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CAS No. : | 3462-95-1 | MDL No. : | MFCD00031637 |
Formula : | C25H21ClFP | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CBHDAHHYMRXLIP-UHFFFAOYSA-M |
M.W : | 406.86 | Pubchem ID : | 2733554 |
Synonyms : |
|
Num. heavy atoms : | 28 |
Num. arom. heavy atoms : | 24 |
Fraction Csp3 : | 0.04 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 121.31 |
TPSA : | 13.59 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -3.8 cm/s |
Log Po/w (iLOGP) : | -0.8 |
Log Po/w (XLOGP3) : | 7.02 |
Log Po/w (WLOGP) : | 2.59 |
Log Po/w (MLOGP) : | 7.06 |
Log Po/w (SILICOS-IT) : | 6.57 |
Consensus Log Po/w : | 4.49 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -7.09 |
Solubility : | 0.0000331 mg/ml ; 0.0000000814 mol/l |
Class : | Poorly soluble |
Log S (Ali) : | -7.12 |
Solubility : | 0.0000308 mg/ml ; 0.0000000756 mol/l |
Class : | Poorly soluble |
Log S (SILICOS-IT) : | -10.69 |
Solubility : | 0.0000000083 mg/ml ; 0.0 mol/l |
Class : | Insoluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 4.33 |
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 |
---|---|---|
82% | for 48 h; Reflux | General procedure: The synthesis of trans-3a is used as an example: a mixture of 4.0g (2.78mmol) of 4-fluorobenzyl chloride and 8.73g (3.30mmol) triphenylphosphine in 12mL of benzene was refluxed for 2 days to yield white solid. Collect the solid by suction filtration and (4-fluorobenzyl)-triphenylphosphonium salt was obtained in 82percent yield. Afterward, a mixture of 9.97g (2.5mmol) of the previous salt, 2.37g (2.2mmol) of benzaldehyde, and 0.82g (3.11mmol) of 18-crown-6 in 56mL of dichloromethane was stirred violently and 27mL of 50percent aqueous solution of K2CO3 was added slowly. After addition, the reaction was stirred at room temperature for 3 days. And then the reaction mixture was poured into water and extracted with ethyl acetate for three times. The organic layers were combined and dried with anhydrous MgSO4. The organic solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:10) to afford cis and trans-3a in a 95.1percent yield. Refluxing the previous mixture with catalytic iodine in benzene for 3h and then purify the resulting products by column chromatography on silica gel (ethyl acetate/hexane=1:10) afforded trans-3a in 92percent yield. |
30% | Reflux | General procedure: To a solution of substituted benzyl halide in toluene was added triphenylphosphine (1.5 eq) and the mixture was refluxed. After cooling, the precipitate was filtered to give the target compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In benzene; for 48h;Reflux; | General procedure: The synthesis of trans-3a is used as an example: a mixture of 4.0g (2.78mmol) of 4-fluorobenzyl chloride and 8.73g (3.30mmol) triphenylphosphine in 12mL of benzene was refluxed for 2 days to yield white solid. Collect the solid by suction filtration and (4-fluorobenzyl)-triphenylphosphonium salt was obtained in 82% yield. Afterward, a mixture of 9.97g (2.5mmol) of the previous salt, 2.37g (2.2mmol) of benzaldehyde, and 0.82g (3.11mmol) of 18-crown-6 in 56mL of dichloromethane was stirred violently and 27mL of 50% aqueous solution of K2CO3 was added slowly. After addition, the reaction was stirred at room temperature for 3 days. And then the reaction mixture was poured into water and extracted with ethyl acetate for three times. The organic layers were combined and dried with anhydrous MgSO4. The organic solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:10) to afford cis and trans-3a in a 95.1% yield. Refluxing the previous mixture with catalytic iodine in benzene for 3h and then purify the resulting products by column chromatography on silica gel (ethyl acetate/hexane=1:10) afforded trans-3a in 92% yield. |
30% | In toluene;Reflux; | General procedure: To a solution of substituted benzyl halide in toluene was added triphenylphosphine (1.5 eq) and the mixture was refluxed. After cooling, the precipitate was filtered to give the target compound. |
In benzene;Reflux; | General procedure: A mixture of 1.67 g (10.70 mmol) of 1-(chloromethyl)-4-methoxybenzene, 3.35 g (12.8 mmol) of triphenylphosphine, and 11 mL of ethyl acetate was stirred and refluxed for 24 hours and the salt, (4-methoxybenzyl)triphenylphosphonium chloride, was gradually formed and then collected and dried by suction filtration after cooling down. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With 18-crown-6 ether; potassium carbonate; In dichloromethane; water; at 20℃; for 24h; | General procedure: Afterward another mixture of 3.93 g (9.4 mmol) of previous phosphonium salt, 1.18 g (8.92 mmol) of trans-cinnamaldehyde, 0.44 g (1.68 mmol) of 18-crown-6, 22 mL of dichloromethane, and 10.8 mL of 50 % K2CO3(aq) was prepared in a flask and stirred at room temperature for 24 hours. Then the reaction was extracted with ethyl acetate for 3 times. Collected the organic layers and dried the resulting solution with anhydrous MgSO4. Removed the organic solvent by rotary vacuum dryer and the residue was purified by silica gel chromatography (hexane/dichloromethane = 8/1) to afford compound 1a (1.95 g, 8.27 mmol) with a 77 % yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With n-butyllithium; In tetrahydrofuran; hexanes; at 0 - 20℃; | EXAMPLE 9A 4-(4-(4-fluorobenzylidene)-1-piperidinyl)benzonitrile A suspension of the 4-fluorobenzyl triphenylphosphonium chloride (0.737 g, 1.81 mmol) in THF (10 mL) was treated with nBuLi (724 muL of a 1.6M solution in hexanes, 1.81 mmol) at 0 C., treated with 1-(4'-cyanophenyl)-4-oxopiperidine (prepared according to the procedure described in Synthesis 1981, 606-608, 0.300 g, 1.51 mmol), and gradually warmed to room temperature overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous NH4Cl and the aqueous layer was extracted with ethyl acetate (2*). