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CAS No. : | 41052-75-9 | MDL No. : | MFCD00012928 |
Formula : | C6H8Cl2N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ADODRSVGNHNKAT-UHFFFAOYSA-N |
M.W : | 179.05 | Pubchem ID : | 443287 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 44.51 |
TPSA : | 38.05 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.55 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.59 |
Log Po/w (WLOGP) : | -1.45 |
Log Po/w (MLOGP) : | 2.29 |
Log Po/w (SILICOS-IT) : | 1.01 |
Consensus Log Po/w : | 0.89 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.96 |
Solubility : | 0.196 mg/ml ; 0.0011 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.04 |
Solubility : | 0.164 mg/ml ; 0.000916 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.68 |
Solubility : | 0.373 mg/ml ; 0.00208 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.46 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 PPA; sodium bicarbonate; sulfuric acid; In ethanol; | Example 39 (7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone 2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with ethylpyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give 7-Chloro-1H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. | |
With PPA;sulfuric acid; In ethanol; at 20℃; for 72h;Heating / reflux; | 2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with [ETHYLPYRUVATE] (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give [7-CHLORO-1 H-] indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water {3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7- [CHLORO-1 H-INDOLE-2-CARBOXYLIC ACID] (0.089 g). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N, [N-DIISOPROPYLETHYLAMINE] (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0. [6] mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10% 2 M ammonia in [METHANOL/DICHLOROMETHANE)] to give the title compound (0.56 g).'H NMR (400 MHz, [CDCI3)] : [8] 9.17 [(BR S, 1 H),] 7.47 (d, J = 8.1 Hz, [1H),] 7.21 (dd, J = 7.6, 0.8 Hz, 1 H), 7.01 (t, J = 7.8 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 3.88 {br m, 4H), 2.45 (t, J = 5.1 Hz, 4H), 2.29 (s, 3H). | |
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with ethylpyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give 7-Chloro-1 H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water (3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7-Chloro-1H-indole-2-carboxylic acid (0.089 g). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N, N-diisopropylethylamine (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0.6 mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10% 2 M ammonia in methanol/ dichloromethane) to give the title compound (0.56 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate In nitromethane at 100℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; for 18h;Heating / reflux; | 1) Production of ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate At room temperature, 16.2 mL of N,N-diisopropylethylamine was added to tetrahydrofuran (300 mL) solution of 9.4 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 8.3 g of 2-chlorophenylhydrazine hydrochloride, and heated under reflux for 18 hours. The solvent was concentrated under reduced pressure, water was added to this, and extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain crude ethyl 4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate as a yellow oily substance. | |
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 80℃; for 16h; | Diisopropylethylamine (3.58 g, 27.67 mmol) was added into 4-chloro-2-methylthiopyrimidin-5-ethyl carboxylate (2.80 g, 12.03 mmol) and 2-chloro phenyl hydrazine (2.48 g, 13.83 mmol) in 90 mL THF solution, then heated to 80C and stirred for 16 hours. The reaction was monitored to be complete by LCMS. After concentrated under reduced pressure to remove the solvent, water 50 mL was added, and extracted by 20 mL EtOAc for 3 times, the combined EtOAc phase were washed by brine 20 mL, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the compound 39-A. 1H NMR (400MHz, CDCl3) delta = 9.65 (br d, J=3.8 Hz, 1H), 8.71 - 8.65 (m, 1H), 7.30 (dd, J=1.2, 8.0 Hz, 1H), 7.15 - 7.08 (m, 1H), 6.92 (dd, J=1.6, 8.0 Hz, 1H), 6.84 (dt, J=1.6, 8.0 Hz, 1H), 6.78 (d, J=4.0 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 2.25 (s, 3H), 1.42 (t, J=7.0 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | 4-(4-Chlorophenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester lithium salt I-2b (30.26 g, 116 mmoles) was suspended in 242 ml of ethanol. <strong>[41052-75-9]2-Chlorophenylhydrazine hydrochloride</strong> (20.88 g, 116 mmoles) was added portionwise as a solid over 45 minutes while maintaining an internal temperature between 30-40° C. The reaction mixture went from a yellow suspension to a dark orange suspension. The reaction was allowed to stir for 3 hours while maintaining an internal temperature between 25-35° C. An aqueous potassium hydroxide solution (148 ml of 1.8 M solution, 266 mmoles) was added over 20 minutes while maintaining an internal temperature between 20-30° C. The reaction mixture was held for 2.5 hours. Within 30 minutes of potassium hydroxide solution addition, the reaction turned an almost clear, very dark rust orange in color. Aqueous hydrochloric acid (85 ml of 3.9 M solution, 331 mmoles) was added over 15 minutes while maintaining the reaction temperature between 20-30° C. The product precipitated during hydrochloric acid addition. The precipitated product was granulated for 16 hours at room temperature. The crude product was isolated by filtration and the filtercake was washed with 150 ml of water. The filtercake was a yellowish orange solid. After air-drying for 30 minutes, the filtercake was suspended in 480 ml of methanol. The suspension was heated to reflux to give a clear dark orange solution (all solids in solution within 1 hour of reaching reflux) and then held at reflux for 8 hours. The solution was cooled over 4 hours to room temperature, during which time product had precipitated from solution. The reaction mixture was held at room temperature for 10 hours, followed by cooling to 0° C., and stirring for 1.5 hours. Collection of the precipitate by filtration, washing the resulting filtercake with 150 ml of ice-chilled methanol, and drying at 60° C. in vacuo for 3 hours afforded 1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-2d (29.28 g, 76percent) as an off-white solid. 1H-NMR (CD3CN): delta 7.58-7.45 (m, 4H), 7.31 (d, 2H, J=8.7 Hz), 7.21 (d, 2H, J=8.7 Hz), 7.10 (s, 1H). Mass Spec (ESI): M+1=333.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B) Ethyl 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate 6.5 g of 2-chlorophenylhydrazine hydrochloride are added to a solution of 10 g of the compound obtained in the preceding stage in 100 ml of EtOH and the mixture is left stirring overnight at AT. The precipitate formed is filtered off, washed with EtOH and then with ether and dried under vacuum. The precipitate is taken up in 50 ml of acetic acid and heated at reflux for 4 hours. After cooling to AT, the reaction mixture is poured into 400 ml of ice-cold water and the precipitate formed is filtered off. 4 g of the expected compound are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With 1,3-bis(3-sulfopropyl)-1H-imidazol-3-ium trifluoromethanesulfonate; In water; at 100℃; for 0.333333h;Microwave irradiation; Green chemistry; | General procedure: Cyclohexanone (0.91 g, 10.0 mmol) was mixed with [(HSO3- p)2im][CF3SO3] (0.5 mmol) in water (15 mL), and phenylhydrazine hydrochloride (1.44 g, 10.0 mmol) was added. The mixture was then stirred at 100 8C for about 15 min under microwave irradiation. Reaction progress was monitored by GC-MS. After completion, the reaction mixture was cooled to room temperature, and 1,2,3,4-tetrahydrocarbazole was obtained by filtration. The remaining mixture of [(HSO3-p)2im][CF3SO3]/H2O was reused directly. |
90% | With 1-(3-sulfopropyl)pyridinium p-toluenesulfonate; In water; at 100℃; for 0.25h; | Sulfonic acid ionic liquid 1b (0.125 mmol), orth<strong>[41052-75-9]o-chlorophenylhydrazine hydrochloride</strong> (25 mmol),Cyclohexanone (25 mmol) water 15 mL sequentially added to the reaction vessel,Placed in a reactor, under mechanical stirring at 100 C for 15 minutes,After cooling to room temperature, the mixture was filtered and dried to give 4.86 g, yield 90%. |
