.34 (dt, J = 7.1, 4.4 Hz, 1 H), 5.88-5.76(m, 2 H), 5.20 (dt, J = 3.2, 1.5 Hz, 1 H), 5.07 (dt, J = 3.0, 1.5 Hz, 1 H),4.29-4.19 (m, 1 H), 3.71 (s, 3 H), 2.90-2.84 (m, 2 H), 0.89 (s, 9 H), 0.05 (s, 3 H), 0.04 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 166.7, 146.3, 140.7, 120.5, 114.2, 72.5,50.9, 37.1, 29.6, 25.7, -4.5, -4.9. MS (ESI): m/z = 271 [M + H]+. HRMS: m/z [M + H]+ calcd for C14H27O3Si: 271.1729; found: 271.1718. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 1.5h; Stage #2: 2-(tert-butyldimethylsilyloxy)ethyl bromide In N,N,N,N,N,N-hexamethylphosphoric triamide; N,N-dimethyl-formamide at 20℃; for 48h; | 1.d (d) Preparation of the phosphono ester 6. 2-[P,P-Bis(2',2',2'-trifluoroethyl)phosphono]-4-(tert-butyldimethylsilyloxy)-butyric acid methyl ester (6). To a suspension of NaH (60%, 730 mg; washed with hexane) in anhydrous DMF (6.6 mL) at 0° C. was slowly added a solution of (F3CCH2O)2POCH2COOCH3 (5 g, 15.7 mmol) in anhydrous DMF (6.6 mL). The mixture was stirred at room temperature for 1.5 h and a solution of Br(CH2)2OTBS (8.4 mL, 9.3 g, 39.2 mmol) was added in a freshly distilled HMPA (6.8 mL, 39.2 mmol). After stirring at room temperature for 48 h, the reaction mixture was diluted with ethyl acetate and poured into water. The organic phase was separated and the water layer was extracted with ethyl acetate. The combined organic extracts were washed with water, dried (MgSO4) and evaporated. The oily residue was purified by column chromatography on silica gel using hexane/AcOEt (98.5:1.5) as an eluent to yield a crystalline product 6 (2.3 g, 30%).6: 1H NMR (200 MHz, CDCl3) δ 0.03 [6H, s, Si(CH3)2], 0.87 [9H, s, Si-t-Bu], 0.92 (3H, d, J=6.8 Hz, CH-CH3), 2.08 (1H, m, one of CH2CH2CH), 2.21 (1H, m, one of CH2CH2CH), 3.39 and 3.44 (1H and 1H, each dd, J=10.5, 3.5 Hz, PCHCO), 3.60 and 3.72 (1H and 1H, each m, CH2OTBS), 3.77 (3H, COOCH3), 4.42 (4H, m, 2×CH2OP); HRMS (ESI) exact mass calcd for C15H28F6O6SiP (M+H+) 477.1314, measured 477.1297. |
30% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In hexane; N,N-dimethyl-formamide at 20℃; for 1.5h; Stage #2: 2-(tert-butyldimethylsilyloxy)ethyl bromide With N,N,N,N,N,N-hexamethylphosphoric triamide In hexane; N,N-dimethyl-formamide at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; | 12.3 A solution of potassium bis(trimethylsilyl)amide (414 mg, 1.973 mmol) in tetrahydrofuran (3 ml) was added dropwise at a slow speed to a mixture of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (627 mg, 1.973 mmol), 18-crown-6 (2.048 g, 7.750 mmol) and tetrahydrofuran (20 ml) at -78° C. under argon atmosphere. A solution of the intermediate 12(2) (584 mg, 1.409 mmol) in tetrahydrofuran (3 ml) was added dropwise at a slow speed to the mixture at -78° C. under argon atmosphere, and the mixture was stirred at -78° C. for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. The residue obtained by evaporation of the solvent under reduced pressure was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=15:1) to give the title compound (597 mg, 90.1%) as a pale yellow oil.1H-NMR (CDCl3) δ: 1.32 (9H, s), 3.71 (3H, s), 6.04 (1H, d, J=12.6 Hz), 6.90-6.98 (3H, m), 7.20-7.31 (3H, m), 7.36 (2H, d, J=9.6 Hz), 7.44 (1H, dd, J=2.4, 8.4 Hz), 7.59 (2H, d, J=8.7 Hz), 7.95 (1H, d, J=2.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 60% 2: 25% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: (2-ethoxyphenyl)[2-trifluoromethyl-4-formyl phenyl]sulfide In tetrahydrofuran at -78 - 20℃; for 1h; | 199.199A Example 199; (2-Ethoxyphenyl)[2-trifluoromethyl-4-(Z-((4-acetylpiperazin-1-yl)carbonyl)ethenyl) phenyl]sulfide; Example 199A; (2-Ethoxyphenyl)[2-trifluoromethyl-4-(Z-((4-carbomethoxyethenyl)phenyl]sulfide Bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (1.20 g, 3.71 mmole), and 18-crown-6 (3.56 g, 13.48 mmol) were dissolved in 22 ML of dry THF. The mixture was cooled to -78° C. and KN(SiMe3)2 (0.5 M in THF, 4.04 mmol) was added and stirred for 30 min. (2-Ethoxyphenyl)[2-trifluoromethyl-4-formyl phenyl]sulfide (1.10 g, 3.77 mmol, prepared according to the procedure of Example 1) in 13 ML of THF was added via cannulation.After 1 hr at that temperature, the cooling bath was removed and the mixture allowed to warm to ambient temperature.Saturated NH4Cl soln. was added and the mixture was extracted with ethyl acetate three times.The combined organics were dried over sodium sulfate, concentrated in vacuo and purified by medium pressure chromatography on silica gel to give 772 mg (60% yield) of the cis-isomer (Jolefinic=12.5 Hz) along with 322 mg (25% yield) of the trans-isomer (Jolefinic=12.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1-ethyl-piperidine; stannous trifluoromethanesulfonate In dichloromethane at 150℃; for 0.333333h; Microwave irradiation; Inert atmosphere; optical yield given as %de; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.1% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: 4-[4-(tert-butyl)phenoxy]-4'-(trifluoromethoxy)biphenyl-3-carbaldehyde In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; | 12.3 (3) Preparation of the intermediate 12(3).; A solution of potassium bis(trimethylsilyl)amide (414 mg, 1.973 mmol) in tetrahydrofuran (3 ml) was added dropwise at a slow speed to a mixture of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (627 mg, 1.973 mmol), 18-crown-6 (2.048 g, 7.750 mmol) and tetrahydrofuran (20 ml) at -78 °C under argon atmosphere. A solution of the intermediate 12(2) (584 mg, 1.409 mmol) in tetrahydrofuran (3 ml) was added dropwise at a slow speed to the mixture at -78 °C under argon atmosphere, and the mixture was stirred at -78 °C for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction mixture. The residue obtained by evaporation of the solvent under reduced pressure was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane : ethyl acetate = 15 : 1) to give the title compound (597 mg, 90.1 %) as a pale yellow oil. 1H-NMR (CDCl3) δ: 1.32 (9H, s), 3.71 (3H, s), 6.04 (1H, d, J = 12.6 Hz), 6.90-6.98 (3H, m), 7.20-7.31 (3H, m), 7.36 (2H, d, J = 9.6 Hz), 7.44 (1H, dd, J = 2.4, 8.4 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.95 (1H, d, J = 2.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: C13H14O3 In tetrahydrofuran; mineral oil at -78℃; for 1h; Inert atmosphere; | 4.1.13. (5R,2Z,6E)-Methyl 5-acetoxy-7-phenylhepta-2,6-dienoate 17 To an ice-cold solution of IBX (0.51 g, 0.18 mmol) in DMSO (2 mL), was added a solution of 13 (0.2 g, 0.91 mmol) in anhydrous CH2Cl2 and the reaction mixture was stirred at 25 °C for 3 h. The mixture was diluted with CH2Cl2 (2 mL). The solution was stirred for 4 h, filtered through a Celite pad, and the pad was washed with CH2Cl2 (3 mL). The combined filtrates were washed with H2O (4 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the aldehyde, (0.18 g, 92%) which was used directly after flash chromatography for the next reaction.CommentTo a suspension of NaH (60% dispersion in mineral oil, 0.034 g, 0.90 mmol) under an N2 atmosphere in dry THF (2 mL) was added bis-(2,2,2-trifluoroehtyl)(methoxy-carbonyl methyl) phosphonate (0.3 mL, 0.99 mmol) at 0 °C. After the mixture was stirred for 30 min at the same temperature, the reaction mixture was cooled to -78 °C, and then a solution of the aldehyde (0.18 g, 0.82 mmol) in dry THF was added dropwise. After stirring for 1 h, the reaction mixture was diluted with 5 mL of ether and quenched by the slow addition of 2 mL of water. The reaction mixture was extracted with ether (2 × 3 mL). The combined organic extracts were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue upon purification by column chromatography (ethyl acetate/hexane, 2:8) afforded pure (5R,2Z,6E)-methyl-5-acetoxy-7-phenylhepta-2,6-dienoate 17 (0.16 g, 84%) as a colorless oil; (c 1.45, CHCl3); IR: ν 1720, 1628, 1485, 1260 cm-1; 1H NMR (200 MHz, CDCl3): δ 7.40-7.22 (5H, m), 6.62 (1H, d, J = 16.0 Hz), 6.27 (1H, dd, J = 16.0, 7.0 Hz), 6.11 (1H, dd, J = 8.0, 5 Hz), 5.89 (1H, d, J = 8.0 Hz), 5.52 (1H, m), 3.72 (3H, s), 3.11 (2H, t, J = 7.0 Hz), 2.08 (3H, s); 13C NMR (50 MHz): δ 17.5, 166.8, 144.2, 133.1, 131.9, 129.1, 128.8, 127.9, 126.5, 122.0, 73.7, 51.2, 34.0, 21.1; ESIMS: m/z 297 (M+Na)+ Anal. Calcd for C16H18O4: C, 70.07; H, 6.57. Found: C, 70.18; H, 6.62. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.333333h; Inert atmosphere; Stage #2: C14H18BrNO2 In tetrahydrofuran; toluene at -78℃; for 1h; Inert atmosphere; | Z-Enoate 4: To a solution of 18-crown-6 (3.2 g, 12.0 mmol, 5 equiv.) in THF (18 mL) at -78 °C was added (CF3CH2O)2POCH2CO2CH3 (764 μL, 3.60 mmol, 1.5 equiv.), followed by dropwise addition of KHMDS in toluene (0.5M, 7.2 mL, 1.5 equiv.). After 20 min, exo aldehyde 12 (750 mg, 2.40 mmol, 1 equiv.) in THF (9.6 mL) was added via cannula. After 1 hour, excess anion was quenched at -78 °C by the addition of saturated aqueous ammonium chloride solution:water [1:1] (10 mL) and the reaction mixture was allowed to warm to room temperature. The solvent was removed under reduced pressure and the mixture was extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, eluting with 50% ethyl acetate:hexanes) provided Z-enoate 4 (703 mg, 80%) as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 29% 2: 15% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran Inert atmosphere; Stage #2: C12H12O6 In tetrahydrofuran at -10℃; for 22h; Inert atmosphere; stereoselective reaction; | 4.1.3. (+)-goniobutenolide A (1) and (-)-goniobutenolide B (2) Solution of 12 (0.364 g,1.24 mmol) in 90% TFA (5 mL) was stirredfor 30 min minutes at 0 C and then for additional 1 h at roomtemperature. The mixture was concentrated by co-distillation withtoluene and the residue was purified by flash column chromatography(24:1 CH2Cl2/MeOH) to afford pure hygroscopic syrup 14(0.347 g, 100%), [a]D 73.8 (c 1.0, EtOH), Rf 0.26 (24:1 CH2Cl2/MeOH). IR (KBr): nmax 3411 (OH), 1786 (C O). HRMS (ESI): m/e297.0602 (M HCOO), calcd for C13H13O8: 297.0616. To a cooled(10 C) and stirred suspension of 95% NaH (0.036 g, 1.51 mmol) indry THF (4 mL) was added dropwise [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (reagent B; 0.3 mL,1.45 mmol). The resulting mixturewas stirred in argon atmospherefor 0.5 h and a solution of 14 (0.190 g, 0.75 mmol) in dry THF (4 mL)was added. After being stirred at 10 C in argon atmosphere for22 h the mixture was poured into 5% aq HCl (20 mL) and theresulting suspension was extracted first with Et2O (3 10 mL) andthen with EtOAc (3 10 mL). Combined organic solutions werewashed with brine, dried and concentrated. Purification by flashcolumn chromatography (4:1 Et2O/light petroleum) followed bypreparative TLC (19:1 iPr2O/MeOH, three successive developmentsfor 1 and 2) afforded pure 1 (0.052 g, 29%) and 2 (0.026 g, 15%).4.1.3.1. ()-goniobutenolide A (1). Colourless syrup, [a]D86.8 (c0.4, CHCl3), Rf 0.28 (19:1 iPr2O/MeOH), lit [1]. [a]D82.0 (c 0.25,CHCl3). Both 1H and 13C NMR data of compound 1 are consistentwith the naturally occurring goniobutenolide A [1], and are in goodagreement with the data previously reported by us [16].4.1.3.2. ()-goniobutenolide B (2). Colourless sticks, mp142e145 C (CH2Cl2), [a]D 39.0 (c 0.1, CHCl3), Rf 0.33 (19:1DIPE/MeOH), lit [1]. mp 148e149 C, [a]D36.5 (c 0.2, CHCl3). 1Hand 13C NMR data of compound 2 are consistent with the naturallyoccurring goniobutenolide B [1], and are in good agreement withthe data previously reported by us [16]. |
33.333 % de | With sodium hydride In tetrahydrofuran at -10℃; for 22.5h; Inert atmosphere; Overall yield = 45 %; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: (R)-5-acetoxy-2(E)-hexenal In tetrahydrofuran; mineral oil at -78℃; for 2.16667h; Inert atmosphere; | Compound 6 A solution of compound 4 (790 mg, 6.12 mmol) and acrolein (1.23 mL, 18.48 mmol) in dry CH2Cl2 (110 mL) was first bubbled with nitrogen flow, to which Hoveyda Grubbs second generation catalyst (0.038, 0.061 mmol) was added at once and the resulting mixture was heated under nitrogen at 40oC for 30 min. After completion of the reaction, the mixture was cooled to room temperature and the solvent was evaporated in vacuum. The crude residue was purified by flash column chromatography on silica gel (30/70 v/v ethyl acetate/hexane) to give compound 5 (885 mg, 92%). To a cooled (0oC) suspension of NaH (274 mg, 11.34 mmol) in dry THF (5 mL) under N2 atmosphere was added bis-(2,2,2-trifluoroethyl)(methoxy carbonyl methyl)phosphonate (1.2 g, 5.67 mmol) in dry THF (5 mL) and was allowed to stir for 30 min and the reaction temperature to brought -78oC, then a solution of aldehyde (885mg, 5.67 mmol) in dry THF (5 mL) was added drop wise over a period of 10 min. The resulting mixture was stirred for 2 h at -78oC. After completion of the reaction, the reaction mixture was quenched with saturated NH4Cl and extracted into diethyl ether (3 x 10 ml). The combined organic phase was dried over anh. Na2SO4 and solvent was evaporated under reduced pressure to obtain crude product, which was purified over silica gel column chromatography using (20/80 v/v ethyl acetate/hexane) to afford compound 6 (0.91 g, 76% yield) as pale colourless liquid. [α]D25 = -4.7 (c 1, CHCl3). IR (Neat): 2923, 2852, 1736, 1719, 1640, 1602, 1439, 961, 823, 771 cm-1. 1HNMR (300MHz, CDCl3): δ 7.38 (dd, 1H, J = 11.9, 14.9 Hz); 6.52 (t, 1H, J = 11.0 Hz), 5.96 (dd, 1H, J = 8.0, 15.0 Hz), 5.60 (d, 1H, J = 11.0 Hz), 5.01-4.94 (m, 1H), 3.70 (s, 3H), 2.50-2.38 (m, 2H), 2.00 (s, 3H), 1.21(d, 3H, J = 11.0 Hz). 13CNMR (75MHz, CDCl3): δ 170.4, 166.6, 144.5, 139.2, 129.4, 116.9, 69.6, 51.0, 39.2, 21.7, 19.6. HRMS (ESIMS) for C11H16O4Na (M+Na) : m/z 235.0952 cal 235.0946. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; Inert atmosphere; Stage #2: (3α,5α,6β,22R)-22-tert-butyldimethylsilyloxy-3,5-cyclo-6-methoxy-24-norcholan-23-al In tetrahydrofuran; toluene at -78 - -40℃; for 0.5h; Inert atmosphere; | 6 2.2.6 (3α,5α,6β,22S,23Z)-22-tert-Butyldimethylsilyloxy-3,5-cyclo-6-methoxy-26,27-dinorcholest-23-en-25-oic acid methyl ester (14) 2.2.6 (3α,5α,6β,22S,23Z)-22-tert-Butyldimethylsilyloxy-3,5-cyclo-6-methoxy-26,27-dinorcholest-23-en-25-oic acid methyl ester (14) A solution of methyl O,O'-bis(2,2,2-trifluoroethyl)phosphonoacetate (400 μl, 1.97 mmol) and 18-crown-6 (2.6 g, 9.85 mmol) in anhydrous THF (5 ml) was cooled to -78 °C under argon and treated with 0.5 M KN(TMS)2 in toluene (3.94 ml, 1.97 mmol). Aldehyde 12 (760 mg, 1.64 mmol) was added and the resulting mixture was warmed to -40 °C and stirred for 30 min. Then saturated NH4Cl was added and the organic phase was extracted with EtOAc. The extracts were dried over anhydrous Na2SO4 and the solvent was evaporated. The residue was purified by column chromatography (petroleum ether/EtOAc = 10:1) to give α,β-unsaturated ester 14 (700 mg, 83%) as colorless oil; 1H NMR (500 MHz, CDCl3) δ: -0.04 (3H, s, OSiMe2t-Bu), 0.03 (3H, s, OSiMe2t-Bu), 0.43 (1H, dd, J 7.9, 5.1 Hz, H-4), 0.64 (1H, m, H-4), 0.72 (3H, s, H-18), 0.89 (9H, s, OSiMe2t-Bu), 0.92 (3H, d, J 6.7 Hz, H-21), 1.01 (3H, s, H-19), 2.78 (1H, m, H-6), 3.33 (3H, s, OMe), 3.72 (3H, s, CO2Me), 5.27 (1H, d, J 7.8 Hz, H-24), 5.69 (1H, dd, J 11.9, 1.1 Hz, H-22), 6.32 (1H, dd, J 11.9, 7.8 Hz, H-23); 13C NMR (125 MHz, CDCl3) δ: -4.97 q, -4.11 q, 12.17 q, 12.95 q, 13.06 t, 18.10 s, 19.27 q, 21.46 d, 22.78 t, 24.27 t, 24.94 t, 25.81 (3q), 27.45 t, 30.52 d, 33.34 t, 34.97 t, 35.26 s, 40.42 t, 42.63 s, 43.35 s, 43.46 d, 47.92 d, 51.28 q, 52.24 d, 56.56 q, 56.69 d, 70.55 d, 82.42 d, 116.72 d, 155.79 d, 166.07 s. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; Inert atmosphere; Stage #2: 22(R)-22-acetoxy-3α,5-cyclo-6β-methoxy-24-nor-5α-cholane-23-al In tetrahydrofuran; toluene at -78 - -40℃; for 0.5h; Inert atmosphere; | 6 (3α,5α,6β,22S,23Z)-22-Acetoxy-3,5-cyclo-6-methoxy-26,27-dinorcholest-23-en-25-oic acid methyl ester (15) Compound 15 (544 mg, 82%, de 80%) was prepared as colorless oil from aldehyde 13 (prepared according to [19], 600 mg, 1.440 mmol) in the same manner as described for alkene 12; 1H NMR (500 MHz, CDCl3) δ: 0.42 (1H, dd, J 7.6, 5.2Hz, H-4), 0.64 (1H, t, J 4.2Hz, H-4), 0.73 (3H, s, H-18), 0.99 (3H, d, J 7.0Hz, H-21), 1.01 (3H, s, H-19), 2.06 (3H, s, OAc), 2.76 (1H, br s, H-6), 3.31 (3H, s, OMe), 3.73 (3H, s, CO2Me), 5.81 (1H, d, J 11.5Hz, H-22), 6.15 (1H, dd, J 11.5, 7.2Hz, H-23), 6.20 (1H, d, J 7.2Hz, H-24); 13C NMR (125 MHz, CDCl3) δ: 12.21q, 13.01t, 13.82q, 19.26q, 21.05d, 21.47q, 22.80t, 24.04t, 24.93t, 26.97t, 30.52d, 33.32t, 34.86t, 35.26 s, 40.28t, 40.59d, 42.71s, 43.31s, 47.98d, 51.49d, 52.60q, 56.50d, 56.54q, 74.20d, 82.32d, 119.25d, 149.675d, 165.64s, 170.64s; MS (APCI) m/z (rel. int., %): 413 [MH-AcOH]+ (20), 381 [MH-OAc-MeOH]+ (100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: (2S,3R,4S,5S)-2,3,4,5-tetrakis(benzyloxy)hexanal