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting residue was purified by silica gel chromatography eluding with 10% ethyl acetate in hexanes to give the desired product. (0.268 g, 61%). MS (ESI) m/e 292 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In tetrahydrofuran; mineral oil; | 4-(4-Fluorobenzylidene)piperidine-1-carboxylic Acid Tert-Butyl Ester (Compound 82). 4-Fluorobenzyl triphenylphosphonium chloride (54.2 g, 133.2 mmol) was suspended in 400 ml of anhydrous THF. Sodium hydride (60% dispersion in mineral oil; 5.35 g, 133.2 mmol) was added to the suspension and stirred at room temperature for 3 hours. A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (25 g, 125.5 mmol) in 150 ml of anhydrous THF was added dropwise over 1 hour. The reaction was heated to reflux for 8 hours and then cooled to room temperature, filtered, and the filtrate evaporated in vacuo to afford the crude product as a yellow viscous oil. The crude product was purified by flash chromatography (SiO2) eluted with a gradient of hexane to hexane-ethyl acetate (7:3). The pure fractions were combined and evaporated to afford 25.83 g (70% yield) of Compound 82 as a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; | Part I Preparation of t-Butyl 3-(4-fluorobenzylidene)-1-piperidinecarboxylate To a stirring solution of <strong>[3462-95-1](4-fluorophenylmethyl)-triphenylphosphonium chloride</strong> (17.68 g, 43.5 mmol) in dry tetrahydrofuran (60 mL) at -78 C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0 C. for 1 hr and t-Butyl 3-oxo-1-piperidinecarboxylate (3.46 g, 17.4 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 1 hr and the heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction was extracted with ethyl acetate three times (100 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 9:1) to yield 3.82 g of a mixture of E and Z isomers as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34 H), 4.00 (s, 0.66H) 3.50 (t, J=5, 2H), 2.47 (t, J=5, 0.66 H), 2.39 (t, J=5, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; | Part B. Preparation of tert-Butyl 3-(4-fluorobenzylidene)-1-piperidinecarboxylate To a stirring solution of <strong>[3462-95-1](4-fluorophenylmethyl)triphenylphosphonium chloride</strong> (17.68 g, 43.5 mmol) in dry THF (60 mL) at -78 C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0 C. for 1 hr and the piperidone from Part A (3.46 g, 17.4 mmol) in THF (60 mL) was added. The mixture was stirred at room temperature for 1 hr and the heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of sat. aq NH4Cl. The reaction was extracted with EtOAc (3*100 mL). The organic layers were combined, washed with brine, dried over MgSO4, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:EtOAc 9:1) to yield 3.82 g of a mixture of E and Z isomers of product as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34H), 4.00 (s, 0.66H) 3.50 (app t, J=5.5 Hz, 2H), 2.47 (t, J=5.1 Hz, 0.66H), 2.39 (t, J=5.1 Hz, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In toluene; | 3-(4-Fluoro-benzylidene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic Acid Tert-Butyl Ester To a solution of (4-fluoro-benzyl)-triphenyl-phosphonium chloride (27.0 g, 66.5 mmol) in toluene (500 ml) is added sodium hydride (60% dispersion, 2.66 g, 66.5 mmol). The resulting suspension is stirred at ambient temperature for 90 minutes. To the reaction mixture is then added 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (13.6 g, 60.5 mmol). The resulting reaction mixture is refluxed overnight, and then cooled to ambient temperature, diluted with water and extracted with diethyl ether. The organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography gave the title compound (17.61 g, 92%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With n-butyllithium; ammonium chloride; In hexane; toluene; pentane; | Stage a) In a reactor protected from moisture there are introduced 42 g (0.103 mol) of p-fluorobenzyltriphenyl phosphonium chloride in 235 ml of toluene dehydrated on molecular sieve. 60 ml of a 2.5M solution of n-butyllithium in hexane are then introduced during 10 min. The red suspension is kept stirring for 2 h at 20-25 C., after which 20 g (0.094 mol) of the previously obtained acetaldehyde (formula VI; n=1) in 42.2 ml of toluene are introduced. The dark red suspension obtained is kept stirring for 16 h, after which 80 ml of a saturated ammonium chloride solution are introduced with cooling to 20 C. After 15 min of stirring, the insoluble matter is filtered out and discarded. After settling has taken place, the toluene phase of the filtrate is separated, dried over Na2 SO4 and evaporated. The oily brown residue is solidified in 300 ml of n-pentane, and the new insoluble matter is filtered out and removed; the filtrate is concentrated. This last purification step is repeated. 