In acetic acid; at 40 - 120℃; for 22h;Heating / reflux; | A sample of 2-chlorophenylhydrazine -HCl, 1.7g (9.5 x 10"3 mol), acetic acid,2.5ml, cyclohexanone, 984mul, (9.5 x 10" mol), were combined in a 25ml round bottom flask with magnetic stirring bar. Heated mix to reflux at 12O0C for 4 hours then cooled to 4O0C. After 18 hours TLC with 1 :4 ethyl acetate / hexane showed a new spot with higher Rf. Diluted mix with equal parts ethanol / water, stirred for several hours, extracted with ethyl acetate and evaporated organic layer. Column purified using Biotage SP4 40+M silica cartridge with ethyl acetate / hexanes solvent system. Freeze dried the resulting oil, collected solids provided 8-Chloro-l,2,3,4- tetrahydrocarbazole.NMR 500 MH D6DMSO: 7.30. d. IH, 7.04, d, IH, 6.93, t, IH, 2.73, t, 2H, 2.62, t, 2H, 1.98-1.76, m, 4H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In ethanol; for 5h;Heating / reflux; | A mixture of 2-dichlorophenyl hydrazine hydrochloride (13.4 g, 75 mmol) and diethylacetylene dicarboxylate (12.0 ml, 75 mmol) in dry ethanol (200 ml) was treated with solid potassium carbonate (20.7 g, 150 mmol) and the resulting slurry mixture was heated at reflux for 5 hrs. The reaction mixture was cooled to room temperature and concentrated down to about 150 ml. A 1N HCl solution (100 ml) was added to the ethanol mixture to acidify the mixture, followed by 300 ml of water to precipitate out the product as an orange solid I-1a (17.4 g, 87percent). The solid was isolated by filtration, washed with water, and dried in the oven overnight. 1H NMR (400 MHz, CD3OD) delta 7.62-7.46 (m, 4H), 6.00 (s, 1H), 4.35 (q, 2H), 1.36 (t, 3H); MS (m/z) 267.3 (M+); HPLC (method A): retention time: 1.7 min. |
87% | A mixture of 2-dichlorophenyl hydrazine hydrochloride (13.4 g, 75 mmol) and diethylacetylene dicarboxylate (12.0 ml, 75 mmol) in dry ethanol (200 ml) was treated with K2CO3 (20.7 g, 150 mmol) and the resulting slurry mixture was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature, concentrated down to about 150 ml, and acidified with 1 N HCI (~100 ml). Addition of H20 (350 mi) resulted in the formation of orange precipitate which was collected by filtration and dried in an oven overnight to yield the product, 5-chloro-1- (2-chloro-phenyl)-4-formyl-1 H-pyrazole-3- carboxylic acid ethyLester 1-1a (17.4g, 87percent) :'H NMR (400 MHz, CD30D) 8 7.62-7. 46 (m, 4H), 6.00 (s, 1 H), 4.35 (q, 2H), 1.36 (t, 3H); MS (m/z) 267.3 (M+); HPLC (method A): retention time: 1.7 minutes | |
64% | With potassium carbonate; In ethanol; at 90℃; for 24h; | Reference Example 199 Ethyl 5-hydroxy-1-(2-chlorophenyl)-1H-pyrazole-3-carboxylate A mixture of 2-chlorophenylhydrazine hydrochloride (10 g), diethyl but-2-ynedioate (9.5 g) and potassium carbonate (15.5 g) was stirred in ethanol (200 mL) at 90° C. for 24 hr. The reaction mixture was allowed to cool to room temperature, acidified with 6 mol/L hydrochloric acid, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate-diisopropyl ether to give the title compound as an orange solid (9.6 g, yield 64percent). 1H-NMR (DMSO-d6) delta: 1.28 (3H, t, J=7.2 Hz), 4.25 (2H, q, J=7.2 Hz), 5.90 (1H, s), 7.47-7.66 (3H, m), 7.67 (1H, d, J=7.5 Hz), 11.82 (1H, brs). |
With potassium carbonate; In ethanol; for 18h;Heating / reflux; | To a stirred solution of 2-chlorophenylhydrazine hydrochloride (22.4 g) and potassium carbonate (34.5 g) in ethanol (250 ml) was added diethyl acetylenedicarboxylate (20 ml) and the resulting mixture was heated at reflux for 18 hours. The reaction mixture was cooled, 6 N hydrochloric acid (75 ml) and water (500 ml) were added sequentially. The reaction mixture was extracted with ethyl acetate, the organic layer washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The resulting gum was stirred with isopropyl ether (250 ml) to afford the title compound (I-1a) as a tan solid, (23 g) after filtering and drying in vacuo |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 17h; | Example 4 Preparation of 2-(4-Chloro-phenyl)-5-cyclopentyl-1-(2-fluoro-phenyl)-5 6-dihydro-1H-pyrrolo[3.4-d]imidazol-4-one (4A-1) A mixture of 2-(4-chloro-phenyl)-5-cyclopentylaminomethyl-1-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid I-5k (1.2 g, 2.59 mmol), EDC (994 mg, 5.18 mmol), HOAt (704 mg, 5.18 mmol), and triethylamine (1.1 ml, 7.76 mmol) in CH2Cl2 (200 ml) was stirred for 17 hours at room temperature. The reaction mixture was washed with sat'd aq NaHCO3 and sat'd aq. NaCl, dried and concentrated in vacuo. The crude residue was purified on SiO2-gel using a solvent gradient of 30percent EtOAc/hexanes to 60percent EtOAc/hexanes to give 4A-1 as a white solid (752 mg, 73percent): +APCI MS (M+1) 396.2; 1H NMR (CDCl3): delta 7.61-7.59 (m, 2H), 7.42-7.37 (m, 6H), 4.60 (m, 1H), 4.50 (s, 2H), 2.0 (m, 2H), 1.8-1.65 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | 4-(4-Chlorophenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester lithium salt I-6a (30.26 g, 116 mmoles) was suspended in 242 ml of ethanol. <strong>[41052-75-9]2-Chlorophenylhydrazine hydrochloride</strong> (20.88 g, 116 mmoles) was added portionwise as a solid over 45 minutes while maintaining an internal temperature between 30-40 C. Note: Reaction mixture goes from a yellow suspension to a dark orange suspension. Reaction stirred for 3 hours while maintaining internal temperature between 25-35 C. An aqueous potassium hydroxide solution (148 ml of 1.8 M solution, 266 mmoles) was added over 20 minutes while maintaining an internal temperature between 20-30 C. The reaction mixture was held for 2.5 hours. Note: Within 30 minutes of potassium hydroxide solution addition, reaction turned almost clear, very dark rust orange in color. Aqueous hydrochloric acid (85 ml of 3.9 M solution, 331 mmoles) was added over 15 minutes while maintaining reaction temperature between 20-30 C. Note: Product precipitated during hydrochloric acid addition. The precipitated product was granulated for 16 hours at room temperature. The crude product was isolated by filtration and the filtercake was washed with 150 ml of water. Note: Filtercake was a yellowish orange solid. After air-drying for 30 minutes, the filtercake was suspended in 480 ml of methanol. This suspension was heated to reflux to give a clear dark orange solution (all solids in solution within 1 hour of reaching reflux) that was held at reflux for 8 hours. The solution was cooled over 4 hours to room temperature, during which time product had precipitated from solution. The reaction mixture was held at room temperature for 10 hours, followed by cooling to 0 C., and stirring for 1.5 hours. Collection of the precipitate by filtration, washing the resulting filtercake with 150 ml of ice-chilled methanol, and drying at 60 C. and 1 mm for 3 hours afforded 1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid I-6b (29.28 g, 76percent) as an off-white solid. 1H-NMR (CD3CN): ? 7.58-7.45 (m, 4H), 7.31 (d, 2H, J=8.7 Hz), 7.21 (d, 2H, J=8.7 Hz), 7.10 (s, 1H). Mass Spec (ESI): M+1=333.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With sodium ethanolate; In ethanol; at 140℃; | To a solution of sodium ethoxide (42 mmol) in absolute ethanol (22 ml) were added diethylmalonate (2.12 ml, 14.0 mmol) and 2-chlorophenylhydrazine hydrochloride (2.5 g, 14.0 mmol). The volatiles were immediatly distilled at atmospheric pressure and the resulting residue was further heated at 140°C to dryness. After cooling to room temperature, the residue was dissolved in water (50 ml). Neutral was removed from the aqueous solution by extraction with diethyl ether (2 x 100 ml). The aqueous phase was then acidified to pH 1 by addition of 1N aqueous HC1 and extracted with EtOAc (3 x 100 ml). The combined organic phases were washed with H, O (50 ml), brine (50 ml), dried over MGSO4, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel using a gradient of MEOH in CH2CL2 as eluent to yield the title compound (500 mg, 17percent) as a pale brown solid: TR = 3.48 MIN, MS (POS. ) : m/z 211.1 [M+H] + ; MS (NEG. ) : m/z 208.8 [M-H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine; In methanol; at 0 - 20℃; for 24.25h;Heating / reflux; | Intermediate 30: N'-(2-Chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester A solution of di-tert-butyl dicarbonate (101.2 