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CAS No. : | 5527-95-7 | MDL No. : | MFCD00143288 |
Formula : | C7H4ClFO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 158.56 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.8 |
TPSA : | 17.07 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.77 cm/s |
Log Po/w (iLOGP) : | 1.56 |
Log Po/w (XLOGP3) : | 2.11 |
Log Po/w (WLOGP) : | 2.71 |
Log Po/w (MLOGP) : | 2.48 |
Log Po/w (SILICOS-IT) : | 3.04 |
Consensus Log Po/w : | 2.38 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.53 |
Solubility : | 0.468 mg/ml ; 0.00295 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.1 |
Solubility : | 1.26 mg/ml ; 0.00796 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.23 |
Solubility : | 0.0938 mg/ml ; 0.000592 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.16 |
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 |
---|---|---|
With sodium hydroxide; hydroxylamine hydrochloride; In ethanol; water; at 0 - 20℃; for 3h; | To a suspension of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (5.00 g, 31.5 mmol) in 90 mL 95% aqueous ETOH was added HCL H2NOH (2.63 g, 37.8 mmol) followed by a solution OF NAOH (1.90 g, 47.3 mmol) in 3 mL of water at 0C. The suspension was stirred at room temperature for 3 h, then poured into 200 mL ice/water and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (2 x 80 mL), brine (80 mL), dried (NA2SO4) and evaporated. The residue was dissolved in 25 mL DMF and N-CHLOROSUCCINIMIDE (4.23 g, 34.7 mmol) was added in portions at 30-40C. The mixture was stirred at room temperature for 1 h, then poured into 200 mL ice/water and extracted with ethyl acetate (2 x 100 mL). The combined organic extract was washed with water (3 x 80 mL), brine (80 mL), dried (NA2SO4) and evaporated yielding the hydroxyiminoyl chloride (3.71 g. , 62%). Data : LHNMR (300 MHz, CDC13,) : 8 8.15 (s, 1H), 7.60-7. 51 (m, 2H), 7.41-7. 32 (m, 1H). | |
With hydroxylamine hydrochloride; sodium carbonate; In methanol; water; at 20℃; for 2h; | General procedure: To a mixture of aldehyde (10.0 mmol) in 30% methanol aqueous solution, NH2OH·HCl (0.695 g, 10.0 mmol) was added slowly. After the NH2OH·HCl was fully dissolved, Na2CO3 (0.53 g 5.0 mmol) was added and then the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried to afford intermediate a' as white solids. | |
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; water; at 20℃; for 2h; | General procedure: Hydroxylamine hydrochloride (2.0 mmol) was dissolved in water (10.0 mL) and neutralized with aqueous sodium hydrogen carbonate (10%). This mixture was added to the solution of the substituted benzaldehyde (compound 1) (2.0 mmol) in methanol and stirred in room temperature for 2 hours until the starting material disappeared (monitored by TLC with EtOAc/petroleum ether = 1/10, V/V). The reaction mixture was added in water to precipitate crude white product compound 2. |
With hydroxylamine hydrochloride; sodium carbonate; In methanol; water; at 20℃; for 2h; | General procedure: To a mixture of aldehyde 1 (10.0 mmol) in 30% methanol aqueous solution, NH2OH·HCl (0.695 g, 10.0 mmol) was added slowly. After the NH2OH·HCl was fully dissolved, Na2CO3 (0.53 g 5.0 mmol) was added and then the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried to afford intermediate 2 as white solids. | |
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; water; at 20℃; for 2h; | <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (1 mmol) was dissolved in methanol (10 mL)NaHCO3 (1.1 mmol)And an aqueous solution of NH2OH.HCl (1.1 mmoL) (10 mL)Stirred at room temperature for 2 h,Add water to the white solid precipitation,filter,Dried to give the compound <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> oxime. | |
With hydroxylamine hydrochloride; sodium hydrogencarbonate; In methanol; water; at 20℃; for 2h; | <strong>[5527-95-7]3-fluoro-4-chlorobenzaldehyde</strong> (1 mmol) was dissolved in methanol (10 mL),NaHCO3 (1.1 mmol) and NH2OH.HCl (1.1 mmoL) in water (10 mL) were added,Stir at room temperature for 2h, add water until white solid precipitates, and filter.Dry to give compound <strong>[5527-95-7]3-fluoro-4-chlorobenzaldehyde</strong> oxime. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at -78 - 20℃; for 1.05h; | <strong>[5527-95-7]4-Chloro-3-fluoro-benzaldehyde</strong> (5.14 g, 32.4 mmol) was dissolved in THF (100 mL) and place at -78C under nitrogen atmosphere. Methyl Lithium (1.6 M in diethyl ether, 22.3 mL) was added to the reaction during a period of 3 minutes maintaining the same temperature. After the addition, the reaction was stirred at room temperature for 1 h. Then, the reaction was poured over ice water and extracted with ethyl acetate and hydrochloric acid IN. The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum to produce a crude, which it was chromatograph over silica gel using 50% hexane- ethyl Acetate as solvent to yield 5.1 g of 1-(4-chloro-3-fluorophenyl)-ethanol. 1H NMR (400 MHz, Cl3CD) delta 7.37 (t, J= 8.14 Hz, 1H), 7.20 (dd, J = 1.86, 10.00 Hz, 1H), 7.09 (dd, J = 1.86, 8.14 Hz, 1H), 4.89 (m, 1H), 1.93 (br s, 1H), 1.49 (d, J = 6.51, 3 H). | |
In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 1.05h; | <strong>[5527-95-7]4-Chloro-3-fluoro-benzaldehyde</strong> (5.14 g, 32.4 mmol) was dissolved in THF (100 mL) and place at -78 C. under nitrogen atmosphere. Methyl Lithium (1.6 M in diethyl ether, 22.3 mL) was added to the reaction during a period of 3 minutes maintianing the same temperature. After the addition, the reaction was stirred at room temperature for 1 h. Then, the reaction was poured over ice water and extracted with ethyl acetate and hydrochloric acid 1N. The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum to produce a crude, which it was chromatograph over silica gel using 50% hexane-ethyl Acetate as solvent to yield 5.1 g of 1-(4-chloro-3-fluoro-phenyl)-ethanol. 1H NMR (400 MHz, Cl3CD) delta 7.37 (t, J=8.14 Hz, 1H), 7.20 (dd, J=1.86, 10.00 Hz, 1H), 7.09 (dd, J=1.86, 8.14 Hz, 1H), 4.89 (m, 1H), 1.93 (br s, 1H), 1.49 (d, J=6.51, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methylmagnesium bromide; ammonium chloride; In tetrahydrofuran; | Step A: Methylmagnesium bromide was added dropwise over 5 minutes to a stirred solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (10.86 g, 68.5 mmol) in anhydrous tetrahydrofuran (100 ml) at -78 C. under nitrogen. After stirring for 15 minutes, the cooling bath was removed, and the solution allowed to warm to room temperature. After stirring 3 hours, the solution was poured slowly with stirring into saturated ammonium chloride (100 ml), then diluted with water (50 ml) and extracted with diethyl ether. The organic extracts were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to provide the benzylic alcohol (11.89 g) as a clear, yellow oil: 1H NMR (300 MHz, CDCl3) delta 7.35 (t, J=7.8 Hz, 1H), 7.18 (dd, J=2.0, 10.0 Hz, 1H), 7.07 (dd, J=10.7, 8.1 Hz, 1H), 4.83-4.92 (m, 1H), 2.01 (d, J=3.6 Hz, 1H), 1.47 (d, J=6.3 Hz, 3H), CI MS m/z=175 [C8H8CIFO+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.8% | Example 4; Preparation of rRV2-amino-3-(4-chloro-3-fluorophenylV 1 -((S)-4-(r5R.7RV7-methoxy-5-methyl- J-dihydro-SH-cvclopentafdipyrimidin^-ylVS-methylpiperazin-l-vDpropan-l-one dihydrochloride; Step 1:; 1,1,3,3-Tetramethylguanidine (2.11 ml, 16.8 mmol) was added to a O0C soution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)-acetate (5.00 g, 16.8 mmol) in DCM (70 mL). The reaction mixture was stirred at O0C for 30 minutes. Then a solution of 4- chloro-3-fluorobenzaldehyde (2.67 g, 16.8 mmol) in DCM (10 mL) was added by syringe. The reaction mixture was stirred for 10 minutes, then warmed to room temperature and stirred for another 1 hour. H2O was then added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting solids were recrystallized from IPA to give (Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate (3.76 g, 67.8% yield) as a white powder (2 crops). LCMS (APCI") m/z 328 [M-H]". | |
67.8% | Step 7: 1,1,3,3-tetramethylguanidine (2.11 ml, 16.8 mmol) was added to a O 0C soution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)-acetate (5.00 g, 16.8 mmol) in DCM (70 mL). The reaction mixture stirred at O0C for 30 minutes, then a solution of 4-chloro-3- fluorobenzaldehyde (2.67 g, 16.8 mmol) in DCM (10 mL) was added by syringe. The reaction mixture was stirred for 10 minutes. The reaction mixture was then warmed to room temperature and stirred for 1 hour. H2O was then added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO^, filtered, and concentrated. The resulting solids were recrystallized from IPA to give (Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3- fluorophenyl)acrylate (3.76 g, 67.8% yield) as a white powder (2 crops). LCMS (APCI") m/z 328 [M-H]'. | |
67.8% | Example 3; (R)-2-amino-3-(4-chloro-3-fluoroDhenyl)-l-((S)-3-methyl-4-((R)-5-methyl-6.7-dihvdro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin- 1 -vDpropan- 1 -one dihydrochloride; [00287] Step 1 : 1,1,3,3-Tetramethylguanidine (2.11 mL, 16.8 mmol) was added to a 0C solution of methyl 2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)-acetate (5.00 g, 16.8 mmol) in DCM (70 mL). The reaction mixture stirred at O0C for 30 minutes, then a solution of 4-chloro-3- fluorobenzaldehyde (2.67 g, 16.8 mmol) in DCM (10 mL) was added by syringe. The reaction mixture was stirred for 10 minutes and then warmed to room temperature with continued stirring <n="77"/>for 1 hour. H2O was then added, and the mixture was extracted with DCM. The combined extracts were dried (Na2SO4), filtered, and concentrated. The resulting solids were recrystallized from IPA to give (Z)-methyl 2-(tert-butoxycarbonyl)-3-(4-chloro-3-fluorophenyl)acrylate (3.76 g, 67.8% yield) as a white powder (2 crops). LCMS (APCF) m/z 328 [M-H]". |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With piperidine; In toluene; at 20 - 100℃; for 7h; | Example 4; 2-raminomethylV3-(4-chloro-3-fluorophenylVl-r(S)-3-methyl-4-((R)-5-methyl-6.7-dihvdro-5H- cyclopenta[d]pyrimidin-4-yl)piperazin- 1 -vDpropan- 1 -one dihvdrochloride; [00294] Step 1: <strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (1.0 g, 6.3 mmol) was added to a solution of ethyl 2-cyanoacetate (0.71g, 6.3 mmol) and piperidine (0.081 ml, 0.82 mmol) in toluene (10 mL) at room temperature. The mixture was heated at 100C for 7 hours. Upon cooling to room temperature, the mixture was concentrated in vacuo and rinsed with hexane to give ethyl 3-(4- chloro-3-fluorophenyl)-2-cyanoacrylate (1.4 g, 88%). LCMS (APCI+) [M+H]+ 253.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chlorite; aminosulfonic acid; In water; tert-butyl alcohol; at 0 - 20℃; for 96h; | sodium chlorite (17 g) was added portionwise to a mixture solution composed of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, and the mixture was stirred for 4 days while the temperature of the system was gradually raised to room temperature.. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride.. After the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g).1H-NMR (DMSO-d6) delta: 7.72(1H,dt,J=8.3,1.5Hz), 7.77(1H,dt,J=8.3,1.6Hz), 7.82(1H,dt,J=9.7,1.5Hz), 13.45(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In isopropyl alcohol; at 80℃; for 48h; | <strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (2.35 g, 15 mmol), n-butyltriphenylphosphonium bromide (7.38 g, 19 mmol), and potassium carbonate (2.57 g, 19 mmol) were suspended in isopropanol and heated for 48 hr at 80 C. The mixture was concentrated, and then diluted with water (150 mL) and hexane (50 mL). This mixture was filtered, and the hexane layer was separated. The aqueous layer was extracted with additional hexane (2*50 mL). The combined hexane phases were washed with water (50 mL), and then dried over magnesium sulfate. Concentration afforded the desired olefin as a clear yellow oil (2.62 g, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | EXAMPLE 1 1-[4-(4-{2-[2-(E)-(4-Chloro-3-fluoro-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole A mixture of 25.0 g (158 mmol) <strong>[5527-95-7]4-chloro-3-fluoro-benzaldehyde</strong>, 16.4 g (158 mmol) malonic acid, 1.34 g (15.8 mmol) piperidine and 15.0 ml pyridine was kept at reflux temperature until carbon dioxide development ceased (2 h). After cooling to room temperature, the reaction mixture was poured onto 150 g ice and 30 ml 12N HCl. The precipitate was isolated, washed with water and dried. Yield: 26.8 g (85%) 3-(4-chloro-3-fluoro-phenyl)-acrylic acid, melting at 240-245 C. MS: M=199.2 (API-) 1H-NMR(400 MHz, D6-DMSO): delta=6.64(d, 1H, 2-H), 7.61(m, 2H, Ar-H), 7.63(d, 1H, 3-H), 7.84(dd, 1H, Ar-H), 12.6(br, 1H, COOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In tetrahydrofuran; for 24h; | <strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (0.793 g) and tert-butyl 4-piperidinylcarbamate (1.00 g) were stirred under nitrogen in dried tetrahydrofuran (25 ml). Sodium triacetoxyborohydride (1.266 g) was then added and left for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave tert-butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) as a white solid. MS (+veAPC) 343 ((M+H)+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran; toluene; at -78 - 0℃; | Step 1: 1-(4-Chloro-3-fluorophenyl)ethanol Methylmagnesium bromide (22.5 mL, 31.5 mmol; 1.4 M solution in toluene/tetrahydrofuran) was added dropwise to a solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (5.0 g, 31.5 mmol) in 100 mL of dry tetrahydrofuran at -78 C. over 15 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into saturated NH4Cl (100 mL). The aqueous layer was extracted with diethyl ether (3*150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1-(4-chloro-3-fluorophenyl)ethanol (5.50 g, 100%) as a yellow oil which was used in the next step without further purification, MS (ES) m/z 175 [M+H+]. |
In tetrahydrofuran; diethyl ether; at -78 - -50℃; for 3h; | Reference Example 9: 1- (4-chloro-3-fluorophenyl) ethanone To a solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (leq) in THF (0.3 M) at-78C was added 3M/Et20 MeMgBr (1.5 eq). The reaction mixture was stirred at-50C for 3hrs, quenched with aqueous saturated NH4C1 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to give 1- (4-chloro-3-fluorophenyl) ethanol, which was used as such for the next step. To a solution of the above alcohol (leq) in CH2C12 (0. 3M) at rt was added Dess-Martin periodinane (1.5 eq). The reaction mixture was stirred for 45 minutes at rt and H2O (10 eq) was added. The mixture was stirred for 30 minutes and filtered through silica gel pad eluted with 30% EtOAc/hexane and concentrated. The residue was purified by flash chromatography on silica gel eluted with 20% EtOAc/hexane to give the title compound. | |
Step A: Methylmagnesium bromide was added dropwise over 5 minutes to a stirred solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (10.86 g, 68.5 mmol) in anhydrous tetrahydrofuran (100 ml) at -78 C. under nitrogen. After stirring for 15 minutes, the cooling bath was removed, and the solution allowed to warm to room temperature. After stirring 3 hours, the solution was poured slowly with stirring into saturated ammonium chloride (100 ml), then diluted with water (50 ml) and extracted with diethyl ether. The organic extracts were washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuo to provide the benzylic alchohol (11.89 g) as a clear yellow oil: 1H NMR (300 MHz, CDCl3) delta 7.35 (t, J=7.8 Hz, 1H), 7.18 (dd, J=2.0, 10.0 Hz, 1H), 7.07 (dd, J=1.7, 8.1 Hz, 1H), 4.83-4.92 (m, 1H), 2.01 (d, J=3.6 Hz, 1H), 1.47 (d, J=6.3 Hz, 3H), CI MS m/z=175 [C8H8ClFO+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.6% | piperidine; acetic acid; In isopropyl alcohol; at 20℃; for 60h; | A mixture of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (2.47 g, 15.5 mmol), acetoacetamide (1.57 g, 15.5 mmol), AcOH (35 muL, 0.62 mmol) and piperidine (61 muL, 0.62 mmol) in isopropyl alcohol (30 mL) was stirred at room temperature for 2.5 days and evaporated under reduced pressure. The crude product was purified by a silica gel column (120 g) eluting from 50% to 80% EtOAc in hexanes to afford 2-(4- chloro-3-fluorobenzylidene)-3-oxobutanamide (2.54 g, 67.6%) as an off-white solid. EPO <DP n="71"/>[00185] 1H NMR (400 MHz, d6-DMSO) delta 7.89 (s, br, 1H), 7.67 (m, 3H), 7.54 (dd, J= 2.2, 8.35 Hz, 1H), 7.50 (s, 1H), 2.43 (s, 3H).[00186] HPLC Phenomenex Luna, 5u, 4.6 x 50 mm, detection at 220 nm, flow rate 4 mL/min, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, 94% purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaH; In tetrahydrofuran; water; ethyl acetate; pentane; | Preparation 93 3-(4-Chloro-3-fluorophenyl)-2-propenenitrile Diethylcyanomethyl phosphonate (3.2 ml, 18.9 mmol) was taken up in dry THF (20 ml) at 0 C. under nitrogen, and stirred as a 60% oil dispersion of NaH (756 mg, 18.9 mmol) was added portionwise over ca. 10 min. The resulting grey suspension was then stirred at 0 C. for 1 h, before a solution of <strong>[5527-95-7]4-chloro-3-fluoro benzaldehyde</strong> (Lancaster Synthesis) (3g, 18.9 mmol) in 5 ml THF was added dropwise. The whole reaction was then allowed to warm to room temperature over 60 h. Water (5 ml) was added, and the mixture extracted with EtOAc (3*50 ml). The combined organics were were dried (MgSO4) and evaporated to a yellow oil which was purified by column chromatography using 5% EtOAc in pentane as eluant to provide the title product as a mixture of geometric isomers (2.4g, 70%); 1H-NMR (400 MHz, CDCl3) delta: 5.82 (d, 1H), 7.19 (d, 1H), 7.23 (d, 1H), 7.30 (d, 1H), 7.42 (app.t, 1H); LRMS TS+199.1 (M+NH4+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With toluene-4-sulfonic acid; In methanol; cyclohexane; water; | EXAMPLE 5 Preparation of Bis(4-chloro-3-fluorobenzylidene)sorbitol A one liter four-necked cylindrical shaped reaction flask equipped with a Dean-Stark trap, condenser, thermometer, nitrogen inlet, and a mechanical stirrer was charged with 42.00 g of sorbitol (0.2306 mole), 600 mL of cyclohexane, 73.11 g of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (0.4611 moles), 3.00 g of p-toluenesulfonic acid, 2.5 mL of water, and 210 mL of methanol. The reaction was stirred and heated under reflux with removal of water through the Dean Stark trap. The reaction becomes very thick and additional solvent is added as needed. After about six hours, the reaction is cooled, neutralized with potassium hydroxide, and filtered. The wet cake is washed thoroughly with water and cyclohexane, dried in a vacuum oven at 110 C. to give 93.02 g of Bis(4-chloro-3-fluorobenzylidene)sorbitol (as determined through standard analyses). The purity was about 95% as judged by GC. The melting point was measured (DSCa20 C/min) to be about 262.0 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In methanol; | 6-Chloro-7-fluoroindole Methyl 2-azido-3-(4-chloro-3-fluorophenyl)propenoate Sodium (2.32 g, 100 mmol) was added portionwise to stirred methanol (200 mL) at 0 C. under Ar. The mixture was stirred for 1 h and cooled to -15 C. A solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (4.0 g, 25 mmol), methyl azidoacetate (8.7 g, 75 mmol) in methanol (20 mL) was added. The mixture was stirred for 3 h, warmed to 4 C. and stirred for 16 h and partitioned between water (300 mL) and ether (3*200 mL). The organic extracts were combined and washed with brine (2*), dried (magnesium sulfate) and concentrated in vacuo to give an orange solid. Recrystallisation (methanol) gave the product (5.09 g, 80% yield) as a pale yellow solid: IR numax (Nujol)/cm-1 2115, 1708, 1616, 1234, 1060, 896, 818 and 616; NMR deltaH (400 MHz, CDCl3) 3.82 (3H, s) 6.64 (1H, s) 7.35-7.46 (2H, m) 7.74-7.78 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of the intermediate: (3-Bromo-phenyl)-(4-chloro-3- fluoro-benzyl)-amine; To 3-bromoaniline (1.58g, 12.4mmol) and <strong>[5527-95-7]4-chloro-3-fluoro-benzaldehyde</strong> (1.93g, 12.4mmol) in dry DCM (75ml) was added sodium triacetoxyborohydride (3.89g, 18.6mmol) and stirred at room temperature overnight. The reaction was then quenched with NaHCO3 (aq), diluted with DCM, washed with water, dried (MgSO4), evaporated and purified on silica gel by flash chromatography eluting with petroleum ether: ethyl acetate (1 : 1) to give (3-Bromo-phenyl)-(4-chloro-3-fluoro-benzyl)-amine (1.17g). IH (400MHz, CDCI3) 4.18 (IH, bs, NH), 4.30 (2H, d, J = 5.6Hz), 6.49-6.50 (IH, m, Ar), 6.72-6.73 (IH, m, Ar), 6.85-6.98 (IH, m, Ar), 7.00-7.20 (3H, m, Ar), 7.30-7.50 (IH, m, Ar); m/z (ES) : 312 (M-I). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Synthesis of the intermediate: (5-Bromo-pyridin-3-yl)-(4-chloro-3- fluoro-benzyl)-amine; To 5-Bromo-pyridin-3-ylamine (2.2g, 17.34mmol) and 4-chloro-3-fluoro- benzaldehyde (2.75g, 17.34mmol) in dry DCM (25ml) was added sodium triacetoxyborohydride (5.51g, 26.01mmol) and stirred at room temperature overnight. The reaction was then quenched with NaHCO3 (aq), diluted with DCM, washed with water, dried (MgSO4), evaporated and purified on silica gel by flash chromatography eluting with petroleum ether: ethyl acetate (1:1) to give (5-Bromo-pyridin-3-yl)-(4-chloro-3- fluoro-benzyO-amine (2.16g). IH (400MHz, CDCI3) 4.11-4.15 (IH, bs, NH), 4.31-4.33 (2H, m), 6.97-6.98 (IH, m, Ar), 7.06-7.15 (2H, m, Ar), 7.37-7.41 (IH, m, Ar), 7.95-7.96 (IH, m, Ar), 8.04 (IH, s, Ar); m/z 316 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With ammonium acetate; In acetic acid; for 1.5h;Heating / reflux; | <strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (13 g, 82 mmol) and ammonium acetate (14.6 g, 189 mmol) were dissolved in acetic acid (150 ml) and nitromethane (12.6 ml, 234 mmol) was added. The solution was heated to reflux for 1.5 h. After cooling to RT water (120 ml) was added. A solid precipitated. The reaction was extracted three times with methylene chloride. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography (Ethyl acetate/cyclohexane:1/4). The crude product was suspended in heptane, filtered and dried to yield 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (10.9 g, 66%) as a light yellow solid. 1H NMR (CDCl3, 300 MHz): delta 7.29 (d, J=7.8 Hz, 1H), 7.33 (d, J=9.3 Hz, 1H), 7.50 (t, J=7.5H7, 1H), 7.54 (d, J=13.6 Hz, 1H), 7.92 (d, J=13.6 Hz, 1H). |
44% | With sodium hydroxide; In ethanol; at 0℃; for 2h; | Preparation of Intermediate 1-Chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (I-33a) Using the same reaction procedure and workup as described in Example 1, <strong>[5527-95-7]4-chloro-3-fluoro-benzaldehyde</strong> (2 g, 12.61 mmol) in ethanol (20 mL) was reacted with nitro methane (0.7 mL, 12.61 mmol), 10N NaOH solution (529 mg, 12.61 mmol) at 0 C. for 2 hours to afford 1.1 g of the product (44% yield). 1H NMR (300 MHz, CDCl3): delta 8.0-7.9 (d, 1H), 7.60-7.45 (m, 2H), 7.40-7.25 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57.7% | b. Preparation of compound 204; CH3COOH (0.25 ml) was added to a stirring mixture of intermediate 62 (0.84 g, 0.0027 mol) (see Al Ig), <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (0.65 g, 0.0041 mol), sodium triacetoxyborohydride (1.73 g, 0.0082 mol) and DCM (20 ml; p. a.). The reaction mixture was stirred at room temperature for 18 hours. An aqueous HCl solution (1 N, 10 ml) was added to the reaction mixture and then stirred for 20 minutes. The precipitate was filtered off, washed with DCM and H2O and dried (vacuum, 50 0C). The residue was recrystallized from H2O/HC1 (30 ml/1 ml). The precipitate was filtered off hot, washed with H2O and dried (vacuum, 55 0C). Yield : 0.765 g of compound 204 (57.7 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.4% | Example B20; a. Preparation of compound 203; CH3COOH (0.22 ml, 0.0037 mol) was added to a stirring mixture of intermediate 63 (0.75 g, 0.0024 mol) (see A1 Ih), 4-chloro-3-fiuorobenzaldehyde (0.578 g, 0.0037 mol), sodium triacetoxyborohydride (1.55 g, 0.0073 mol) and DCM (20 ml, p. a.). The reaction mixture was stirred at room temperature for 18 hours. An aqueous HCl solution (1 N, 10 ml) was added to the reaction mixture and then stirred vigorously for 25 minutes. The reaction mixture was left standing for 24 hours. The precipitate was filtered off, washed with DCM and H2O and dried (vacuum, 55 0C). The residue was recrystallized from H2O/HCI (35 ml/(l ml, 1 N)). The precipitate was filtered off hot, washed with H2O and dried (vacuum, 55 0C). The residue was recrystallized from EtOH (35 ml). The precipitate was filtered off, washed with EtOH and dried (vacuum, 55 0C). Yield : 0.455 g of compound 203 (38.4 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example B8; a) Preparation of compound 26; A mixture of 2-(p-fluorophenyl)-2-(4-piperidyl)-glutarimide (0.000128 mol), 4-chloro- 3-fluorobenzaldehyde (0.00022 mol) and NaBH(OAc)3 (0.00064 mol) in DCM, p.a. (8 ml) was shaken at room temperature. Acetic acid, p.a. (0.00022 mol) was added. The reaction mixture was stirred for 18 hours at room temperature. The solvent was evaporated. The residue was purified by reversed-phase high-performance liquid chromatography (Column: Xterra Prep MS C18, Length: 10 cm, LD. : 19 mm, particle size: 5 mum; eluent: (NH4OAc in H2O)/CH3OH/CH3CN gradient). The desired fractions were combined, collected and the solvent was evaporated. Yield: fraction A (still a salt because of the NH4OAc used in the chromatography). This fraction was stirred vigorously for 2 hours in a biphasic mixture of DCM (4 ml) and a saturated aqueous NaHCO3 solution (1 ml). The mixture was filtered and dried through an Isolute HM-N filter and the filtrate was evaporated. Yield: 0.0423 g of compound 26. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.5% | d) Preparation of compou; A mixture of intermediate (prepared according to Al .f) (0.000227 mol),<strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (0.00034 mol) and NaBH(OAc)3 (0.00068 mol) in DCM p. a. (4 ml) was stirred. Acetic acid (0.00034 mol) was added and the reaction mixture was stirred at room temperature for 3 days. HCl (2 ml; IN) was added and stirring was continued for 1 hour. Then NaHCO3 was added till pH >8 (foaming). The separated water layer was extracted with DCM/CH3OH 98/2. The combined organic layers were dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by reversed-phase high-performance liquid chromatography (Column: Xterra Prep MS C 18, Length: 10 cm, LD. : 19 mm, particle size: 5 mum; eluent: (0.2 % NH4HCO3 in H2O)/CH3OH/CH3CN gradient). The product fractions were combined, the solvent was evaporated and two times co-evaporated with CH3OH. Yield: 0.027 g of compound 29 (28.5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 42h; | b) Preparation of compound 27; A mixture intermediate 21 (prepared according to A5.e) (0.000164 mol), 4-chloro-3- fluorobenzaldehyde (0.000197 mol) and NaBH(OAc)3 (0.00049 mol) in DCM, p.a. (6 ml) was stirred at room temperature. Acetic acid, p.a. (0.000197 mol) was added. The reaction mixture was stirred for 18 hours at room temperature. More 4-chloro-3- fluorobenzaldehyde (0.2 ml) and acetic acid, p.a. (0.015 ml) were added and the reaction mixture was stirred for 24 hours at room temperature. The solvents were evaporated. The residue was purified by reversed-phase high-performance liquid chromatography (Column: Xterra Prep MS C18, Length: 10 cm, LD. : 19 mm, particle size: 5 mum; eluent: (0.2% NH4HCO3 in H2O)/CH3OH/CH3CN gradient). The desired fractions were combined, collected and the solvent was evaporated. Methanol was added and co-evaporated.Yield: 0.0375 g of compound 27. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | f) Preparation of compound 31; A mixture of 3-phenyl-[3,4'-bipiperidine]-2,6-dione (0.00019 mol), 4-chloro-3- fluorobenzaldehyde (0.0002 mol) and NaBH(OAc)3 (0.121 g) in DCM p.a. (8 ml) was shaken at room temperature. Acetic acid (0.0002 mol) was added. The reaction mixture was shaken for 40 hours at room temperature, then quenched with 2 drops of 6N HCl/2-propanol. The solvents were evaporated. The residue was purified by reversed- phase high-performance liquid chromatography (Column: Xterra Prep MS C 18, Length: 10 cm, LD. : 19 mm, particle size: 5 mum; eluent: (0.2 % NH4HCO3 in H2theta)/CH3OH/CH3CN gradient). The product fractions were collected and the solvent <n="96"/>was evaporated. Methanol was added and co-evaporated. Yield: 0.004 g of compound 31 (5 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | g) Preparation of compound 76; A mixture of 3-phenyl-[3,4'-bipiperidine]-2,6-dione (0.03 mol), 4-chloro-3- fluorobenzaldehyde (0.032 mol) and NaBH(OAc)3 (0.09 mol) in DCM p.a. (200 ml) was stirred at room temperature. Acetic acid, p.a. (0.032 mol) was added slowly. The reaction mixture was stirred for 65 hours at room temperature. Water (150 ml) was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM/CH3OH 98/2). The desired fractions were collected and the solvent was evaporated. The residue was dissolved in hot 2-propanol (100 ml) and converted into the hydrochloric acid salt (1:1) with 6 N HCl/2-propanol (13 ml). The precipitate was filtered off (at room temperature), washed with 2-propanol, and dried (vacuum, 60 0C, over the weekend). Yield: 11.7 g of compound 76 (86.4 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In water; | REFERENTIAL EXAMPLE 376 4-Chloro-3-fluorobenzoic acid: Sodium chlorite (17 g) was added portionwise to a mixture solution composed of 4-chloro-3-fluorobenzaldehyde (10 g), amidosulfuric acid (18 g), tert-butyl alcohol (50 ml) and water (50 ml) under ice cooling, and the mixture was stirred for 4 days while the temperature of the system was gradually raised to room temperature. The reaction mixture was diluted with ethyl acetate and washed with water, 1N hydrochloric acid and saturated aqueous solution of sodium chloride. After the resultant organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, the resultant residue was recrystallized from a mixed solvent of diisopropyl ether and hexane to obtain the title compound (11.2 g). 1H-NMR (DMSO-d6) δ: 7.72(1H,dt,J=8.3, 1.5 Hz), 7.77(1H,dt,J=8.3, 1.6 Hz), 7.82(1H,dt,J=9.7, 1.5 Hz), 13.45(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
toluene-4-sulfonic acid; In toluene; for 2h;Heating / reflux; | 3.2 g (20 mmol) of the aldehyde 18 and 4.7 g (30 mmol) of the 1,3-diol are dissolved in 50 ml of toluene, 0.4 g of p-toluenesulfonic acid is added, and the mixture is heated on a water separator for 2 h. The cooled solution is washed with sat. sodium hydrogencarbonate solution and evaporated. The residue is passed through silica gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | Example 7. Step F, Method A; A 50 ml round-bottomed flask was charged with 8 (17 mg, 0.041 mmol), <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (28 mg, 0.17 mmol), sodium triacetoxyborohydride (30 mg, 0.145 mmol), triethylamine (0.3 ml, ~2.1 mmol), and 1 ,2-dichloromethane (5 ml). The suspension was stirred at room temperature for 20 hours, diluted with ethyl acetate (10 ml), and washed with 1.0 M sodium hydroxide and water. The solution was dried with sodium sulfate, concentrated on vacuum, and purified by silica preparative TLC (5% methanol in dichloromethane as the eluent) to provide the title compound as a white gel (7 mg, 33%). MS [M+H]=526.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In methanol; for 1.5h;Heating / reflux; | A mixture of 1-(1-isocyanoethylsulfonyl)-4-methylbenzene (1.56 g, 7.44 mmol), <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (1.18 g, 7.44 mmol), and K2CO3 (2.06 g, 14.9 mmol) in MeOH (35 mL) was heated to reflux. After 1.5 hr water (200 mL) was added and the product was extracted with EtOAc (200 mL). The organic layer was washed with brine and dried over Na2SO4, filtered, and concentrated to an orange oil. Chromatography on silica gel (Analogix SF25-40G, 0%-30% EtOAc/hexanes, 30 mL/min) afforded 1.35 g (86%) of the title compound as a yellow solid. 1H NMR (300 MHz, CH3OH-d4) delta 8.18 (s, 1H), 7.62-7.55 (m, 1H), 7.52 (dd, J=1.9, 10.3, 1H), 7.49-7.44 (m, 1H), 2.42 (s, 3H). MS (DCI+) m/z 212 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 25.0 g (158 mmol) <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> in 130 ml methanol and 175 ml methanol saturated with ammonia were added 54.9 ml (52.7 g, 185 mmol) tetraisopropyl orthotitanate and the mixture stirred at ambient temperature for 1.5 hours. Then 20.35 ml (16.14 g, 163 mmol) trimethylsilyl cyanide were added drop-wise and the resulting mixture stirred at ambient temperature for further 2 hours. The reaction mixture was poured onto 1500 ml iced water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by flash-chromatography on silica gel with a gradient of heptane and 0 to 50% ethyl acetate. rac-Amino-(4-chloro-3-fluoro-phenyl)-acetonitrile was obtained as orange oil: MS (ISN): 183.2 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrogenchloride; potassium hydroxide; sodium tris(acetoxy)borohydride; In 1,1-dichloroethane; | Method 8 4-(4-Chloro-3-fluorobenzyl)morpholine <strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (1.0 g, 6.31 mmol), morpholine (0.546 ml, 6.31 mmol) and sodium triacetoxyborohydride (1.938 g, 9.14 mmol) were mixed in dichloroethane (19 ml) and the reaction stirred at ambient temperature under an atmosphere of argon over night. 1M HCl (aq, 25 ml) was added. The mixture was extracted with dichloromethane (*4). The pH was adjusted to ca 12 by adding KOH (s). The mixture was extracted with dichloromethane (*4). The combined organic phases were dried over MgSO4 filtered and concentrated in vacuo to give 4-(4-chloro-3-fluorobenzyl)morpholine (0.875 g, 60%) as a liquid. 1H NMR (500 MHz, CHLOROFORM-d) delta ppm 7.50-7.54 (m, 1H) 7.54-7.59 (m, 2H) 4.28-4.36 (m, 2H) 4.09-4.15 (m, 2H) 3.95-4.01 (m, 2H) 3.33 (d, 2H) 2.80-2.91 (m, 2H). MS (ES+) m/z 230 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | To a dry flask charged with anhydrous DMF (1000 ml) under nitrogen was addedNaCN (8.05 g, 0.05 eq) at ambient temperature. The mixture was stirred for 15 minutes and cooled to (-15)-(-10) 0C. In a separate flask, a solution of 4-chloro-3-fluoro- benzaldehyde (514.1 g, 3.28 mole) in DMF (750 ml) was prepared, and was then slowly added to the NaCN/DMF solution via additional funnel. The reaction temperature was maintained between -15 to -5 0C. A solution of n-butyl acrylate (433.45 g, 1.03 eq) in DMF (500 ml) was prepared, and was slowly added into the reaction mixture via additional funnel. The reaction temperature was maintained between -15 to -5 0C. The reaction was stirred at -15-0 0C for 10-20 minutes. The reaction progress was monitored by HPLC (Note: it normally takes about 10-20 minutes.). The reaction mixture was poured into water (18-20 vol) and stirred at 0-10 0C for 1-2 hr. The solid product was filtered and washed with cold water twice (0-10 0C) (2 vols). The precipitate was air-dried via vacuum suction for 30 minutes to afford the desired product 1.25 kg. To the resulting solid was added n-propanol (3 L) at ambient temperature. The mixture was heated to 50-60 0C and stirred for 15-30 minutes until a solution was observed. The solution was cooled to -2-0 0C and stirred for 1-2 hr. The resulting precipitate was filtered and washed with cold n- <n="9"/>propanol (500 ml). The resulting ester product was dried under reduced pressure to a constant weight at 1 atm (18-20 0C) to afford the desired 1.23 kg product (1.23 kg, 67% yield - 99.2% purity) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; at 110℃; for 12h; | General procedure: A mixture of 11a (55 mg, 0.2 mmol) and 2-hydroxybenzaldehyde (13.5 mg, 0.22 mmol) in n-butanol (10 mL) were heated to 110 C for 12 h, after which the solvent was distilled off. The residue was purified by flash column chromatography on silica gel, eluted with a mixture of EtOAc/petroleum ether (3:1, v/v), to afford 1 (53 mg, 70%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; at 110℃; for 12h; | General procedure: A mixture of 11a (55 mg, 0.2 mmol) and 2-hydroxybenzaldehyde (13.5 mg, 0.22 mmol) in n-butanol (10 mL) were heated to 110 C for 12 h, after which the solvent was distilled off. The residue was purified by flash column chromatography on silica gel, eluted with a mixture of EtOAc/petroleum ether (3:1, v/v), to afford 1 (53 mg, 70%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In butan-1-ol; at 110℃; for 12h; | General procedure: A mixture of 11a (55 mg, 0.2 mmol) and 2-hydroxybenzaldehyde (13.5 mg, 0.22 mmol) in n-butanol (10 mL) were heated to 110 C for 12 h, after which the solvent was distilled off. The residue was purified by flash column chromatography on silica gel, eluted with a mixture of EtOAc/petroleum ether (3:1, v/v), to afford 1 (53 mg, 70%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1,4-diaza-bicyclo[2.2.2]octane; In acetonitrile; at 20℃; for 72h; | To a mixture of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (50 g, 315 mmol) and methyl acrylate (42.6 mL, 473 mmol) in MeCN (160 mL) was added 1,4-diazabicyclo[2.2.2]octane (10.6 g, 94.6 mmol) at room temperature. The mixture was stirred at room temperature for 3 days, and then concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexane/EtOAc) to give 17b (69.1 g, 90%) as a colorless oil. 1H NMR (300 MHz, CDCl3) delta 3.19 (1H, d, J = 6.1 Hz), 3.75 (3H, s), 5.51 (1H, d, J = 6.1 Hz), 5.84 (1H, s), 6.36 (1H, s), 7.11 (1H, d, J = 8.3 Hz), 7.20 (1H, dd, J = 9.8, 1.9 Hz), 7.32-7.42 (1H, m). |
With 1,4-diaza-bicyclo[2.2.2]octane; In acetonitrile; at 10 - 35℃; for 72h; | Example 13[(6RS,7SR)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methanol monohydrochlorideA) methyl 2-[(4-chloro-3-fluorophenyl)(hydroxy)methyl]prop-2-enoateTo a solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (50.0 g) and methyl acrylate (42.6 mL) in acetonitrile (158 mL) was added 1,4-diazabicyclo[2.2.2]octane (10.6 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (69.1 g).1H NMR (300 MHz, CDCl3) delta 3.19 (1H, d, J=6.1 Hz), 3.75 (3H, s), 5.51 (1H, d, J=6.1 Hz), 5.84 (1H, s), 6.36 (1H, s), 7.11 (1H, d, J=8.3 Hz), 7.20 (1H, dd, J=9.8, 1.9 Hz), 7.32-7.42 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With ammonium acetate In ethanol; water at 80℃; for 0.666667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With ammonium acetate; acetic acid; In acetic acid; for 5h;Reflux; | Step 1. (E)-1-chloro-2-fluoro-4-(2-nitrovinyl)benzene To a solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (8 g, 50.5 mmol) and ammonium acetate (9.72 g, 126 mmol) in acetic acid (168 mL) was added nitromethane (8.16 mL, 151 mmol). The reaction mixture was heated at reflux for 5 h and cooled down. Water (100 mL) was added, and the mixture was stirred at room temperature for 1 h. The solid was filtered, washed by water, and dried under vacuum. The solid was purified by flash chromatography (0-20% EtOAc/heptane) to yield clean product 4.2 g in 41% yield. 1H NMR (400 MHz, CDCl3) delta ppm 7.92 (d, J=13.7 Hz, 1H), 7.54 (d, J=13.8 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.33 (dd, J=2.0, 9.3 Hz, 1H), 7.31-7.28 (m, 1H). |
13.65% | With ammonium acetate; acetic acid; at 120℃; for 18h; | step 1: To a solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (10 g, 63.07 mmol) and ammonium acetate (4.861 g, 63.07 mmol) in HOAc (50 mL) was added nitromethane (14.12 mL, 252.3 mmol) and the reaction mixture was heated to reflux (120 C oil bath) for 18 h. The reaction was cooled and diluted with water. The reaction mixture was filtered and solids were purified by Si02 chromatography eluting with a EtOAc/hexane gradient (0 to 5% EtOAc) to afford 1.736 g (13.65%) of(E)-l-chloro-2-fluoro-4-(2-nitrovinyl)benzene (86). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With acetic acid; for 4h;Reflux; | To a solution of 2-(pyrrolo[2,l-f][l,2,4]triazin-4-yl)aniline 22h (0.2 g, 0.95 mmol) in acetic acid (5 mL) was added <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> 29bf (0.163 g, 1.03 mmol) and heated at reflux for 4 h. The reaction mixture was concentrated in vacuum to remove AcOH. The residue was purified by flash column chromatography (silica gel, eluting with ethyl acetate/methanol (9: 1) in hexane (0-100%)) to furnish 3-(4-chloro-3-fluorophenyl)- 3,4-dihydro-4,9,l 1,1 la-tetraazadibenzo[cd,f]azulene 29bg (0.22 g, 66 %) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) ? 8.53 (s, 1H), 8.48 (dd, J= 8.1, 1.6 Hz, 1H), 8.09 (d, J = 2.5 Hz, 1H), 7.43 (t, J= 8.1 Hz, 1H), 7.31 (ddd, J= 8.4, 7.0, 1.7 Hz, 1H), 7.21 (dd, J = 10.6, 1.9 Hz, 1H), 7.07 (d, J= 4.5 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.98 - 6.86 (m, 2H), 6.79 (d, J= 2.6 Hz, 1H), 5.83 (d, J= 4.3 Hz, 1H); 19F NMR (282 MHz, DMSO-d6) ? -116.38; MS (ES+) 351.014 (M+l), (ES-) 348.555 (M-l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | General procedure: To each reaction tube in a 24-position Bohdan MiniBlock XT was added the appropriate aldehyde (5.0 equiv, 1.15 mmol), which was dissolved in MeCN (1 mL). A solution of 2-(benzo[d][1,3]dioxol-5- yl)pyrimidin-4-amine (8) in MeCN (0.13 M, 1.8 mL, 0.23 mmol, 1.0 equiv) was then dispensed into each tube. ClTi(Oi-Pr)3 (95%, 0.35 mL, 1.38 mmol, 6.0 equiv) was added to each tube, followed by AcOH (3 drops). The reactions were shaken at 450 rpm for 5 minutes, and then solid NaBH(OAc)3 (95%, 257 mg, 1.15 mmol, 5.0 equiv) was added to each tube. The reactions were shaken at 450 rpm for an additional 1.5 hours, and then a solution of 15% aqueous NH4OH (2 mL) and CH2Cl2 (2 mL) were added to each tube causing white solids to precipitate. Shaking was continued for 30 minutes at 450 rpm. Using stackable 24-position Bohdan MiniBlock XTs, the liquid portions of the crude reaction mixtures were passed into phase separators, to which H2O (2 mL) was added. The biphasic mixtures were mixed by hand using pipettes, and then the heavier organic layers were passed from the phase separators into new reaction tubes. The white solids in the original reaction tubes were washed with CH2Cl2 (2 mL) and the washings were passed into the closed phase separators. The biphasic mixtures were again mixed by hand using pipettes and the heavier organic layers were passed into the reaction tubes containing the organic layers from the first separation. The crude reaction mixtures were then placed on a sample concentrator to remove the solvents. TFA/MeOH (1:19, 3 mL) was added to each crude reaction mixture, and the samples were then shaken at 450 rpm for 1 hour. The solutions were then passed onto columns of Dowex 50WX4-400 ion exchange resin (2.0 g, pre-washed with TFA/MeOH (1:99, 5 mL)). Each reaction tube was washed with MeOH (2 mL) and the washings were allowed to pass onto the Dowex columns. The columns were washed with MeOH (3 mL) and the washings discarded. The products were then eluted into collection tubes using a mixture of Et3N/MeOH (1:9, 10 mL). Solvents were removed using a sample concentrator and the products were subjected to reverse-phase preparative HPLC purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; | [00248] Step A: Sodium hydride (8.549 g, 213.7 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0C) solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (26.07 g, 164.4 mmol) and methyltriphenylphosphonium bromide (70.48 g, 197.3 mmol) in THF (400 mL). The reaction mixture was allowed to warm up to room temperature overnight. The solids were removed by filtration, and the filter cake was washed with ether. The filtrate was concentrated (water bath about 20C), and the residue was suspended in hexanes and stirred for 30 minutes. The solids (mostly PPh30) were removed by filtration, and the filter cake was washed with hexanes. The filtrate was concentrated, and the crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (25:1) to give l-chloro-2-fluoro- 4-vinylbenzene (12.1 g, 47%) as an oil. 1H NMR (400 MHz, CDC13) delta 7.33 (m, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 5.74 (d, J=17.4 Hz, 1H), 5.32 (d, J=10.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In acetone; at 20℃; | 1004161 Step A: Proline (23 mg, 0.20 mmol) was added to a solution of 4-chloro-3- fluorobenzaldehyde (159 mg, 1.00 mmol) in acetone (2.5 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was then treated with saturated ammonium chloride. After partitioning, the aqueous layer was extracted with ethyl acetate (3 X 25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1:4) to afford 4-(4-chloro-3-fluorophenyl)-4-hydroxybutan-2- one (160 mg, 73% yield) as a solid. ?H NMR (500 MHz, CDC13) 6 7.36 (m, 1H), 7.19 (m, 1H), 7.06 (m, 1H), 5.13 (t, J = 6.5 Hz, 1H), 3.43 (br s, 1H), 2.82 (d, J = 6.5 Hz, 1H), 2.21 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.7% | With pyridine; at 50 - 100℃; for 17h; | 1002741 Step A: <strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (15.0 g, 94.6 mmol) was combined with malonic acid (10.8 g, 104 mmol) and pyridine (11.5 mE, 142 mmol). The mixture was heated to 50C and agitated 1 hour. Then it was heated to 100C and agitated 16 hours. Ice (100 g) and 6M HC1 (25 mE) were added, and the mixture was agitated one hour. Precipitation was filtered, washed with water and dried in vacuo to give (E)-3-(4-chloro-3- fluorophenyl)acrylic acid (17.6 g, 87.7 mmol, 92.7% yield) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | 168. f+)-2-f(3.,4-trans)-l-f4-chloro-3-fluorobenzyl)-4-methylpyrroli(iin-3- yl)-7-ftetrahvdro-2H-pyran-4-yl)imidazo[5,l- l [l,2,41triazin-4f3H -one [1127] To a stirred solution of (-)-2-((3,4-trans)-4-methylpyrrolidin-3-yl)-7- (tetrahydro-2H-pyran-4-yl)imidazo[5,l: ][l,2,4]triazin-4(3H)-one (75 mg, 0.24 mmol) in MeOH (10 mL) was added <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (51 mg, 0.32 mmol) at room temperature and stirred for 2 h under argon atmosphere. To the resulting solution was added NaCNBH3 (46.78 mg, 0.74 mmol) and stirring was continued for another 8 h at room temperature. The volatiles were evaporated under reduced pressure. The residue was diluted with water and extracted with CH2CI2 (2 x 50 mL). Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford (+)-2-((3,4-trans)-l-(4-chloro-3- fluorobenzyl)-4-methylpyrrolidin-3 -yl)-7-(tetrahydro-2H-pyran-4-yl)imidazo [5,1- J[l,2,4]triazin-4(3H)-one (42 mg, 38%) as an off-white solid. 1H-NMR (DMSO-d6, 400 MHz): delta 11.56 (bs, 1H), 7.64 (s, 1H), 7.53 (t, 1H), 7.34 (d, 1H), 7.18 (d, 1H), 3.96-3.94 (m, 2H), 3.67-3.65 (m, 2H), 3.51-3.48 (m, 2H), 3.42-3.41 (m, 1H), 2.98- 2.97 (m, 1H), 2.83-2.79 (m, 1H), 2.74-2.72 (m, 1H), 2.67-2.64 (m, 2H), 2.33-2.31 (m, 1H), 1.87-1.81 (m, 4H), 1.08 (d, 3H); Mass (ESI): 446.5 [M++l]; LC-MS: 98.55%; 446 (M++l); (column; X-bridge C-18, (50x3.0 mm, 3.5mu); RT 2.33 min. 0.05% TFA (Aq): ACN; 0.8 ml/min); HPLC (purity): 99.11%; (column; Eclipse XDB C-18, 150x4.6 mm, 5.0mu; RT 10.56 min. 5mM NH4OAc (Aq): ACN; 1.0 ml/min.; Chiral HPLC: 98.97%, R,= 11.97 min (Chiralpak IA, 250 x 4.6mm, 5mu; mobile phase (A) 0.1% DEA in n-Hexane (B) DCM:MeOH (80:20) (A: B : 85: 15); flow Rate: 1.00 mL/min); Optical rotation [a]D2: + 6.32 (c = 0.25, DCM). TLC: 5% MeOH/DCM (Rf: 0.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Step 17.4: Ethyl 2-bromo-5-((4-chloro-3-fluorophenyl)(hvdroxy)methyl)-1-isopropyl-1 H- imidazole-4-carboxylate To a solution of the product of step 4.6 (9.47 g, 36.3 mmol) in 176 ml THF cooled to - 78C, 28.2 ml (50.8 mmol) of a 1.8M LDA in heptane solution was added slowly (over 15 min). The reaction mixture was stirred at -78C for 2h50. Then a solution of 8.05 g (50.8 mmol) <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> in 40 ml THF was added over 20 min. The brown suspension was stirred at -78C for 30 min, and then allowed to warm up to -20C in 1 hour. The mixture was stirred at between -20C and -8C for 1 h10, then cooled again to - 20C and quenched with 4.98 ml (87 mmol) acetic acid. The reaction mixture was taken into EtOAc / water. The phases were separated and the organic phase was washed with water and brine. The organic phase was dried on Na2S04, filtered and evaporated. By reducing the volume, crystals were precipitated. They were filtered and washed with heptanes, then dried overnight under vacuum to give 12.33 g (29.4 mmol, 81 % yield) of the title compound as beige crystals. LCMS: (M+H) = 419/421 ; tR = 1.14 min (LC-MS 4). HPLC: tR = 3.39 min (HPLC 5). 1 H-NMR (d6-DMSO, 400 MHz) delta ppm 7.58 (m, 1 H) 7.36 (d, 1 H) 7.05 (d, 1 H) 6.88 (m, 2H) 4.69 (quin, 1 H) 4.27 (m, 2H) 1.48 (d, 3H) 1.29 (t, 3H) 0.97 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium hydroxide; In ethanol;Reflux; | General procedure: The 2-thioxo-4-thiazolidinone (1mmol), benzaldehydes (1 mmol) and NaOH (1.0 mmol) were added to ethanol withtotal volume of 15 mL. The reaction mixture was heated to reflux and stirredfor 2-24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, neutralized to pH 7.0 with dilute hydrochloric, and then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; | step 1: Sodium hydride (8.549 g, 213.7 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0C) solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (26.07 g, 164.4 mmol) and methyltriphenylphosphonium bromide (70.48 g, 197.3 mmol) in THF (400 mL). The reaction mixture was allowed to warm up to RT overnight. The solids were removed by filtration, and the filter cake was washed with ether. The filtrate was concentrated (water bath about 20C), and the residue was suspended in hexanes and stirred for 30 minutes. The solids (mostly PPh30) were removed by filtration, and the filter cake was washed with hexanes. The filtrate was concentrated, and the crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (25: 1) to give l-chloro-2-fluoro-4-vinylbenzene (12.1 g, 47%) as an oil. NMR (400 MHz, CDC13) delta 7.33 (m, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 6.63 (m, 1H), 5.74 (d, J=17.4 Hz, 1H), 5.32 (d, J=10.8 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | To a stirred solution of (S)-dimethyl (2-oxo-2-(2-oxo-5-phenyloxazolidin-3- yl)ethyl)phosphonate (3.00 g, 9.03 mmol) in THF (20.0 mL) was added potassium tert-butoxide (1.01 mL, 1M in THF, 17.7 mmol) and mixture was stirred at room temperature for 20 mm. Asolution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (1.43 g, 9.03 mmol) was added dropwise and reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with H20 (50.0 mL), extracted with EtOAc (2 x 100 mL). The organic layer was washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by 120 g Si02 column using a gradient elution of 0-50% EtOAc in hexanes. Fractionscontaining product were combined and the solvents were removed in vacuo to provide the product (2.17 g, 70%) as a white solid. MS: m/z= 346 (M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; at 20℃; | General procedure: In the first synthetic step (step a, Scheme 1), a series of (Z)-substituted diarylacrylonitrile analogues were synthesized by reacting substituted benzyl carbaldehydes with their corresponding substituted phenylacetonitriles in 5% NaOMe in methanol. The reaction mixture was stirred at room temperature for 2-3 h for the reaction to complete and the final product precipitated of the solution. The precipitate was filtered, washed with water and dried to yield the final compound in yields ranging from 70 to 95% (Scheme 1) [16]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine; In ethanol; at 20℃; for 3h; | General procedure: Biscoumarins 1-4 were synthesized according to the methods of a previous report [15]. A mixtureof 3,4-dimethylbenzaldehyde (3-hydroxy-4-methoxybenzaldehyde, 3-bromo-4-fluorobenzaldehyde,<strong>[5527-95-7]3-fluoro-4-chlorobenzaldehyde</strong>) (10 mmol) and 4-hydroxycoumarin (20 mmol) was dissolved in 100 mLof EtOH. A few drops of piperidine were added, and the mixture was stirred for 3 h at roomtemperature. After reaction completion as determined by TLC, water was added until precipitationoccurred. The solid was filtered off and then recrystallized from ethanol to give compounds 1-4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With chloranil; trifluoroacetic acid; at 20℃; for 24h; | The compound (0.5 mol) prepared in the above step 2 was added to trifluoroacetic acid (2 mL)p-Chloranyl (0.5 mol) and<strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (0.5 mol) was treated, which was stirred at room temperature for 1 day.After removing volatiles,The residue was subjected to SiO2 column chromatography to give the desired compound in the form of a gray solid (yield:67%). |
With chloranil; trifluoroacetic acid; at 20℃; for 24h;Inert atmosphere; | General procedure: Anilinolactone (0.5 mol) in trifluoroacetic acid (2 mL) was treated with p-chloranil (0.5 mol) and substituted benzaldehyde (0.5 mol), and the reaction mixture was then stirred at room temperature for 1 day. After removal of the volatile materials, the residue was purified by SiO2 column chromatography to afford the desired 4-aza-daurinolanalogues. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of the requisite aldehyde 3 (0.12 mmol), diethyl 2-aminomalonate(2; 17.5 mg, 0.1 mmol) and AcOH (0.17 mul, 0.03 mmol) intoluene (0.5 mL) was stirred at r.t. for 20 min. To this resultant mixturewas added the appropriate unsaturated pyrazolone 1 (0.12mmol) and an additional 0.5 mL of toluene. The reaction mixture wasstirred at r.t. for 12 h. The resultant solution was evaporated underthe reduced pressure and the residue was purified by flash columnchromatography on silica gel (eluent: PE-EtOAc, 15:1 ? 5:1) to affordthe respective pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: A solution of the requisite aldehyde 3 (0.12 mmol), diethyl 2-aminomalonate(2; 17.5 mg, 0.1 mmol) and AcOH (0.17 mul, 0.03 mmol) intoluene (0.5 mL) was stirred at r.t. for 20 min. To this resultant mixturewas added the appropriate unsaturated pyrazolone 1 (0.12mmol) and an additional 0.5 mL of toluene. The reaction mixture wasstirred at r.t. for 12 h. The resultant solution was evaporated underthe reduced pressure and the residue was purified by flash columnchromatography on silica gel (eluent: PE-EtOAc, 15:1 ? 5:1) to affordthe respective pure product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In methanol; at 20℃; for 16h; | General procedure: 2?,4?-Bis(methoxymethoxy)-6?-hydroxyacetophenone (178 mg, 0.7 mmol, 1.0 equiv) and benzaldehyde (0.71 mmol, 1.02 equiv) were added to a solution of KOH (394 mg, 7.0 mmol, 10.0 equiv) in 10 mL MeOH. The reaction mixture was stirred at room temperature for 16 h. The mixture was then extracted with EtOAc (3 25 mL) and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The resulting crude product was was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With sodium tris(acetoxy)borohydride; In dichloromethane; at 0 - 20℃; | 1-[2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl]piperazine (200mg, 0.649mmol) in dichloromethane solution (2 ml) <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> in (103mg, 0.649mmol) was added and sodium triacetoxyborohydride (206mg, 0.974mmol) at 0C , and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography and purified by (elution solvent ethyl acetate / n-hexane = 1/4) to give a pale title compound yellow oil (yield 65.4 mg, 22% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In benzene; at 50℃; for 2h;Inert atmosphere; | The reaction flask was charged with II-1 (2 g, 6.6 mmol), 40 mL of benzene was added, and the mixture was stirred to dissolve. Followed by the addition of a catalytic amountGlacial acetic acid, heating to 50 C, slowly dropping III-4 (1.0g, 6.6mmol) of toluene solution to reduce the toxicity of benzene hazards. The temperature was raised to reflux under a nitrogen atmosphere, and the reaction was carried out for 2 hours.The water produced during the reaction was removed with a water separator. After the completion of the reaction, the solvent was evaporated to give a red-brown oil. The resulting oil was dissolved in absolute ethanol and allowed to cool to give a solid precipitate. (Yield: 68.0%, purity 97.3% by HPLC normalization), ESI-MS (m / z): 444.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In toluene; benzene; at 50℃; for 2h;Inert atmosphere; | The reaction flask was charged with II-2 (2 g, 6.6 mmol), 40 mL of benzene,Stirring to dissolve. Followed by the addition of a catalytic amountGlacial acetic acid, heated to 50 C,A solution of III-4 (1.0 g, 6.6 mmol) in toluene was slowly added dropwise,To reduce the toxicity of benzene hazards. The temperature was raised to reflux under a nitrogen atmosphere, and the reaction was carried out for 2 hours.The water produced during the reaction was removed with a water separator. After the completion of the reaction, the solvent was evaporated to give a red-brown oil. The resulting oil was dissolved in absolute ethanol and allowed to cool to give a solid precipitate. The product was obtained in a yield of 64.2%, purity 97.0% (HPLC normalization method), ESI-MS (m / z): 444.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.9g | With toluene-4-sulfonic acid; In toluene;Inert atmosphere; Reflux; Dean-Stark; | Under a nitrogen atmosphere, 4-chloro-3-fluorobenzaldehyde (25 g), <strong>[2612-28-4]2-propyl-1,3-propanediol</strong> (18.6 g), and p- toluenesulfonic acid monohydrate (0 the .90g) was dissolved in toluene (500mL), it was brought to reflux.The resulting water was removed using a Dean-Stark apparatus, and stirred for further 30 minutes.Was allowed to cool to room temperature, the addition of a saturated aqueous solution of sodium hydrogen carbonate (200mL) were separated, and the organic layer was washed with saturated brine (200mL), and dried over anhydrous sodium sulfate, evaporated under reduced pressure and the organic solvent did.The residue was purified by silica gel column chromatography, and recrystallized from methanol to give 2- (4-chloro-3-fluoro-phenyl) -5-propyl-1,3-dioxane (30.9g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With indium(III) chloride; at 80℃; for 7.5h; | General procedure: To a mixture of alpha-oxoketene-N,S-arylaminoacetals (1.0mmol), aldehyde (1.0mmol), and malononitrile (1.0mmol), InCl3 (0.1mmol) was added and the reaction mixture was heated at 80C till the completion of the reaction. After completion of the reaction (monitored by TLC), water (20mL) was added to the reaction mixture followed by extraction with ethyl acetate (2×10mL). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under vacuo. The crude residue thus obtained was purified by column chromatography over silica gel using ethyl acetate/hexane as eluent to afford pure 4-amino-1,2-dihydropyridines 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With toluene-4-sulfonic acid; In di-isopropyl ether; cyclohexane; water; for 2h;Inert atmosphere; Reflux; | (2-1)Under a nitrogen atmosphere,<strong>[5527-95-7]4-Chloro-3-fluorobenzaldehyde</strong> (27.6 g),Bis (hydroxymethyl) malonate (50.0 g),P-toluenesulfonic acid monohydrate(1.7 g),A mixture of cyclohexane (135 mL) and diisopropyl ether (30 mL) was heated at reflux for 2 hours, Dehydration was performed using a Dean-Stark apparatus. After spontaneous cooling, a saturated aqueous solution of sodium hydrogencarbonate (20 mL) and water (100 mL)The precipitated white precipitate was washed with water and dried under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 60 g;Hexane / toluene = 1/2 mixed solvent), followed by reprecipitation from a mixed solvent of ethanol / hexane = 3/1 to obtainTo a solution of 2- (4-chloro-3-fluorophenyl) -5,5-bis (methoxycarbonyl) -1,3-dioxane (49.7 g, yield86%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With piperidine; acetic acid; In toluene; at 80℃;Dean-Stark; | Thiazolidine-2,4-dione 1g (0.008538 mol), <strong>[5527-95-7]4-Chloro-3-fluoro-benzaldehyde</strong> 1.354 g, Piperidine 0.422 ml, Acetic acid (0.182 ml) and toluene (20 ml) in a dean-stark apparatus at 80 C, After reacting for 12 hours or longer, it was recrystallized to obtain pure 5- (4-Chloro-3-fluoro-benzylidene) -thiazolidine-2,4-dione. Yield: 81%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With methyl triphenylphosphonium bromide; sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 30℃;Inert atmosphere; | 1. Charge compound 1 and MeBrPPh3 to a four-necked jacketed flask with a paddle stirrer under N2 2. Charge THF (5.0V., KF<0.02%) to the flask (Note: V is the volume of solution to mass of limited reagent or L/Kg) 3. Stir the suspension at 0 C. 4. Add the NaH (60% suspended in mineral oil) portionwise to the flask at 0 C. 5. Stir at 0 C. for 30 min 6. Heat to 30 C. and stir for 6 hrs 7. Cool to 0 C. 8. Charge PE (petroleum ether) (5.0V.) to the flask 9. Add the crystal seed of TPPO (triphenylphospine oxide)(1 to about 5% wt of total TPPO) to the flask 10. Stir at -10 C. for 2 hrs 11. Filter, and wash the cake with PE (5.0V.) 12. Concentrate the filtrate to dryness 13. Purification of the product by distillation under reduced pressure affords 2 as colorless oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | General procedure: To an equimolar mixture of amine 1 (1 equiv), aldehyde 2 (1equiv), phenylpropiolic acid 3 (1 equiv) in methanol (3mL), was added isocyanide 4 (1 equiv) and the reaction mixture was stirred at RT for 8-12h. After completion of the reaction (as observed by TLC analysis), potassium carbonate (3 equiv) was added to the solution. A clear formation of product 6 was observed by TLC analysis. Solvent was evaporated and the crude was diluted with ethyl acetate followed by washing with water and brine. The organic layer was concentrated in vacuo and crude was purified by the silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | General procedure: To an equimolar mixture of amine 1 (1 equiv), aldehyde 2 (1equiv), phenylpropiolic acid 3 (1 equiv) in methanol (3mL), was added isocyanide 4 (1 equiv) and the reaction mixture was stirred at RT for 8-12h. After completion of the reaction (as observed by TLC analysis), potassium carbonate (3 equiv) was added to the solution. A clear formation of product 6 was observed by TLC analysis. Solvent was evaporated and the crude was diluted with ethyl acetate followed by washing with water and brine. The organic layer was concentrated in vacuo and crude was purified by the silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | General procedure: To an equimolar mixture of amine 1 (1 equiv), aldehyde 2 (1equiv), phenylpropiolic acid 3 (1 equiv) in methanol (3mL), was added isocyanide 4 (1 equiv) and the reaction mixture was stirred at RT for 8-12h. After completion of the reaction (as observed by TLC analysis), potassium carbonate (3 equiv) was added to the solution. A clear formation of product 6 was observed by TLC analysis. Solvent was evaporated and the crude was diluted with ethyl acetate followed by washing with water and brine. The organic layer was concentrated in vacuo and crude was purified by the silica gel column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium dithionite; In dimethyl sulfoxide; at 120℃; | General procedure: Typical procedure for one-pot synthesis of alpha-aminophosphonates: A mixture of nitro compound (1.0 mmol), aldehyde (1.0 mmol), DEP (1.0 mmol), and sodium dithionite (1.0 mmol) in DMSO (1.0 mL) were stirred at 120 C for the appropriate amount of time (3-4 h). After completion of the reaction as indicated by the TLC and LCMS, the reaction mixture was poured into water (5 mL), and then extracted with ethyl acetate (2 10 mL). The combined organic extracts were washed with saturated brine solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from diethyl ether (solid products) or purified by column chromatography using silica gel (100-200 mesh size) and eluting with hexane/ethyl acetate of increasing polarity to obtain the pure compound. When the above reaction was performed with 5-nitrobenzofuran (entry 16 in Table 2), the double bond between 2 and 3 carbons gets reduced by the sodium dithionite. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.5% | General procedure: Synthetic procedure was based on this elaborated earlier byOleksyszyn and Soroka [34-36]. Thus, acetamide 1.18 g (0.02 mol)was dissolved in glacial acetic acid (4 mL, 4.20 g, 0.07 mol). Thesolution was cooled in an ice-bath at 0 C and acetyl chloride(0.71 mL, 0.78 g, 0.01 mol) was added observing the formation of acrystalline by-product. After a few minutes appropriate aldehyde(0.01 mol) was added, and the mixture was kept in ice-bath for30 min and then left for 1 day at room temperature with constantstirring. Then the mixturewas cooled again to 0 C and phosphorustrichloride was added dropwise (0.87 mL, 1.37 g, 0.01 mol). Afterstirring for 30 min the mixture was allowed to warm to roomtemperature, and finally heated for 1-1.5 h at 75-80 C. Evaporationof the volatile components of the reaction mixture resulted inan oily product, which was refluxed for 8 h in concentrated hydrochloricacid (50 mL). After the removal of volatile components ofthe reaction mixture oily product was dissolved in ethanol (10 mL)and left for crystallization. Resulting aminobenzylphosphonic acidwas then recrystallized from ethanol or ethanol-water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With toluene-4-sulfonic acid; In benzene; at 0℃; for 12h;Reflux; | <strong>[54107-66-3]5,7-dimethoxychroman-4-one</strong>(30 mg, 0.144 mmol)And 4-chloro-3-fluorobenzaldehyde(34 mg, 0.216 mmol) and para-toluenesulfonic acid(5 mg, 0.02 mmol) was dissolved in benzene (2 ml) at 0 C and reacted under reflux conditions for 12 hours.After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (23 mg, 40% ) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.3% | 0.15 g (1.05 mmol) of 5-aminomethyl-2-chloropyridine and 0.20 g (1.26 mmol) of 4-chloro-3-fluorobenzaldehyde were added to a 25 mL three-necked flask, and then 25 mL of methanol was added thereto. Stir at room temperature overnight. Then, 0.10 g (2.63 mmol) of sodium borohydride was slowly added thereto, and the mixture was stirred at room temperature for 20 minutes, and the reaction was quenched to give a colorless, clear solvent. 