In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; | To a stirred suspension of NaH (0.087, 3.6 mmol) indry THF (6 mL) at 0 °C under a nitrogen atmosphere was addedbis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (0.68 mg,2.17mmol) in dry THF (3 mL). The mixture was stirred for 30 min at 0 °C and thenthe temperature was brought to -78 °C. To this mixture, a solution of aldehyde 27 (0.95g, 1.81 mmol) in dry THF (5 mL)was added dropwise and stirred it for another 1h. After completion of thereaction, the mixture was diluted with Et2O (5 mL) and quenched byslow addition of water (3 mL) and extracted with Et2O. The organicextract was washed with brine solution, dried over Na2SO4and concentrated under reduced pressure. The residue was purified on silica gel columnchromatography (hexane/EtOAc, 9:1) to give the 28b (0.88 g, 84%) as a viscous liquid. [α]25D = -42.9 (c = 0.9,CHCl3); IR (neat): umax 2925, 2856, 1721, 1454,1199, 1063, 737, 697 cm-1; 1H NMR (300 MHz, CDCl3):δ 7.38-7.22 (m, 20H), 6.30 (m, 1H), 5.80 (d, J = 12.0 Hz, 1H), 5.26 (dd, J= 5.3, 6.0 Hz, 1H), 4.8-4.20 (m, 8H), 3.93 (dd, J = 7.5, 3.0 Hz, 1H), 3.74 (dd, J= 7.5, 3.7 Hz, 1H), 3.54 (s, 3H), 3.38 (m, 1H), 1.05 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ165.9, 148.3, 138.9, 138.7, 138.3, 137.9, 128.5, 128.4, 128.3, 128.2, 127.8,127.5, 127.2, 121.3, 81.5, 80.9, 74.9, 74.6, 73.9, 71.1, 51.2, 15.7; HRMS (ESI)calcd. for C37H40O6Na, [M+Na]+603.2723, found: 603.2726. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.25h; Stage #2: 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetaldehyde In tetrahydrofuran; toluene at -78℃; for 0.75h; | 32.32A (Z)-Methyl 5-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate 32A. (Z)-Methyl 5-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)pent-2-enoate To a solution of bis (2,2,2-trifluoroethyl)(methoxycarbonylmethyl) phosphonate (0.113 mL, 0.535 mmol) and 18-crown-6 (471 mg, 1.78 mmol) in THF (10 mL) at -78° C. was added KHMDS (1.07 mL of a 0.5 M solution in toluene; 0.535 mmol) dropwise. The reaction mixture was stirred at -78° C. for 15 min, and then a solution of 2-(1-(3-phenoxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetaldehyde (11B compound; 120 mg, 0.357 mmol) in THF (4 mL) was added slowly over 15 min. The reaction mixture was stirred at -78° C. for 30 min and then was quenched with sat. aq. NH4Cl (1 mL), warmed to rt and extracted with EtOAc (3*5 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 20% gradient EtOAc:hexanes) to give the title compound (130 mg, 0.331 mmol, 93% yield) as a clear, light yellowish oil. LCMS, [M+H]+=393.2. 1H NMR (CDCl3) δ: 7.38-7.31 (m, 2H), 7.31-7.26 (m, 1H), 7.19-7.13 (m, 2H), 7.12-7.07 (tt, J=7.4, 1.1 Hz, 1H), 7.04-6.98 (m, 2H), 6.89-6.84 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 6.28-6.20 (dt, J=11.4, 7.5 Hz, 1H), 5.82-5.77 (dt, J=11.3, 1.6 Hz, 1H), 3.85 (s, 2H), 3.74 (s, 3H), 2.69-2.60 (m, 2H), 2.12-1.97 (m, 4H), 1.79-1.65 (m, 4H), 1.35-1.27 (m, 2H); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Stage #2: (S)-2-(tert-butyldimethylsilanyloxy)hexanal In tetrahydrofuran; mineral oil at -78℃; for 2h; | 4 4.1.4. (S,Z)-Methyl 4-(tert-butyldimethylsilyloxy)oct-2-enoate 10 To a solution of 6 (4.5 g, 19.40 mmol) in EtOAc (100 mL) was added IBX (13.6 g, 48.49 mmol) at room temperature and then refluxed for 4 h. After completion of the reaction, the reaction was filtered through a short pad of Celite and the Celite pad was washed with EtOAc (2 x 50 mL). The organic layer was washed with a saturated NaHSO3 solution (2 x 50 mL), brine (1 x 50 mL), and dried over anhydrous Na2SO4 and concentrated. The crude residue was purified by column chromatography using (hexane/ethylacetate) (90:10) as eluent to obtain pure aldehyde (4.1 g, 92% yield) as a colorless liquid. To a cooled solution (0°C) of Still-Gennari phosphonate (6.08 g, 19.13 mmol) in dry THF (50 mL), was slowly added NaH (60%) (0.765 g, 19.13 mmol) and the reaction mixture was stirred for 30 min at same temperature. The reaction mixture was cooled to -78°C and a solution of aldehyde obtained above in THF (30 mL) was added dropwise and stirred for 2 h. After completion of the reaction, it was quenched with saturated NH4Cl, and extracted into ethylacetate. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography using (hexane/ethylacetate) (94:6) to give product 10 (4.22 g, 85% yield) as a colorless liquid. [α]D25 =+70.4 (c 2.8, CHCl3). IR (neat): 2955, 2932, 2858, 1726, 1649, 1465, 1254, 1184, 1083, 834, 776 cm-1. 1H NMR (300 MHz, CDCl3): δ = 6.16 (dd, J = 11.7, 8.2 Hz, 1H), 5.69 (dd, J = 11.7, 1.2 Hz, 1H), 5.31-5.26 (m, 1H), 3.71 (s, 3H), 1.57-1.24 (m, 6H), 0.89-0.86 (m, 12H), 0.05 (s, 3H) 0.01 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.3, 154.3, 116.9, 68.7, 51.2, 37.0, 27.3, 25.8, 22.5, 18.1, 14.0, 4.6, 4.9 ppm. HRMS (ESI): calcd for C15H30O3NaSi[M+Na]+ 309.1856; found 309.1852. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at 0℃; for 0.5h; Stage #2: C25H42O5Si In tetrahydrofuran at -78℃; for 2h; | 12 4.1.12 (2Z,4S,5S,6Z,8S)-Methyl 4-(benzyloxy)-8-(tert-butyldimethylsilyloxy)-5-(methoxymethoxy)dodeca-2,6-dienoate 17 To a cooled (0°C) solution of alcohol 16 (327 mg, 0.723 mmol) in dry DCM (10 mL) was added Dess-Martin reagent (613 mg, 1.446 mmol) and stirred at room temperature for 4 h. After completion of the reaction, a saturated Na2S2O3 solution was added and stirring was continued for 10 min. The reaction mixture was diluted with a saturated NaHCO3 solution and the aqueous layer was extracted into DCM (3 x 30 mL), and dried over anhydrous Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate 92:8) to give the corresponding aldehyde (299 mg, 92% yield), which was used as such for further reaction. To cooled (0°C) solution of (F3CCH2O)2POCH2COOMe (329 mg, 1.034 mmol), 18-crown-6 (853 mg, 3.23 mmol) in anhydrous THF (10 mL) was added KHMDS (0.97 mL, 0.969 mmol) and the reaction mixture was stirred for 30 min at same temperature. The reaction mixture was cooled to -78°C, after which a solution of aldehyde (291 mg, 0.646 mmol) in dry THF (5 mL) was added and stirred for 2 h at the same temperature. After completion of the reaction, the reaction was quenched with saturated NH4Cl, and extracted into ethyl acetate. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate (93:7) to give product 17 (281 mg, 86% yield) as colorless liquid. [α]D25 = +80.2 (c 1.9, CHCl3). IR (neat): 3028, 2953, 2931, 2857, 1723, 1648, 1463, 1393, 1252, 1197, 1151, 1102, 1071, 1037, 833, 774, 697 cm-1. 1H NMR (300 MHz, CDCl3): δ = 7.35-7.23 (m, 5H), 6.38 (dd, J = 11.6, 8.6 Hz, 1H), 5.95 (d, J = 11.6 Hz, 1H), 5.63 (dd, J = 11.3, 9.0 Hz, 1H), 5.46-5.41 (m, 1H), 5.02 (dd, J = 8.3, 2.7 Hz, 1H), 4.66 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 12.0 Hz, 1H), 4.55-4.50 (m, 2H), 4.49-4.44 (m, 1H), 4.41 (d, J = 12.0 Hz 1H), 3.68 (s, 3H), 3.29 (s, 3H), 1.42-1.21 (m, 6H), 0.90-0.83 (m, 12H), 0.04 (s, 3H), 0.01 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8, 148.6, 139.5, 137.8, 128.2, 128.1, 127.6, 124.9, 121.4, 93.5, 77.3, 73.3, 72.0, 68.8, 55.4, 51.3, 38.4, 27.5, 25.8, 22.7, 18.1, 14.1, -4.4, -4.9 ppm. HRMS (ESI): calcd for C28H50O6NSi [M+NH4]+ 524.3402; found 524.3400. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.666667h; Stage #2: (3aS,4R,6R,6aS)-6-(benzyloxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde In tetrahydrofuran; toluene at -78℃; for 2h; stereoselective reaction; | (Z)-Methyl 3-((3aR,4S,6R,6aS)-6-(benzyloxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)acrylate (8) Asolution of ethyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (1.0mL, 4.11 mmol) and 18-crown-6 (2.3 g, 8.55 mmol) in THF (60 mL), was cooled to-78 °C and treated dropwise over 30 min with a solution of potassiumbis(trimethylsilyl)amide (8.2 mL, 4.11 mmol) in toluene (0.5 M in Toluene).After an additional 10 min, a solution of aldehyde 7 (1.0 g, 3.42 mmol)in THF (7.5 mL) was transferred to the reaction mixture. After the reaction wasstirred for 2 h at -78 °C, a saturated solution of NH4Cl (100 mL)was added. The mixture was warmed to 23 °C, and extracted with EtOAc (2 x 100mL). The combined organic layers were dried over anhydrous Na2SO4,filtered, and concentrated. Purification of the crude product (Z/E =83:17) by flash chromatography (hexanes/EtOAc 10:1) furnished pure 8 (715mg, 60%) as colorless oil. [α]20D = 87.5 (c =1.2, CHCl3); 1H NMR(CDCl3, 300 MHz): δ 7.38-7.28(m, 5H), 6.43-6.33 (m, 1H), 5.96 (d, J = 11.8 Hz, 1H), 5.07-5.01 (m, 2H), 4.77-4.71 (m, 1H), 4.67 (d, J =12.1 Hz, 1H), 4.54 (d, J = 12.1 Hz, 1H), 3.85-3.74 (m, 3H), 3.72(s, 3H), 1.44 (s, 3H), 1.28 (s, 3H) ; 13CNMR (CDCl3, 125 MHz): δ166.2, 145.6, 138.1, 128.4, 127.9, 127.7, 120.2, 112.5, 82.6, 81.1, 80.7, 79.1,73.6, 68.1, 51.5, 25.9, 24.8; HRMS(ESI) calculated for C19H24O6Na [M+Na]+:371.1456; found: 371.1465. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | General procedure: To a solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1) (40 muL, 0.188 mmol) inanhydrous THF (1.9 mL) was added i-PrMgBr (0.77 mol/L in THF, 269 muL, 0.207 mmol), and thesolution was stirred at 0 C for 1 h under argon. After adding triethylamine (53 muL, 0.377 mmol)and 2-phenylpropionyl chloride (5a) (56 muL, 0.377 mmol), the mixture was stirred at 0 C for 1 hunder argon. The reaction mixture was treated with sat. NH4Cl aq (2 mL) and then extracted withCHCl3 (20 mL x 3). The extract was dried over anhydrous MgSO4, filtered, and concentrated invacuo. The oily residue was purified by silica gel column chromatography [n-hexane-AcOEt (12.5:1 to 11:1)] to afford allenyl ester 6a (34.7 mg, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With isopropylmagnesium bromide In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: diphenylacetic acid chloride With triethylamine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | General procedure for the preparation of allenyl esters 6a-e, 8a,f-h General procedure: To a solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1) (40 μL, 0.188 mmol) inanhydrous THF (1.9 mL) was added i-PrMgBr (0.77 mol/L in THF, 269 μL, 0.207 mmol), and thesolution was stirred at 0 °C for 1 h under argon. After adding triethylamine (53 μL, 0.377 mmol)and 2-phenylpropionyl chloride (5a) (56 μL, 0.377 mmol), the mixture was stirred at 0 °C for 1 hunder argon. The reaction mixture was treated with sat. NH4Cl aq (2 mL) and then extracted withCHCl3 (20 mL x 3). The extract was dried over anhydrous MgSO4, filtered, and concentrated invacuo. The oily residue was purified by silica gel column chromatography [n-hexane-AcOEt (12.5:1 to 11:1)] to afford allenyl ester 6a (34.7 mg, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With isopropylmagnesium bromide In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: α-methyl-4-nitro-phenylacetyl chloride With triethylamine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | General procedure for the preparation of allenyl esters 6a-e, 8a,f-h General procedure: To a solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1) (40 μL, 0.188 mmol) inanhydrous THF (1.9 mL) was added i-PrMgBr (0.77 mol/L in THF, 269 μL, 0.207 mmol), and thesolution was stirred at 0 °C for 1 h under argon. After adding triethylamine (53 μL, 0.377 mmol)and 2-phenylpropionyl chloride (5a) (56 μL, 0.377 mmol), the mixture was stirred at 0 °C for 1 hunder argon. The reaction mixture was treated with sat. NH4Cl aq (2 mL) and then extracted withCHCl3 (20 mL x 3). The extract was dried over anhydrous MgSO4, filtered, and concentrated invacuo. The oily residue was purified by silica gel column chromatography [n-hexane-AcOEt (12.5:1 to 11:1)] to afford allenyl ester 6a (34.7 mg, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With isopropylmagnesium bromide In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: α-methyl 4-methoxyphenylacetyl chloride With triethylamine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | General procedure for the preparation of allenyl esters 6a-e, 8a,f-h General procedure: To a solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1) (40 μL, 0.188 mmol) inanhydrous THF (1.9 mL) was added i-PrMgBr (0.77 mol/L in THF, 269 μL, 0.207 mmol), and thesolution was stirred at 0 °C for 1 h under argon. After adding triethylamine (53 μL, 0.377 mmol)and 2-phenylpropionyl chloride (5a) (56 μL, 0.377 mmol), the mixture was stirred at 0 °C for 1 hunder argon. The reaction mixture was treated with sat. NH4Cl aq (2 mL) and then extracted withCHCl3 (20 mL x 3). The extract was dried over anhydrous MgSO4, filtered, and concentrated invacuo. The oily residue was purified by silica gel column chromatography [n-hexane-AcOEt (12.5:1 to 11:1)] to afford allenyl ester 6a (34.7 mg, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With isopropylmagnesium bromide In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: 2-phenylpropionyl chloride With triethylamine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | General procedure for the preparation of allenyl esters 6a-e, 8a,f-h To a solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (1) (40 μL, 0.188 mmol) inanhydrous THF (1.9 mL) was added i-PrMgBr (0.77 mol/L in THF, 269 μL, 0.207 mmol), and thesolution was stirred at 0 °C for 1 h under argon. After adding triethylamine (53 μL, 0.377 mmol)and 2-phenylpropionyl chloride (5a) (56 μL, 0.377 mmol), the mixture was stirred at 0 °C for 1 hunder argon. The reaction mixture was treated with sat. NH4Cl aq (2 mL) and then extracted withCHCl3 (20 mL x 3). The extract was dried over anhydrous MgSO4, filtered, and concentrated invacuo. The oily residue was purified by silica gel column chromatography [n-hexane-AcOEt (12.5:1 to 11:1)] to afford allenyl ester 6a (34.7 mg, 98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: C21H23IN4O4S With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: C22H48O3Si2 at 20℃; Stage #3: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate Further stages; | 16 Example 16 Compound 7 (300mg, 0.54mmol) was dissolved in THF (3mL) in, and cooled to -78 . LHMDS (0.56ml, 1M)Was added dropwise. After stirring for 30 minutes, the aldehyde 19 (140mg, 0.34mmol) was added dropwise. After 30 minutes, the system was raised to room temperature.Stirred overnight. Saturated NH4Cl solution (20 mL) quenched the reaction. With ethyl acetate (3x30mL) repeatedly extracted. The combined organicPhase was washed with saturated brine (30 mL), dried over anhydrous Na2SO4. After the spin-dry a silica gel column to give a colorless oil 20. 20 (100 mg, 0 . 13mmol) dissolved in MeOH (5 ml) in, and to 0 °C. CSA (10 mg, 0 . 04mmol) into the system. 0 °C conditions, reaction 3 hours. Et3N (5uL, 0 . 04mmol) quenching reaction. Decompression turns on lathe does low-boiling point solvent. Silica gel column to separate to obtain a colorless oily 21 (83 mg, 98%, C10/11E/Z=6:1). 0 °C conditions, NaHCO3(69 mg, 0 . 82mmol) and Dess-Martinperiodinane (150 mg, 0 . 35mmol) successive added to the compound 6 (150 mg, 0 . 24mmol) of the DCM (5 ml) solution. Reaction to continue to 1 hour later, pressure directly turns on lathe does colorless oily obtained by separation of the silica gel column (140 mg, 94%), and used in the next step directly.KHMDS (714uL, 0 . 36mmol, 0 . 5M) at -78 ° C slowly added under the condition of 18-crown -6 (100 mg, 0 . 36mmol) and (CF3CH2) P (O) CH2CO2Me (114 mg, 0 . 36mmol) THF of (7 ml) in the system. 15 minutes later, the-step reaction of aldehydes on THF solution is added dropwise to the reaction system. - 78 °C under the conditions of reaction sleepovers. Saturated NH4Cl solution (20 ml) quenching the reaction. Ethyl acetate (3x30mL) repeated extraction. Combined with the phase, using the saturated salt water (30 ml) washing, anhydrous Na2SO4drying. turns on lathe does silica gel column to separate to obtain a colorless oily after 23 (147 mg, 96%, C10/11E/Z=6:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With Tris(3,6-dioxaheptyl)amine; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Stage #2: 2-(3,5-bis(trifluoromethyl)phenyl)pyrimidine-4-carbaldehyde In tetrahydrofuran at -78℃; for 2h; | 1 (Z)-methyl 3 -(2-(3 , 5 -bi s(trifluoromethyl)phenyl)pyrimidin-4-yl)acrylate Methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (827 mg, 2.6 mmol) and tn s(2-(2- methoxyethoxy)ethyl)amine (840 mg, 2.6 mmol) were dissolved in 50 mL of THF. The mixture was cooled to -78 °C. KHIVIDS (5 mL, 2.5 mmol, 0.5 N in THF) was added. After stirring at -78 °C for 0.5 h, 2-(3 , 5 -bi s(trifluoromethyl)phenyl)pyrimidine-4-carbaldehyde (6; 770 mg, 2.4 mmol) in 10 mL of THF was added. The mixture was stirred at -78 °C for 2 h, quenched with NH4C1 aqueous solution and extracted with EtOAc (50 mL X 3). The