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CAS No. : | 4009-98-7 | MDL No. : | MFCD00011800 |
Formula : | C20H20ClOP | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SJFNDMHZXCUXSA-UHFFFAOYSA-M |
M.W : | 342.80 | Pubchem ID : | 2723798 |
Synonyms : |
|
Num. heavy atoms : | 23 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.1 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 102.76 |
TPSA : | 22.82 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -4.58 cm/s |
Log Po/w (iLOGP) : | -1.17 |
Log Po/w (XLOGP3) : | 5.37 |
Log Po/w (WLOGP) : | 0.59 |
Log Po/w (MLOGP) : | 4.78 |
Log Po/w (SILICOS-IT) : | 4.62 |
Consensus Log Po/w : | 2.84 |
Lipinski : | 1.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.6 |
Solubility : | 0.000866 mg/ml ; 0.00000253 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.6 |
Solubility : | 0.000855 mg/ml ; 0.0000025 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -8.06 |
Solubility : | 0.00000297 mg/ml ; 0.0000000086 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.48 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P501-P270-P264-P280-P337+P313-P301+P312+P330 | UN#: | N/A |
Hazard Statements: | H302-H315-H319 | 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 |
---|---|---|
97.3% | at 95℃; for 16 h; | 20 g of triphenylphosphine was placed in a round bottom flask, dissolved in toluene, heated to 95 ° C, and 6.37 mL of chloromethyl methyl ether was added, and the reaction was carried out for 16 hours. After the reaction is complete,Cool to room temperature, filter, filter cake washed with toluene three times, dry,Obtained 25.4 g of white phosphonium salt, yield 97.3percent |
88.5% | at 37 - 47℃; for 6 h; Inert atmosphere | Under nitrogen, 50 mL of anhydrous acetone was added to the reactor,Then 32 g of triphenylphosphine was added,While stirring, the temperature was raised to 37 ° C,While maintaining the temperature, 20 g of methyl chloromethyl ether was added to the reactor,Followed by reaction at 37 ° C for 3 h,The temperature was gradually raised to 47 ° C at a rate of 1 ° C / min and the reaction was continued for 3 h,The reaction was stopped, filtered, washed with anhydrous ether, dried,To give 37.0 g (methoxymethyl) triphenylphosphonium chloride in a yield of 88.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium hexamethyldisilazane In tetrahydrofuran | Step A 2-[4-[(E)-2-methoxyethenyl]phenyl]-pyrazine Sodium hexamethyldisilazide (10.80 mL, 10.80 mmol, 11.0M in THF) was added to a suspension of methoxymethyltriphenylphosphonium chloride (3.72 g, 10.80 mmol) in THF (20 mL) at -10° C., and the red-orange mixture was stirred for 15 min at -10° C. A solution of 4-pyrazinylbenzaldehyde (1.00 g, 5.43 mmol) prepared as described in reference example 17) in THF (3 mL) was added dropwise, and stirring was continued at -10° C. for 1 h. The reaction mixture was quenched with sat. aq. NH4Cl, extracted with ethyl acetate, the organic layer dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded 820 mg (71percent) of the title compound (E:Z=1:1). MS 213 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation Example 267 To a suspension of (methoxymethyl)(triphenyl)phosphonium chloride (164.57 g) which had been cooled in a dry ice-acetone bath in THF (500 ml) was added dropwise a solution of n-butyllithium in hexane (concentration 1.65 M, 281.3 ml) at -55C or lower under a nitrogen air flow. Then, the mixed reaction liquid was warmed, followed by stirring at room temperature for 1 hour. After stirring, the mixed reaction liquid was cooled under ice, and a solution of <strong>[17429-02-6]4-hydroxy-4-methylcyclohexanone</strong> (20.51 g) in THF (205 ml) was added dropwise thereto. After dropwise addition, the mixed reaction liquid was warmed to room temperature, followed by stirring for 15 hours. To the mixed reaction liquid were sequentially added water and EtOAc, followed by stirring, and then the organic layer was collected by separation. The aqueous layer was further extracted with EtOAc, and the organic layer was combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was removed, the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (hexane-EtOAc) to obtain 4-(methoxymethylene)-1-methylcyclohexanol (21.37 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
820 mg (71%) | With sodium hexamethyldisilazane; In tetrahydrofuran; | Step A 2-[4-[(E)-2-methoxyethenyl]phenyl]-pyrazine Sodium hexamethyldisilazide (10.80 mL, 10.80 mmol, 11.0M in THF) was added to a suspension of methoxymethyltriphenylphosphonium chloride (3.72 g, 10.80 mmol) in THF (20 mL) at -10 C., and the red-orange mixture was stirred for 15 min at -10 C. A solution of 4-pyrazinylbenzaldehyde (1.00 g, 5.43 mmol) prepared as described in reference example 17) in THF (3 mL) was added dropwise, and stirring was continued at -10 C. for 1 h. The reaction mixture was quenched with sat. aq. NH4Cl, extracted with ethyl acetate, the organic layer dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 3:1 hexane/ethyl acetate) yielded 820 mg (71%) of the title compound (E:Z=1:1). MS 213 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.4% | With sodium hydroxide; sodium tetrahydroborate; In tetrahydrofuran; hydrogenchloride; ethanol; water; | Production Example 30 Synthesis of 5-(2-bromoethyl)-3-methoxypyridine Methoxymethyltriphenylphosphonium chloride (3.0 g) was suspended in tetrahydrofuran (10 ml). Under ice cooling, potassium t-butoxide (0.98 g) was added thereto followed by stirring for 15 min. Next, <strong>[113118-83-5]5-methoxy-3-pyridinecarboxyaldehyde</strong> (0.4 g) synthesised as reported in Heterocycles, 2159 (1987). and dissolved in tetrahydrofuran (5 ml) was added thereto and the resultant mixture was stirred at room temperature for 2 hr. After adding water and ethyl acetate thereto, the layers were separated and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give a yellow oil (0.364 g). This product was dissolved in 1 N hydrochloric acid (44 ml) and stirred at 60 C. for 3 hr. After allowing to cool, the reaction solution was basified with an aqueous solution of sodium hydroxide, extracted with chloroform, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow oil (0.220 g). This product was dissolved in ethanol (7.2 ml) and sodium tetrahydroborate (0.054 g) was added thereto under ice cooling. After stirring at room temperature for 30 min, the resultant mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a pale yellow oil (0.188 g). This product was treated as in the above Production Example 1 to give the title compound (0.181 g) as a brown oil (yield: 28.4%). 1H-NMR (400 MHz, CDCl3): delta(ppm) 3.16(2H, t, J=6.4Hz),3.57(2H, t, J=6.4Hz), 3.88(3H, s), 7.08(1H, s), 8.10(1H, s), 8.21(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; potassium tert-butylate; In hexane; | EXAMPLE 3 This Example illustrates an alternative synthesis of (E)-methyl 3-methoxy-2-[2-(3-methylphenoxy)phenyl]propenoate. A mixture of methyl ortho-bromophenylacetate (4.10 g, prepared as described in Example 1) and selenium dioxide (4.92 g) was stirred for 25 hours at 190 C. After cooling, the mixture was diluted with dichloromethane (100 ml) then filtered through `Supercel`. The filtrate was washed successively with saturated aqueous sodium bicarbonate (*2) and brine, then dried and concentrated to give a yellow liquid (3.60 g) containing (52% by GC-MS) <strong>[122394-38-1]methyl (2-bromobenzoyl)formate</strong> and unreacted methyl ortho-bromophenylacetate. Potassium tert-butoxide (2.33 g) was added to a vigorously-stirred suspension of (methoxymethyl)triphenylphosphonium chloride (7.90 g) in ether (80 ml) at room temperature. After 15 minutes, a solution of the crude <strong>[122394-38-1]methyl (2-bromobenzoyl)formate</strong> (3.60 g) in ether (10 ml) was added in a single portion. After a further 15 minutes, the reaction mixture was poured into water (150 ml), the aqueous and organic layers were separated, and the former was extracted with a further portion of ether (100 ml). The combined ether layers were washed successively with water (*2) and brine, then dried and concentrated to give a yellow oil (5.81 g) containing, in a ratio of about 6:5, the (E)- and (Z)-isomers respectively of methyl 2-(2-bromophenyl)-3-methoxypropenoate. Chromatography using ether:hexane (1:1) as eluant allowed the pure (Z)-isomer (0.450 g) to be isolated as a pale yellow oil, IR (film) 1712, 1638 cm-1, 1 H n.m.r delta 3.71 (3H, s), 3.95 (3H, s), 6.57 (1H, s) p.p.m. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 13h;Heating / reflux; | Example 3 : rralphaw.s'-2-(ammome1hyl)-5-(5'-fluoro-2'-methoxybenzyl)tetrahydrofuran[0195] S-Fluoro-2-methoxyphenacetaldehyde:; To a suspension of methoxymethyltriphenylphosphonium chloride (10.0 g, 30.0 mmol) in THF (30 mL) under Ar(g) was added NaH (60% in mineral oil, 1.2 g, 30 mmol) and the mixture thus obtained was heated to reflux for 1 h. The orange suspension thus obtained was cooled to O0C and 5- fluoro-2-methoxybenzaldehyde (4.2 g, 26.0 mmol) was added and the reaction was continued for 12 h while warmed to room temperature. The reaction mixture was poured in to a separatory funnel containing ammonium chloride aqueous solution (sat. NH4Cl: H2O=I :1, 100 mL). The organic fraction was extracted with ethyl acetate (3 x 80 mL) and the combined organic layers were washed with brine (60 mL) and dried over sodium sulfate. The solvent was then removed in vacuo and crude product thus obtained was dissolved in acetone (50 mL) and H2SO4 (1 M, 1.5 mL) was added and the mixture thus obtained was heated to reflux for 6 h. It was then cooled to room temperature and the crude product obtained after the removal of the solvent was purified by flash column chromatography (10% ethyl acetate in hexane, Rf = 0.15) to give the product (2.63 g, 66%) as an oil.; [0287] 5-Fluoro~2-methoxyphenylacetaldehyde (2a): To a suspension of methoxymethyltriphenylphosphonium chloride (10.0 g, 30.0 mmol) in THF (30 niL) under Ar was added NaH (60% in mineral oil, 1.2 g, 30 mmol) and then heated to reflux for 1 h. The orange colored suspension was cooled to 0C and <strong>[19415-51-1]5-fluoro-2-methoxybenzaldehyde</strong> (4.2 g, 26.0 mmol) was added and the mixture was stirred for 12 h at room temperature. The reaction mixture was then poured into a separatory funnel containing ammonium chloride aqueous solution (sat. NH4C1/H20, 1:1, v:v, 100 niL). The organic material was extracted with ethyl acetate (3 x 80 mL) and the combined organic layers were washed with brine (60 mL) and dried over Na2SO4. The solvent was then removed in vacuo and the crude product (2a) obtained was dissolved in acetone (50 mL). H2SO4 (1 M, 1.5 mL) was then added and the mixture obtained was heated to reflux for 6 h while stirring. The reaction was then cooled to room temperature and the solvent was removed in vacuo to obtain the crude product that was then purified by flash column chromatography (Rf = 0.15, EtOAc/Hexane, 10:90, v:v) to afford the product (2.63 g, 66%) as an oil: 1H NMR (CDCl3, 500 MHz): delta 9.68 (s, 1 H), 6.97 (dt, J= 3.1, 8.7 Hz, 1 H), 6.89 (dd, J= 3.1, 8.7 Hz, 1 H), 6.83 (dd, J= 4.3, 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.63 (d, J= 1.7 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example I: 5-(2-Methoxyvinyl)-1-methylpyrazole; Experimental procedure:; Under N2-atmosphere dry MeOCH2P+Ph3Cl- (16.2 g, 47.2 mmol) was weight into and suspended in abs. THF (100 mL) for 30 minutes. Subsequently the suspension was cooled to -50 C with a mixture of dry ice and acetone and subsequently a solution of KOtBu in THF (1M, 54.5 mL, 54.5 mmol) was added slowly. After a further 15 minutes of stirring, the aldehyde of Example H (4 g, 36.3 mmol) was dissolved in abs. THF (30 mL) and added dropwise at -50 C. The reaction mixture was slowly brought to room temperature over night while stirring. After addition of water (? 40 mL) it was extracted 3 times with CH2Cl2. The pooled organic phases were dried over K2CO3, filtered and the solvent removed under vacuum (35 C, 150 mbar) upto a volume of approx. 15 mL. The crude product was purified using flash-chromatography (Ø= 8 cm, h = 18 cm, n-hexane:ethylacetate = 5:5, 65 mL, Rf = 0.20). Slightly yellow product, that was directly reacted further. C7H10N2O (138.2) MS (ESI): m/z (rel.Int) = 139 [MH+, 22], 294 [2 x M + NH4+, 100]. IR (neat): nu (cm-1) = 2940 (C-H aliphat.), 1644 (C=C Alken), 1100 (C-O). 1H-NMR (CDCl3): delta (ppm) = 3.70 (s, 3H, OCH3, trans-Isomer), 3.79, 3.80, 3.81 (je s, 9H, NCH3, cis-Isomer + trans-Isomer (6H), OCH3 cis-Isomer (3H)), 5.23 (d, J = 6.7 Hz, 1H, CH=CHOCH3, cis-Isomer), 5.60 (d, J = 12.9 Hz, 1H, CH=CHOCH3, trans-Isomer), 6.11 (d, J = 1.6 Hz, 1H, Pyrazole-4-CH, trans-Isomer), 6.20 (d, J = 6.7 Hz, 1H, CH=CHOCH3, cis-isomer), 6.55 (d, J = 1.6 Hz, 1H, Pyrazole-4-CH, cis-Isomer), 6.96 (d, J = 12.9 Hz, 1H, CH=CHOCH3, trans-Isomer), 7.36 (d, J = 1.6 Hz, 1 H, Pyrazole-3-CH, trans-Isomer), 7.41 (d, J = 1.2 Hz, 1H, Pyrazole-3-CH, cis-Isomer). In the spectrum the signals of the solvent (ethylacetate) are also visible. The ratio of the both isomers cis/trans is 2:3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example D: 5-(2-Methoxyvinyl)-1-phenylpyrazole; Experimental procedure:; Under N2-atmosphere dried MeOCH2P+Ph3Cl- (6.22 g, 18.1 mmol) was weighed out and suspended in abs. THF (60 mL) for 30 minutes. Subsequently the suspension was cooled to -50 C and following that KOtBu-Solution in THF (1M, 16.5 mL, 16.5 mmol) was slowly added dropwise. After stirrig for another 15 minutes, the aldehyd of example A (1.42 g, 8.3 mmol) was dissolved in abs. THF (40 mL) and added dropwise at -50 C. The reaction mixture was slowly heated to room temperature over night while sttirring. After adittion of water (? 25 mL) it was extracted 3-times using ethylacetatet. The organic phases were dried over K2CO3, filtered and the solvent removed under vacuum. The crude product (7.59 g) was purified using flash-chromatography (Ø= 8 cm, h = 12 cm, n-hexane:ethylacetate = 9:1, 40 mL, Rf = 0.10). Colourless Oil, Yield 1.53 g (92%) C12H12N2O (200.3) MS (EI): m/z (rel. Int) = 200 [M+, 93], 169 [M - OCH3, 100]. IR (neat): nu (cm-1) = 3098 (C-H aromat.), 2935 (C-H aliphat.), 1644 (C=C Alken), 1597, 1529 (C=C aromat.), 1093 (C-O), 761, 696 (C-H). 1H-NMR (DMSO-D6): delta (ppm) = 3.56 (s, 3H, OCH3, trans-Isomer), 3.77 (s, 3H, OCH3, cis-Isomer), 5.18 (d, J = 6.8 Hz, 1 H, CH=CHOCH3, cis-Isomer), 5.59 (d, J = 12.8 Hz, 1H, CH=CHOCH3, trans-Isomer), 6.37 (d, J = 6.8 Hz, 1H, CH=CHOCH3, cis-Isomer), 6.47 (d, J = 1,6 Hz, 1H, Pyrazole-4-CH, trans-Isomer), 6,63 (d, J = 1.6 Hz, 1H, Pyrazole-4-CH, cis-Isomer), 7.26 (d, J = 12.8 Hz, 1 H, CH=CHOCH3, trans-isomer), 7.39 - 7.54 (m, 10H, aromat. H, cis-Isomer (5H), trans-Isomer (5H)), 7.55 (d, J = 1.6 Hz, 1H, Pyrazole-3-CH, trans-Isomer), 7.58 (d, J = 1.2 Hz, 1H, Pyrazole-3-CH, cis-Isomer). The ratio of the isomers cis/trans is 1:3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a cooled [(0C)] slurry of methoxymethyltriphenylphosphonium chloride (39g) in a mixture of diethyl ether (200ml) and tert-butanol [(50ML)] was added potassium tert-butoxide (12.8g) portion wise. The resulting mixture was stirred at [0C] for 1 hour, then a solution of <strong>[4506-45-0]2-formyl-5-chlorobenzoic acid</strong> (prepared as described in [J.] Org. Chem. 61,3402 (1996) ) (10g) in diethyl ether [(50ML)] was added dropwise over 15 minutes. The resulting mixture was stirred for 1 hour at [0C,] then warmed to ambient and stirred for an additional 90 minutes. The mixture was diluted with water (200ml) and the organic phase removed. The aqueous phase was acidified to pH 1 with 1M HC1 and extracted with ethyl acetate [(3X50ML).] The combined extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated. The residue was purified by flash chromatography (50% ethyl acetate/hexane) to afford the sub-title compound as a yellow solid (9.13g, [80%). 1H NMR] (400MHz, [CDCL3)] [6] 3.70-3. 81 (3H, s), 6.20 (0.3H, d, cis alkene), 6.30 (0.3H, d, cis alkene), 6. 80 (0.7H, d, trans alkene), 7.01 (0.7H, d, trans alkene), 7.30-8. 15 (3H, m) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