23.6 g (yield: 82%) of crude N-Boc-2-(p-fluorocinnamyl)pyrrolidine are obtained (formula V; Ar=p-fluorophenyl, n=1) in the form of an orange oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(a) [(4-Fluorophenyl)methyl]triphenylphosphonium chloride A stirred solution of 79.0 g. (0.3 mole) of triphenylphosphine in 400 ml. of xylene is treated with 43.3 g. (0.3 mole) of 4-fluorobenzyl chloride. The resulting solution is heated (product begins to crystallize at this point) and refluxed for six hours. After standing overnight at room temperature, the solid is filtered, washed with xylene and then with ethyl acetate, and dried in a desiccator to yield 73.3 g. (60%) of [(4-fluorophenyl)methyl]-triphenylphosphonium chloride; m.p. 295-298. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; sodium hydroxide; n-butyllithium; sodium borohydrid; sulfuric acid; dihydrogen peroxide; sodium ethanolate; trifluoroborane diethyl ether; In 1,2-dimethoxyethane; ethanol; water; ethyl acetate; acetone; | EXAMPLE 7 Preparation of rac-(9abetaH)-7beta-(o-chlorophenyl)octahydro-2H-quinolizin-2alpha-yl)p-fluorophenyl ketone 14.5 g of p-fluorobenzyl-triphenyl-phosphonium chloride are suspended in 100 ml of abs. diethyl ether and treated at 0 C. with 20 ml of n-butyl lithium (1.8 molar) and stirred at 0-5 C. for 1 hour. Subsequently, there is added dropwise thereto a solution of 8.8 g of rac-(9abetaH)-7beta-(o-chlorophenyl)octahydro-2H-quinolizin-2-one in 150 ml of abs. diethyl ether and then the mixture is heated at reflux temperature for 4 hours. The cooled solution is hydrolyzed with 30 ml of saturated ammonium chloride solution and then partitioned between ethyl acetate and 0.5 N sodium hydroxide. The ethyl acetate phase, dried over anhydrous magnesium sulfate, is evaporated and chromatographed over 100 g of silica gel with ethyl acetate-n-hexane=1:1. An oily E/Z mixture of rac-(9abetaH)-7beta-(o-chlorophenyl)-2-((p-fluorophenyl)methylene)octahydro-2H-quinolizine is eluted. This mixture is dissolved in 115 ml of ethyleneglycol dimethyl ether (dried neutral over aluminum oxide, activity grade I), treated with 1.77 g of sodium borohydride and there is added dropwise at room temperature a solution of 11.5 g of boron trifluoride etherate in 77 ml of ethyleneglycoldimethyl ether. After 1 hours stirring at room temperature, the mixture is cooled down to 0-5 C. and there is cautiously added dropwise a solution of 1.23 g of potassium hydroxide in 50 ml of water and subsequently 4.6 ml of hydrogen peroxide (60%) and then the mixture is heated at reflux temperature. The cooled reaction mixture is partitioned between 2 N sodium hydroxide and ethyl acetate, the organic phase is dried over anhydrous magnesium sulfate and evaporated to dryness. This crude product is dissolved in 240 ml of acetone, cooled to 0-5 C. and 32 ml of Jones reagent (manufactured from 80 g of chromium trioxide, 64 ml of conc. sulfuric acid, 300 ml of water) are added dropwise thereto and the mixture is stirred at 0-5 C. for 1 hour. Subsequently, the reaction mixture is partitioned between 150 ml of sat. sodium acetate solution and 250 ml of ethyl acetate as well as 200 ml of 2 N sodium hydroxide. The organic phase, dried over anhydrous magnesium sulfate, is evaporated to dryness. The crude product is again dissolved in 30 ml of ethyl alcohol and treated with 0.3 g of sodium ethylate. After 3 hours stirring at room temperature, the mixture is partitioned between 2 N sodium hydroxide and ethyl acetate, the organic phase is dried over anhydrous magnesium sulfate, treated with 1 g of active charcoal and warmed to 50 C., filtered off and evaporated to dryness. By crystallization from ethyl alcohol-ethyl acetate there is obtained rac-(9abetaH)-7beta-(o-chlorophenyl)octahydro-2H-quinolizin-2alpha-yl) p-fluorophenyl ketone (m.p. 145-147 C.). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dimethyl sulfoxide; | (b) N-Carbobenzyloxy-4-[(4-fluorophenyl)methylene]-L-proline Interaction of 7.6 g. (0.16 mole) of sodium hydride (50% suspension) with 150 ml. dimethylsulfoxide, followed by treatment with 65.0 g. (0.16 mole) of [(4-fluorophenyl)methyl]triphenylphosphonium chloride and the reaction with 13.2 g. (0.05 mole) of N-carbobenzyloxy-4-keto-L-proline according to the procedure of Example 24(a) gives 7.0 g. (39%) of pale yellow N-carbobenzyloxy-4-[(4-fluorophenyl)methylene]-L-proline, Rf 0.31 (85:15 toluene:acetic acid). This material is dissolved in 20 ml. of acetonitrile and treated with 3.6 g. of dicyclohexylamine. The dicyclohexylamine salt rapidly crystallizes from solution. After standing overnight in the cold, the product is filtered and washed with cold acetonitrile and ether to give 8.0 g. (30%) of colorless N-carbobenzyloxy-4-[(4-fluorophenyl)methylene]-L-proline, dicyclohexylamine salt, m.p. 159-161; [alpha]D25 +7.0 (c, 1% in chloroform). Anal. Calc'd. for C20 H18 FNO4.C12 H23 N.1/4H2 O: C, 71.02; H, 7.73; N, 5.18; F, 3.51, Found: C, 71.35; H, 7.86; N, 4.89; F, 3.14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride; potassium tert-butylate; In