combined organic solvents were dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography (25% EtOAc/petroleum ether) to give 690 mg of (Z)-methyl 3 -(2-(3 , 5 -bi s(trifluoromethyl)phenyl)pyrimidin-4-yl)acrylate 7 (76% yield). LCMS: m/z 377.0 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.0833333h; Stage #2: (4S)-4-(tert-butyl(dimethyl)silyloxy)pentanal In tetrahydrofuran; toluene at -78 - -60℃; | 4.2.12. Methyl (6S,2Z)-6-tert-butyldimethylsilyloxyhept-2-enoate(38). A solution of bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (95%, 1.25mL, 11.1mmol) and 18-crown-6 (7.23g, 22.2mmol) in THF (100mL) was cooled to -78°C. Potassium hexamethyldisilazide (0.5M in toluene, 10.9mL, 5.5mmol) was added. After 5min, the aldehyde 37 (1.2g, 5.55mmol) in THF (19mL) was added dropwise so that the temperature remained below -60°C. The reaction mixture was stirred for 30min at -78°C before saturated aqueous ammonium chloride (18mL) and water (50cm) were added. The mixture was extracted using ether (3×50mL) and the organic extracts were washed with water (50mL) and brine (50mL) then dried (MgSO4). After concentration under reduced pressure, chromatography of the residue using 2% ether in light petroleum gave the title compound 38 (1.06g, 70%), Rf 0.16 in 2% ether in light petroleum, [α]D23 +14.9 (c 1.37 in CHCl3); νmax/cm-1 2956, 2931, 2858, 1730, 1647, 1439, 1257, 1174, 1092, 1041, 1007, 835 and 775; δH (CDCl3, 300MHz) 0.08 (6H, s, 2× SiCH3), 0.91 [9H, s, SiC(CH3)3], 1.18 (3H, d, J 6.0, 7-H3), 1.51-1.66 (2H, m, 5-H2), 2.68-2.78 (2H, m, 4-H2), 3.74 (3H, s, OCH3), 3.87 (1H, sext, J 6.0, 6-H), 5.80 (1H, dt, J 11.5, 2.0, 2-H) and 6.28 (1H, dt, J 11.5, 7.5, 3-H); δC (CDCl3, 75MHz) -4.5, -4.1, 18.4, 24.0, 26.0, 26.1, 39.1, 51.3, 68.5, 119.4, 151.0 and 167.1; m/z (CI) 290 (M++18, 10%) and 273 (M++1, 100); HRMS: M++NH4, found 290.2149. C14H32NO3Si requires 290.2146. The second fraction was the (E)-isomer of the title compound (52mg, 3%), Rf 0.10 in 2% ether in light petroleum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: C15H20O4 In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; | (Z)-Methyl 4-((4S,5R)-5-((S)-methoxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate General procedure: To a stirred solution of alcohol 9 (0.2 g, 0.75 mmol) in dry CH2Cl2 (4 mL) was added Dess-Martin periodinane (0.382 g, 0.90 mmol) at 0 °C, and the mixture was stirred for 1 h at rt. Then, the reaction mixture was quenched with a 1:1 mixture of saturated solutions of Na2S2O3 and NaHCO3 (10 mL), and extracted with CH2Cl2 (2 x 10 mL). The combined organic layer was washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated to furnish the corresponding aldehyde as a yellow liquid which was directly used in the next reaction. To a pre-cooled (0 oC) solution of Stille-Gennari phosphonate (0.240 mL, 1.13 mmol) in dry THF (2 mL), was added NaH (0.036 g, 1.5 mmol) and was stirred for 30 min at same temperature. The reaction mixture was cooled to -78 oC and a solution of aldehyde (0.2 g, 0.75 mmol) in THF (5 mL) was added drop wise and was stirred for 1 h. After completion of the reaction (monitored by tlc), it was cautiously quenched by addition of saturated NH4Cl solution (3 mL), poured into water (10 mL) and extracted with diethyl ether (3 x 15 mL). Combined organic layers were washed with brine (2 x 5 mL) and dried over Na2SO4. Evaporation of solvent gave the crude residue, which was concentrated and purified by column chromatography (Silica gel, 60-120 mesh, EtOAc:n-hexane, 0.5:9.5) to give 2 (0.180 g, 75 %) as a yellow syrup. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran at 0℃; for 0.5h; Inert atmosphere; Stage #2: C15H20O4 In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; | (Z)-Methyl 4-((4S,5R)-5-((S)-methoxy(phenyl)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-enoate General procedure: To a stirred solution of alcohol 9 (0.2 g, 0.75 mmol) in dry CH2Cl2 (4 mL) was added Dess-Martin periodinane (0.382 g, 0.90 mmol) at 0 °C, and the mixture was stirred for 1 h at rt. Then, the reaction mixture was quenched with a 1:1 mixture of saturated solutions of Na2S2O3 and NaHCO3 (10 mL), and extracted with CH2Cl2 (2 x 10 mL). The combined organic layer was washed with H2O (10 mL) and brine (10 mL), dried (Na2SO4) and concentrated to furnish the corresponding aldehyde as a yellow liquid which was directly used in the next reaction. To a pre-cooled (0 oC) solution of Stille-Gennari phosphonate (0.240 mL, 1.13 mmol) in dry THF (2 mL), was added NaH (0.036 g, 1.5 mmol) and was stirred for 30 min at same temperature. The reaction mixture was cooled to -78 oC and a solution of aldehyde (0.2 g, 0.75 mmol) in THF (5 mL) was added drop wise and was stirred for 1 h. After completion of the reaction (monitored by tlc), it was cautiously quenched by addition of saturated NH4Cl solution (3 mL), poured into water (10 mL) and extracted with diethyl ether (3 x 15 mL). Combined organic layers were washed with brine (2 x 5 mL) and dried over Na2SO4. Evaporation of solvent gave the crude residue, which was concentrated and purified by column chromatography (Silica gel, 60-120 mesh, EtOAc:n-hexane, 0.5:9.5) to give 2 (0.180 g, 75 %) as a yellow syrup. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; Inert atmosphere; | |
92% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.583333h; Inert atmosphere; | 3 Methyl (2Z,4£)-5-(tributylstannyl)penta-2,4-dienoate (69a) To a stirred solution of 18-crown-6 (13.1 g, 49.6 mmol, 4.0 equiv) and methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (67, 3.41 mL, 16.12 mmol, 1.3 equiv) in THF (62 mL) cooled to -78 °C was added KHMDS (0.5 M in toluene, 29.6 mL, 14.8 mmol, 1.2 equiv) and the solution was stirred for 5 min at -78 °C before the introduction of aldehyde 66 (4.28 g, 12.4 mmol, 1.0 equiv) in THF (5 mL). The resulting mixture was stirred 30 min at -78 °C and quenched with an aqueous saturated solution of NH4CI. The aqueous phase was extracted three times with EtOAc (3 x 40 mL) and the combined organic extracts were dried over MgS04, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (S1O2, hexanes:EtOAc, 19: l→9:l) to yield 69a (4.59 g, 11.4 mmol, 92% yield) as a pale yellow oil. 69a: Rf=0.31 (hexanes:EtOAc, 19: 1); IR (film): 2852, 1689, 1463, 1071, 990 cm"1; NMR (600 MHz, CDCI3) δ 7.82 (ddd, 7= 18.8, 10.7, 1.1 Hz, 1 H), 6.76 (dd, 7= 18.8, 1.0 Hz, 1 H), 6.51 (dd, 7= 11.0, 11.0Hz, 1 H), 5.59 (dt, 7= 11.4, 1.0Hz, 1 H), 3.74 (s, 3 H), 1.55-1.48 (m, 6H), 1.32 (h, 7=7.3 Hz, 6H), 0.98-0.94 (m, 6 H), 0.89 (t, 7=7.3 Hz, 9H) ppm;13C NMR (151 MHz, CDCI3) δ 166.85, 148.49, 147.05, 142.61, 115.51, 51.31, 29.21, 27.40, 13.83, 9.83 ppm; HR-MS (ESI-TOF): calcd for Cisfts W [M+H]+: 403.1657, found: 403.1649. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at 0 - 20℃; for 1.5h; Stage #2: 2-[(4S,5S)-5-{(S)-1-[(tert-butyldimethylsilyl)oxy]allyl}-2,2-dimethyl-1,3-dioxolan-4-yl]acetaldehyde In tetrahydrofuran; mineral oil at 0℃; for 1h; | 2.6 Synthesis of compound 17 A solution of (CF3CH2O)2P(O)CH2CO2CH3 (285 mg, 0.9 mmol) in dry THF (10 mL) was cooled at 0 °C and treated with NaH (45 mg, 60% in mineral oil, 1.12 mmol). The mixture was allowed to warm to room temperature and stirred for 1.5 h. Aldehyde 15 (210 mg, 0.67 mmol) in 5 mL of dry THF was added to the above suspension at 60 °C. After 1 h, the mixture was quenched with saturated aqueous NH4Cl (5 mL), extracted with EtOAc (3 × 10 mL), and dried. Removal of the solvent gave an oil which was subjected to silica gel flash column chromatography (EtOAc/petroleum ether, 1:16) to provide 17 (203 mg, 82%) as a colorless oil. [α]D24 = -164 (c 0.5, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 6.93 (dt, J = 11.6, 12.8 Hz, 1H), 5.94 (ddd, J = 16.4, 10.4, 5.6 Hz, 1H), 5.88 (d, J = 11.2 Hz, 1H), 5.40 (d, J = 17.2 Hz, 1H), 5.23 (d, J = 9.6 Hz, 1H), 4.27 (t, J = 6.4 Hz, 1H), 4.15-4.10 (m, 1H), 3.99 (t, J = 6.8 Hz, 1H), 3.71 (s, 3H), 3.08 (dd, J = 15.2, 7.6 Hz), 2.83 (ddd, J = 16.0, 10.4, 6.8 Hz, 1H), 1.47 (s, 3H), 1.33 (s, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.8, 147.1, 136.9, 120.7, 117.0, 108.4, 81.2, 72.6, 51.2, 30.0, 27.9, 25.9, 25.8, 18.5, -4.5, -4.6 ppm. HRMS (ESI): calcd. for C19H34O5SiNa [M + Na]+ , 393.2073; found 393.2059. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; Stage #2: tert-butyl 4-(formylmethyl)piperidine-1-carboxylate In tetrahydrofuran; toluene at -78 - 20℃; for 0.5h; | 18-1 (Z) -tert-butyl 4- (4-methoxy-4-oxobut-2-enyl) piperidine-1-carboxylate To a solution of methyl 2- (bis (2, 2, 2-trifluoroethoxy) phosphoryl) acetate (1.9 g, 6 mmol) and 18-crown-6 (3.96 g, 15 mmol) in dry THF (70 mL) at -78 was dropwise added KHMDS (15 mL, 7.5 mmol, 0.5 M in toluene) . After stirring at -78 for 0.5h, tert-butyl 4- (2-oxoethyl) piperidine-1-carboxylate (1.14 g, 5 mmol) in dry THF (5 mL) was added to the mixture at -78 and the resulting mixture stirred at rt for 0.5h. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and extracted with DCM (100 mL×3) . The combined organic layers was washed with brine (50 mL) , dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography (silica gel: 300-400 mesh, PE/EtOAc 40/1 to 20/1) to afford (Z) -tert-butyl 4- (4-methoxy-4-oxobut-2-enyl) piperidine-1-carboxylate (1.1 g, 78) . LRMS m/z (M-100) 184.1 found, 184.1 required |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: methyl 2-(bis((trimethylsilyl)oxy)phosphoryl)acetate With iodine; triphenylphosphine In chloroform at 20℃; for 0.25h; Inert atmosphere; Stage #2: With 1H-imidazole In chloroform at 20 - 50℃; for 0.75h; Inert atmosphere; Stage #3: 2,2,2-trifluoroethanol In chloroform at 60℃; for 5h; Inert atmosphere; | Methyl Bis(2,2,2-trifluoroethyl)phosphonoacetate (Still-Gennari reagent, 1) TMSBr (90 L, 0.691 mmol) was added at r.t. to a solution of trimethyl phosphonoacetate (2; 50.3mg, 0.276 mmol) in anhydrous CH2Cl2 (0.55 mL). After stirring at r.t. for 5 h under argon,evaporation of the reaction mixture in vacuo gave methyl2-{bis[(trimethylsilyl)oxy]phosphoryl}acetate (4), which was used without further purification.Ph3P (181 mg, 0.691 mmol) and I2 (175 mg, 0.691 mmol) were added to a solution of 4 in anhydrous CHCl3 (1.8 mL) at r.t. under argon. After stirring at r.t. for 15 min under argon, imidazole(188 mg, 2.76 mmol) was added. The reaction mixture was stirred for 15 min at r.t. and then for 30min at 50 °C. Afterwards, 2,2,2-trifluoroethanol (79 l, 1.10 mmol) was added and the reactionmixture was stirred at 60 °C for 5 h. After filtration of the reaction mixture, the filtrate wasevaporated in vacuo to give a crude product 1, which was purified by column chromatography[Silica Gel PSQ 60B: n-hexane-EtOAc (2:1)] to afford 1 (82.3 mg, 94%) as a colorless oil. IR (neat) 1747, 1265, 1174, 1072, 963 cm-1. 1H NMR (500 MHz, CDCl3) δ = 4.51-4.42 (m, 4H),3.78 (s, 3H), 3.17 (d, 2JH,P = 21.1 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ = 165.2 (d, 2JC,P = 4.5Hz), 122.5 (qd, 1JC,F = 277.1 Hz, 3JC,P = 8.2 Hz), 62.7 (qd, 2JC,F = 38.2 Hz, 2JC,P = 5.5 Hz), 53.1,33.8 (d, 1JC,P = 145.1 Hz). HRMS (ESI): m/z [M + Na]+ calcd for C7H9F6O5PNa: 340.9990; found:340.9982. Anal. Calcd for C7H9F6O5P: C, 26.43; H, 2.85. Found: C, 26.28; H, 2.89. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: phosphonoacetic acid trimethyl ester With iodine; triphenylphosphine In chloroform at 20℃; for 0.25h; Inert atmosphere; Stage #2: With 1H-imidazole In chloroform at 20 - 50℃; for 0.75h; Inert atmosphere; Stage #3: 2,2,2-trifluoroethanol In chloroform at 60℃; for 5h; Inert atmosphere; | Methyl Bis(2,2,2-trifluoroethyl)phosphonoacetate (Still-Gennari reagent, 1) General procedure: TMSBr (90 L, 0.691 mmol) was added at r.t. to a solution of trimethyl phosphonoacetate (2; 50.3mg, 0.276 mmol) in anhydrous CH2Cl2 (0.55 mL). After stirring at r.t. for 5 h under argon,evaporation of the reaction mixture in vacuo gave methyl2-{bis[(trimethylsilyl)oxy]phosphoryl}acetate (4), which was used without further purification.Ph3P (181 mg, 0.691 mmol) and I2 (175 mg, 0.691 mmol) were added to a solution of 4 in anhydrous CHCl3 (1.8 mL) at r.t. under argon. After stirring at r.t. for 15 min under argon, imidazole(188 mg, 2.76 mmol) was added. The reaction mixture was stirred for 15 min at r.t. and then for 30min at 50 °C. Afterwards, 2,2,2-trifluoroethanol (79 l, 1.10 mmol) was added and the reactionmixture was stirred at 60 °C for 5 h. After filtration of the reaction mixture, the filtrate wasevaporated in vacuo to give a crude product 1, which was purified by column chromatography[Silica Gel PSQ 60B: n-hexane-EtOAc (2:1)] to afford 1 (82.3 mg, 94%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: dimethyl 1-oxopropylphosphonate In tetrahydrofuran for 2h; Inert atmosphere; | Still-Gennari Reaction; General Procedure General procedure: In a round-bottomed flask under argon atmosphere, bis(2,2,2-trifluo-roethyl) 2-oxopropylphosphonate (4a; 302 mg, 1 mmol) or methyl[di(2,2,2-trifluoroethoxy)phosphoryl]acetate (4b; 318 mg, 1 mmol) was added to a solution of t-BuOK (112 mg, 1 mmol) in anhyd THF (2mL) at -78 °C, and the mixture was stirred for 30 min. Then a solutionof appropriate dialkyl acylphosphonate (1 mmol) in THF (1 mL) wasadded. The reaction mixture was stirred for 2 h and slowly warmed tor.t. THF was then evaporated under reduced pressure, H 2 O was addedto the residue, and the mixture was extracted with CH 2 Cl 2 (3 ×). Thecombined organic extracts were dried (MgSO 4 ) and concentrated.Products were purified using column chromatography (silica gel, EtOAcor CH 2 Cl 2 /MeOH 100:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 63% 2: 27% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With potassium <i>tert</i>-butylate In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: diethyl (1-oxopropyl)phosphonate In tetrahydrofuran for 2h; Inert atmosphere; Overall yield = 91%; diastereoselective reaction; | Still-Gennari Reaction; General Procedure General procedure: In a round-bottomed flask under argon atmosphere, bis(2,2,2-trifluo-roethyl) 2-oxopropylphosphonate (4a; 302 mg, 1 mmol) or methyl[di(2,2,2-trifluoroethoxy)phosphoryl]acetate (4b; 318 mg, 1 mmol) was added to a solution of t-BuOK (112 mg, 1 mmol) in anhyd THF (2mL) at -78 °C, and the mixture was stirred for 30 min. Then a solutionof appropriate dialkyl acylphosphonate (1 mmol) in THF (1 mL) wasadded. The reaction mixture was stirred for 2 h and slowly warmed tor.t. THF was then evaporated under reduced pressure, H 2 O was addedto the residue, and the mixture was extracted with CH 2 Cl 2 (3 ×). Thecombined organic extracts were dried (MgSO 4 ) and concentrated.Products were purified using column chromatography (silica gel, EtOAcor CH 2 Cl 2 /MeOH 100:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.09 g | With lithium chloride; sodium hydroxide; In tetrahydrofuran; water; at 0 - 30℃;Inert atmosphere; | Under nitrogen protection,Methyl [bis(2,2,2-trifluoroethoxy)phosphinyl]acetate (3.18 g, 1 eq) was dissolved in tetrahydrofuran and lithium chloride (0.42 g, 1 eq) was added.Add sodium hydroxide in water (2.0 g, 5 eq, 1 mol/L) solution,Control temperature is 0 ° C to 30 ° C,Join again2-(Dimethylamino)acetaldehyde sulfite (3.4 g, 2 eq),Stir the reaction for 3 hours,After the reaction is completed, it is acidified,Extraction and column purification gave (2Z)-4-(dimethylamino)-2-butenoic acid hydrochloride (1.09 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: C13H24O4 In tetrahydrofuran at -78 - 0℃; for 4.33333h; Inert atmosphere; | 8 Example 8 Under argon protection,Phosphate compound 19 (3.46 g, 10.9 mmol, 1.6 equiv.) and 18-crown-6 (3.23 g, 12.2 mmol, 1.8 equiv.) were dissolved in dry THF (60 mL).After cooling to -78 ° C, KHMDS (10 mL, 10 mmol, 1.0 M in THF, 1.5 equiv.) was slowly added dropwise to the system.Stirring was continued at this temperature for 0.5 hours.A solution of aldehyde compound 18 (1.45 g, 6 mmol, 1.0 equiv.) in tetrahydrofuran (10 mL) was slowly added dropwise to the above reaction system.After maintaining at this temperature for about 20 minutes, the reaction system was slowly warmed to zero (6 hours) and held at zero for 2 hours.After the reaction is completed, the reaction is quenched by adding a saturated ammonium chloride solution.The reaction mixture was extracted with ethyl acetate (3×50 mL).Dry anhydrous sodium sulfate solid.After filtration, the filtrate was concentrated under reduced pressure by a vacuum pump.The crude product obtained was subjected to silica gel column chromatography (ethyl acetate / n-hexane = 1:3) to give an unsaturated lactone compound 7(1.7g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.166667h; Inert atmosphere; Stage #2: 6-(benzyloxy)-2'-((1R,6S,9aS)-1-((tert-butyldimethylsilyl)oxy)-1,3,4,6,7,9a-hexahydro-2H-quinolizin-6-yl)-4',5'-dimethoxy-[1,1'-biphenyl]-3-carbaldehyde In tetrahydrofuran; toluene at -78℃; for 2h; Inert atmosphere; stereoselective reaction; | General Method for the Still-Gennari Modified Horner-Wadsworth-Emmons Reaction 4.31.1 Synthesis of methyl (Z)-3-(6-(benzyloxy)-2'-((1R,6S,9aS)-1-((tert-butyldimethylsilyl)oxy)-1,3,4,6,7,9a-hexahydro-2H-quinolizin-6-yl)-4′,5′-dimethoxy-[1,1′-biphenyl]-3-yl)acrylate (34a) General procedure: To a solution of 18-crown-6 (66.5mg, 0.2515mmol, 5.0 equiv) in anhydrous THF (1.0mL) at-78°C was added KHMDS (0.15mL, 0.0755mmol, 0.5M in toluene, 1.5 equiv) and the mixture was stirred for 10min. Bis(2,2,2-trifluoro-ethyl)(methoxycarbonylmethyl)phos-phornate (24.0mg, 0.0755mmol, 1.5 equiv) was added and the reaction mixture was stirred for 10min. A solution of aldehyde 33a (30.9mg, 0.0503mmol, 1.0 equiv) in THF (0.11mL) was added slowly and stirring was continued for 2h. The reaction was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc (3×5mL). The combined organic layer was brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 30:70 EtOAc/hexanes to afford the title compound 34a as a pale yellow oil (20.9mg, 60%). 