N-butyl lithium (13.7 mL, 34.88 mmol) was added to a solution of (methoxymethyl)(triphenyl)phosphonium chloride (11.9 g, 34.88 mmol) in tetrahydrofuran (50 mL) that was cooled to -50 C. The reaction mixture was stirred at -25 C. for 30 minutes followed by the dropwise addition of a solution of the compound obtained from step-I above (5 g, 23.25 mmol) in tetrahydrofuran (10 mL) at the same temperature. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue thus obtained washed with hexane, dried under reduced pressure and the residue thus obtained was diluted with tetrahydrofuran followed by the addition of aqueous hydrochloric acid (20%, 30 mL). The reaction mixture was stirred at room temperature for 5 hours and then the organic layer was evaporated under reduced pressure. The aqueous layer was basified with aqueous potassium hydroxide and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue thus obtained was diluted with saturated solution of sodium metabisulphite. The organic layer was separated and neutralized with sodium carbonate. The reaction mixture was extracted with ethyl acetate, the organic layer was concentrated under reduced pressure and the residue thus obtained was treated with methanol-water-sodium hydroxide. The solution was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and the residue thus obtained was diluted with water. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried under reduced pressure, filtered and concentrated under reduced pressure to furnish the title compound. Yield: 2.2 g.1H NMR (CDCl3) delta: 9.62 (s, 1H), 7.32-7.22 (m, 5H), 3.51 (s, 2H), 2.79-2.75 (m, 2H), 2.51 (bs, 2H), 2.25 (s, 1H), 2.13-2.05 (m, 2H), 1.79-1.77 (m, 2H), 1.60-1.57 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Step 1 : Potassium tert-butoxide (4.49 mL, IM in THF) was added over about5 minutes to (methoxymethyl) triphenylphosphonium chloride (1.42 g, 4.15 mmol) suspended in anhydrous THF (25 mL) at O0C. The resulting suspension was stirred at about this temperature for about 45 minutes at which time, tert-butyl 2-benzyl-4-oxopiperidine-l- <n="111"/>carboxylate (1.Og, 3.46 mmol) dissolved in THF (5 niL) was added. The reaction mixture was allowed to warm to ambient and stir for another 6h. The reaction was quenched by the addition of ammonium chloride solution and then taken up in EtOAc. After washing twice with water and once with brine, the organic portion was dried over magnesium sulfate, filtered and concentrated. The resulting semi-solid residue was purified via silica gel chromatography to give (Z)-tert-butyl 2-benzyl-4-(methoxymethylene)piperidine-l- carboxylate (375 mg, 34%). LCMS (APCI+) m/z 218.1 [M+H]+; Rt = 4.51 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
660 mg (1.9 mmol) of methoxymethyl-triphenylphosphonium chloride was dissolved in 10 ml of tetrahydrofuran, then n-butyl lithium was added to the resulting at - 78C. After 30 minutes, the reaction was heated to 0C and 2 ml of hexamethylphosphoamide was added thereto, then 220 mg (1.3 mmol) of 1-phenyl-lH- pyrrazole-3-carbaldehyde dissolved in 3 ml of tetrahydrofuran was further added thereto. After stirring for 1 hour, ethylacetate was added, followed by washing with ammonium chloride solution. The organic solution thus obtained was dried over anhydrous ammonium sulfate, the residue was purified by column chromatography to obtain 3- (2- methoxy-vinyl)-1-phenyl-lH-pyrazole. This compound was dissolved in a mixture of 3 ml of 3 N hydrogen chloride solution and 20 ml of tetrahydrofuran, then the resulting solution was stirred with heating for 2 hours. Ethylacetate was added thereto and the resulting solution was washed with water, then the organic solution thus obtained was dried over anhydrous magnesium sulfate, and the residue was purified by column chromatography to obtain 130 mg of the title compound in a yield of 36%. Mass (EI) 187 (M++1) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Preparation 10; 2-(4'-Trifluoromethyl-biphenyl-4-yl)-ethanol ;Step A. 4-(2-Methoxy-vinyl)-4'-trifluoromethyl-biphenyl; To an ambient temperature suspension of potassium tert-butoxide (449 mg, 4.00 mmol) in THF (20 mL) is added (methoxymethyl) triphenylphosphonium chloride (1.37 g, 4.00 mmol) and is stirred at room temperature for 30 min. 4'-trifluoromethyl-biphenyl-4- carbaldehyde (500 mg, 2.00 mmol) is added and the reaction mixture continues to stir at room temperature. After 2h TLC (30% EtOAc/hexane) indicates complete consumption of starting material. The reaction is quenched with saturated aqueous NH4Cl and concentrated. The residue is partitioned between EtOAc (50 mL) and water (20 mL). The aqueous layer is extracted with EtOAc (50 mL) and the combined organic layers are washed with brine (100 mL), dried (MgS04), filtered, concentrated and chromatographed (40 g Si02, 5% EtOAc/Hexanes) to yield the title compound (482 mg, 87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(Methoxymethyl)triphenylphosphonium chloride (1133 g, 3.7 mol) was suspended in tetrahydrofuran (7.0 L) under argon atmosphere, and stirred with ice-water cooling. t-BuOK (397 g, 3.54 mol) was added in portions. Then a solution of 4-bromo-2,6- difluorobenzaldehyde (340 g, 1.54 mol) in tetrahydrofuran (2.7 L) was added and the reaction was stirred at room temperature for 6 hours. The solution was then poured into ice-water and extracted with ethyl acetate (2x). The combined organic phases were dried and concentrated in vacuo. This material was purified by flash chromatography to afford the title compound. 1H NMR (400 MHz, CDCl3): delta 7.02 (d, 2H), 6.30 (d, 0.3H), 5.70 (d, 0.6H), 5.10 (d, 0.3H), 3.75 (S, 3H). | ||
Step 2. 2-(4-Bromo-2,6-difluorophenyl)vinyl methyl ether (Methoxymethyl)triphenylrhohosrhohonium chloride (1133 g, 3.7 mol) was suspended in tetrahydrofuran (7.0 L) under argon atmosphere, and stirred with ice-water cooling. r-BuOK (397 g, 3.54 mol) was added in portions. Then a solution of 4-bromo-2,6- difluorobenzaldehyde (340 g, 1.54 mol) in tetrahydrofuran (2.7 L) was added and the reaction was stirred at room temperature for 6 hours. The solution was then poured into ice-water and extracted with ethyl acetate (2x). The combined organic phases were dried and concentrated in vacuo. This material was purified by flash chromatography to afford the title compound. 1HNMR (400 MHz, CDCl3): delta 7.02 (d, 2H), 6.30 (d, 0.3H), 5.70 (d, 0.6H), 5.10 (d, 0.3H), 3.75 (s, 3H). | ||
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 6h;Inert atmosphere; | (Methoxymethyl)triphenylphosphonium chloride (1133 g, 3.7 mol) was suspended in tetrahydrofuran (7.0 L) under an argon atmosphere, and stirred with ice-water cooling, t- BuOK (397 g, 3.54 mol) was added in portions. Then a solution of 4-bromo-2,6- difluorobenzaldehyde (34O g, 1.54 mol) in tetrahydrofuran (2.7 L) was added and the reaction was stirred at room temperature for 6 hours. The solution was then poured into ice- water and extracted with ethyl acetate (2x). The combined organic phases were dried and concentrated in vacuo. This material was purified by flash chromatography to afford the title compound. <n="84"/>1H NMR (400 MHz, CDCl3): delta 7.02 (d, 2H), 6.30 (d, 0.3H), 5.70 (d, 0.6H), 5.10 (d, 0.3H), 3.75 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (methoxymethyl)triphenylphosphonium chloride (7.93 g, 23.1 mmol) in tetrahydrofuran (38.5 ml) was added potassium tert-butoxide (2.60 g, 23.1 mmol) at -15C, and the resultant was stirred at the same temperature for 30 minutes. A solution of <strong>[130753-13-8]8-benzyloxycarbonyl-8-azabicyclo[3.2.1]octan-3-one</strong> (Reference Example 171) (5.00 g, 10.9 mmol) in tetrahydrofuran (38.5 ml) was added dropwise to the reaction solution at -15C, and the mixture was then stirred at room temperature for 15 hours. An aqueous solution of 6M hydrochloric acid was added to the reaction solution, and the mixture was then stirred for 5 hours. Distilled water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and then concentrated under a reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to give a title compound (2.23 g, 8.16 mmol, 42%) as a colorless oil product. 1H-NMR (400 MHz, CDCl3) delta:1.63-1.84 (6H, m), 2.01-2.08 (2H, m), 2.72-2.77 (1H, m), 4.41-4.44 (2H, m), 5.14 (2H, s), 7.29-7.37 (5H, m), 9.54 (1H, m). ESI-MS: m/z = 274 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.7% | Fifth Step: Well-dried methoxymethyltriphenylphosphonium chloride (112.1 g) and THF (1000 ml) were mixed under a nitrogen atmosphere, and cooled to -30 C. Then, potassium t-butoxide (t-BuOK; 36.7 g) was put in thereto in twice in the temperature range of -30 C to 20 C. After the mixture had been stirred at -20 C for 30 minutes, the compound (35) (41.9g) dissolved in THF (200 ml) was added dropwise thereto in the temperature range of -30 C to -20 C. After the reaction had been stirred at -10 C for 30 minutes, it was poured into a mixture of water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and an extractive operation was carried out. The organic phase obtained was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified with a fractional operation by means of column chromatography using toluene as the eluent and silica gel as the stationary phase powder. The eluent obtained was concentrated under reduced pressure, giving 45.0 g of 1-(3-fluorophenyl)-4-methoxymethylenecyclohexane (36). The yield based on the compound (35) was 93.7%. |
Yield | Reaction Conditions | Operation in experiment |
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6-Chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (12).; A suspension of (methoxymethyl)triphenyl-phosphonium chloride (11, 276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to -2 C. and 1M KOtBu in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 hr at -2 to -3 C. The deep red-orange mixture was stirred for 1 hr at -2 to -3 C. 4-Amino-6-chloropyrimidine-5-carbaldehyde (10, 115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from -3 to 13 C. and a brown color developed. When the reaction temperature dropped to 10 C., the cooling bath was removed and the reaction mixture was allowed to warm to room temperature and stirred 42 hr. The reaction mixture was cooled to -2 C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2N HCl (4×250 mL) followed by 3N HCl (2×250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6N aqueous NaOH solution and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 hr. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 hr to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (12, 72.3 g, 136.2 g theoretical, 53.1%). The crude 12 was used in the following reaction without further purification. A sample of crude 12 (2.3 g) was purified by chromatography on silica gel, eluting with 0-35% EtOAc/heptane to give 1.7 g of pure 12 as a white solid, which is a 1:2 mixture of E/Z isomers. For 12: 1H NMR (DMSO-d6, 300 MHz) for E-isomer: delta ppm 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) and for Z-isomer: delta ppm 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H); C7H8ClN3O (MR, 185.61), LCMS (EI) m/e 186/188 (M++H). | ||
6-Chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (28) [0170] A suspension of (methoxymethyl)triphenylphosphonium chloride (276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to -2 C. and 1 M potassium tert-butoxide (KOtBu) in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 h at -2 to -3 C. The deep red-orange mixture was stirred at -2 to -3 C. for 1 h. 4-Amino-6-chloropyrimidine-5-carbaldehyde (115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from -3 to 13 C. and a brown color developed. When the reaction temperature dropped to 10 C., the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 42 h. The reaction mixture was cooled to -2 C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2 N HCl (4×250 mL) followed by 3 N HCl (2×250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6 N aqueous NaOH solution and extracted with EtOAc (3×1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 h. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with n-heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 h to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (72.3 g, 136.2 g theoretical, 53.1%). The crude desired product was used in the following reaction without further purification. A sample of crude product (2.3 g) was purified by silica gel column chromatography on, eluting with 0-35% EtOAc/n-heptane to give 1.7 g of pure 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine as a white solid, which was found to be a 1 to 2 mixture of E/Z isomers. 1H NMR (300 MHz, DMSO-d6) for E-isomer: delta 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) ppm and for Z-isomer: delta 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H) ppm; C7H8ClN3O (MW, 185.61), LCMS (EI) m/e 186/188 (M++H). | ||
6-Chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (28) A suspension of (methoxymethyl)triphenylphosphonium chloride (276.0 g, 0.807 mol, 1.1 equiv) in THF (1.5 L) was cooled in an ice/salt bath to -2 C. and 1 M potassium tert-butoxide (KOtBu) in THF (807 mL, 0.807 mol, 1.1 equiv) was added over 1.5 h at -2 to -3 C. The deep red-orange mixture was stirred at -2 to -3 C. for 1 h. 4-Amino-6-chloropyrimidine-5-carbaldehyde (115.2 g, 0.7338 mol, 1.0 equiv) was then added portion wise to the reaction mixture as a solid form using THF (200 mL) to rinse the container and funnel. During the addition the reaction temperature increased from -3 to 13 C. and a brown color developed. When the reaction temperature dropped to 10 C., the cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred at ambient temperature for 42 h. The reaction mixture was cooled to -2 C. before being quenched by the slow addition of saturated NH4Cl aqueous solution (750 mL). The mixture was concentrated under reduced pressure to remove most of the THF. The residue was partitioned between EtOAc (3 L) and H2O (1 L). The organic phase was filtered to remove insoluble material at the interface, then extracted with 2 N HCl (4*250 mL) followed by 3 N HCl (2*250 mL). The combined HCl extracts were back-extracted with EtOAc (500 mL) then filtered through Celite to remove insoluble material. The filtrate was cooled in an ice/brine bath, adjusted to pH 8 with a 6 N aqueous NaOH solution and extracted with EtOAc (3*1 L). The combined EtOAc extracts were washed with brine (1 L), dried over Na2SO4, stirred with charcoal (10 g) and silica gel (10 g) for 1 h. The mixture was filtered through Celite, washing the Celite pad with EtOAc (1 L). The filtrate was concentrated, co-evaporating residual EtOAc with n-heptane (500 mL). The resulting tan solid was pumped under high vacuum for 2 h to afford crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (72.3 g, 136.2 g theoretical, 53.1%). The crude desired product was used in the following reaction without further purification. A sample of crude product (2.3 g) was purified by silica gel column chromatography on, eluting with 0-35% EtOAc/n-heptane to give 1.7 g of pure 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine as a white solid, which was found to be a 1 to 2 mixture of E/Z isomers. 1H NMR (300 MHz, DMSO-d6) for E-isomer: delta 8.02 (s, 1H), 7.08 (bs, 2H), 6.92 (d, 1H, J=13.1), 5.35 (d, 1H, J=13.0 Hz), 3.68 (s, 3H) ppm and for Z-isomer: delta 8.06 (s, 1H), 7.08 (bs, 2H), 6.37 (d, 1H, J=6.8 Hz), 5.02 (d, 1H, J=6.7 Hz), 3.69 (s, 3H) ppm; C7H8ClN3O (MW, 185.61), LCMS (EI) m/e 186/188 (M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | PREPARATION 44; F2-(4-Methylpiperazin-1-yl)phenyllacetaldehyde.Potassium t-butoxide was added to a ~-10°C solution of (methoxymethyl)triphenylphosphonium chloride (7.4 g, 21.5 mmol) in THF (60 mL), and stirred for 15 min giving a red solution. PP57 (2.0Og, 9.79 mmol) in THF (40 mL) was added and the mixture was stirred overnight at rt. After concentration, 1 N HCI (150 mL) was added and this was stirred for 2.5 days. The reaction mixture was extracted with EtOAc (2x150 mL), then carefully made basic with K2CO3. This aqueous phase was then extracted with EtOAc (3X100 mL). These extracts were washed with brine, dried (MgSO4) and concentrated to yield 2.13 g (99percent) of PP44 as an orange oil: NMR (CDCI3) 9.53 (t, J = 2.5 Hz, 1 H), 7.28 (dt, J = 7.7, 1.5 Hz, 1 H), 7.20-7.17 (m, 2H), 7.10 (dt, J = 7.3, 1.2 Hz, 1 H), 3.57 (d, J = 2.5 Hz, 2H), 2.90-2.88 (m, 4H), 2.51 (br s, 4H), 2.32 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Sodium bis(trimethylsilyl)amide (2 mL, 4 mmol, 2M in THF) was added to a stirred suspension of (methoxy methyl)triphenylphosphonium chloride (1.47 g} 4.29 mmol) in dry THF (20 mL) at 0 0C for 35 min and a solution of l-oxo-2,3-dihydro-l H-indene-4-carbonitrile (450 mg, 2.86 mmol) in THF (10 mL) added over 10 min. The mixture was stirred at 0 0C for 2 h and at room temperature for 1 h. Water was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried and concentrated. The crude product was purified via prep- TLC (PE:EtO Ac=I 0:1) to afford (1 E)-I- [(methyloxy)rnethylidene] -2,3-dihydro- lH-indene-4- carbonitrile. 1H-NMR (400 MHz, CDCl3) delta ppm 8.00 (d, J=8.3 Hz5 0.4H), 7.42 (d, /=8.3 Hz, 0.6H), 7.30-7.40 (m, IH), 7.18-7.22 (m, IH), 6.70 (s, 0.6H), 6.22 (s, 0.4H), 3.72 (s, 3H), 3.15 (t, J=5.7 Hz5 2H), 2.70-2.82 (m, 2H). | ||
Sodium bis(trimethylsilyl)amide (2 mL, 4 mmol, 2M in THF) was added to a stirred suspension of (methoxy methyl)triphenylphosphonium chloride (1.47 g, 4.29 mmol) in dry THF (20 mL) at 0 C for 35 min and a solution of <strong>[60899-34-5]1-oxo-2,3-dihydro-1H-indene-4-carbonitrile</strong> (450 mg, 2.86 mmol) in THF (10 mL) added over 10 min. The mixture was stirred at 0 C for 2 h and at room temperature for 1 h. Water was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried and concentrated. The crude product was purified via prep-TLC (PE:EtOAc=10:1) to afford (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile. 1H-NMR (400 MHz, CDCl3) delta ppm 8.00 (d, J=8.3 Hz, 0.4H), 7.42 (d, J=8.3 Hz, 0.6H), 7.30-7.40 (m, 1H), 7.18-7.22 (m, 1H), 6.70 (s, 0.6H), 6.22 (s, 0.4H), 3.72 (s, 3H), 3.15 (t, J=5.7 Hz, 2H), 2.70-2.82 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Step 1. 2,6-dichloro-3-[2-methoxyvinyl]pyridineTo a solution of (methoxymethyl)(triphenyl)phosphonium chloride (9.97 g, 29.1 mmol) in THF (80 mL) at 0 C. under an atmosphere of nitrogen was added 1.0 M of potassium tert-butoxide in THF (29.1 mL, 29.1 mmol). After stirring for 30 min, a solution of 2,6-dichloronicotinaldehyde (3.01 g, 17.1 mmol, Aldrich) in THF (22 mL) was added drop-wise. The resulting solution was stirred at 0 C. for 20 min, then at RT for 1 h.The reaction was quenched by the addition of water and the product was extracted with three portions of ethyl acetate. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with a gradient from 0-10% ethyl acetate in hexanes to afford the product as a mixture of olefin isomers (3.1 g, 80%). 1H NMR, a 1:1 mixture of olefin isomers (300 MHz, CDCl3): delta 8.34 (d, 1H), 7.60 (d, 1H), 7.19 (d, 1H), 7.17 (d, 1H), 7.04 (d, 1H), 6.36 (d, 1H), 5.94 (d, 1H), 5.53 (d, 1H), 3.83 (s, 3H), 3.75 (s, 3H); LCMS (M+H)+: 204.0. |
Yield | Reaction Conditions | Operation in experiment |
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Step 1 : 1 ,3 ,5-Trifluoro-2- KE, Z)-2-methoxyyrnyl"]benzeneA suspension of (memoxymethyl)triphenylphosphonium chloride (25.7 g, 75.0 mmol) in tetrahydrofuran (110 mL) under argon was charged with potassium tet-butoxide (8.06 g, 71.8 mmol) to give a red suspension. After 30 minutes a solution of 2,4,6- trifluorobenzaldehyde (5 g, 31.2 rnmol) in tetrahydrofuran (40 mL) was added via cannula.After stirring for 75 minutes, the suspension was filtered, the collected solids were washed with ethyl acetate (15 mL), and the filtrate was concentrated. Addition of hexanes (60 mL) and sonication, a precipitate formed that was removed by filtration; the solids were washed with additional hexanes (50 mL). The filtrate was diluted with ethyl acetate (30 mL) and the combined organic layers were washed with aqueous saturated ammonium chloride solution (2 x 30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (5% ethyl acetate / hexanes) to afford the title compound. 1H NMR (600 MHz, DMSO) (^denotes minor isomer): delta 7.22 (d, J- 13.2 Hz, 1 H), 7.14 (m, 2 H), 7.08 (m, 2 H)*, 6.44 (d, J= 6.8 Hz, 1 H)*, 5.57 (d, J = 13.2 Hz, 1 H), 5.02 (d, J= 6.2 Hz, 1 H)*, 3.64 (s, 3 H)5 3.62 (s, 3 H)*. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | To a 0 C solution of 3.03 g of (methoxymethyl)triphenylphosphonium chloride (8.84 mmol, 1.3 eq) in 25 mL of abs. tetrahydrofuran were added 5.1 mL of lithium diisopropylamide (2 M in hexane, tetrahydrofuran, ethylbenzene, 10.18 mmol, 1.5 eq) dropwise. The mixture was stirred additional 30 min at 0 C. Then the solution was cooled to -78 C and a solution of 0.87 g of 4-methoxycyclohexanon, S19, (6.79 mmol, 1.0 eq) in 500 mL of abs. tetrahydrofuran was added dropwise. The reaction mixture was stirred for 1 hour at -78 C and additional 18 hours without replacing the cooling. Next 2 M hydrochloric acid was added till ph 2 and the solution was stirred for 3 hours at room temperature. After addition of 50 mL water the mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetat 4:1) yielding 203 mg (21%) of a colorless oil. 14% starting material could be recovered. | |
Step 1:Preparation of 4-methoxy-cyclohexanecarbaldehvde; To a stirred suspension of methoxymethyl triphenylphosphonium chloride (20.8 g, 60 mmol) in dry THF (60 ml) is added dropwise to a solution of lithium diisopropylamide (38 ml, 69 mmol, 1.8 M in hexane / THF / ethylbenzene), at 0-5 0C. The resulting reaction mixture is stirred for 30 minutes and then cooled to -78 C. At this temperature, a solution of methoxycyclohexanone (6 g, 47 mmol) in tetrahydrofuran (600ml) is added over a period of 30 minutes. Once the addition is completed the reaction mixture is stirred at -78 0C for 1 hour and then allowed to warm to room temperature and stirred overnight. The reaction mixture is then diluted to pH=2 with a 2N aqueous solution of hydrochloric acid and stirred for 3 hours at room temperature. The reaction was diluted with water and extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is purified by flash chromatography to give 4-benzyloxy-cyclohexanecarbaldehyde (5.1g). |
Yield | Reaction Conditions | Operation in experiment |
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Then, the obtained aldehyde compounds (2a to 2d) are subjected to, for example, a Wittig reaction using MeOCH2 P(Ph3)Cl and C6H18KNSi2 in toluene (step iv), and furthermore, for example, to acid treatment using hydrochloric acid in acetone (step v), thereby obtaining phenyl aldehyde compounds (3a to 3d) that have an extended carbon chain. The phenyl aldehyde compounds (3a to 3d) are converted to phenylacetic acid compounds (4a to 4d) by the oxidation reaction using periodic acid in the presence of 2% by mole of PFC (step vi). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃; for 18h; | Step A: 5-(MethoxymethylideneV5,6J-8-tetrahydronaphthalene-2-carbonitrileIn a 250 mL round bottom flask, (methoxymethyl) (triphenyl)phosphonium chloride (4.0 g, 12 mmol) was dissolved in THF (20 mL). The solution was cooled to -78 C. To above solution was added n-butyl lithium (3.50 mL, 2.50 M in Hexane, 8.8 mmol) dropwise. The mixture was cooled to -78 C and to it was added <strong>[90401-84-6]5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile</strong>[prepared from 6-bromo-tetralone following the the procedure described in PCT Publication WO2004/071389A2, Intermediate 32] ( 1 g, 5.77 mmol). The reaction was let warm to RT and stirred at r.t for 18 hours. The reaction was then quenched with addition of saturated ammonium chloride (5 mL) and extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2S04, filtered, concentrated and purified by flash column chromatography (Hexane/EtOAc 0-50%) to obtain the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step B: Methyl 3-(methoxymethylidene)cvclobutanecarboxylateTo a suspension of methoxymethyltriphenylphosphonium chloride (1350 g, 3.90 mol) in anhydrous benzene (12 L), a solution of sodium tert-pentoxide (435 g, 3.90 mol) in anhydrous benzene (4 L) was added slowly under nitrogen atmosphere. The resulting red solution was stirred for 15 minutes at ambient temperature. Then, a solution of methyl 3- oxocyclobutanecarboxylate (250 g, 1.95 mol) in anhydrous benzene (1 L) was added slowly and the reaction mixture was heated at 70 C for 2 hours. Saturated aqueous ammonium chloride (~ 4 L) was added to the reaction mixture and extracted with diethyl ether (5 L). The organic layer was washed with water (5 L x 2), brine (5 L), dried over anhydrous Na2S04 and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (mesh 60-120; eluent: 10% diethyl ether in hexane) to afford the title compound as a pale yellow liquid. 1H NMR (300 MHz, CDC13): delta 2.89-2.92 (m, 2H), 2.96-3.0 (m, 2H), 3.14-3.17 (m, 1H), 3.56 (s, 3H), 3.70 (s, 3H), 5.81-5.83 (m, 1H). GC-MS: [M + m/z = 156. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | General procedure: Under argon atmosphere, to a suspension of MeOCH2P+Ph3Cl- (32.0?g, 93.4?mmol) in toluene (200?mL) was added t-BuOK (10.5?g, 93.4?mmol) and the mixture was stirred at room temperature for 20?min. To this mixture was added a solution of tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (18) (17.2?g, 71.9?mmol) in toluene (160?mL), and the mixture was stirred at 70?C for 4?h. The reaction was quenched with saturated aqueous NH4Cl solution under ice cooling and the resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (5-20% EtOAc in hexanes) to afford 28 as a pale yellow oil (12.8?g, 67% yield). | |
1.71 g | To a suspension of (methoxymethyl)triphenylphosphonium chloride (5.13 g, 14.96 mmol) in THF (70 ml) at rt was added added potassium tert-butoxide (1.679 g, 14.96 mmol) in one portion. The mixture immediately turned into a dark brown color. The mixture was stirred for 1 h at rt then <strong>[873924-08-4]tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate</strong> (2 g, 7.48 mmol) was added in one portion as a solid. The mixture was stirred for about 1 h then diluted with aqueous ammonium chloride solution. The slurry was extracted 3 times with ethyl ether and the combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by chromatography eluting with 0-10%-30% ethyl acetate-hex to give 1.71 g of tert-butyl 9-(methoxymethylene)-3-azaspiro[5 .5]undecane-3-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | LiHMDS (53 mL, 1 .0 N, 53 mmol) was added to a stirred suspension of KR-Si(7.20 g, 35 mmol) in THE (120 mL) at -20C over a period of 20 mm undernitrogen. The resulting solution was stirred at -10C for 1 hr, and thenmethoxymethyl(triphenyl)phosphonium;chloride (i8.i3 g, 53 mmol) in THE (10 mL) was added over a period of 15 mm under nitrogen. The resulting solution was stirred at room temperature for 15 hrs. The reaction was quenched aq.NH4CI and then extracted with EtOAc (200 mL). The combinedorganic phase was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column to give the pure reagent R-32a(4.6i g, 56% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | 10183] To a mixture of PPh3CH2OCH3Cl (68 g, 0.2 mol) in THF (400 mE), was added n-8uEi (2.5 M, 80 mE, 0.2 mol) dropwise at 0 C. for 30 mm. A solution of 8-10(20.0 g, 0.08 mol) in THF (100 mE) was added to the PPh3÷CH2OCH3Cr solution at the same temperature. The mixture was slowly warmed to RT and stirred for 1 h. The solution was quenched with sat. aq. NH4C1 and extracted with EtOAc (3x400 mE). The combined organic phases were washed with brine, dried over with Mg2SO4 and concentrated. The residue was purified by silica gel chromatography (PE) to give 8-11 as a colorless oil (18 g, 81%); ?H NMR (400 MHz, CDC13): oe 7.39 (s, 1H), 7.34 (s, 1H), 7.24-7.23 (m, 1H), 7.23-7.21 (m, 3H), 7.21-7.20 (m, 2H), 7.06-7.05 (m, 1H), 6.48 (m, 1H), 3.66 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃; for 18h; | In a 250 mL round bottom flask, (methoxymethyl) (triphenyl)phosphonium chloride (4.0 g, 12 mmol) was dissolved in THF (20 mL). The solution was cooled to -78 C. To above solution was added n-butyl lithium (3.50 mL, 2.50 M in Hexane, 8.8 mmol) dropwise. Reaction color changed to orange. The mixture was cooled to -78 C and to it was added <strong>[90401-84-6]5-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile</strong> (1 g, 5.77 mmol). The reaction was let warm to RT and stirred at r.t for 18 hours. The reaction was then quenched with addition of saturated ammonium chloride (5 mL) and extracted with dichloromethane. The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography (Hexane/EtOAc 0-50%). The desired product was obtained. 1H NMR (500 MHz, CDCl3, delta in ppm): 7.0 -7.6 (3H, aromatic), 6.75 (1H, s), 3.88 (3H, s, Me), 3.0 (1H, t), 2.63 (2H, t), 2.23 (1H, t), 2.18 (1H, t), 1.65 (1H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | To a stirring solution of (methoxymethyl)triphenylphosphonium chloride (3.74 g, 10.91 mmol) in THF (16 mL) was added potassium tert-butoxide (1.224 g, 10.91 mmol) portionwise. The solution was stirred at room temperature for 50 min then a solution of <strong>[56309-94-5]4-(1,4-dioxaspiro[4.5]decan-8-yl)cyclohexanone</strong> (2 g, 8.39 mmol) in THF (16 mL) was added slowly. The reaction mixture was stirred for 3.5 h. The solvent was removed under vacuum. The residue was treated with Et2O (44 mL) and stirred for 1 h. The mixture was filtered, washed with Et2O (2 x 50 mL) and the filtrate was evaporated. The crude product was purified by column chromatography (EA/Iso- hexane) to afford 1.8 g (76percent) of 8-(4-(methoxymethylene)cyclohexyl)-l ,4- dioxaspiro[4.5]decane as a colourless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Methoxymethyltriphenylphosphonium chloride (1.2 eq.) was dissolved in anhydrous THF (2ml/mmol) under an argon atmosphere. The solution was cooled to -78C in an acetone/dry ice bathand then BuLi (1.6M in hexanes, 1.2 eq.) added dropwise. The initially yellow solution was stirredfor 2h at -78C and gradually turned dark red. The aldehyde, (1 eq.) dissolved in anhydrous THF (1ml / mmol), was added dropwise and the reaction was stirred for an additional 3h at -78C. The reaction was quenched by the addition of saturated aqueous NaHCO3, and extracted with ether. Theorganic layer was separated, dried over MgSO4, filtered and the solvents were removed on a rotaryevaporator. The crude product was purified by flash column chromatography on silica gel using acyclohexane/ethyl acetate mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: 5-[(E)-2-Methoxyvinyl]-2-(trifluoromethyl)pyridine and 5-[(Z)-2-methoxyvinyl]-2- (trifluoromethyl)pyridine [00329] (Methoxymethyl)triphenylphosphonium chloride ( 1 1.7 g, 34.3 mmol) was placed in a 250ml two-neck round bottom flask under an atmosphere of argon. THF ( 1 .00e2 ml, 1230 mmol) was added and the suspension was cooled at -78 C. 2.5 M of n-BuLi in hexane ( 12.8 ml, 32.0 mmol) was added drop wise. The reaction turned an orange color but remained a suspension. The reaction was warmed at 0 C and turned a dark orange color and presented as a solution which was stirred at 0 C for 30 min under an atmosphere of argon. 5-formyI-2- (trifluoiOmethyl)pyridine (4.00 g, 22.8 mmol) in THF ( 10.0 ml, 123 mmol) was added dropwise quickly to the solution at 0 c. The reaction was stirred for 30min at 0 C under an atmosphere of argon. The reaction was warmed to rt and quenched. TLC ( 10% EtOAc in hexanes) showed no starting material remaining with a major spot just above it. The reaction was quenched with water and saturated NH4C1. The reaction was extracted 3x with DCM. The combined organics were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The residue was loaded with DCM onto a 220g gold isco column ( 10% EtOAc in hexanes isocratic lOOml/min) to give the product as a 1 : 1 mixture of the title products as a yellow oil. LCMS (FA) 203.9 (m + 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1 : To a solution of (methoxymethyl)triphenylphosphonium chloride (1.5 equiv.) in THF (0.3 M) at 0 C was added NaHMDS (1M in THF, 1.55 equiv.) and the red solution was stirred in the cold bath for 30 min at which point 5-bromo-2- methoxynicotinaldehyde (1.0 equiv.) was added. After stirring in the cold bash for 30 min, the solution was allowed to warm to rt, stirred for 2 hours, then partitioned between ethyl acetate and sat. sodium bicarbonate. The layers were mixed, separated, the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified via siiica gel chromatography (0-30% ethyl aeetate/n-heptanes) to yield 5-bromo-2- methoxy-3-(2-methoxyvinyl)pyridine contaminated with the starting aldehyde. This mixture was dissolved in methanol and 0.5 equiv. of sodium borohydride were added. After stirring at rt for 10 min, the volatiles were removed in vacuo and the residue was partitioned between ethyl acetate and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. Purification via silica gel chromatography (ISCO, 0-15% ethyl acetate/n- heptanes) afforded 5-bromo-2-methoxy-3-(2-methoxyvinyl)pyridine in 11% yield as a mixture of enol ethers isomers. LCMS (m/z) (M+H) - 244.0/246.0, Rt = 0.97 and 1.01 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Into a 250 ml 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed chloro(methoxymethyl)triphenylphosphorane (10.8 g, 31.51 mmol, 1.50 equiv.), tetrahydrofuran (30 ml), to the above was added NaHMDS (1M/L in THF,32 ml) dropwise at -10 C, stirred for 1 h at -10 C, then was added 4- methoxycyclohexan-1-one (2.7 g, 21.07 mmol, 1.00 equiv.) in THF dropwise at -10 C. The resulting solution was stirred for 3 h at -10 C. The reaction was then quenched by the addition of 30 ml of NH4C1 (sat. aq.). The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3x50 ml of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 1.33 g of the title compound as a light yellow oil (40%). ?H NMR (300 MHz, CDC13) & 5.76 (s, 1H), 3.54 (s, 3H), 3.40-3.20 (m, 4H), 2.70-2.50 (m, 1H), 2.19-2.02 (m, 1H), 1.93-1.80 (m, 4H), 1.48-1.30 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In tetrahydrofuran; at 0 - 25℃; | Potassium tert-butoxide (4.47 g, 39.8 mmol) was added portionwise to a suspension of (methoxymethyl)triphenylphosphonium chloride (12.4 g, 36.1 mmol) and tert-butyl 8-oxo-3- azabicyclo[3.2.1]octane-3-carboxylate (4.49 g, 19.9 mmol) in THF (100 mL) at 0 C. After 45 min, the cold bath was removed and the reaction was stirred overnight at 25 C. The reaction was recooled at 0 C and a saturated solution of NH4CI was added until pH = 6. After warming to 25 C, the mixture was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried with Na2S04, filtered and concentrated. The resulting oil was diluted with a small amount of ether and a large volume of heptane. After vigorous stirring for 1 h, the resulting solid was filtered off and washed with additional heptane. The filtrate was concentrated and the resulting oil was purified by silica gel chromatography (heptane: EtOAc, 100/0-70/30) to provide the title compound (4.73 g, 94%). LC/MS [M-Me] = 239.1 ; 1H NMR (400 MHz, CDCI3) delta 5.86 (s, 1 H), 4.02 (t, J=12.1 Hz, 1 H), 3.79-3.94 (m, 1 H), 3.57 (s, 3H), 2.76-3.05 (m, 3H), 2.41 (m, 1 H), 1.58-1.65 (m, 4H), 1.47 (br s, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.2% | With potassium tert-butylate; In tetrahydrofuran; at -3 - 15℃; for 12h;Inert atmosphere; | Under nitrogen, 38.94 g (0.169 mol) of (2S) -N-Boc-4-oxopyrrolidine-2-carboxylic acid was added to a 1 L reaction flask,77.8 g (0.227 mol) of methoxymethyltriphenylphosphonium chloride,Cooled to -3 - 0 C, potassium t-butoxide (47.0 g, 0.137 mol) was added in portions.Heating to 15 C reaction, orange-red solution,The temperature was lowered to -3 C, 40 g (0.17 mol, 1 eq) of a 150 mL THF solution was added dropwise,After the dropwise addition, the temperature was raised to 15 C for 12 h, and the reaction was quenched by dropwise addition of saturated sodium bicarbonate solution.The solvent was distilled off under reduced pressure, 500 mL of water was added, stirred for 30 min, filtered,The filter cake was washed with 3 x 50 mL of water. The aqueous phases were combined, extracted with 250 mL x 2 methyl tert-butyl ether,Water phase retained. 40% citric acid was added into the aqueous phase, pH was adjusted to 3 ~ 4,Then extracted three times with 800 mL of ethyl acetate, the organic phases were combined,Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give an oil (33.3 g, yield 76.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | To a suspension of potassium t-butoxide (3.4 g, 28.8 mmol) in THE (100 mL) was added (methoxymethyl)triphenylphosphonium chloride (11.20 g, 31.7 mmol). The reaction mixture was stirred at ambient temperature for 30 mm, and the red solution was transferred into a closed flaskcontaining <strong>[90484-53-0]methyl 3-bromo-4-formylbenzoate</strong> (3.5 g, 14.40 mmol) via a syringe and stirred at ambient temperature for 1 h. The reaction mixture was quenched with saturated ammoniumchloride and partitioned between EtOAc and water. The aqueous layer was extracted again withEtOAc and the combined organic layers dried (Na2504), concentrated in vacuo and purified on silica (EtOAc/hexanes, 0-5%) to obtain methyl 3-bromo-4-(2-methoxyvinyl)benzoate (3.5 g, 12.26 mmol,85 % yield, mixture of E and Z isomers) as a white solid. LC/MS (m/z) ES: 271 (M÷1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | To a stirred suspension of (melhoxymethyi)triphenyiphosphonium chloride (17.0 g, 49.6 mrnol)) in THF (41 mL)was added slowly a solution of potassium 2-methyipropan-2-olate (41 niL, 41 mniol) at 0C via cannula under nitrogen. The resulting cherry-red solution was stirred at 0 C for I h. A solution of 2-chioro- 7.8-dihydroquinoiin-5(6H)-one (3.00 g, 16.5 mmoi) in THF (10.0 mL) was added dropwaise. The reaction mixture was stirred at r.t. for I h. The reaction quenched with water (5 mL). It was concentrated at 35 C to about 40 rnL, then aqueous30% H2S04(15 mL) was added at ri. and it was stirred al 50 C for 16 h. The reaction mixture was gradually poured into saturated sodium carbonate solution (70 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2x30 mL). The combined organic phases were washed with brine and dried over anhydrous Mg504. After concentration the residue was loaded on a 80gISC() Gold column and eluted with 0 % to 9() % F:tOAc /hexane to provide the title compound (3.0 g. 15.3mmol. 93% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(3) (methoxymethyl)triphenylphosphine chloride (1.05 eq) was weighed and THF (30 volumes) was added.Stir and under nitrogen protection, cool down to -5C, add t-BuOK (1.05 eq) to it, and add, feed solution 0C,Stir 1h. Add <strong>[14160-93-1]4-amino-6-chloropyrimidine-5-carboxaldehyde</strong> in batches to the above feed solution.The solution was naturally warmed to room temperature and the reaction was stirred for 30 h. TLC test showed that the basic reaction of the raw material was complete.The feed solution was cooled to 0 C., saturated ammonium chloride solution was added to quench the reaction, and concentrated hydrochloric acid was added to the feed solution.Adjust the pH to 1~2, and the material liquid is extracted with ethyl acetate (2 times volume*2, extract impurities).The aqueous layer was further adjusted to pH 8-9 with 6N NaOH solution and extracted with ethyl acetate (10 volumes*3).The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude 6-chloro-5-(2-methoxyvinyl)pyrimidin-4-ylamine (yield: 60%), which was used directly in the next step. reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of (methoxymethyl)triphenylphosphonium chloride (2.92 g, 8.52 mmol) in THF (20 mL) was added dropwise LDA (4.47 ml, 8.95 mmol, 1.0 M in THF) over 20 mm under N2 at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Then a solution of tertbutyl 6-oxo-2-azaspiro[3.3jheptane-2-carboxylate (900 mg, 4.26 mmol) in THF (10 mL) was added dropwise to the mixture. The reaction mixture was stirred at 60 °C for 3 h, thenquenched with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with water (40 mL) and brine (40 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel eluted with PE / EtOAc (50:1- 20: 1, v/v) to give the title compound. ?H NMR (400 MI-Tz, CDC13): oe = 5.81 (s, 1H), 3.93(s, 4H), 3.56 (s, 3H), 2.87 (s, 2H), 2.79 (s, 2H), 1.44 (s, 12H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Compound 3 was prepared according to a similar procedure previously described for the synthesis of the corresponding methyl ester. 39 Under nitrogen atmosphere, a solution of t-BuOK (1.5?eq, 341?mg) in THF (1?mL) was added dropwise to a suspension of (methoxymethyl)triphenylphosphonium chloride (1.2?eq, 825?mg) in THF (2?mL) in ice bath. The reaction mixture turned red. After 15?min, <strong>[65874-27-3]tert-butyl 4-formylbenzoate</strong> (1?eq, 412?mg, 2?mmol) in THF (2?mL) was added dropwise over a period of 10?min. Ice bath was removed and the orange mixture was stirred for 2?h at r.t. Water (0.6?mL) was added, the mixture was concentrated in vacuum (40?C) and partitioned between H2O and EtOAc. The organic layer was washed with brine and dried over MgSO4. Chromatographic purification (silica gel, eluted with 1,2-dichloroethane) yielded the title compound as equimolecular mixture of Z- and E-isomers in 75% yield. 