methanol; dichloromethane; ethyl acetate; | EXAMPLES 6 AND 7 A suspension of 4-fluoro-alpha-(imidazol-1-yl)acetophenone (1.0 g), <strong>[3462-95-1](4-fluorobenzyl)triphenylphosphonium chloride</strong> (3.85 g), potassium tert-butoxide (1.1 g) and 18-crown-6 (1,4,7,10,13,16-hexaoxacyclooctadecane, 0.1 g) in dichloromethane (150 ml) was stirred at room temperature for 1 h. Saturated ammonium chloride (100 ml) was then added, and the organic layer was separated. The aqueous layer was extracted twice with dichloromethane and the combined organic extracts were dried over sodium sulphate and evaporated to dryness. The resultant brown oil, a mixture of E and Z isomers and triphenylphosphine oxide, was separated by flash column chromatography on silica, using ethyl acetate and then ethyl acetate/methanol (95:5 v/v) as eluent, into a more and less polar fraction. The less polar fraction, a colourless oil which did not crystallise, was converted into a solid hydrochloride salt by dissolution in ether and treatment with 2 ml of a solution of ethereal hydrogen chloride. The resulting white solid was filtered off and washed with diethyl ether, to give the Z-isomer of 1,2-bis(4-fluorophenyl)-3-(1-imidazolyl)prop-1-ene hydrochloride, m.p. 203 C. (Example 6). The more polar fraction was triturated with diethyl ether to give the E-isomer of the same compound, m.p. 121 C. (Example 7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | sodium ethanolate; In ethanol; | 1-Phenyl-3,3,3-trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propene, applied as starting substance, is prepared according to the method of Example 1 as follows: 4'-Methoxy-2,2,2-trifluoroacetophenone (R. Fuchs: J. Org. Chem. 22, 993-994 (1957)) is reacted with triphenyl(4-fluorobenzyl)-phosphonium chloride (see Example 18) in ethanol in the presence of sodium ethoxide. 3,3,3-Trifluoro-1-(4-fluorophenyl)-2-(4-methoxyphenyl)-propene is obtained with a yield of 87%; b.p.: 138-142 C./0.5 mm Hg. Analysis: calculated for C16 H12 F4 O: C: 64.86%, H: 4.08%, F: 25.65%; found: C: 65.03%, H: 4.27%, F: 25.40%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | 2.8.a) Synthesis of (E /Z) -methyl 4-(4-fluorobenzylidene)-l ,4,5,6- tetrahydrocyclopenta[b]pyrrole-2-carboxylate[0316] The title compound was synthesized from methyl 4-oxo-l,4,5,6- tetrahydrocyclopenta[delta]pyrrole-2-carboxylate (0.4 g, 2.2 mmol) and 4-fluorobenzyl triphenylphosphonium chloride salt (1.09 g, 2.7 mmol) according to General Procedure 2. The crude product was purified by flash chromatography (0-50% EtO Ac/heptane) to afford 31.1 mg of (£7Z)-methyl 4-(4-fluorobenzylidene)- 1,4,5, 6-tetrahydrocyclopenta[delta]pyrrole-2- carboxylate in 5% yield. 1H NMR (400 MHz, CDCl3) delta ppm 8.93 (br. s., 1 H), 7.43 - 7.50 (m, 2 H), 7.04 - 7.09 (m, 2 H), 6.89 (d, J=I.61 Hz, 1 H), 6.47 (t, J=2.03 Hz, 1 H), 3.36 (td, J=5.79, 2.55 Hz, 2 H), 2.93 - 2.99 (m, 2 H); 19F NMR (376 MHz, CDCl3) delta ppm -116.03 (s, I F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | 4-Fluorobenzyl triphenylphosphonium chloride (54.2 g, 133.2 mmol) was suspended in 400 ml of anhydrous THF. sodium hydride (60% dispersion in mineral oil; 5.35 g, 133.2 mmol) was added to the suspension and stirred at room temperature for 3 hours.A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (25 g, 125.5 mmol) in 150 ml of anhydrous THF was added dropwise over 1 hour.The reaction was heated to reflux for 8 hours and then cooled to room temperature, filtered, and the filtrate evaporated in vacuo to afford the crude product as a yellow viscous oil.The crude product was purified by flash chromatography (SiO2) eluted with a gradient of hexane to hexane-ethyl acetate (7:3).The pure fractions were combined and evaporated to afford 25.83 g (70% yield) of Compound 82 as a white crystalline solid. | |
39% | General procedure: Appropriate Witting reagent synthesized according to the general procedure A (1.1equiv.) was dissolved in anhydrous THE (30 mL) under argon atmosphere. Sodiumbis(trimethylsilyl)amide-NaHMDS (2N solution in THE, 1 .2 equiv.) was added to the resulting suspension at room temperature. The orange-red colored reaction mixture was then stirred for 30 mm under argon, followed by a drop-wise addition of N-Boc protected 4- formylpiperidine (1.0 equiv.) solution in anhydrous THE (10 mL). Thereaction mixture was stirred at room temperature overnight (16-24 h), and then quenched by adding saturated aqueous NaHCO3 solution (10-15 mL). The solvent was evaporated and the white residue was resuspended in EtOAc (50 mL) and saturated aqueous NaHCO3 solution (50 mL), and transferred into a separating funnel. The phases were separated and the aqueous phase was additionallyextracted with EtOAc (2 x 50 mL). Combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2504, and evaporated under reduced pressure. The crude product was purified by flash column chromatography to yield pure trans (Z) isomer and a mixture of both isomers that was used for reduction of the double bond.; Synthesized from tert-butyl 4-oxopiperidine-1 -carboxylate (1 .00 g, 5.02 mmol, 1 .0 equiv.) and 4-(fluorobenzyltriphenyl)phosphonium chloride (0.94 g, 5.02 mmol, 1 .0equiv., prepared via general procedure A) via general procedure B (potassium tedbutoxide was used instead of NaHMDS). The compound was purified by flash column chromatography using petroleum ether/Et20 = 10/1 (v/v) as eluent. Yield: 39% (0.57 g); Rf = 0.12 (petroleum ether/Et20 = 10/1, vlv); white amorphous solid,mp 50-52 00; 1H NMR (400 MHz, CDCI3): 6 1.47 (s, 9H), 2.32 (t, J = 5.6 Hz, 2H),2.41 (t, J = 5.6 Hz, 2H), 3.40 (t, J = 5.8 Hz, 2H), 3.50 (t, J = 5.6 Hz, 2H), 6.31 (s, 1 H),6.97-7.03 (m, 2H), 7.12-7.17 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ozonolysis [OF 7D (R9=2-METHYLBUTYL)] in anhydrous dichloromethane followed by treatment with DMS at-78C afforded aldehyde 8a (77%). 4-Fluorobenzyl phosphonium chloride (0.87 g, 2.13 mmol) and potassium t-butoxid (0.17 g, 1.48 mmol) were suspended in toluene under nitrogen with vigorous stirring. After 4 h, a solution of aldehyde 8a (204 mg, 0.59 mmol) in toluene (4.6 [ML)] was added drop-wise. The reaction mixture was stirred at rt for 2 h and diluted with ethyl acetate (50 mL). The organic layer was washed with water (2 x 20 mL), brine, dried and concentrated. The residue was purified by chromatography to give a clear syrup 8b (R9'=3- (4-fluorophenyl) prop-2-enyl) (171 mg). [0198] To a solution of 8b [(R9 =3-(4-FLUOROPHENYL)] prop-2-enyl) (171 mg, 0.39 mmol) in MeOH (25 mL) in a Parr bottle was added 10% palladium on carbon (Degussa wet form 50% w/w water) (200 [MG).] The bottle was purged and charged with H2 to 40 psi, and shaken for 4 h. The reaction mixture was filtered through celite and rinsed with MeOH. The filtrate was concentrated to give a yellow oil 8c (R9=3- (4-fluorophenyl) propyl) (120 mg). [[0199]] MS (ESPOS): 374.5 [M +Na] [+,] MS (ESNEG): 350.3 [[M-H].] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a stirred solution of <strong>[3462-95-1](4-fluorophenylmethyl)-triphenylphosphonium chloride</strong> (17.68 g, 43.5 mmol) in dry tetrahydrofuran (60 mL) at -78 C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0 C. for 1 hr. After tis time, t-butyl 3-oxo-1-piperidinecarboxylate (3.46 g, 17.4 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 1 hr and then heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction was extracted with ethyl acetate three times (100 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 9:1) to yield 3.82 g of a mixture of E and Z isomers as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34 H), 4.00 (s, 0.66H) 3.50 (t, J=5, 2H), 2.47 (t, J=5, 0.66 H), 2.39 (t, J=5, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | 4-Fluorobenzyl triphenylphosphine chloride (1 g, 2.46 mmol) in DMSO (2 mL) was added to a flask charged with sodium hydride (60% dispersion in oil, 124 mg, 3.10 mmol) and DMSO (2 mL). The reaction mixture was stirred at 70 0C for 3 hours and then (S)-l-(2-(1H-l,2,4-triazol-l-yl)acetyl)-N-(4-(4- fluorophenoxy)phenyl)-4-oxopyrrolidine-2-carboxamide (0.11 g, 0.25 mmol) in DMSO (2 mL) was added. The mixture was stirred for 16 hours at 70 0C and then quenched with saturated ammonium chloride (aq., 10 mL). This mixture was extracted with ethyl acetate (20 mL) and the extract was washed with deionized water (10 niL). Product was purified from the mixture directly by column chromatography (EtOAc to EtOAc/MeOH (9:1) + 1% NEt3) to give with (S)- 1-(2-( IH-1, 2,4-triazol-l- yl)acetyl)-4-(4-fluorobenzylidene)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2- carboxamide (15 mg, 0.027 mmol, 11% yield) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of 22.8 g (54.9 mmol) 4-Fluorobenzyl-triphenylphosphoniumchloride, 1 ml (4.9 mmol) 15- Crown-5 and 2.16 g (54.0 mmol) NaH in 100 ml anhydrous THF is stirred at O0C for 45 min. Then, a solution of 10.7 g (49.1 mmol) terf-Butyl(3RS)-3-fluoro-4-oxopiperidine-1-carboxylate (compound A15) in 53 ml anhydrous THF is slowly added to the reaction mixture at O0C. After stirring for 10 min at O0C and 1 h at room temperature 150 ml of a half saturated aqueous NaHCO3 solution is poured into the reaction solution and the resulting mixture is extracted three times with ethyl ace- tate. The combined organic phases are dried over Na2SO4, filtered and concentrated in vacuo.Subsequent purification of the resulting residue by silica gel chromatography [PE/EA (95:5?85:15, (v/v))] affords the title compound as colourless oil. The mass spectrum shows the molecular peak MH+-BoC of 209.9 Da. TLC: [PE/EA (8:2; (v/v))], Rf=0.55 EF: C17 H21 02 N F2; MW: calc: 309.36 MS: fnd.: 209.9 (MH+-BoC) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether; potassium carbonate; In dichloromethane;Reflux; | General procedure: To a solution of nitrobenzaldehyde in dehydrated CH2Cl2 were added benzyltriphenylphosphonium salt (1.0 eq), potassium carbonate (1.1 eq) and 18-crown-6 (0.18 eq) and the mixture was refluxed, then filtered and concentrated. The residue was purified by silica gel colum chromatography to give the target compound as EZ mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether; potassium carbonate; In dichloromethane; water; at 20℃; for 72h; | General procedure: The synthesis of trans-3a is used as an example: a mixture of 4.0g (2.78mmol) of 4-fluorobenzyl chloride and 8.73g (3.30mmol) triphenylphosphine in 12mL of benzene was refluxed for 2 days to yield white solid. Collect the solid by suction filtration and (4-fluorobenzyl)-triphenylphosphonium salt was obtained in 82% yield. Afterward, a mixture of 9.97g (2.5mmol) of the previous salt, 2.37g (2.2mmol) of benzaldehyde, and 0.82g (3.11mmol) of 18-crown-6 in 56mL of dichloromethane was stirred violently and 27mL of 50% aqueous solution of K2CO3 was added slowly. After addition, the reaction was stirred at room temperature for 3 days. And then the reaction mixture was poured into water and extracted with ethyl acetate for three times. The organic layers were combined and dried with anhydrous MgSO4. The organic solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:10) to afford cis and trans-3a in a 95.1% yield. Refluxing the previous mixture with catalytic iodine in benzene for 3h and then purify the resulting products by column chromatography on silica gel (ethyl acetate/hexane=1:10) afforded trans-3a in 92% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether; potassium carbonate; In dichloromethane; water; at 20℃; for 72h; | General procedure: The synthesis of trans-3a is used as an example: a mixture of 4.0g (2.78mmol) of 4-fluorobenzyl chloride and 8.73g (3.30mmol) triphenylphosphine in 12mL of benzene was refluxed for 2 days to yield white solid. Collect the solid by suction filtration and (4-fluorobenzyl)-triphenylphosphonium salt was obtained in 82% yield. Afterward, a mixture of 9.97g (2.5mmol) of the previous salt, 2.37g (2.2mmol) of benzaldehyde, and 0.82g (3.11mmol) of 18-crown-6 in 56mL of dichloromethane was stirred violently and 27mL of 50% aqueous solution of K2CO3 was added slowly. After addition, the reaction was stirred at room temperature for 3 days. And then the reaction mixture was poured into water and extracted with ethyl acetate for three times. The organic layers were combined and dried with anhydrous MgSO4. The organic solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:10) to afford cis and trans-3a in a 95.1% yield. Refluxing the previous mixture with catalytic iodine in benzene for 3h and then purify the resulting products by column chromatography on silica gel (ethyl acetate/hexane=1:10) afforded trans-3a in 92% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether; potassium carbonate; In dichloromethane; water; at 20℃; for 72h; | General procedure: The synthesis of trans-3a is used as an example: a mixture of 4.0g (2.78mmol) of 4-fluorobenzyl chloride and 8.73g (3.30mmol) triphenylphosphine in 12mL of benzene was refluxed for 2 days to yield white solid. Collect the solid by suction filtration and (4-fluorobenzyl)-triphenylphosphonium salt was obtained in 82% yield. Afterward, a mixture of 9.97g (2.5mmol) of the previous salt, 2.37g (2.2mmol) of benzaldehyde, and 0.82g (3.11mmol) of 18-crown-6 in 56mL of dichloromethane was stirred violently and 27mL of 50% aqueous solution of K2CO3 was added slowly. After addition, the reaction was stirred at room temperature for 3 days. And then the reaction mixture was poured into water and extracted with ethyl acetate for three times. The organic layers were combined and dried with anhydrous MgSO4. The organic solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:10) to afford cis and trans-3a in a 95.1% yield. Refluxing the previous mixture with catalytic iodine in benzene for 3h and then purify the resulting products by column chromatography on silica gel (ethyl acetate/hexane=1:10) afforded trans-3a in 92% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With hydrogenchloride; In methanol; for 1h;Reflux; | General procedure: [4FBzTPP]Cl (0.82 g, 2 mmol) and CoCl2·6H2O (0.24 g,1 mmol) were dissolved in 30 mL methanol acidified with 3 mL of concentrated hydrochloric acid. The blue solution was heated and stirred under reflux for 1 h. [4FBzTPP]2[CoCl4] (1) was obtained by evaporation of the solution at room temperature. [4ClBzTPP]2[CoCl4]·3H2O (2) was prepared by a method analogous to that of 1 while with [4ClBzTPP]Cl instead of [4FBzTPP]Cl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 50℃; for 2h; | A mixture of pyrazolopyridine aldehyde (1-52) (48 mg, 0.165 mmol, 1 .0 equiv.) and Wittig salt (74 mg, 0.18 mmol, 1.1 equiv.) in acetonitrile was treated with DBU (28 mg, 0.18mmol, 1 .1 equiv.). The resulting mixture was allowed to stir at 50 C for two hours, and then the reaction mixture was concentrated. The residue was purified by silica gelchromatography, eluting with hexanes/EtOAc to give the desired olef in. A solution ofolefin (22 mg, 0.0575 mmol, 1 .0 equiv.) in 5 mL EtOH was purged with nitrogen gas, then 10% Pd/C (5 mg) was added. The resulting mixture was purged with hydrogen gas andallowed to stir at room temperature overnight under an atmosphere of hydrogen gas. The mixture was then filtered through Celite and purified by mass-triggered HPLC to provide the desired product. 1H NMR (400 MHz, CDCI3) 68.40 (d, J= 7.6, 1H), 8.12 (5, 1H), 7.66 (d, J= 8.3, 2H), 7.59 (d, J= 8.2, 2H), 7.42 (5, 1H), 7.10 (dd, J= 5.4, 8.6, 2H), 6.96 (t, J= 8.7, 2H), 6.63 (dd, J= 1.8, 7.1, 1H), 2.95 (5, 4H). ESI-MS (m/z): [M÷H] 385.2, RT2.5863 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | With hydrogenchloride; In methanol; water; for 0.5h;Reflux; | [4FBzTPP]Cl (0.41 g, 1 mmol) and MnCl2¢4H2O (0.10 g,0.5 mmol) were dissolved in 20 mL of methanol acidifiedwith 3 mL of concentrated hydrochloric acid. The solutionwas heated and stirred under reflux for 0.5 h. The pale yellowcrystals (0.34 g) were obtained by evaporation of the solutionat room temperature. Yield: 76.5%. Anal. Calcd. forC50H42Cl4F2MnP2: C, 63.91; H, 4.51%; Found: C, 63.84; H,4.62%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23%; 29% | With dibenzo-18-crown-6; potassium carbonate; In dichloromethane; at 20℃; for 24h; | General procedure: The corresponding phosphonic salt (0.70mmol) was suspended in 5mL of anhydrous dichloromethane, to which were added under stirring 1.75mmol of potassium carbonate and dibenzo-18-crown-6 as a catalyst. Then a solution of 0.70mmol of aldehyde (9) in 5mL of anhydrous dichloromethane was added. The mixture was stirred for 24h, after which the residue was filtered off and the solvent was evaporated in vacuo. Purification of the organic residue on 20g of silica gel (eluent: petroleum ether-ethyl acetate (3:2)) afforded the title compound (10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: n-BuLi (2.5 M in hexane, 4 mL, 10.0 mmol) was added dropwise under argon to a 0 C suspension of the respective alkylphosphoniumchloride (10.0 mmol) in THF (50 mL). The mixture was stirred for 30 min whereupon a solution of 10 (2.42 g, 9.0 mmol) in THF (10 mL) was added. The reaction mixture was allowed to warnup to rt and stirred at that temperature for 18 h. At that point, sat. aq NH4Cl (25 mL) was added and the mixture was diluted with ethyl acetate (50 mL) and water (20 mL). Organic phase was separated and the aqueous phase was additionally extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was fractionated on silica gel using 0?5% ethyl acetate in hexanes as eluent. Fractions containing the olefination product (according to LC MS analysis) were pooled and concentrated to dryness. The material thus obtained was used in the subsequent steps without further purification.To a solution of this material in EtOH (20 mL/mmol assuming 100% purity of the product in the previous step) HCOONH4 (4 mmol/mmol) and 10% Pd on carbon (37 mg/mmol) were added and the resulting mixture was heated at reflux for 12 h. The mixture was cooled to rt and filtered through a plug of Celite (subsequently washing the latter with EtOH). The combined filtrate and washings were concentrate to dryness. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated and the aqueous layer was additionally extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with 3% aqueous citric acid, 5% aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Without further purification, the residue was dissolved in CH2Cl2 (3 mL/mmol calculated assuming 100% purityof the material obtained in the previous step), the solution was cooled to 0 C and TFA (1 mL/mmol) was added. The mixture thus obtained was stirred at 0 C for 6 h and then concentrated to dryness to provide, after crystallization from isopropyl alcohol, the target spirocyclic piperidine as a trifluoroacetate salt. Compounds 3h, 3j, 3m-n were converted to hydrochloride salts by treatment of their rt solutions in 1,4-dioxane with 4 M HCl in 1,4-dioxane followed by stirring for 3 h, evaporation of the volatiles in vacuo and crystallization from isopropyl alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In acetone; | A mixture of 0.182 g (0.11 mmol)of 4-fluorobenzyl)triphenylphosphonium chloride and0.05 g (0.11 mmol) of tetrachloroauric acid hexahydrate was dissolved with stirring in 15 mL of acetone. After evaporation of the solvent yellow crystals formed. Yield 0.050 g (63%), decomposition temperature 133C. IR spectrum nu, cm-1 : 3061, 2936,2884, 1601, 1587, 1485, 1510, 1439, 1400, 1314,1229, 1161, 1109, 997, 847, 829, 787, 741, 718, 689,554, 513, 507, 484, 474, 442. Found, %: C 42.13; H3.02. C25H21AuCl4FP. Calculated %: C 42.27; H 2.96. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | (S)-Ethyl 2-( tert-butoxy)-2-( 4-(4, 4-dimethylpiperidin-l-yl)-5-( 4-( 4-fluorostyryl)phenyl)- 2,6-dimethylpyridin-3-yl)acetate: To a stirred white slurry of (4- fluorobenzyl)triphenylphosphonium, chloride salt (0.169 g, 0.416 mmol) in THF (5 mL) was added dropwise 2M BuLi/hex (0.208 ml, 0.416 mmol) at 0 C. AfterlO min, cold bath was removed and the orange reaction mixture was stirred additional 30 min at rt. Then, solid (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(4- formylphenyl)-2,6-dimethylpyridin-3-yl)acetate (0.1 g, 0.208 mmol) was added at once and stirred for 1 h. Then, concentrated and purified by flash chromatography using 10 and 20% EtO Ac/Hex to afford (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l- yl)-5-(4-(4-fluorostyryl)phenyl)-2,6-dimethylpyridin-3-yl)acetate (0.097 g, 0.169 mmol, 81 % yield) as white solid. 1HNMR indicates that this is a 2: 1 mixture of isomers. 1H MR (500 MHz, CDC13) delta 7.58-7.61 (m, IH), 7.52-7.56 (m, IH), 7.36 (dd, J=1.7, 7.9 Hz, IH), 7.26-7.30 (m, 3H), 7.14-7.19 (m, 2H), 7.08-7.13 (m, 2H), 7.06 (dd, J=1.7, 7.9 Hz, IH), 6.90-6.95 (m, 2H), 6.68 (d, J=12.3 Hz, IH), 6.62 (d, J=12.3 Hz, IH), 6.08 (s, 1.5H), 4.14-4.31 (m, 3H), 3.17-3.23 (m, 1.5H), 2.83-2.94 (m, 1.5H), 2.62 (s, 1.5H), 2.61 (s, 3H), 2.28-2.36 (m, 1.5H), 2.23 (s, 1.5H), 2.20 (s, 3H), 2.06-2.18 (m, 1.5H), 1.33-1.62 (m, 6H), 1.25-1.29 (m, 4.5H), 1.22 (s, 4.5H), 1.21 (s, 9H), 0.94 (s, 3H), 0.90 (br.s., 1.5H), 0.73 (s, 3H), 0.65 (br. s., 1.5H). LCMS (M+H) = 573.