1H NMR analysis revealed the presence of two biphenyl axis rotamers in a 71:29 ratio. Rf=0.25 (EtOAc:hexanes=30:70). IR (neat): νmax 2927, 1723, 1626, 1598, 1515, 1495, 1462, 1250, 1192, 1169, 1114, 1042, 835, 773, 696cm-1 [α]25D [α]D25 + 30 (c 0.19, CHCl3). 1H NMR (500MHz, the asterisk* denotes the signal of the minor rotamer, CDCl3): δ 7.78* (dd, J=8.7, 2.3Hz, 0.29H, H-4′), 7.72 (dd, J=8.5, 2.3Hz, 0.71H, H-4′), 7.54 (d, J=2.3Hz, 0.71H, H-2′), 7.42* (d, J=2.3Hz, 0.29H, H-2′), 7.34-7.16 (m, 5H, ArH), 7.15* (s, 0.29H, H-3″), 7.10 (s, 0.71H, H-3″), 7.01* (d, J=8.7Hz, 0.29H, H-5′), 6.93-6.81 (m, 1.71H, H-3 and H-5′), 6.79* (s, 0.29H, H-6″), 6.68 (s, 0.71H, H-6″), 6.10 (d, J=9.8Hz, 1H, H-9‴), 5.96* (d, J=10.1Hz, 0.29H, H-8‴), 5.89-5.82 (m, 0.71H, H-8‴), 5.86 (d, J=12.6Hz, 1H, H-2), 5.15* (d, J=12.3Hz, 0.29H, PhCHAHBO (minor)), 5.03 (dd, J=13.7, 7.1Hz, 1.71H, PhCHAHBO (minor) and PhCH2O), 4.26* (d, J=6.8Hz, 0.29H, H-6‴), 3.96 (d, J=7.1Hz, 0.71H, H-6‴), 3.88 (s, 2.73H, OCH3), 3.85* (s, 0.87H, OCH3), 3.83 (s, 2.73H, OCH3), 3.77* (s, 0.87H, OCH3), 3.71 (s, 3H, OCH3), 3.32-3.22 (m, 1H, H-1‴), 2.78* (d, J=18.3Hz, 0.29H, H-7‴A (minor)), 2.74-2.60 (m, 1.71H, H-7‴A and H-9a′′′), 2.31* (d, J=17.4Hz, 0.29H, H-7‴B (minor)), 2.18-1.93 (m, 1.71H, H-4‴A and H-7‴B), 1.87-1.72 (m, 2H, H-2‴A and H-4‴B), 1.47-1.30 (m, 2H, H-3‴), 1.19-1.11 (m, 1H, H-2‴B), 0.88 (s, 6.39H, (CH3)3CSi), 0.87* (s, 2.61H, (CH3)3CSi), 0.05 (s, 2.13H, CH3Si), 0.03* (s, 0.87H, CH3Si), 0.02 (s, 2.13H, CH3Si), 0.00* (s, 0.87H, CH3Si). 13C NMR (125MHz, the asterisk* denotes the signal of the minor rotamer, CDCl3): δ 166.7 (C-1), 166.6* (C-1), 157.0* (C-6′), 156.9 (C-6′), 148.3 (C-4″), 147.3 (C-5″), 146.7* (C-5″), 143.5* (C-3), 143.4 (C-3), 137.0* (ArC), 136.95 (ArC), 135.0* (C-2′), 134.7 (C-2′), 132.5 (C-2″), 132.1* (C-2″), 131.2 (C-1′), 131.2* (C-4′), 131.0 (C-4′), 130.7 (C-1″), 130.6* (C-1′), 130.0* (C-1″), 128.7* (0.58× ArCH), 128.6 (1.42× ArCH), 127.9 (0.71× ArCH), 127.8* (0.29× ArCH), 127.7* (C-9‴), 127.6 (C-3′), 127.4 (C-9‴), 127.1* (C-3′), 126.9 (1.42× ArCH), 126.5* (0.58× ArCH), 125.7 (C-8‴), 125.2* (C-8‴), 117.3 (C-2), 113.7* (C-5′), 113.2 (C-5′), 112.0* (C-6″), 112.0 (C-6″), 110.6* (C-3″), 110.3 (C-3″), 72.7 (C-1‴), 72.5* (C-1‴), 70.6 (PhCH2O), 69.9* (PhCH2O), 61.7* (C-9a′′′), 61.4 (C-9a′′′), 56.1 (C-6‴), 55.9 (OCH3), 55.89* (OCH3), 54.5* (C-6‴), 51.4 (OCH3), 51.3 (C-4‴), 50.6* (C-4‴), 35.1* (C-2‴), 35.0 (C-2‴), 32.8* (C-7‴), 32.1 (C-7‴), 26.0 ((CH3)3CSi), 23.7 (C-3‴), 23.3 (C-3‴), 18.2 ((CH3)3CSi),-3.8 (CH3Si),-3.9* (CH3Si),-4.5 (CH3Si). HRMS (ESI): m/z calcd for C40H52NO6Si [M+ H]+: 670.3564; found: 670.3581. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.166667h; Inert atmosphere; Stage #2: 6-(benzyloxy)-2'-((1R,6S,9aR)-1-((tert-butyldimethylsilyl)oxy)-1,3,4,6,7,9a-hexahydro-2H-quinolizin-6-yl)-4',5'-dimethoxy-[1,1'-biphenyl]-3-carbaldehyde In tetrahydrofuran; toluene at -78℃; for 2h; Inert atmosphere; stereoselective reaction; | General Method for the Still-Gennari Modified Horner-Wadsworth-Emmons Reaction General procedure: To a solution of 18-crown-6 (66.5mg, 0.2515mmol, 5.0 equiv) in anhydrous THF (1.0mL) at-78°C was added KHMDS (0.15mL, 0.0755mmol, 0.5M in toluene, 1.5 equiv) and the mixture was stirred for 10min. Bis(2,2,2-trifluoro-ethyl)(methoxycarbonylmethyl)phos-phornate (24.0mg, 0.0755mmol, 1.5 equiv) was added and the reaction mixture was stirred for 10min. A solution of aldehyde 33a (30.9mg, 0.0503mmol, 1.0 equiv) in THF (0.11mL) was added slowly and stirring was continued for 2h. The reaction was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc (3×5mL). The combined organic layer was brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with 30:70 EtOAc/hexanes to afford the title compound 34a as a pale yellow oil (20.9mg, 60%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 3h; | 1 Synthesis of dimethyl (2Z,21Z)-12-(benzoyloxy)tricosa-2,21-dienedioate (compound 4.1) [0322] To a solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (2.5 g, 7.9 mmol) in anhydrous THF (90 mL), 18-crown ether (9.5 g, 36 mmol) and 3.16 was added. The resulting suspension was cooled with dry ice-acetone, and KHMDS (0.5M in toluene, 15.8 mL, 7.9 mmol) was added slowly with stirring. After the addition, the resulting reaction mixture was stirred at - 78 °C for 3 h. The reaction was quenched with saturated aqueous N H4CI solution and extracted with EtOAc (100 mL x 3). The combined organic phases were dried with Na2S04. After filtration, the solvent was evaporated. The resulting residue was purified by MPC (120 g column, eluted with EtOAc/Hexanes (0-30%), to provide 1.1 g (58%) of the desired product compound 4.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With i-PrMgBr In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: α-methyl 4-chlorophenylacetyl chloride With triethylamine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | 2.1 Synthesis of allenyl esters General procedure: To a solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (630 mg, 1.98 mmol) inanhydrous THF (20 mL) was added i-PrMgBr (0.77 mol/L in THF, 2.83 mL, 2.18 mmol) and thesolution was stirred at 0 °C for 1 h under argon. After adding triethylamine (554 μL, 3.96 mmol)and 2-(4-chlorophenyl)propionyl chloride (634 μL, 3.96 mmol), the mixture was stirred at 0 °C for1 h under argon. The reaction mixture was treated with sat. NH4Cl aq (10 mL) and then extractedwith CHCl3 (30 mL x 3). The extract was dried over anhydrous MgSO4, filtered, and concentratedin vacuo. The oily residue was purified by column chromatography [Silica Gel PSQ 60B:n-hexane-AcOEt (20 : 1)] to afford 1d (410 mg, 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With i-PrMgBr In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; Stage #2: α-methyl 4-methylphenylacetyl chloride With triethylamine In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | 2.1 Synthesis of allenyl esters General procedure: To a solution of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (630 mg, 1.98 mmol) inanhydrous THF (20 mL) was added i-PrMgBr (0.77 mol/L in THF, 2.83 mL, 2.18 mmol) and thesolution was stirred at 0 °C for 1 h under argon. After adding triethylamine (554 μL, 3.96 mmol)and 2-(4-chlorophenyl)propionyl chloride (634 μL, 3.96 mmol), the mixture was stirred at 0 °C for1 h under argon. The reaction mixture was treated with sat. NH4Cl aq (10 mL) and then extractedwith CHCl3 (30 mL x 3). The extract was dried over anhydrous MgSO4, filtered, and concentratedin vacuo. The oily residue was purified by column chromatography [Silica Gel PSQ 60B:n-hexane-AcOEt (20 : 1)] to afford 1d (410 mg, 93%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; Inert atmosphere; Stage #2: 1,3,5,7-adamantanetetracarboxaldehyde In tetrahydrofuran; toluene at -78 - -20℃; for 2.5h; Inert atmosphere; | Tetramethyl 3,3',3'',3'''-(Adamantane-1,3,5,7-tetrayl)(2Z,2'Z,2''Z,2'''Z)-tetraacrylate (20). KN(TMS)2 in PhMe (0.5 M; 4.26 mL, 2.13 mmol) was added dropwise with stirring to 18-crown-6 (2.80 g, 10.6 mmol) and bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (762 mg, 2.40 mmol) in THF (3 mL) at -78 oC. After 30 min, tetra-aldehyde 19 (66 mg, 0.266 mmol) in THF (4 mL) was added and the mixture was allowed to warm up to -20 oC over 2.5 h, when reaction was quenched with saturated aqueous NH4Cl (5 mL). The separated aqueous layer was extracted with EtOAc (3 x 8 mL) and the combined organic layers were washed with brine, dried (MgSO4), concentrated in vacuo and the residue chromatographed (hexanes : EtOAc, 8 : 1) to give the tetra-ester 20 (80 mg, 64%) as a thick oil: Rf 0.57 (hexanes : EtOAc, 2 : 1); IR (film) 2951, 2920, 1726 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.85 (d, J 13.1 Hz, 4H, CH=CHCO2Me), 5.70 (d, J 13.1 Hz, 4H, CH=CHCO2Me), 3.72 (s, 12H, OCH3), 1.97 (s, 12H, CH2); 13C NMR (75 MHz, CDCl3) δ 166.8, 153.6, 119.3, 51.4, 42.0, 37.8; MS (EI) m/z 472 (M+.); HRMS (EI) m/z calc for C26H32O8 472.2097, found: 472.2101. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.5h; Inert atmosphere; Stage #2: 1-Adamantanecarbaldehyde In tetrahydrofuran; toluene at -78 - 20℃; for 5h; Inert atmosphere; | Methyl (Z)-3-(Adamantan-1-yl)acrylate (24). KN(TMS)2 in PhMe (0.5 M; 7.32 mL, 3.66 mmol) was added dropwise with stirring to 18-crown-6 (4.83 g, 18.3 mmol) and bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl) phosphonate (1.28 g, 4.02 mmol) in THF (4 mL) at -78 oC. After 30 min, aldehyde 23 (300 mg, 1.83 mmol) in THF (10 mL) was added with stirring and, after further stirring at -78 oC for 1 h, 0 oC for 2 h and room temperature for 2 h, reaction was quenched with saturated aqueous NH4Cl (20 mL). The separated aqueous layer was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with brine (30 mL), dried (MgSO4), concentrated in vacuo and the residue chromatographed (hexanes : EtOAc, 50 : 1) to give the methyl ester 2446 (116 mg, 30%) as a colorless oil: Rf 0.46 (hexanes : EtOAc, 15 : 1); IR (film) 2904, 2849, 1729, 1194 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.78 (d, J 13.2 Hz, 1H, CH=CHCO2Me), 5.65 (d, J 13.2 Hz, 1H, CH=CHCO2Me), 3.72 (s, 3H, OCH3), 1.98 (s, 3H, adamantane methine), 1.86 (d, J 2.1 Hz, 6H, CH2), 1.71 (s, 6H, CH2); 13C NMR (75 MHz, CDCl3) δ 167.4, 155.1, 117.9, 51.3, 40.9, 36.6, 36.2, 28.5; MS (EI) m/z 220 (M+.); HRMS (EI) m/z calc for C14H20O2 220.1463, found: 220.1462. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.3% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran; toluene at -78℃; for 0.416667h; Stage #2: tert-butyl (R)-(1-(benzyloxy)-3-oxopropan-2-yl)carbamate In tetrahydrofuran at -78℃; for 2.75h; | b Step b. A solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (6.607 g, 20.77 mmol) and 18-crown-6 (21.96 g, 83.08 mmol; dried by co-evaporation with toluene prior to use) in dry THF (30 ml_) was cooled to -78°C and a solution of KHMDS in toluene (0.7 M, 4.15 g, 29.7 ml_, 20.8 mmol) was added within 10 min. The mixture was stirred for 15 min at -78°C and a solution of tert-butyl (R)-(1-(benzyloxy)-3-oxopropan-2-yl)carbamate (4.65 g, 16.6 mmol) in anhydrous THF (20 ml_) was added dropwise within 15 min. The mixture was stirred for 2.5 h at -78 °C. A sat. aq. NH4CI (100 ml_) was added and the biphasic mixture was warmed to rt. The phases were separated and the aqueous phase was extracted into EtOAc (2 x 50 ml_). The combined organic phases were washed with brine, dried over Na2SC>4 and evaporated to afford 11.6 g of a yellow oil. Purification by column chromatography (0-10% EtOAc in heptanes) afforded methyl (S,Z)-5-(benzyloxy)-4-((tert- butoxycarbonyl)amino)pent-2-enoate (3.70 g, 66.3%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With sodium hydride In tetrahydrofuran; mineral oil at -78℃; for 0.5h; Inert atmosphere; Stage #2: 4,5-dichloro-2-methoxybenzaldehyde In tetrahydrofuran; mineral oil at -78℃; for 1.5h; Inert atmosphere; | 46.a Step a: To a stirred solution of methyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (2.64 g, 8.29 mmol) in THF (25.0 mL) was added NaH (0.29 g, 7.32 mmol, 60% in mineral oil) at -78oCunder nitrogenatmosphere. The mixture was stirred for 0.5 h at -78oCunder nitrogenatmosphere. Then to the above mixture was added 4,5-dichloro-2-methoxybenzaldehyde (1.00 g, 4.88 mmol) at -78oCunder nitrogenatmosphere. The mixture was stirred for 1.5 h at -78oCunder nitrogenatmosphere. The reaction was quenched with water (50 mL) at room temperature. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5/1) to afford methyl (2Z)-3-(4,5-dichloro-2- methoxyphenyl)prop-2-enoate as a dark yellow solid (1.14 g, 90%): LCMS (ESI) calc’d for C11H10Cl2O3 [M + H]+: 261, 263 (3 : 2), found 261, 263 (3 : 2);1H NMR (400 MHz, CD3OD) δ 7.69 (s, 1H), 7.17 (s, 1H), 7.05 (d, J = 12.5 Hz, 1H), 6.05 (d, J = 12.5 Hz, 1H), 3.86 (s, 3H), 3.70 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: bis-(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate With 18-crown-6 ether; potassium hexamethylsilazane In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 4-bromo-benzaldehyde In tetrahydrofuran at -78℃; | 24.1; 25.1 Step 1: (Z)-Methyl 3-(4-bromophenyl)acrylic acid ester (Compound 22c) To a tetrahydrofuran (6 mL) solution of 18 crown 6 (1.9886 g, 7.52 mmol) and KHMDS (7.5 mL) was added compound 22b (2.493 g, 7.84 mmol), and the mixture was stirred at 0°C for half an hour. After the reaction was cooled to -78°C, a solution of compound 22a (1.16 g, 6.27 mmol) in tetrahydrofuran (6 mL) was added. The mixture was fully reacted at -78°C. The mixture was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (40 mL×3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain a crude product . Purified by silica gel column chromatography (eluent: 0-3% ethyl acetate in petroleum ether) to obtain compound 22c (565 mg, yield 37%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate With lithium dipropan-2-ylazanide In tetrahydrofuran at -40℃; for 0.5h; Stage #2: (1R,3s,5S)-tert-butyl 3-(6-chloro-4-formylpyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate In tetrahydrofuran at -40℃; for 0.5h; | 17.1 Step 1: Synthesis of tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop- 1-en-1-yl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (4.56 g, 14.34 mmol) in THF (50 mL) was added LDA (7.2 mL, 14.34 mmol, 2M in THF) at -40 °C. After stirring at -40 °C for 30 min, tert-butyl (1R,3s,5S)-3-((6-chloro-4-formylpyridazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 9.56 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred at -40 °C for further 30 min, quenched with saturated aqueous NH4Cl (10 mL), and the solution extracted with EtOAc (100 mL x 2). The combined organic solvents were washed with brine (100 mL), dried over anhydrous MgSO4, concentrated in vacuo, and purified by silica gel flash chromatography (5-30% EtOAc/petroleum ether) to give tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop-1-en-1-yl)pyridazin-3- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (4.0 g, 99% yield) as a yellow solid. LCMS: m/z = 423.2 [M+18]+ , tR = 1.83 min. |
99% | Stage #1: methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate With lithium dipropan-2-ylazanide In tetrahydrofuran at -40℃; for 0.5h; Stage #2: (1R,3s,5S)-tert-butyl 3-(6-chloro-4-formylpyridazin-3-ylamino)-8-azabicyclo[3.2.1]octane-8-carboxylate In tetrahydrofuran at -40℃; for 0.5h; | 17.1 Step 1: Synthesis of tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop- 1-en-1-yl)pyridazin-3-yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate. To a stirred solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate (4.56 g, 14.34 mmol) in THF (50 mL) was added LDA (7.2 mL, 14.34 mmol, 2M in THF) at -40 °C. After stirring at -40 °C for 30 min, tert-butyl (1R,3s,5S)-3-((6-chloro-4-formylpyridazin-3-yl)amino)-8- azabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 9.56 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred at -40 °C for further 30 min, quenched with saturated aqueous NH4Cl (10 mL), and the solution extracted with EtOAc (100 mL x 2). The combined organic solvents were washed with brine (100 mL), dried over anhydrous MgSO4, concentrated in vacuo, and purified by silica gel flash chromatography (5-30% EtOAc/petroleum ether) to give tert-butyl (1R,3s,5S)-3-((6-chloro-4-((Z)-3-methoxy-3-oxoprop-1-en-1-yl)pyridazin-3- yl)amino)-8-azabicyclo[3.2.1]octane-8-carboxylate (4.0 g, 99% yield) as a yellow solid. LCMS: m/z = 423.2 [M+18]+ , tR = 1.83 min. |
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.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :