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CAS No. : | 2924-15-4 | MDL No. : | MFCD00012927 |
Formula : | C6H8ClFN2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | VFZYLSYYMHFPSY-UHFFFAOYSA-N |
M.W : | 162.59 | Pubchem ID : | 2723910 |
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 : | 2.0 |
Molar Refractivity : | 40.57 |
TPSA : | 38.05 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.83 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.06 |
Log Po/w (WLOGP) : | 2.14 |
Log Po/w (MLOGP) : | 2.13 |
Log Po/w (SILICOS-IT) : | 0.79 |
Consensus Log Po/w : | 1.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.52 |
Solubility : | 0.487 mg/ml ; 0.00299 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.49 |
Solubility : | 0.529 mg/ml ; 0.00325 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.33 |
Solubility : | 0.766 mg/ml ; 0.00471 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.45 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-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 ethanolate; In ethanol; at 20 - 82℃; for 30 - 50.5h; | To a suspension of the <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> 1-1 (50 g, JEMCO, Inc.) IN ETOH (300 mL) was added 20 weight % NaOEt in ETOH (292.97 g, Nihon Soda). The ethoxyacrylonitrile 1-2 (53.76 g, Degussa) was then added at ambient temperature. The reaction mixture was warmed to about 82C and aged for 20 to 28 hours. The reaction mixture was cooled to ambient temperature. To the batch was added water (250 mL, 5 volumes) and 6N HC1 to adjust the mixture to a pH between about 2.9-3. 1. The resulting aqueous EtOH solution was stirred at 20C to 25C for 1 to 2 hours. After treatment with 5N NAOH to adjust the solution to a pH of about 6.5 to 8.0, the reaction mixture was concentrated to circa 600 mL (12 volumes), then IPAC (750 mL) was added. The layers were separated and the organic LAYERWASWASHEDWITHL0TAQUEOUSNACL (200ML). ACTIVATEDCARBON (Sirasagi P, 1.75g, 3.5 weigh % to 2-fluorophenylhydrazine HC1) was added to the resulting solution at ambient temperature. After 1 to 20 hours treatment of the activated carbon, the cake was washed with IPAC (4 volumes to a weight % to 2-fluorophenylhydrazine HC1, 200mL). The combined organic layers were concentrated to about 410-510 mL (10-12.5 volumes to assay gram of pyrazole 1-3) to give 1-(2-FLUOROPHENYL)-LH-PYRAZOLE-3-AMINE 1-3. Selected Signals 1H NMR (300 MHz, DMSO-d6) : 8 7.84 (d, J=2.6 Hz, 1H), 7.72 (dd, J=8.2, 1.8 Hz, 1H), 7.34 (ddd, J=11. 1, 7.9, 1.7 Hz, 1H), 7.28-7. 14 (m, 2H), 5.77 (d, J=2.6 Hz, 1H), 5.10 (brs, 2H).To a suspension of the <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> 1-1 (12.5 g, 76.9 mmol, JEMCO) in EtOH (75 mL, 6 volumes) was added 20 weight % NaOEt in ETOH (72.9 g) while keeping the temperature less than 30C. The ethoxyacrylonitrile 1-2 (13.4 g, Degussa) was then added at 25C. The reaction mixture was warmed to about 82C over 30 minutes and then aged for 20 to 28 hours. The reaction mixture was cooled to ambient temperature. Water (62.5 mL, 5 volumes) and 6N HC1, to adjust the mixture to a pH between 2.9 to 3.1, were slowly added to the reaction mixture while keeping the temperature below 30C. The resulting aqueous ethanol solution was stirred at a temperature of about 20C to 25C for 1 to 2 hours, then treated with 5N NAOH, to adjust the pH to between 6.5 to 8.0. The resulting solution was concentrated to 150 mL (12 volumes) in vacuo at 40C, and then extracted with toluene (125 mL) two times. The organic layer was washed with 10% aqueous NaCl (62.5 mL, 5 volumes). Activated carbon (Shirasagi P, 3.5 weight % to 2-FLUOROPHENYLHYDRAZINE HC1, 473. 5 mg) was added to the resulting solution at ambient temperature and stirred for about 15 to 20 hours. The cake (activated carbon) was washed with toluene (4 volumes to assay grams of pyrazole, 40.9 mL). The washings were combined with the filtrate to give 1-(2-FLUOROPHENYL)-LH-PYRAZOLE-3-AMINE 1-3. Selected Signals: 1H NMR (300 MHz, DMSO-d6): 8 7.84 (d, J=2.6 Hz, 1H), 7.72 (dd, J=8.2, 1.8 Hz, 1H), 7.34 (ddd, J=11. 1, 7.9, 1.7 Hz, 1H), 7.28-7. 14 (m, 2H), 5.77 (d, J=2.6 Hz, 1H), 5.10 (brs, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1) The product (1.92 g) of Example 35(1) was dissolved in ethanol (50 mL) and <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (1.16 g) was added at room temperature. The mixture was stirred for 4 hr. Pyridine (1 mL) was added to the reaction solution and the solvent was evaporated under reduced pressure. The residue was dissolved in pyridine (30 mL) and phosphorus oxychloride (1.33 mL) was added at room temperature. The mixture was stirred for 19 hr. The reaction solution was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate. The extract solution was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 1-tert-butoxycarbonyl-4-[1-(2-fluorophenyl)-3-methyl-5-pyrazolyl]piperazine (0.640 g) as an oil.(2) The above-mentioned compound (640 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) was added at room temperature. The mixture was stirred for 3 hr. The solvent was evaporated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added to the residue. The mixture was extracted with chloroform. The extract solution was dried and evaporated under reduced pressure to give 1-[1-(2-fluorophenyl)-3-methyl-5-pyrazolyl]piperazine (430 mg) as an oil.(3) In the same manner as in Example 29(1) and using the above-mentioned compound (430 mg) and the title compound (472 mg) of Reference Example 3, 3-((2S,4S)-1-tert-butoxycarbonyl-4-{4-[1-(2-fluorophenyl)-3-methyl-5-pyrazolyl]-1-piperazinyl}-2-pyrrolizinylcarbonyl)-1,3-thiazolidine (778 mg) was obtained as a pale-yellow powder.(4) The above-mentioned compound (778 mg) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added at room temperature. The mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL). To this solution was added 4 mol/L hydrochloric acid/ethyl acetate (1.5 mL), and the precipitate was collected by filtration to give the title compound (608 mg) as a white solid.1H-NMR(500MHz,DMSO-d6)delta 2.03-2.25(1H,m), 2.16(3H,s), 2.72-4.00(16H,m), 4.45-4.71(3H,m), 5.91(1H,s), 7.32-7.35(1H,m), 7.40-7.44(1H,m), 7.51-7.57(2H,m), 9.02(1H,brs), 10.41(1H,brs). | ||
General procedure: To a solution of 11d (6.24 g, 23.1 mmol) in ethanol (500 mL) was added phenylhydrazine (2.27 mL, 23.1 mmol) and methanesulfonic acid (0.35 mL, 5.4 mmol) at room temperature. The mixture was stirred for 14 h, and then pyridine (6 mL) was added. The mixture was concentrated under reduced pressure. A solution of the residue and phosphorus oxychloride (5.0 mL, 54 mmol) in pyridine (250 mL) was stirred for 20 h at room temperature, and then concentrated under reduced pressure. The residue was acidified with dilute hydrochloric acid to pH 3. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried and concentrated under reduced pressure. The residue was purified by silica gel chromatography with n-hexane/ethyl acetate (7:3, v/v) to give 1-tert-butoxycarbonyl-4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazine (935 mg, 12%) as an oil. 1H NMR (500 MHz, DMSO-d6): delta 1.39 (9H, s), 2.15 (3H, s), 2.73 (4H, m), 3.37 (4H, m), 5.83 (1H, s), 7.28 (1H, t, J = 7.4 Hz), 7.46 (2H, t, J = 7.4 Hz), 7.76 (2H, d, J = 7.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With triethylamine; In isopropyl alcohol; at 100℃; for 18h; | A mixture of N-cyano-N'-(2,4-dimethoxyphenyl)-O-phenylisourea (0.10 g, 0.34 mmol), 2-fluoro-phenylhydrazine hydrochloride (0.08 g, 0.50 mmol) and triethylamine (0.01 mL, 0.68 mmol) in isopropanol (3 mL) was heated at 100C for 18h and evaporated. Purification by flash chromatography (SiO2) eluted with 1:1 ethyl acetate : hexanes provided the title compound (0.10 g, 85% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With triethylamine; In N,N-dimethyl acetamide; at 120℃; for 20.5h; | A solution of 2-fluoro-phenylhydrazine hydrochloride (0.15 g, 0.91 mmol) and triethylamine (0.13 mL, 0.91 mmol) in dimethylacetaimde (1 mL) was stirred 0.5h at room temperature. N-cyano-N'-(4-(3-diethylamino-propoxy)-3,5-dimethoxy-phenyl)-O-phenylisourea (0.30 g as a mixture with triethylamine-trifluoroacetic acid salt, 0.45 mmol) in dimethylacetamide (1 mL) was added and the reaction was stirred at 120C for 20h. The precipitate was removed and the filtrate was washed with ether. The remaining aqueous phase was evaporated and was purified by semi-preparative HPLC to provide the title compound (0,01 g, 4% yield) as a yellow lyophilate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With hydrogenchloride; In water; at 20℃; | Sodium mesoxalate monohydrate (2. 21 g, 12. 3 mmol) was dissolved in 1 M hydrochloric acid (50 ml) to give A COLOURLESS CLOUDY SOLUTION. 2-FLUORO- phenylhydrazine hydrochloride (2.00 g, 12.3 MMOL) was added portionwise at room temperature to the stirred mixture. A yellow precipitate formed, the mixture was diluted with water (50 ml) and stirring continued overnight. Ethyl acetate (150 ml) was added, the phases were mixed vigorously until the solids had dissolved. The phases were separated and the aqueous phase was washed with ethyl acetate (50 ML). The combined organic phases were dried over magnesium sulfate, filtered and the solvent removed under vacuum. The title compound was isolated as a yellow powder (2.55 g, 11.7 mmol, 92%). LCMS: m/z 227 [M-H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Example 47 Step A: Triethyl amine (6.67 g, 66 mmol) was added dropwise to a stirred suspension of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (10. 73 g, 66 mmol) in absolute ethanol (200 mL). After 10 min ethoxylidenemalononitrile (8.05 g, 66 mmol) was added in portions over a period of 30 min. The solution was stirred at rt overnight. An identical reaction at the same scale was run concurrently. Both reactions were combined and concentrated. The residue was diluted with dichloromethane (200 mL) and washed with 1 N aq. HC1 solution (100 mL, 2x). The aq. layers were combined, extracted with dichloromethane (100 ML, 2x). Dichloromethane extracts were combined, washed with brine (100 ML, 2x), dried (MGS04), filtered, and concentrated under reduced and ITT vacuo. The residue was diluted with ether (50 mL) and the soild was filtered, washed with ether: hexanes (40 mL, 1: 1) to obtain 1 (19 g, HPLC purity 90%) which was stirred with ether: hexanes mixture (200 mL, 1: 4) for 16 h to obtain the title compound 47A (17.84 g, 67% yield). HPLC retention time: 0.89 min; LC/MS: 202.94 (M+H) +. | |
With triethylamine; | EXAMPLE 12A 5-Amino-1-(2-fluorophenyl)-1H-pyrazole-4-carbonitrile In analogy to the preparation of Example 10A, 5.13 g (88% purity, 84% of theory) of the desired product are obtained starting from 5.0 g (30.8 mmol) of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong>, 3.27 g (26.7 mmol) of ethoxymethylenemalononitrile and 11.3 ml (81.3 mmol) of triethylamine. MS (ESI pos): m/z=203 (M+H)+ 1H-NMR (300 MHz, DMSO-d6): delta=6.7 (s, 2H), 7.3-7.6 (m, 4H), 7.8 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | 2-Amino-5-fluoro-benzoic acid (20.0 g, 129 mmol) was dissolved in dry THF (390 ml). 1,1'-Carbonyldiimidazole (CDI, 22.0 g, 135 mmol) was added in one portion. Some gas evolution was observed and a very thick beige solid precipitated out. The suspension was stirred for 1 hour 20 minutes at room temperature. Eventually, the precipitate thinned out. N,N-diisopropylethylamine (DIPEA, 27 ml, 155 mmol) was added, which caused the precipitate to fully dissolve, followed by the addition of (2-fluoro-phenyl)-hydrazine hydrochloride (23.1 g, 142 mmol). The mixture was stirred at room temperature for 18 hours. The reaction was carefully quenched with water (1L) and ethyl acetate (500 ml) was added. The two layers were separated and the aqueous layer was washed twice with 200 ml of water, then twice with 100 ml of saturated, aqueous NaHCO3 solution, then with saturated brine, and dried over MgSO4. The solvent was removed to give 32.21 g (95% yield) of Intermediate 22 (2-amino-5-fluoro-benzoic acid N'-(2-fluoro-phenyl)-hydrazide) as a brown-red solid. MS (APCI): (M+1)=264. 1H and 19F NMR spectra agreed with the structure. The solid was used in the next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | <strong>[434-76-4]2-Amino-6-fluorobenzoic acid</strong> (2.00 g, 12.89 mmol) was combined with 2-fluorophenylhydrazine hydrochloride (2.096 g, 12.89 mmol) and HOBt (3.949 g, 25.79 mmol) in dry THF (75 ml) and cooled to about -12 C. N-Methylmorpholine (2.835 ml, 25.79 mmol) was added, the mixture was stirred for 5 minutes, then EDC hydrochloride (2.66 g, 13.88 mmol) was added. The mixture was maintained at a temperature between -14 and -10 C. for 1 hour, then allowed to slowly warm to room temperature and stirred for 18 hours. The mixture was cooled to 0 C., then filtered through CELITE (diatomaceous earth). The filtrate was diluted with EtOAc, treated with saturated NaHCO3 and the layers separated. The organic layer was washed twice with 50% saturated NaHCO3 and then dried over MgSO4 and concentrated. The resulting solid was triturated with dichloromethane, filtered, rinsed with a very small amount of dichloromethane and dried. The filtrate from the trituration was re-triturated with a small amount of dichloromethane, filtered, rinsed with a tiny amount of dichloromethane and dried. The filtrate was concentrated to dryness, triturated with a small amount of Et2O, filtered, rinsed with a tiny amount of ether and dried. The three solids were combined to afford a total of 2.182 g (64%) of <strong>[434-76-4]2-amino-6-fluoro-benzoic acid</strong> N'-(2-fluoro-phenyl)-hydrazide (Intermediate 44) as an off-white solid. MS (APCI): (M-1)=262.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate; acetic acid; In methanol; water; | Example 2 SYNTHESIS OF 4,5-DIHYDRO-1-(2-FLUOROPHENYL)-3-METHYL-1,2,4-TRIAZOL-5(1H)-ONE USING TRIMETHYL ORTHOACETATE One gram (0.008 mole) of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> was dissolved in a dilute aqueous solution of potassium carbonate, and the solution was extracted with two 50 mL portions of methylene chloride. The combined extracts containing the free hydrazine and 1.1 grams (0.010 mole-1.3 eq.) of TMOA were dissolved in 10 mL of methanol, and the stirred solution was heated at reflux for one hour to obtain the intermediate N-phenyl-N'-(1-methoxyethylidene)hydrazine. The progress of the reaction was monitored by GC. The reaction mixture was then cooled to ambient temperature, and 0.8 gram (0.010 mole-1.3 eq.) of potassium cyanate was added. The reaction mixture was cooled in an ice-water bath (0 C.), and 0.6 gram (0.010 mole-1.3 eq.) of acetic acid was added dropwise. The reaction mixture was then allowed to warm to ambient temperature, and one mL of water was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was washed with three 15 mL portions of hexane, yielding about 0.9 gram (57% yield) of 4,5-dihydro-1-(2-fluorophenyl)-3-methyl-1,2-4-triazol-5(1H)-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 48 7-fluoro-1H-indole-3-ethanamine STR118 The desired 7-fluoro-1 H-indole-3-ethanamine was prepared substantially as described in Example 49 infra. except that <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (25.5 g) was used. Additionally, reverse phase HPLC was required for final purification. Yield: 4 g melting point: 187-189 C. | ||
EXAMPLE 48 7-fluoro-1H-indole-3-ethanamine STR118 The desired 7-fluoro-1H-indole-3-ethanamine was prepared substantially as described in Example 49 infra. except that <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (25.5 g) was used. Additionally, reverse phase HPLC was required for final purification. Yield: 4 g melting point: 187-189 C. Elemental Analysis: C 55.12; H 5.48; N 12.60. | ||
EXAMPLE 80 7-fluoro-1H-indole-3-ethanamine STR65 The desired 7-fluoro-1H-indole-3-ethanamine was prepared substantially as described in Example 81 infra. except that <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (25.5 g) was used. Additionally, reverse phase HPLC was required for final purification. Yield: 4 g Melting point: 187-189 C. |
EXAMPLE 48 STR118 The desired 7-fluoro-1H-indole-3-ethanamine was prepared substantially as described in Example 49 infra. except that <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (25.5 g) was used. Additionally, reverse phase HPLC was required for final purification. Yield: 4 g melting point: 187-189 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With MP-carbonate; In methanol; at 20℃; for 1h; | Example 2; 3 - { 1 -[(2-Fluoro-phenyl)-hydrazonoi -ethyl } -4-hydroxy-6-methyl-p yran-2-one; To 2-fluorophenyl hydrazine hydrochloride (0.16g, 1.0 mmol) in methanol (8ml) add MP- carbonate (1.0g, 3.3 equivalents). Shake this mixture at room temperature for 1 hour. Filter the resin and wash with methanol. To the filtrate add (2-fluorophenyl)-hydrazine (0.134g, 0.80mmol). Shake the reaction mixture at room temperature for 2 hours after which evaporate the solvent under reduced pressure. Recrystallize the solid from a minimum amount of EPO <DP n="26"/>methanol and obtain 0.185g (0.67mmol) of 3-{1-[(2-fluoro-phenyl)-hydrazono]-ethyl}-4- hydroxy-6-methyl-pyran-2-one.LCMS (M+H): m/z 277, retention time 2.74 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In methanol; for 2h;Heating / reflux; | Intermediate 25: 2,6-Dibromo-4-methylbenzaldehvde (2-fluorophenyl)hvdrazone; EPO <DP n="50"/>2,6-Dibromo-4-methylbenzaldehyde (60Og, 2.16mmol), <strong>[2924-15-4](2-fluorophenyl)hydrazine hydrochloride</strong> (351 mg, 2.16mmol) and sodium acetate (180mg, 2.19mmol) were heated in methanol (15ml_) under reflux for 2 hours. The methanol was evaporated and the residue partitioned between dichloromethane (3OmL) and aqueous brine (3OmL). The organic phase was separated, combined with additional dichloromethane extracts (2x15mL), washed with aqueous sodium bicarbonate (2x15mL), passed through a hydrophobic frit and evaporated to the title compound (767mg). LCMS: tRET = 4.24 min; MH+ = 387 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; ethanol; chloroform; toluene; | -- A solution of 7.8 g. of <strong>[27514-08-5]4-acetamidocyclohexanone</strong> and 8.1 g. of 2-fluorophenylhydrazine hydrochloride in 75 ml. of absolute ethyl alcohol and 25 ml. of 5-N hydrogen chloride in absolute ethyl alcohol was heated under reflux for two hours, cooled, filtered, and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and adsorbed on a column of aluminum oxide. Dilution with ether yielded first a small amount of side-product followed by the desired product which was recrystallized by dissolving in methyl alcohol, adding toluene, and evaporation of the methyl alcohol, to give 10.5 g. of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 202-204C. Following a reductive procedure similar to that described in Example 260 but substituting for 3-(N-methylbenzamido-6,8-difluoro-1,2,3,4-tetrahydrocarbazole an equivalent amount of 3-acetamido-8-fluoro-1,2,3,4-tetrahydrocarbazole there can be obtained 3-(ethylamino)-8-fluoro-1,2,3,4-tetrahydrocarbazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane; | EXAMPLE 5 2-(2-Fluorophenyl)-2,5,6,7,8,9-hexahydropyrazolo[4,3-c]cinnolin-3-one 4-Chloro-5,6,7,8-tetrahydrocinnoline-3-carboxylic acid ethyl ester (0.5 g), <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (0.34 g) and Hunig's base (0.73 ml) in xylene were heated under reflux for 3 h. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 99:1 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 98:2 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 97:3 (500 ml), CH2Cl2/(MeOH/NH3 10:1) 96:4 (500 ml), CH2Cl2(MeOH/NH3 10:1) 95:5 (500 ml). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (250 mg, 42%). deltaH (360 MHz; DMSO) 1.83 (4H, m, CH2), 2.61 (2H, t, J=5.3 Hz, CH2), 2.75 (2H, t, J=5.3 Hz, CH2), 7.30-7.57 (4H, m, ArH), m/z (ESP+) 285 (MH+). C15H13FN4O requires C, 63.37; H, 4.61; N, 19.71; found C, 63.18; H, 4.70; N, 19.35%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium nitrite; In diethyl ether; water; at 0 - 20℃; for 2h;Product distribution / selectivity; | Production of 1-azido-2-fluorobenzene Sodium nitrite (510 mg) dissolved in 2 ml of water was dropped, under cooling with ice, into a solution of 1.0 g of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> in 5 ml of concentrated hydrochloric acid and 6 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 2 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 402 mg of the crude title compound as a brown oily substance; Production of 1-azido-2-fluorobenzene Sodium nitrite (510 mg) dissolved in 2 ml of water was dropped, under cooling with ice, into a solution of 1.0 g of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> in 5 ml of concentrated hydrochloric acid and 6 ml of diethyl ether. Temperature of the reaction solution was raised to room temperature followed by stirring for 2 hours. The reaction solution was diluted with diethyl ether, washed with water and then with a saturated saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 400 mg of the title compound as a brown oily crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triethylamine; In methanol; hexane; at 0 - 20℃; for 2.16667h; | Intermediate 29: N'-(2-Fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester Di-tert-butyl dicarbonate (4.40 g, 20.2 mmol) was added in one portion to a cooled (0 C.) solution of triethylamine (8.3 mL, 59.6 mol) and <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (3.00 g, 18.5 mmol) in methanol (50 mL). The reaction mixture was stirred at 0 C. for 10 min, and at room temperature for 2 h. The solvent was evaporated and ethyl acetate (100 mL) was added. The solution was washed with water (2*25 mL) and brine (25 mL). The organic phase was dried (sodium sulfate), filtered, evaporated, and co-evaporated with hexane. A solution of 5% ethyl acetate/hexane (25 mL0 was added to the resulting gummy yellow solid and the mixture was stirred at room temperature for 20 min and then in an ice-bath at 0 C. for 1 h. The solid was filtered off, washed with hexane, and dried to give N'-(2-fluoro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (2.97 g, 71%) as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; at 20℃; | Example 5; Preparation of N-[2-[1-((N'-methyl-N'-2-fluorophenyl)amino)imino)ethyl]-4-chloro-phenyl]trifluoromethanesulfonamide (Compound 49); a) Benzaldehyde (3.26 g, 30.75 mmol) was added to a mixture of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (5.00 g, 30.75 mmol) and potassium carbonate (4.25 g, 30.75 mmol) in ethanol (110 ml). The reaction was stirred at RT over night. The reaction mixture was concentrated under vacuum and the residue partitioned with EtOAc and water. The organic layer washed with brine (×2) and dried (MgSO4). Removal of the solvent under vacuum gave benzaldehyde N-(2-fluoro)phenylhydrazone as a yellow solid (6.22 g) which was used for the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: A mixture of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (25 g, 153.8 mmol) and trifluoroacetic acid (34.3 mL, 461.4 mmol) in toluene (770 mL) and acetonitrile (77 mL) was degassed with nitrogen for 20 minutes prior to the addition of a degassed solution of isobutyraldehyde (14 mL, 153.8 mmol). The reaction mixture was heated to 35 C. for 12 hours. Upon disappearance of the hydrazine, the reaction was cooled to 0 C. and sodium borohydride (7 g, 184.6 mmol) added carefully. After completion, toluene was removed in vacuo and a 10% aqueous solution of potassium carbonate (500 mL) was added. The mixture was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over sodium sulfate, concentrated, and purified via silica gel column (ISCO, 0-100% ethyl acetate/hexane) to give 7-fluoro-3,3-dimethylindoline as an off-white solid. MS (ES) m/z 166.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Reference Example 192 Ethyl 1-(2-fluorophenyl)-5-hydroxy-1H-pyrazole-3-carboxylate To a solution of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (1.62 g) in ethanol (40 mL) were added potassium carbonate (2.76 g) and diethyl but-2-ynedioate (1.7 g) at room temperature, and the mixture was stirred for 4 hr with heating under reflux. The reaction mixture was allowed to cool, 1 mol/L hydrochloric acid (70 mL) and water (70 mL) were added, and the mixture was stirred for 1 hr. The precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound as a colorless solid (2.11 g, yield 84%). 1H-NMR (DMSO-d6) delta: 1.24-1.31 (3H, m), 4.21-4.31 (2H, m), 5.92 (1H, s), 7.32-7.40 (1H, m), 7.41-7.50 (1H, m), 7.50-7.60 (2H, m), 11.94 (1H, s). | |
55% | With potassium carbonate; In ethanol; for 5h;Heating / reflux; | Formula TCI5-Chloro-1 -(2-fluoro-phenyl)-3-[4-(4-fluoro-phenyl)-4-hvdroxy-piperidine-1 -carbonyll-1 H- pyrazole-4-carbaldehvde fC111-(2-Fluoro-phenyl)-5-hvdroxy-1H-pyrazole-3-carboxylic acid ethyl ester(2-Fluoro-phenyl)-hydrazine hydrochloride (12.2Og, 75mmol) followed by potassium carbonate (20.74g, 150mmol) were added to a solution of diethylacetylene dicarboxylate (12.01ml, 75mmol) in ethanol (200ml) and the resulting suspension stirred at reflux for 5 hours. The mixture was cooled to room temperature, diluted with water (400ml) and acidified by dropwise addition of 2M hydrochloric acid. After stirring for 2 hours, the resulting solid was collected by filtration, washed with water (3x50ml) and dried in vacuo to give the sub-title compound (11.4g, 41 mmol, 55%).LCMS: RT = 1.752min. (M+H)+ = 251. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With caesium carbonate;palladium dichloride; tri tert-butylphosphoniumtetrafluoroborate; In N,N-dimethyl-formamide; at 130℃; for 5h;Product distribution / selectivity; | The reaction was performed according to example 1 using 113.8 mg 2-fluorophenyl- hydrazine hydrochloride, 439.9 mg Cs2CO3 (2.7 equiv.) and a reaction time of 5 hours at 130 0C. This afforded 123.0 mg (81%) of the title compound. 1H-NMR (DMSO-d6) delta 4.33 (s, 2H), 6.92 (d, 2H, J = 6.7 Hz), 7.05 (ddd, 1 H1 J = 8.2, 6.5, 0.9 Hz), 7.12-7.21 (m, 3H), 7.31 (ddd, 1H, J = 8.6, 6.6, 0.9 Hz), 7.40 (dd, 1 H, J = 7.6, 0.9 Hz), 7.49 (ddd, 1 H, J = 8.6, 8.2, 1.2 Hz), 7.57 (ddd, 1 H, J = 8.2, 7.8, 1.6 Hz), 7.61-7.66 (m, 3H); 13C- NMR (DMSO-de) delta 30.2, 116.6 (d, J = 19.5 Hz), 117.1 , 120.4, 120.5, 121.1 , 125.0 (d, J = 3.7 Hz), 126.4, 126.6, 127.1 (d, J = 12.0 Hz), 128.1 , 128.3, 129.4, 131.8 (d, J = 8.2 <n="43"/>Hz), 136.3, 137.3, 148.3, 156.3 (d, J = 250.6 Hz); HRMS (FAB): Calculated for C20Hi6N2F (M+H+) 303.1297, found 303.1292. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; for 5h;Heating / reflux; | In a flask were <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (12.2g, 75 mmol), diethylacetylene dicarboxylate (12.8 g, 75 mmol), potassium carbonate (20.7 g, 150 mmol), and ethanol (200 ml) placed and the resulting slurry heated at reflux for 5 hours. The mixture was <n="64"/>cooled to room temp, diluted with water (400ml) and acidified carefully with 2M hydrochloric acid. The mixture was stirred for 2h then the resulting suspended solid collected by filtration, washed with water (3 x 50ml) and dried in vacuo giving 11.4 g of 5- Chloro-1-(2-fluoro-phenyl)-1 H-pyrazole-3-carboxylic acid ethyl ester [U 1]. 1H NMR (300MHz., DMSO) : delta 1.29 (3H,t), 4.25 (2H,q), 5.92 (1 H,s), 7.34-7.60 84H,m), 11.90 (1 H,s,br). LCMS (Method A) : RT = 1.75 min, (M+H)+= 251. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In ethanol; at 80℃; for 24h; | Step 2: Preparation of 5-(biphenyI-4-ylmethyl)-2-(2-fluorophenyI)-5,6,7,8-tetrahydrocyclopenta[b]pyrazolo[3,4-d]pyridine-3(2H)-one: ethyl 1-(biphenyl-4-ylmethyl)-4-thioxo-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridme-3-carboxylate (0.30 g, 0.77 mmol) was suspended in ethanol (10 mL) and treated with <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (0.38 g, 2.3 mmol, 3 equiv) and potassium carbonate (0.64 g, 4.6 mmol, 6 equiv). The mixture was placed into a preheated oil bath at 80 C for 24 hours, cooled to ambient temperature and concentrated in vacuo. The residue was treated with water (20 mL) and extracted with ethyl acetate (2 X 50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (100:0 to 90:10; chloroform : methanol), providing the titled compound: 1H-NMR (400 MHz, CDC13) delta 8.29 (1H, s), 7.61-7.56 (5H, m), 7.47-7.44 (2H, m), 7.40-7.30 (2H, m), 7.21-7.19 (2H, m), 5.20 (2H, s), 3.08 (2H, t, J= 7.5 Hz), 2.94 (2H, t, J- 7.5 Hz), 2.23 (2H, quin, J= 7.5 Hz) ppm; low resolution mass spectrometry (ES+) m/z 436.1 [(M+H)+; calculated for C28H23FN3O: 436.2]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In methanol; at 0 - 20℃; for 17h; | Methyl 1 -(2-fluoro-phenyl)-5-hydroxy-1 H-pyrazole-3-carboxylateDimethyl acetylenedicarboxylate (87.4 g, 757 mmol) was added to a solution of 2-fluoro-phenylhydrazine hydrochloride (100 g, 615 mmol) in methanol (1 I) at 0 C. Then triethylamine (125 g, 1 .23 mol) was added slowly during 60 min. The solution was stirred for 16 h at room temperature, the solvent then removed under reduced pressure and the residue dissolved in EA (500 ml). After washing with aqueous hydrochloric acid (500 ml), the solvent was removed under reduced pressure. The title compound was obtained as an almost white solid in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sulfuric acid; In water; for 2.41667h; | Synthesis example 11 -(2-Fluoro-phenyl)-5-hydroxy-1 H-pyrazole-3-carboxylic acidSulfuric acid (400 ml) was added slowly to water (400 ml). After cooling to 5 C,2-fluoro-phenylhydrazine hydrochloride (123 g, 757 mmol) was added resulting in a brown suspension. Then a solution of oxalacetic acid (100 g, 757 mmol) in water (400 ml) was added slowly during a period of 25 min. After 2 h the conversion was complete and the solid was filtered. After washing with water the solid was dried. The product was obtained as light brown solid (151 g, 90 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol; at 70℃; for 5h; | Step 2: Preparation of 5-ethoxy-2-(2-fluorophenyI)-2,4-dihydro--?H-pyrazol-3-one: (2-Fluorophenyl)hydrazine hydrochloride (1.00 g, 6.15 mmol) was suspended in ethanol (10 mL), treated with ethyl 3-amino-3-ethoxyacrylate hydrochloride (1.20 g, 6.15 mmol, 1.00 equiv), and placed into a preheated oil bath at 70 C for 5 hours. The mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (3 x 75 mL). The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography ( 00:0 to 0:100 hexanes : ethyl acetate), providing the titled compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | In ethanol; at 55 - 60℃; | To a solution of raw methyl 3-(2-chloro-6-fluorophenyl)-5-[2-(dimethylamino)-1-formylvinyl]isoxazole-4-carboxylate (36 mg, 0.102 mmol) in ethanol (460 mg), 2-fluorophenyl hydrazine hydrochloride (16 mg, 0.100 mmol) was added. The mixture was warmed to 55-60 C. until a TLC sample showed no starting enamine. The solution was evaporated to dryness in vacuum, the reside was extracted with 3×10 ml of boiling hexane, and the hexane extracts were combined and concentrated and cooled to room temperature. Crystallization gave 25 mg of desired product (example 89) (yield 60%). Result of LC/MS MH+: 416.05; 1H NMR (CDCl3): 3.67 (s, 3H), 7.30 (t, 1H), 7.45 (m, 4H), 7.57 (m, 1H), 7.93 (t, 1H), 8.50 (s, 1H), 9.13 (s, 1H). |
60% | In ethanol; at 55 - 60℃; | To a solution of raw methyl 3-(2-chloro-6-fluorophenyl)-5-[2-(dimethylamino)-1-formylvinyl]isoxazole-4-carboxylate (36 mg, 0.102 mmol) in ethanol (460 mg), 2-fluorophenyl hydrazine hydrochloride (16 mg, 0.100 mmol) was added. The mixture was warmed to 55-60 C. until a TLC sample showed no starting enamine. The solution was evaporated to dryness in vacuum, the reside was extracted with 3×10 ml of boiling hexane, and the hexane extracts were combined and concentrated and cooled to room temperature. Crystallization gave 25 mg of desired product (example I-89) (yield 60%). Result of LC/MS MH+: 416,05; 1H NMR (CDCl3): 3.67 (s, 3H), 7.30 (t, 1H), 7.45 (m, 4H), 7.57 (m, 1H), 7.93 (t, 1H), 8.50 (s, 1H), 9.13 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sulfuric acid; In N,N-dimethyl acetamide; water; at 100℃; for 2.5h; | Other bromoethylarenes were prepared according to literature procedures as shown in the schemes below. Additional bromoethylindoles were prepared by Fischer-type indole synthesis followed by bromination (Campos, K.R. et al . 2004; Mewshaw, R.R. et al . 2004) (Scheme 16), acylation of substituted indoles with oxalyl chloride (Woodward, R.B. et al . 1958) followed by reduction (Feldman, et al . 1986) and bromination (Scheme 17) . 3- (2-bromoethyl) benzofuran (Kozikowski, A. P. et al . 2007; Tomaszewski, Z. et al . 1992) and 3- (2-bromoethyl ) benzothiophene were prepared according to the protocols in Scheme 18. 3-indolylacetaldehyde was prepared by Parikh-Doering oxidation of tryptophol (Sugawara, S. et al . 2009), 3- ( 2-oxoethyl ) -lH-indole-2-carboxylate was prepared from 2- (carboethoxy) indole via literature procedures (Buechi, G. et al . 1977; Vega, A.M. et al . 1981) , and 2- (2-chloroethyl ) benzimidazole was prepared by condensation of o-phenylenediamine and 3- chloropropionic acid (Cowart, M. et al . 2004) (Scheme 19) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In isopropyl alcohol;Reflux; | General procedure: A mixture of compound 10 (0.376 g, 1 mmol) and various phenylhydrazines 6a-6ad (0.145-0.225 g, 1 mmol) in isopropanol (10 mL) were stirred under reflux. After completion of the reaction monitored by TLC, the reaction mixture was concentrated under vacuum, and extracted with CH3CO2C2H5 and H2O. At last the organic layer was washed with saturated NaCl aqueous solution, dried with Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica to give product 11a-11ad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In ethanol; at 78℃; | General procedure: A mixture of compound 5 (0.360 g, 1 mmol) and various phenylhydrazines 6a-6ad (0.145-0.225 g,1 mmol) in dry EtOH (10 mL) were stirred at 78C in the presence of CH3COONa (0.099 g,1.2 mmol). After completion of the reaction monitored by TLC, the solution was then poured into water (10 mL), the white precipitate was filtered and washed with water and dried. The crude product was recrystallized from ethyl acetate/light petroleum ether to give compounds 7a-7ad. Then to a solution of compounds 7a-7ad(0.450-0.529 g, 1 mmol) in toluene (5 mL), 48% BF3*OEt2 (48% solution in Et2O, 0.05 mL, 0.17 mmol) was added dropwise and the mixture was heated under a nitrogen atmosphere at 118C. After completion of the reaction monitored by TLC, water (10 mL) was added to the mixture, which was next neutralized with NaHCO3, and the organic phase was separated and dried over Na2SO4. After evaporation in vacuo, the crude product was purified by column chromatography to give product 9a-9ad. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With sodium acetate; In ethanol; for 1h;Reflux; | General procedure: Arylhydrazine hydrochlorides (0.01mol) were reacted with (1-ethoxyethylidene)malononitrile (0.01 mol) and sodium acetate (0.02mol) in ethanol (40mL), under reflux, during 1h. After, the mixture was poured in cold water and the precipitate formed was filtered out and recrystallized from ethanol/water. The reactions were accomplished by means of TLC using silica gel plate with fluorescent indicator and hexane/ethyl acetate(1:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.2% | With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 90℃; for 3h;Sealed tube; Molecular sieve; | General procedure: To a stirred mixture of 2-bromobenzaldehyde (0.5 mmol) and the corresponding hydrazinehydrochloride (0.6 mmol) in DMF taken in a 25 mL sealed tube, was added Pd(OAc)2 (5 mol %), dppf (6 mol %), molecular sieves (W/W), DBU (1.25 mmol), and Co2(CO)8 (0.15 mmol). The reaction vessel was closed immediately and heated at 90 C for 3 h. The reaction mixture was cooled to room temperature, filtered through celite bed. The filtrate was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over MgSO4, evaporated in vacuum and purified using column chromatography on silica gel (60-120 mesh) to afford the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.5% | With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 90℃; for 3h;Sealed tube; Molecular sieve; | General procedure: To a stirred mixture of 2-bromobenzaldehyde (0.5 mmol) and the corresponding hydrazinehydrochloride (0.6 mmol) in DMF taken in a 25 mL sealed tube, was added Pd(OAc)2 (5 mol %), dppf (6 mol %), molecular sieves (W/W), DBU (1.25 mmol), and Co2(CO)8 (0.15 mmol). The reaction vessel was closed immediately and heated at 90 C for 3 h. The reaction mixture was cooled to room temperature, filtered through celite bed. The filtrate was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over MgSO4, evaporated in vacuum and purified using column chromatography on silica gel (60-120 mesh) to afford the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 90℃; for 3h;Sealed tube; Molecular sieve; | General procedure: To a stirred mixture of 2-bromobenzaldehyde (0.5 mmol) and the corresponding hydrazinehydrochloride (0.6 mmol) in DMF taken in a 25 mL sealed tube, was added Pd(OAc)2 (5 mol %), dppf (6 mol %), molecular sieves (W/W), DBU (1.25 mmol), and Co2(CO)8 (0.15 mmol). The reaction vessel was closed immediately and heated at 90 C for 3 h. The reaction mixture was cooled to room temperature, filtered through celite bed. The filtrate was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine solution, dried over MgSO4, evaporated in vacuum and purified using column chromatography on silica gel (60-120 mesh) to afford the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; at 20℃; | General procedure: The compound 3 or 6a-b (0.005 mol) was dissolved in absolute ethanol (10 mL), and substituted phenylhydrazine hydrochloride (0.006 mol) and triethylamine (0.006 mol) was added. The mixture was stirred at room temperature. When TLC (ethyl acetate/ light petroleum/ methanol/acetic acid, v/v, 10:2:2:0.2) showed the starting material had been almost completely converted, the reaction was stopped. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved in light petroleum/ ethyl acetate (v/v, 1:2) to be recrystallized at 0 oC. The precipitate was filtered off, washed with water and dried to provide the target compounds 7a-7k, 8a-8k and 9a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; at 20℃; | General procedure: The compound 3 or 6a-b (0.005 mol) was dissolved in absolute ethanol (10 mL), and substituted phenylhydrazine hydrochloride (0.006 mol) and triethylamine (0.006 mol) was added. The mixture was stirred at room temperature. When TLC (ethyl acetate/ light petroleum/ methanol/acetic acid, v/v, 10:2:2:0.2) showed the starting material had been almost completely converted, the reaction was stopped. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was dissolved in light petroleum/ ethyl acetate (v/v, 1:2) to be recrystallized at 0 oC. The precipitate was filtered off, washed with water and dried to provide the target compounds 7a-7k, 8a-8k and 9a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid;Reflux; | General procedure: Curcumin pyrazole, and N-(substituted) phenyl pyrazolesderivatives of curcumin were prepared according to previouslyreported procedure by us and others with some modifications(Schemes 1 and 2) [1,20,21]. Curcumin (1 mmol) was dissolved inglacial acetic acid (5 mL), hydrazine hydrate and the various phenylsubstituted hydrazine hydrochlorides (1.2 mmol) were added tothe solution. The solution was refluxed for 8 -24 hr, and then the solvent was removed in vacuum. Residue was dissolved in ethylacetate and washed with water. Organic portion was collected,dried over sodium sulfate, and concentrated in vacuum. Crudeproduct was purified by column chromatography.Knoevenagel condensates of curcumin was prepared bytreatment of curcumin with aromatic aldehyde (4-hydroxy-3-methoxybenzaldehyde; vanillin) in presence of piperidine(as catalyst) and anhydrous DMF (as solvent) to yield 4-(4-Hydroxy-3-methoxybenzylidene) curcumin. Likewise, butylidienecurcumin and benzylidiene curcumin were prepared in good yieldsusing the above procedure wherein isobutyraldehyde and benzyldehydewere used instead of (4- hydroxyl -3-methoxybenzaldehyde) (Scheme 3) [1,22-25]. Reaction mixture was dilutedwith ethyl acetate and washed with water and saturated brine. Theorganic phase was dried over Na2SO4 concentrated under vacuum,and purified by chromatography with EtOAC/hexanes mixtures toprovide pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; acetic acid; In water; at 0 - 20℃; | 5-(2-Chlorophenyl)-1-(2-fluorophenyl)pyrazolidine (R11) (Fig.1B)-2-Fluorophenylhydrazine hydrochloride R10 (25 g, 153.8 mmol) was added to a mixture of water (3.8 ml), acetic acid (31ml), and sulfuric acid (12.5 ml) at 0 C. 2-Chlorostyrene (R3) (21.3 g, 153.8 mmol) and 90% paraformaldehyde (5.1 g, 153.8 mmol) were added to the mixture. After 1 h at 0 C the mixture was left overnight with stirring at ambient temperature. The resulting dark brown solution was diluted with water (100 ml),while maintaining the temperature below 5 C with an ice-water bath. Non-acid soluble side products were extracted with diethyl ether (150 ml). The aqueous layer was made alkaline with sodium hydroxide solution (33%, 100 ml) and the liberated pyrazolidine (R11) was extracted with TBME (1 200 ml, 2 100 ml). Combined extracts were washed with water (50 ml) and brine (50 ml). After drying with sodium sulfate the solvent was evaporated to leave a brownish oil (38.9 g, 85%). HPLC-MS: (M35Cl H) 277.1, (M37Cl H) 279.2, 1H NMR (CDCl3,300 MHz, ppm): 1.8-2.0 (1H, m), 2.9-3.0 (1H, m), 3.0-3.1 (1H, m), 3.2-3.4 (2H, m), 5.0 (1H, d), 6.8-7.7 (8H, m). The oil was used in the next step without purification. Storage at 20 C under a nitrogen atmosphere was used to slow down the oxidation of the pyrazolidine nucleus. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sulfuric acid; for 12h;Reflux; | General procedure: A mixture of hydrazine hydrochloride (1 mmol) and masked aldehyde (1 mmol) in 100 mL of 4% H2SO4 was heated at reflux for 12 h. The reaction mixture was cooled to room temperature and treated with aqueous NaHCO3. The tryptamine product was extracted with CH2Cl2 (4 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified through neutral alumina column chromatography using ethyl acetate:hexane (1:4) as eluent to give indolyl imides 3c, 3f-k as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
250 mg | With acetic acid; at 125℃; for 1h; | 4-(3?-Ethoxy-biphenyl-4-yl)-2-oxo-3-butenoic acid methyl ester (190.0 mg, 0.61 mmol) prepared in Step 3 of Preparation 18 and <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (110.0 mg, 0.67 mmol) were added to acetic acid (3.0 mL). The reaction mixture was stirred at 125 C. for 1 hour and then concentrated under reduced pressure. Ethyl acetate was added to the reaction mixture, which was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/5) to give 250.0 mg of the titled compound as a yellow liquid. (0851) 1H NMR (400 MHz, CDCl3) 7.57 (t, 1H), 7.44 (d, 2H), 7.31-7.19 (m, 3H), 7.09-7.02 (m, 3H), 6.92-6.84 (m, 3H), 5.77 (d, 1H), 4.06 (q, 2H), 3.90 (s, 3H), 3.71 (t, 1H), 3.23 (d, 1H), 1.42 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In water; at 45 - 88℃; for 2.5h; | A stirred suspension of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (1000 g, 5535 mmol) in acetic acid (1000 ml) and water (1000 ml) was heated at 45 C. Ethylacetoacetate (700 ml) was added dropwise over 30 mins and this was stirred at 88 C. for 2 hr. The resulting mixture was cooled to 5 C. and poured onto ice (3000 g) and DCM (4500 ml). 30% NaOH (aq) (2400 ml) was added and the mixture was stirred for 15 mins, then separated and extracted with DCM (1500 ml). The organic extracts were washed with 1M NaOH (aq) (1500 ml). The aqueous phases were combined and ice (1500 g) and DCM (3600 ml) were added. To the stirred mixture was added 32% HCl (aq) (2400 ml) until the pH was adjusted to pH 1-2. The biphasic mixture was separated, extracted with DCM (1500 ml) and the organic extracts washed with brine/water 4:1 (2000 ml), dried over MgSO4 and evaporated to dryness to give a dark solid. To a stirred solution of the crude product in DCM (2000 ml) was added silica gel (350 g). This was filtered and the filtrate was evaporated. Purification by chromatography with MeOH in EtOAc gave the title compound as a light yellow solid. (0612) LC-MS: Rt 0.54 mins; MS m/z 193.1 [M+H]+; Method B (0613) 1H NMR (400 MHz, DMSO-d6) delta 11.20 (1H, br s), 7.48-7.40 (2H, mults), 7.36 (1H, td), 7.29 (1H, td), 5.31 (1H, br s), 2.10 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | In methanol; at 20℃; for 1h; | Cinnamaldehyde (5.0 mmol, 1.0 equiv) was added dropwise to a solution of <strong>[2924-15-4]o-fluorophenylhydrazine hydrochloride</strong> (5.0 mmol, 1.0 equiv) in MeOH (3 mL), and the mixture was stirred for 1 h at ambient temperature. Crystallization occurred in the course of reaction. The crystal was filtered with cooled MeOH to give the pure hydrazone 1f. After solvent of the filtrate was removed in vacuo, the residue was diluted with CHCl3 (10 ml). The organic layer was washed with sat. NaHCO3 (10 mL) and brine (10 mL), dried over Na2SO4 and the solvent was removed in vacuo. The residue was purified by recrystallization in cooled MeOH to give the pure hydrazone 1f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | A suspension of <strong>[2924-15-4]o-fluorophenylhydrazine hydrochloride</strong> (3.3 mmol, 1.1 equiv) and NaOAc (3.3 mmol, 1.1 equiv) in MeOH (6 mL) was stirred for 30 min at ambient temperature. After p-methoxycinnnamaldehyde (3.0 mmol, 3.0 mmol) was added to the solution, the mixture was stirred for 5 min at ambient temperature. Crystallization occurred in the course of reaction. The solid was filtered with water and purified by recrystallization in MeOH to give the pure hydrazone 1l. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In water; for 2h;Reflux; | Example 62 2-(2-(7-Fluoro-1H-indol-3-yl)ethyl)isoindole-1,3-dione Combine 2-fluorohydrazine hydrochloride (3.25 g, 20 mmol) and 2-(4,4-diethoxy-butyl)-isoindole-1,3-dione (6.99 g, 24 mmol) and dissolve in 4% aqueous H2SO4. Heat the reaction to reflux. After 2 hours, cool to ambient temperature. Basify the reaction mixture with 30% aqueous NH4OH to pH of about 11. Extract with dichloromethane (2x100 mL). Combine the organic phases, dry over MgSO4, filter, and remove the solvent leaving an orange oil. Absorb the oil onto silica gel and load on top short column of silica gel equilibrated with 15% EtOAc in hexanes. Eluent with 15% EtOAc in hexanes (1500 mL) and then 30% EtOAc in hexanes (2000 mL) to give, after evaporation, the title compound as a yellow solid: 1H NMR (300MHz, d6-DMSO): 3.03 (t, 2H), 3.85 (t, 2H), 6.91 (m, 2H), 7.25 (m, 1H), 7.36 (d, 1H), 7.83 (m, 4H), 11.32 (bs, 1H); MS (FD): m/z 308 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1h; | To a solution of 2-bromo-6-fluorobenzaldehyde (Combi-Blocks, 10 g, 49.3 mmol) and <strong>[2924-15-4](2-fluorophenyl)hydrazine hydrochloride</strong> (8.01 g, 49.3 mmol) in N-methyl-2-pyrrolidinone (100 ml) at ambient temperature was added cesium carbonate (33.7 g, 103 mmol). The mixture was heated to 140C for 1h. After 1h the reaction mixture was allowed to cool to ambient temperature and water was added (300 ml). The mixture was stirred for 1h and then the solids were isolated via filtration washed with water and dried in a vacuum oven at 50C. to give the title compound (13.0 g, 44.7 mmol, 91% yield). H1 NMR (400 MHz, DMSO-d6) delta ppm 8.41(d, J=0.5 Hz, 1H), 7.72(td, J=7.8, 1.6 Hz, 1H), 7.66-7.38(m, 8H); MS (DCI) m/z 291, 293 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | With toluene-4-sulfonic acid; In ethanol; for 2h;Reflux; | In a 100 ml three-necked flask,30 ml of ethanol,3.7 g of isopropyl methyl ketone,5 g of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong>,11 g of p-toluenesulfonic acid monohydrate was added,And the mixture was stirred at reflux temperature for 2 hours.After completion of heating,The reaction solution was cooled to room temperature,Water and ethyl acetate were added,Then,The solvent of the organic layer was distilled off under reduced pressure to obtain 5 g of 7-fluoro-2,3,3-trimethyl-3H-indole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.4% | In ethanol; water; for 1h;Reflux; | To a solution of the compound obtained in step 2 of example 113 (0.2g, 0.414mmol) in ethanol (9mL) and water (lmL) was added 3,5 difluorophenyl hydrazine hydrochloride (0.082g, 0.456mmol) and the reaction mixture was refluxed for lh. After the completion of reaction, the reaction mixture was concentrated to obtain a crude material which was purified by Combiflash chromatography (5-20% ethyl acetate/petroleum) to afford pure title compound 116 (0.116gm). Yield: 47.4%; JH NMR (DMSO d6): delta 0.80-0.82 (m, 6H), 0.91 (S, 3H), 0.955 (S, 3H), 0.98- 1.00 (d, 6H), 1.06 (S, 3H), 1.26-1.32 (m, 4H), 1.44 (m, 4H), 1.49-1.59 ( m, 5H), 1.76-1.83 (m, 3H), 1.89-1.99 (m, 3H), 2.11-2.13 (d, 1H), 2.6 (m, 1H), 5.21 (S, 1H), 11.97 (S, 1H), 7.27-7.29 (m, 2H) 7.34 (S, 1H) 7.46-7.52 (m, 1H); MS (ES+): 573.6 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.37 g | In ethanol; water; for 2h;Reflux; | To a solution of 2-fluorophenylhydrazinehydrochloride (0.81 g, 5.00 mM) in 30 ml of EtOH/H2O (v/v 5 5/1) <strong>[29882-07-3]4-chloro-1,1-dimethoxybutane</strong> (0.84 g, 5.50 mM) was added and heatedto reflux for 2 hours. Then the solvent was removed under vacuum,and the residue was chromatographed through silica gel eluding withCH2Cl2/MeOH (30:1) to give the 7-fluorotryptamine (0.37 g) as anoil. Subsequently, aq. HCHO (1.56 ml) was added to the solution of7-fluorotryptamine (0.37 g, 2.08mM) in CH3COOH (15ml) in a dropwisemanner. The mixture was stirred at room temperature for 12 hours atthe atmosphere of N2; then the solvent was removed under vacuum, andthe residue was chromatographed through silica gel eluding withCH2Cl2/MeOH (40:1) to afford the 8-fluoro-1,3,4,9-tetrahydro-b-carboline(0.36 g) as a white powder. Finally, to a solution of phenylacetic acid(283 mg, 2.08 mM) in anhydrous N,N-Dimethylformamide (3 ml) wereadded 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(518 mg, 2.70 mM) and N-Hydroxybenzotriazole (309 mg, 2.29 mM)at 0°C, and then 8-fluoro-1,3,4,9-tetrahydro-b-carboline (0.36 g, 1.89mM)was added to the mixture after stirring for 15 minutes. The mixturewas stirred for another 3 hours, diluted with H2O, and extracted withEtOAc. The combined organic phase was dried over anhydrousNa2SO4, concentrated, and chromatographed over silica gel to give 0.54 g of LG308. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With palladium(II) trifluoroacetate; 1,3-bis-(diphenylphosphino)propane; magnesium sulfate; 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 150℃; under 7500.75 Torr; for 21h;Autoclave; | General procedure: 2-Formylaryl tosylate (2 mmol), hydrazine (2 mmol), Pd(TFA)2 (5 mol%), dppp (10 mol%), DBU (2.4 mmol), anhydrous MgSO4 (2 mmol) and CH3CN (30 ml) were charged in a 200 ml-autoclave. The autoclave was flushed using CO three times. The reaction was pressurized with CO to 1.0 MPa, and stirred at 140 C for 21 h. Then the mixture was cooled to room temperature and the excess CO was vented. Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel with petroleum ether-ethyl acetate as the eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.48 g | In a round bottom flask equipped with a reflux condenser, 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3- triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (4.88 g) and <strong>[14401-51-5]4-chlorobenzamidine hydrochloride</strong> (2.90 g) were dissolved into a solution of acetic acid (0.66 mL) and DMF (20 mL) after which Hunig's base (4.0 mL) was added and the resulting brown suspension was stirred at room temperature for 3 hours. Subsequently acetic acid (6.66 mL) was added to this mixture followed by (2- fluorophenyl)hydrazine hydrochloride (1.3 g) at room temperature and the reaction mixture was heated to 80C for 4 hours. The mixture was cooled to ambient temperature then poured into a solution of saturated NaHC03. The resulting mixture was extracted twice with ethyl acetate; the combined organic layers were washed with brine, dried over a2S04 and evaporated under vacuum. The crude material was purified by flash chromatography (S1O2, gradient: ethyl acetate/cyclohexane) to give 3-(4- chlorophenyl)-1-(2-fluorophenyl)-5-methyl-1 ,2,4-triazole (0.48 g) as light yellow solid. 1H-NMR (CDCI3, delta in ppm): 8.1 (d, 2H), 7.55 (m, 2H), 7.45 (d, 2H), 7.35 (m, 2H), 2.5 (s,3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With pyridine; at 22℃; for 12h; | General procedure: To a solution of hexachlorocyclopentadiene (0.16mL, 1.0mmol, 1.0eq) in pyridine (5mL) was added 3-fluorophenyl hydrazine HCl (244mg, 1.5mmol, 1.5eq) at room temperature. The reaction mixture was stirred for 12h at room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate (80mL) and washed with water (2×20mL) and brine (20mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (hexane only) to afford the desired product 3e (212 mg, 65%) as brown solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | General procedure: To a solution of acetonitrile (10 vol.) in 1,3-cyclohexanedione 5 ( 0.01 mol), added the corresponding phenyl hydrazine hydrochloride 6a-j (0.01 mol) and maintained the reaction mixture at 80-85 C for 6-8 h. After completion of the reaction, acetonitrile was removed under vacuum distillation below 45 C to get respective Schiff's base. To which (10 volumes) Con. hydrochloric acid/sulfuric acid was added and maintained at 90-95 C over a period of 8-10 h. After completion of reaction, quenched the reaction mixture with DM water and adjusted the pH to basic using aqueous 30% sodium carbonate solution. The resulting reaction mixture was extracted with ethyl acetate, separated the organic layer, washed with brine solution and distilled out the organic layer completely to get crude. It was further purified by silica gel column chromatography using 0-5% methanol in chloroform. (Note: In the case of 4-methoxyphenyl hydrazine hydrochloride 6d, schiff's base gets cyclized instantaneously without acid to afford 1d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With sodium hydrogencarbonate; In water; isopropyl alcohol; | Preparation 123 N-(2-Fluorophenyl)cyclohexenol-3-hydrazide STR142 A solution of <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (24.8 g, 152.5.6 mmol) in 225 mL of water and 2.25 mL of isopropanol was added dropwise to a solution of 1,3-cyclohexanedione (17.1 g, 152.5 mmol) in 117 mL of water and 1.1 mL of isopropanol. Sodium bicarbonate (12.6 g, 152.5 mmol) was then added. After 3 hours, the orange powder that formed was collected, washed with 200 mL of water, and dried at 45 C. in a vacuum oven to give 31.5 g of the title compound. Yield: 94%. 1 H NMR. MS(FD). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With hydrogenchloride; In water; at 20℃; for 16h;Darkness; | To a solution of hydrochloric acid (12 mL, 0.25 M, 3 mmol) was added potassium thiocyanate (0.291 g, 3 mmol) and <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (3 mmol). 3-pentanone (3 mmol) was added to the solutiondropwise. The reaction was allowed to stir in the dark for 16 hours at room temperature. Theprecipitate that formed was filtered using vacuum filtration and washed with water four times. Theprecipitate was then recrystallized with methanol to yield 5,5-diethyl-2-(2-fluorophenyl)-1,2,4- triazolidine-3-thione as a white solid (m.p = 158 C, 47%). 1H (300 MHz, CDCh) 8 7.91 (brs, 1H),7.65 (m, 1H), 7.31 (m, 1H), 7.17 (m, 2H), 1.81 (m, J=7.5, 4H), 1.02 (t, J=7.5, 6H) ppm; 13C NMR(100 MHz, DMSO-d6) 8 177.9, 158.5, 156.0, 129.7, 129.3, 129.2, 127.6, 127.5, 124.2, 116.4,116.2, 80.8, 28.6, 7.7 ppm; IR Vmax (cm-1) 3157, 2969, 1490, 1405, 908, 764; HRMS (ESI) calcdfor C12H16FN3S [M+Ht 254.11217, found 254.11191. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With acetic acid; In methanol; water; at 60℃; for 0.5h; | General procedure: The warmed solution of phenylhydrazine hydrochloride 2a (0.172 g, 1.2 mmol) and acetic acid (0.5 mL in 1 mL H2O) was added to a stirred solution of 3-formylchromone(0.174 g, 1 mmol) in methanol (2 mL) at room temperature.The reaction mixture was heated to 60 C for 30 min and then cooled to room temperature. The solid separated was filtered, washed with ice-cold water (5 mL) and then recrystallized from hot methanol providing the corresponding hydrazone 3a. Similarly, the other hydrazones 3b-z were prepared from the corresponding 3-formylchromones 1a-f and phenylhydrazine hydrochlorides 2a-i under optimized reaction conditions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acetic acid; In methanol; water; at 60℃; for 0.5h; | General procedure: The warmed solution of phenylhydrazine hydrochloride 2a (0.172 g, 1.2 mmol) and acetic acid (0.5 mL in 1 mL H2O) was added to a stirred solution of 3-formylchromone(0.174 g, 1 mmol) in methanol (2 mL) at room temperature.The reaction mixture was heated to 60 C for 30 min and then cooled to room temperature. The solid separated was filtered, washed with ice-cold water (5 mL) and then recrystallized from hot methanol providing the corresponding hydrazone 3a. Similarly, the other hydrazones 3b-z were prepared from the corresponding 3-formylchromones 1a-f and phenylhydrazine hydrochlorides 2a-i under optimized reaction conditions |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With acetic acid; In ethanol; for 3h;Inert atmosphere; Reflux; | General procedure: Photochromic hydrazone switches are directly synthesized from the corresponding alpha -keto ester and phenylhydrazine derivatives using a modified reported procedures. [Qian, H.; Aprahamian, I. Chem. Commun. 