45 mL of water was added to the residue, followed by extraction with dichloromethane (15 mL×3), and the organic solvent was collected and purified by column chromatography (P/E=2:1) to give 1-(6-chloropyridin-3-yl) )-N-(4-chloro-3-fluorobenzyl)methylamine 0.28 g, yield 93.3percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With acetic acid; at 80℃; for 4h; | General procedure: Aldehyde (1.2 eq), 100 mg 5-(6-bromopyridin-2-yl)-1,3,4-oxadiazol-2-amine (8b, 0.41 mmol, 1 eq), and 128.74 mgtriphenylphosphite (1 eq) were dissolved in 2 cm3 glacialacetic acid and stirred at 80 C for 4 h (TLC analysis showedthe complete consumption of the amine). The solvent wasevaporated and the residue was dissolved in methanol andleft at - 20 C overnight affording the crystalized product.The product was filtered off, washed with cold methanol toafford the corresponding alpha-aminophosphonate derivative 10in a good yield and purity. In case of 10b, 10f, 10i and 10j,the filtered product showed low purity, the column chromatographywas used for the purification using a mixtureof dichloromethane and ethyl acetate (8:2) as an eluent toafford the aminophosphonate derivatives in moderate yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 0 - 15℃; for 3h;Inert atmosphere; | 105561 To a solution of <strong>[5527-95-7]4-chloro-3-fluorobenzaldehyde</strong> (2.0 g, 12.6 mmol) and NH2OH?HC1 (1.05 g,15.1 mmol) in EtOH (20 mL) at 0C was added a solution of NaOH (757 mg, 18.9 mmol) in H20 (5mL) dropwise, and the mixture was warmed to 15 C and was stirred for 3 h. The mixture was diluted with water (20 mL) and was concentrated under reduced pressure to remove EtOH. The aqueous phase was extracted with EtOAc (2 x 10 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue that was used directly. ?H-NMR (400 MHz, CDC13): 8.07 (br d, J 8.8 Hz, 1H), 7.83 (br s, 1H), 7.41 (q, J= 8.0 Hz, 2H), 7.31-7.22 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.1 g | With sodium hydroxide; In methanol; at 20℃; for 16h; | 1N NaOH solution (2 mL) was added to a mixture of the 5-hydroxyindanone (1) (1.0 g, 6.41 mmol) and aldehyde (86) (1.02 g, 7.05 mmol) in the MeOH (2 mL) at room temperature and stirred for 16 hours. The reaction mixture was concentrated to remove the organic solvent. The residue was purified by silica gel column chromatograph (EA:Hex=1 :1) to provide a product, Compound 87, and the yield thereof was 1.1 g (4.06 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium hydroxide; In methanol; at 20℃; | General procedure: A mixture of 4-bromoacetophenone (0.01mol) and a halogensubstituted benzaldehyde (0.01mol) was dissolved in methanol(20 mL). Catalytic amount of 20% NaOH (5 ml) was added to the solution dropwise with vigorous stirring. The reaction mixture was stirred for about 5-6 h at room temperature. The resultant crude products were filtered, washed successively with distilled water and recrystallized from acetone to get the corresponding chalcones(Scheme 1). Crystals suitable for X-ray diffraction studies were obtained by the slow evaporation technique using acetone solvent.The yellow crystals of different shaped for all compounds are shown in Fig. 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With rhodium(III) chloride trihydrate; hydrogen; triethylamine; triphenylphosphine; In N,N-dimethyl acetamide; at 90℃; under 7500.75 Torr; for 12h;Autoclave; | General procedure: All reactions were carried out in an 80 mL Teflon-lined stainless steel reactor equipped with a magnetic stirring bar. Typically, in a glovebox, the aryl iodides (1.0 mmol), RhI3(0.025 mmol), PPh3 (0.1 mmol), Et3N (1.2 mmol), and DMA (2 mL) were loaded into the reactor. Then, the autoclave was screwed up, charged with CO and H2 to a total pressure of 10 bar (1:1) and transferred to an oil bath preheated at 90 C, which was controlled by a Haake-D3 temperature controller. After completion of the reaction, the reactor was cooled in iced water and the gas carefully vented. The conversion and yield of the aryl iodides and arylaldehydes were determined by GC analysis using dodecane as an internal standard. For yield determination of the other products, the reaction mixture was first analyzed by GC-MS to determine the structures of the aromatic aldehyde products. Then, CH2Cl2 (5 mL) was added to the reaction mixture, after which deionized water (10 mL) was added to extract the solvent DMA for 5 times. The organic layer was dried over anhydrous Na2SO4, concentrated by rotary evaporation and finally purified by column chromatography on silica gel using n-hexane/ethyl acetate as eluent to obtain the pure products and isolated yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With piperidine In ethanol Inert atmosphere; Reflux; | 2.1 Preparation of the Alkylidene Oxindoles: General procedure: To the oxindole (A, 1.49 mmol, 1 eq.) and aldehyde (B, 2.24 mmol, 1.5 eq.) in ethanol (3 mL) was added piperidine (0.15 mmol, 0.1 eq.) and the reaction mixture was stirred under reflux overnight. The solution was diluted with ethyl acetate and washed twice with brine. The organic layers were dried over Na2SO4 and evaporated under reduced pressure. The product (1) was isolated as a yellow solid after silica gel column chromatographic purification (cHex/EtOAc 85:15 → EtOAc → ethanol) as a dark yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With manganese(IV) oxide In dichloromethane at 20℃; for 12h; | 167 Synthesis of 4-chloro-3-fluorobenzaldehyde Synthesis of 4-chloro-3-fluorobenzaldehyde A mixture of (4-chloro-3-fluorophenyl)methanol (4 g, 25.0 mmol) and MnO2 (33 g, 375.0 mmol) in DCM (100 mL) was stirred at room temperature for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give crude 4-chloro-3-fluorobenzaldehyde (3.7 g, crude) as a white solid, which was used to the next step without further purification. ESI-MS [M+H]+: 159.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethylamino-sulfur trifluoride In dichloromethane at 0 - 20℃; for 12h; | 167 Synthesis of 1-chloro-4-(difluoromethyl)-2-fluorobenzene Synthesis of 1-chloro-4-(difluoromethyl)-2-fluorobenzene To a solution of 4-chloro-3-fluorobenzaldehyde (3.7 g, 23.4 mmol) in DCM (150 mL) at 0° C. was added DAST (7.5 g, 46.8 mmol). The reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo, H2O (50 mL) was added, and the mixture was extracted with EtOAc (70 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give crude 1-chloro-4-(difluoromethyl)-2-fluorobenzene (3 g crude) as yellow oil, which was used to the next step without further purification. ESI-MS [M+]+: 181.2. | |
With [bis(2-methoxyethyl)amino]-sulfur trifluoride In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | 1 Step 1.1-Chloro-4-(difluoromethyl)-2-fluorobenzene: To a solution of 4-chloro-3- fluorobenzaldehyde (300 g, 1.89 mmol) in DCM (1.5 L) under a nitrogen atmosphere, cooled to 0 °C was added bis(2-methoxyethyl)aminosulfur trifluoride (456 mL, 2.08 mol) drop-wise into the mixture. The reaction mixture was stirred at rt for 12 h. The resulting mixture was poured slowly into an ice-water solution, then extracted with DCM. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound.1H NMR (400 MHz, CDCl3) δ 7.53 (t, J = 8.0 Hz, 1H), 7.34 (d, J =9.6 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 6.64 (t, J = 56 Hz, 1H) | |
With [bis(2-methoxyethyl)amino]-sulfur trifluoride In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | Step 1. l-Chloro-4-(difluoromethyl)-2-fluorobenzene: To a solution of 4-chloro-3- fluorobenzaldehyde (300 g, 1.89 mmol) in DCM (1.5 L) under a nitrogen atmosphere, cooled to 0 °C was added bis(2-methoxyethyl)aminosulfur trifluoride (456 mL, 2.08 mol) drop-wise into the mixture. The reaction mixture was stirred at rt for 12 h. The resulting mixture was poured slowly into an ice-water solution, then extracted with DCM. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.53 (t, J= 8.0 Hz, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 6.64 (t, J = 56 Hz, 1H). |
With [bis(2-methoxyethyl)amino]-sulfur trifluoride In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | Step 1. l-Chloro-4-(difluoromethyl)-2-fluorobenzene: To a solution of 4-chloro-3- fluorobenzaldehyde (300 g, 1.89 mmol) in DCM (1.5 L) under a nitrogen atmosphere, cooled to 0 °C was added bis(2-methoxyethyl)aminosulfur trifluoride (456 mL, 2.08 mol) drop-wise into the mixture. The reaction mixture was stirred at rt for 12 h. The resulting mixture was poured slowly into an ice-water solution, then extracted with DCM. The organic layers were combined and washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 7.53 (t, J= 8.0 Hz, 1H), 7.34 (d, J = 9.6 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 6.64 (t, J = 56 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.4% | Stage #1: 1-(2-(6-methoxy-1,5-naphthyridin-4-yl)ethyl)piperidin-4-amine; 4-chloro-3-fluorobenzaldehyde With acetic acid In methanol at 20℃; for 1h; Stage #2: With sodium cyanoborohydride In methanol at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 2h; Inert atmosphere; | 4.12.1. tert-butyl (E)-2-oxo-3-(pyridin-2-ylmethylene)cyclohexane-1-carboxylate (1c) General procedure: Nitrogen was bubbled into a solution of compound 1b (4 g,20.1 mmol) in THF (25 ml), then add LDA (20 mL, 41 mmol) andaromatic formaldehyde (2 mL, 22.1 mmol), The reaction mixturewas stirred at 78 C for 2 h. The reaction was quenched with60 mL saturated ammonium chloride and extracted with ethylacetate (100 mL 3). The organic phase was dried over Na2SO4 andconcentrated under reduced pressure. The crude product was purifiedby column chromatography (silica gel, PE: EA 1 : 1) to affordthe pure product as a white solid (1 g, 3.47 mmol, 17% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triphenylphosphine In 1-methyl-pyrrolidin-2-one at 100℃; Glovebox; |
Tags: 5527-95-7 synthesis path| 5527-95-7 SDS| 5527-95-7 COA| 5527-95-7 purity| 5527-95-7 application| 5527-95-7 NMR| 5527-95-7 COA| 5527-95-7 structure
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