1H NMR (CDCl3, 700?MHz) delta: 1.58 (s, 9H), 3.69 (s, 1.5H), 3.79 (s, 1.5H), 5.24 (d, J?=?7?Hz, 0.5H), 5.81 (d, J?=?13?Hz, 0.5H), 6.20 (d, J?=?7?Hz, 0.5H), 7.14 (d, J?=?13?Hz, 0.5H), 7.24 (d, J?=?8?Hz, 1H), 7.58 (d, J?=?8?Hz, 1H), 7.87 (d, J?=?8?Hz, 1H), 7.90 (d, J?=?8?Hz, 1H). 13C NMR (CDCl3, 175?MHz) delta: 28.2, 56.7, 60.9, 80.5, 80.6, 104.5, 105.0, 124.6, 127.8, 128.9, 129.0, 129.4, 129.9, 140.2, 140.9, 149.8, 150.6, 165.7, 165.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | To a stirred mixture of methoxymethyl triphenylphosphonium chloride (8.4 g, 24mmol) in toluene (150 mL) was added potassium bis(trimethylsilyl)amide (0.7 M in toluene, 34 mL, 24 mmol) dropwise at -10 C. Stirring was continued for 30 mm at this temperature. Intermediate 1 (2.1 g, 8 mmol) in toluene (20 mL) was added dropwise and after 2 h the r.m. was quenched with water (50 mL) and the layers were separated. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to afford atan oil. This oil was purified by column chromatography (silica, EtOAc/heptane 0/100 to 10/90) to afford intermediate 2 as an oil (1.86 g, 80%). | |
80% | To a stirred mixture of methoxymethyl triphenylphosphonium chloride (8.4 g, 24 mmol) in toluene (150 mL) was added potassium bis(trimethylsilyl)amide (0.7 M in toluene, 34 mL, 24 mmol) dropwise at -10 C. Stirring was continued for 30 min at this temperature. Intermediate 1 (2.1 g, 8 mmol) in toluene (20 mL) was added dropwise and after 2 h the r.m. was quenched with water (50 mL) and the layers were separated. The organic layer was dried over MgSC^, filtered and concentrated in vacuo to afford a tan oil. This oil was purified by column chromatography (silica, EtO Ac/heptane 0/100 to 10/90) to afford intermediate 2 as an oil ( 1.86 g, 80%). | |
80% | To a stirred mixture of methoxymethyl triphenylphosphonium chloride (8.4 g, 24 mmol) in toluene (150 mL) was added potassium bis(trimethylsilyl)amide (0.7 M in toluene, 34 mL, 24 mmol) dropwise at -10 C. Stirring was continued for 30 min at this temperature. Intermediate 1 (2.1 g, 8 mmol) in toluene (20 mL) was added dropwise and after 2 h the r.m. was quenched with water (50 mL) and the layers were separated. The organic layer was dried over MgSC^, filtered and concentrated in vacuo to afford a tan oil. This oil was purified by flash chromatography (silica, EtO Ac/heptane 0/100 to 10/90) to afford intermediate 2 as an oil (1.86 g, 80%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: (Methoxymethyl)triphenylphosphonium chloride (76mg, 0.223mmol) was suspended in dry 52 THF (1.0mL) and then 23 sodium bis(trimethylsilyl)amide (1M solution in THF, 300muL, 0.3mmol) was added at 0C. The solution immediately became dark red colored. After 30min at 0C, aldehyde 203 14a (40mg, 0.255mmol) dissolved in dry THF (1.0mL) was added and the resulting mixture was stirred at 0C for 30min. The reaction was monitored by TLC. After 1h stirring at room temperature, 207 H2O was added and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (10% 46 EtOAc in 201 n-hexane) to afford the 208 title compound as a yellow oil (63% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.7 g | To a 250-mL 3 -necked round-bottom flask was placed a solution of methoxym ethyl )triphenylphosphonium chloride (16.4 g, 53.54 mmol) in THF (150 mL) then LiHMDS (48 mL of 1.1M THF solution) was added dropwise with stirring and the resulting solution was stirred for lh at - 20C. A solution of <strong>[1197-66-6]2,2,6,6-tetramethyltetrahydro-4H-pyran-4-one</strong> (4 g, 25.60 mmol) in THF (0231) (30 mL) was then added dropwise with stirring at -20 C, then warmed to rt and stirred for 12 h. The reaction was quenched by the addition of water and was extracted with DCM. The organic extracts were combined and concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtO Ac/petroleum ether (1 :80) affording 3.7 g of the title compound as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hexamethyldisilazane; In tetrahydrofuran; at 0℃; for 0.5h;Inert atmosphere; | Into a 100-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed (methoxymethyl)triphenylphosphanium chloride (3.2 g, 9.33 mmol), THF (15 mL). This was followed by the addition of LiHIVIDS (1 M, 9.4 mL) dropwise with stirring at 0C. To thiswas added a solution of <strong>[464192-28-7]2-bromo-1,3-thiazole-5-carbaldehyde</strong> (1.5 g, 7.81 mmol) in THF (10 mL) dropwise with stirring at 0C. The resulting solution was stirred for 0.5 h at 0C and then was quenched by the addition of 50 mL of NH4C1 (sat.). The resulting solution was extracted with 3x50 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:100 to 1:80). This resulted in 1.3 g (76%) of the title compound as brown oil. The crude product was used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen, wasplaced (methoxymethyl)triphenylphosphanium chloride (13.16 g, 38.39 mmol) and THF (100mL). This was followed by the addition of LiHMDS (1 M, 38.52 mL) dropwise with stirring at 0C. The resulting solution was stirred for 0.5 h at 0C. To this was added a solution of 1-(2- bromothiazol-5-yl)ethanone (5.29 g, 25.67 mmol) in THF (30 mL) dropwise with stirring at 0C. The resulting solution was stirred for 1 h at RT and then was quenched by the addition of 100mL of NH4C1 (sat.). The resulting solution was extracted with 3x80 mL of DCM and the organic layers combined and dried over anhydrous Na2504, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 4.38 g (73%) of the title compound as light yellow oil. MS-ESI: 235.9,234.0 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.2 g | 37.5 g (109.4 mmol) of methoxymethyltriphenylphosphonium chloride was dispersed in 500 mL of anhydrous THF under nitrogen protection. Cool down to -78 C with liquid nitrogen,12.3 g (109.4 mmol) of potassium t-butoxide was added in portions. After stirring to room temperature for 30 minutes, the temperature was again lowered to -78C, and 19.5 g (91.2 mmol) of <strong>[125114-77-4]7-bromo-1-indanone</strong> was added dropwise. After the addition, the reaction was stirred for 1 hour with stirring, and the reaction was stirred at room temperature. After overnight, 150 mL of a saturated aqueous solution of ammonium chloride was added, and ethyl acetate was evaporated.16.2 g of the compound Int.-1 as an intermediate are obtained as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | To a stirred solution of methoxymethyltriphenylphosphonium chloride (1.47 g, 4.31 mmol) in THF (6 ml), potassium carbonate (0.594 g, 4.31 mmol) was added at 0 deg and stirred for 30 minutes at room temperature. To this <strong>[467442-15-5]3,5-difluoro-4-formylbenzonitrile</strong> (0.6 g, 3.59 mmol) was added at room temperature and heated to reflux at 60 deg for 16 hours. The reaction mixture was quenched with water (30 ml) and extracted with ethyl acetate (2 x 30 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to afford the title compound (0.24 g, 34 %). 1H NMR (400 MHz, DMSO-d6): d 7.72-7.72 (m, 2H), 6.65 (d, / = 6.4 Hz, 1H), 5.20 (d, / = 6.4 Hz, 1H), 3.74 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | A mixture of (methoxymethyl)triphenyl phosphonium chloride (8.5 g, 24.8 mmol) and t-BuOK (4.6 g, 41.3 mmol) in THF (40 mL) was stirred at room temperature for 20 mins. <strong>[123506-66-1]6-methoxy-4-methylnicotinaldehyde</strong> (2.5 g, 16.5 mmol) in 10 mL of THF was added and mixture stirred at room temperature for 2 hours. The reaction mixture was poured into 40 mL of water and extracted with EtOAc (50 mL*2). The organic phase was concentrated in vacuo and the residue purified by reverse phase HPLC on a C18/40 g column (A: water 10 mM NH4HCO3, B: MeOH, 0?100%) to give (E)-2-methoxy-5-(2-methoxyvinyl)-4-methylpyridine as a colorless oil (1.8 g). Yield 61% (ESI 180.1 (M+H)+). |
Tags: 4009-98-7 synthesis path| 4009-98-7 SDS| 4009-98-7 COA| 4009-98-7 purity| 4009-98-7 application| 4009-98-7 NMR| 4009-98-7 COA| 4009-98-7 structure
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P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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