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With hydrogenchloride; In dimethyl sulfoxide; at 20℃; | A mixture of (4-fl uorobenzyl)triphenylphosphoniumchloride (156 mg, 0.38 mmol) and ruthenium(III) chloride hydrate(50 mg, 0.19 mmol) was dissolved with stirring in air indimethyl sulfoxide (2 mL), and then concentrated hydrochloricacid (2 mL) was added. The solvent was evaporated to 0.5 mL,resulting in the formation of dark-brown crystals, which werewithdrawn and dried. The yield was 97 mg (48%). T.decomp.230 . IR, /cm-1: 3053, 3024, 3007, 2989, 2949, 2907, 1508,1483, 1437, 1398, 1313, 1225, 1161, 1138, 1109, 995, 843, 833,770, 746, 718, 704, 689, 554, 503, 480, 442, 417. 1H NMR(500 MHz, DMSO-d6), : 5.04 (d, 2 H, CH2, 2JP,H = 15.4 Hz);7.05 (m, 2 H, H(2), H(6)); 7.10 (t, 2 H, H(3), H(5), 3JH,H == 3JF,H = 8.6 Hz); 7.68 (dd, 6 H, o-H, 4JP,H = 12.4 Hz,3JH,H = 7.8 Hz); 7.76 (td, 6 H, m-H, 3JH,H = 7.8 Hz, 5JP,H == 3.5 Hz); 7.92 (m, 3 H, p-H). 19F NMR (470 MHz, DMSO-d6),: 49.37 (ttd, F(4), 3JF,H = 8.6 Hz, 4JF,H ? 6JF,P ? 5.6 Hz).31P NMR (202 MHz, DMSO-d6), : 23.43 (d, P, 6JF,P = 6.0 Hz).Found (%): , 56.58; , 4.07. C50H42F2P2Cl6Ru. Calculated (%):, 56.79; 3.98. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether; potassium carbonate; In dichloromethane; at 40℃; for 4h; | General procedure: To a solution of hemiacetal 68 (Manuscript compound No. 7a) (0.200 g, 0.81 mmol, 1.0 equiv.) in dichloromethane (4.8 mL, 6 mL/mmol), was added 4-fluorobenzyl triphenylphosphonium chloride (0.362 g, 0.89 mmol, 1.1 equiv.) followed by anhydrous potassium carbonate (0.123 g, 0.89 mmol, 1.1 equiv.) and 18-crown-6 (0.043 g, 0.16 mmol, 0.2 equiv.). This reaction mixture was stirred at 40 oC for 4h (reaction progress was monitored by TLC). Upon completion of reaction, the reaction mixture was diluted with dichlorometane (20 mL). The organic layer was sequentially washed with water (50 mL) and brine (50 mL). The organic layer thus obtained, was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product mixture of E-isomer and Z-isomer which was purified by silica gel column chromatography (eluent: 20-40% ethyl acetate in hexanes) to furnish pure (E)-69 isomer and (Z)-69 isomer. Combined isolated yield: 0.233 g (85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 18-crown-6 ether; potassium carbonate; In dichloromethane; at 40℃; for 4h; | To a solution of hemiacetal 68 (Manuscript compound No. 7a) (0.200 g, 0.81 mmol, 1.0 equiv.) in dichloromethane (4.8 mL, 6 mL/mmol), was added 4-fluorobenzyl triphenylphosphonium chloride (0.362 g, 0.89 mmol, 1.1 equiv.) followed by anhydrous potassium carbonate (0.123 g, 0.89 mmol, 1.1 equiv.) and 18-crown-6 (0.043 g, 0.16 mmol, 0.2 equiv.). This reaction mixture was stirred at 40 oC for 4h (reaction progress was monitored by TLC). Upon completion of reaction, the reaction mixture was diluted with dichlorometane (20 mL). The organic layer was sequentially washed with water (50 mL) and brine (50 mL). The organic layer thus obtained, was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product mixture of E-isomer and Z-isomer which was purified by silica gel column chromatography (eluent: 20-40% ethyl acetate in hexanes) to furnish pure (E)-69 isomer and (Z)-69 isomer. Combined isolated yield: 0.233 g (85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The solution of <strong>[3462-95-1](4-fluorobenzyl)triphenylphosphonium chloride</strong> (2.71 g, 6.66 mmol,1 .1 equiv.) in anhydrous THE (20 mL) was purged under a stream of argon for 5 mm before NaH (60% dispersion on mineral oil, 0.27 g, 6.66 mmol, 1.1 equiv.) was added. The resulting suspension was stirred for 3 h at room temperature, and then the solution of tert-butyl 4-oxoazepane-1-carboxylate (1.29 g, 6.05 mmol, 1.0 equiv.)in THE (15 mL) was added. The reaction mixture was stirred under reflux for 16 h, and then allowed to cool down to room temperature. The precipitate formed was filtered off, and the mother liquor was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography using petroleum ether/Et20 = 9/1 (v/v) as eluent to obtain a mixture of cis/trans isomers (ratio 42/58,estimated from 1 H NMR). Overall yield (both isomers): 35% (649 mg), colorless oil; Rf = 0.12 (petroleum ether/Et20 = 9/1, v/v); 1H NMR (400 MHz, CDCI3): 6 1.29 (5, 5H, cis), 1.43 (5, 4H, cis), 1.45 (5, 12.5H, trans), 1.63 (bs, 4.8H, cis + trans), 2.34-2.37 (m, 4.8H, cis + trans), 2.50 (t, J = 6.1 Hz, 2.8H, trans), 2.58 (td, J = 6.3, 1 .3 Hz, 2H, cis), 3.40-3.48 (m, 9.8H, cis + trans), 6.28 (d, J = 6.9 Hz, 1 .4H, trans), 6.34 (bs, 1 H,cis), 6.96-7.01 (m, 4.8H, cis + trans), 7.13-7.16 (m, 4.8H, cis + trans); MS (ESI+):m/z[M+Na] 328.17; found 327.77. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: (4-fluorobenzyl)triphenylphosphonium chloride With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Tags: 3462-95-1 synthesis path| 3462-95-1 SDS| 3462-95-1 COA| 3462-95-1 purity| 3462-95-1 application| 3462-95-1 NMR| 3462-95-1 COA| 3462-95-1 structure
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P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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