2015, 51, 11158-11161.] Phenylhydrazine derivatives (1 mmol) and catalytic amount of acetic acid (HO Ac) are added to an ethanol solution of alpha -keto ester (1 equiv.) derivatives under N2 atmosphere. The resulting mixture is stirred and refluxed for 3 hrs, and then cooled to room temperature. Ethanol is removed under vacuum. The crude residue is redissolved in methylene chloride, washed with water, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and subject to column chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 4h; | General procedure: To compound 2 (5.0mmol, 0.95g) dissolved in anhydrous CH2Cl2 (30mL) (2-chlorophenyl) hydrazine hydrochloride (6.0mmol, 1.08g) was added and the mixture was stirred at iced water. Once 2 was completely dissolved, DMAP (4-dimethylaminopyridine, 77.2mmol, 1.53g) and EDCI (carbodiimide hydrochloride, 6.0mmol, 1.15g) were added gradually with stirring and cooling for 4h. The reaction mixture was extracted with saturated brine for three times. After took off the solvent, the resulting precipitate was purified by column chromatography to give an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20 - 24℃; for 2h; | Example 17 Preparation of (Z)-N'-(2-fluorophenyl)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2(trifluoromethyl)benzohydrazide (F28) In a one dram vial equipped with a magnetic stir vane were added (Z)-4-(1,4,4,4-tetrafluoro-3-(3,4,5-trichlorophenyl) but-1-en-1-yl)-2-(trifluoromethyl)benzoic acid (C2) (150 mg, 0.303 mmol), N-ethyl-N-isopropylpropan-2-amine (174 muL, 0.999 mmol), and 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (173 mg, 0.454 mmol) in N,N-dimethylformamide (1 mL) to give a brown solution. (2-Fluorophenyl)hydrazine hydrochloride (59.3 mg, 0.364 mmol) was added, and the reaction mixture was left to stir at ambient temperature for two hours. The reaction mixture was diluted with diethyl ether (10 mL) and water (10 mL), the phases where separated, and the aqueous layer was extracted with additional diethyl ether (10 mL) The organic extracts were pooled, washed with brine, dried with magnesium sulfate, filtered, and concentrated. Purification of the resulting residue by flash silica chromatography eluting with hexanes and ethylacetate provided the title compound as a yellow foam (0.108 g, 46%). The following compounds were prepared in like manner to the procedure outlined in Example 17: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With hydrogenchloride; In ethanol; water; at 90℃; for 1h;Inert atmosphere; | To a solution of [1,1'-biphenyl]-3,4'-dicarbaldehyde (210 mg, 1 mmol) in EtOH (20mL), <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (480 mg, 3 mmol) and a catalytic amount of concentrated HCl (0.04 mL) were added. The reaction mixture was stirred at 90 C for 1 h and the resulting solution was filtered. The residue obtained was washed with 2 N HCl (20 mL) and hot EtOH (20 mL) to afford compound 10a (225 mg, 53%) as a yellow solid: 1H NMR (400 MHz, (CD3)2SO, Fig. S7) delta 10.04 (s, 1H), 10.03 (s, 1H), 8.21 (s, 1H), 8.19(s, 1H), 7.93 (s, 1H), 7.80-7.74 (m, 4H), 7.67 (t, J = 9.6 Hz, 2H), 7.59-7.54 (m, 2H), 7.51 (t, J =8.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 2H), 7.12 (t, J = 8.4 Hz, 2H), 6.81-6.75 (m, 2H); 13C NMR (100MHz, (CD3)2SO, Fig. S8) delta 150.3, 147.9 140.1, 139.6, 139.1, 138.8, 136.3, 134.9, 133.4, 133.3,129.4, 127.1, 126.55, 126.47, 125.04, 125.01, 124.0, 118.73, 118.66, 115.1, 115.0, 114.0, 113.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With hydrogenchloride; In ethanol; water; at 80℃; for 0.5h;Inert atmosphere; | To a solution of [1,1'-biphenyl]-4,4'-dicarboxaldehyde (100 mg, 0.48 mmol) in EtOH(8 mL), <strong>[2924-15-4]2-fluorophenylhydrazine hydrochloride</strong> (232 mg, 1.43mmol) and a catalytic amount of concentrated HCl (0.04 mL) were added. The reaction mixturewas stirred at 80 C for 30 min and the resulting solution was filtered. The residue obtained waswashed with hot EtOH (20 mL) to afford compound 10b (92 mg, 45%) as a yellow solid: 1H NMR(400 MHz, (CD3)2SO, Fig. S9) delta 10.29 (s, 2H), 8.14 (s, 2H), 7.72 (br s, 8H), 7.51 (t, J = 8.8 Hz,2H), 7.12 (d, J = 7.8 Hz, 2H), 7.09 (t, J = 8.0 Hz, 2H), 6.74 (m, 2H); 13C NMR (100 MHz,(CD3)2SO, Fig. S10) delta 150.7, 148.3, 139.6, 139.2, 135.2, 133.8, 133.7, 127.2, 126.9, 125.5, 125.4,119.15, 119.08, 115.6, 115.4, 114.33, 114.29. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | A solution of methyl 2- {3 -(4-chlorophenyl)-5-oxo-4- [(2)-3,3 ,3 -trifluoro-2-hydroxypropyl] -4,5-dihydro-1H-l,2,4-triazol-l-yl}ethanimidate (Example 7A, 1.00 g, 2.64 mmol) in tetrahydrofuran (20 ml) was cooled to 0C and treated with methyl chloro(oxo)acetate (270 jil, 2.9 mmol) followed by N,N-diisopropylethylamine (0.5 ml, 2.9 mmol). The resulting mixture was stirred for 30 mm. (2-Fluorophenyl)hydrazine hydrochloride (1:1) (472 mg, 2.90 mmol) and N,Ndiisopropylethylamine (0.5 ml, 2.9 mmol) were added, the reaction mixture was warmed up to room temperature and stirred for 30 mm, followed by 2 h at 80C in a sealed vial under microwave irradiation. The reaction mixture was evaporated and the crude product was purified by preparativeHPLC (Method 5). Lyophilisation of the product containing fractions afforded 983 mg (67% of th.) of the title compound.LC-MS (Method 3): R = 1.94 mm; MS (ESIpos): mlz = 541 [M+H]1H-NMR (400 MHz, DMSO-d6) [ppm]: 3.776 (1.07), 3.793 (16.00), 3.823 (0.85), 3.847 (0.93),3.859 (1.17), 3.883 (1.27), 3.991 (1.20), 3.999 (1.35), 4.028 (0.85), 4.036 (0.81), 5.182 (8.11),6.902 (2.22), 6.918 (2.23), 7.379 (0.90), 7.398 (2.00), 7.417 (1.18), 7.473 (0.83), 7.495 (1.40),7.520 (1.09), 7.615 (4.48), 7.620 (2.00), 7.631 (2.65), 7.636 (6.14), 7.643 (1.67), 7.649 (1.19),7.658 (1.19), 7.663 (1.16), 7.677 (1.69), 7.681 (1.57), 7.696 (0.82), 7.701 (0.77), 7.751 (5.34),7.756 (1.88), 7.767 (1.57), 7.772 (3.95). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In 1,4-dioxane; at 0 - 100℃; for 4h; | To a solution of commercially available <strong>[2924-15-4](2-fluorophenyl)hydrazine hydrochloride</strong> (2 g, 12.34 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (2.45 g, 12.34 mmol) in dioxane (20 mL) was added concentrated H2S04 (2 mL), 0 C. Then the reaction mixture was heated at 100 C for 4 h. After completion of the reaction as evidenced by TLC, the reaction mixture was cooled to 25 C and then concentrated. The crude mixture was basified by 10% NaOH solution and the precipitate was filtered off. The solid was washed with water and dried under vacuum to get the title compound (1.7 g, 75%). MS: 191.0 (M+H)+. | |
With hydrogenchloride; In ethanol; water; at 80℃; for 16h; | General procedure: To a solution of [Int-1.1] (1 g, (0213) 1 eq., 4.21 mmol) and tert-butyl 4-oxopiperidine-l- carboxylate (0.8 g, 1 eq., 4.21 mmol) in EtOH (15 mL) , HC1 36% (4 mL)was added. The reaction mixture was heated at 80 C and stirred for 16 h. The suspension was filtered and washed with Et20 to furnish the title compound as brown solid (0.6 g, 50%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In ethanol; at 80℃; for 9h; | General procedure: A mixture of alkynone 1 or 2 (1 equiv), arylhydrazine 8-14(1.2 equiv), and Et3N (5 equiv) in anhydrous EtOH (50 ml)was refluxed for 9 h. The reaction mixture was evaporated,the residue was purified by silica gel column chromatography(eluent CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In 1,4-dioxane; at 0 - 100℃; for 12h;Inert atmosphere; | To a stirred solution of commercially available (2-fluorophenyl)hydrazine;hydrochloride (10.0 g, 0.0615 mol) and tert-butyl 3-oxopiperidine-1-carboxylate (12.3 g, 0.0615 mol) in 1 ,4-Dioxane (100.0 mL) concentrated H2SO4(10.0 mL) was added (at 0 C), then heated to 100 C for 12 h under nitrogen atmosphere.The reaction mixture was concentrated and the crude product was basified by using 30% NaOH water solution (pH=9-10) followed by dichloromethane extraction. The dichloromethane layer was concentrated under reduced pressure to afford the title compound (10.0 g, Crude) as a brown oil.The crude compound was used for the next step without further purifications.MS: 191.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In ethanol; water; at 100℃; for 2h;Inert atmosphere; Microwave irradiation; | Compound 4 (129 mg, 0.40 mmol) and <strong>[2924-15-4](2-fluorophenyl)hydrazine hydrochloride</strong> (130 mg, 0.80 mmol) in EtOH (4 mL) veas heated in Biotage microwave at 100 C for 2 h and then cooled to room temperature. The mixture was concentrated, and the residue was diluted with CH2CT2. The mixture was washed with 1 N aq. HC1. The organic phase was separated. The aqueous phase was extracted twice with CH2CI2. The combined organic extracts were dried over Na2SOr, filtered and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0% to 40% EtOAc in hexanes) to give compound 15d (155 mg, 94% yield) as a white solid m/z:=:414 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium acetate; In ethanol; water; for 2h; | General procedure: The quinoline-3-carbaldehyde (0.1 mmol) was dissolved in EtOH and reacted with 0.13 mmol of phenyl hydrazine hydrochloride or derivative compounds in the presence of a solution of 0.4 g of sodium acetate in water for about 2 h. The precipitate formed at the end of the reaction was filtered off. The crystals obtained were purified by recrystallization from ethanol. The final compounds were obtained as amixture of E/Z stereoisomers. |
Tags: 2924-15-4 synthesis path| 2924-15-4 SDS| 2924-15-4 COA| 2924-15-4 purity| 2924-15-4 application| 2924-15-4 NMR| 2924-15-4 COA| 2924-15-4 structure
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P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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