g, 464 mmol) in methanol (300 mL) was added dropwise over 15 min to a cooled (~0° C.) solution of triethylamine (162 mL, 1.16 mol), 2-chlorophenylhydrazine hydrochloride (69.4 g, 388 mmol) and methanol (350 mL). The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 2 h, at reflux for 6 h, and then at room temperature for 14 h. A further quantity of di-tert-butyl dicarbonate (4.2 g, 19 mmol) was added and the solution was heated at reflux for 2 h. The mixture was concentrated to dryness and ethyl acetate (1 L) was added. The solution was washed with water (4*1 L), saturated aqueous sodium hydrogen carbonate (600 mL) and brine (400 mL). The organic phase was dried (sodium sulfate), filtered, and evaporated. The resulting red solid was ground and triturated several times with hexanes (total volume: 350 mL) and the resulting material was dried under high vacuum overnight to give N'-(2-chloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (77.8 g, 83percent) as a light tan powder. |
83% | With potassium carbonate; In tetrahydrofuran; water; at 20℃; for 96h; | Dissolve <strong>[41052-75-9]o-chlorophenylhydrazine hydrochloride</strong> (5.0 g, 28.0 mmol), potassium carbonate (138 g, 11.6 mmol) and DI-T-BUTYL-DICARBONATE (11.6 g, 84.0 mmol) in THF (50 mL) and water (50 mL) and stir at RT. After 4 days, evaporate off the organics, add 20percent IPROH/CHCI and wash with saturated aqueous NaHC03, and brine. Dry the organic layer over sodium sulfate, filter, and concentrate to dryness. Purify the residue by chromatography using an EtOAc/hexanes gradient to afford the title compound (5.65 g, 83percent) as a white solid. MS (ES) 241.0 (M-])-; RF= 0. 13 (10percent EtOAc/hexanes); Dissolve 2-chlorophenylhydrazine hydrochloride (5.0 g, 1.0 eq. ) in H20 (50 mL) and THF (50 mL). Add K2CO3 (11.6 g, 3.0 eq) and di-t-butyl-dicarbonate (6.1 g) and stir at RT. After 72 h, concentrate the mixture in vacuo. Dissolve the residue in 20percent IPROH/CHC13 and wash with water, saturated aqueous NaHC03, and brine. Dry the organic layer over NA2SO4, filter, and concentrate. Purify the residue by chromatography over silica gel to provide the title compound. MS (ES-) 241.0 (M-1)-; RF= 0.13 (10percent EtOAc/hexanes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Dissolve sodium metal (1.5 g, 64.4 mmol) in n-butanol (25 mL) then add 2- chlorophenylhydrazine hydrochloride (5.0 g, 28.0 mmol). To this mixture, add methyl acrylate (3.8 mL, 42.0 mmol) in a dropwise fashion, then warm the mixture to reflux. After 5 h. , add water (100 mL) while the solution is still hot, then adjust the pH of the solution with to pH = 6 with 50percent aqueous acetic acid. Wash with water and filter the precipitate. Rinse the precipitate with ether and dry on vacuum pump to afford 3.67 g (67percent) of the title compound as a white solid. MS (ES) 197.1 (M+1) + ; RF= 0.4 |
Yield | Reaction Conditions | Operation in experiment |
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With hydrogenchloride; In water; at 20℃; for 0.833333h; | EXAMPLE 1; Preparation of 3-bromo-1-(2-chlorophenyl)-N-r 4-cyano-2-methyl-6-r((1-methylethvl)amino) -carbonvflphenyfl - lH-pvrazol-5-carboxamide; Step A: Preparation of (2E) -[(2-chlorophenyl)hydrazono]acetic acid; To a solution of 2-chlorophenyl hydrazine hydrochloride (18.8 g, 0.105 mol) in water (300 mL) at room temperature was added concentrated hydrochloric acid (13.2 g, 0.136 mol), followed by dropwise addition over 20 minutes of 50percent glyoxylic acid (17.1 g, 0.115 mol) to form a thick precipitate. The reaction mixture was then stirred for 30 minutes. The product was isolated by filtration, washed with water, and then dissolved in ethyl acetate (400 mL). The resulting solution was dried (MgS04) and concentrated under reduced pressure to afford the title product as a tan solid (20.5 g). 1H NMR (Me2SO-d6) No. 12.45 (s, 1H), 10.7 (s, 1H), 7.59 (d, 1H), 7.54 (s, 1H), 7.40 (d, 1H), 7.23 (t, 1H), 6.98 (t, 1H). | |
20.5 g | With hydrogenchloride; In water; at 20℃; for 0.333333h; | Step A: Preparation of (2E)-[(2-chlorophenyl)hydrazono]acetic acid To a solution of 2-chlorophenyl hydrazine hydrochloride (18.8 g, 0.105 mol) in water (300 mL) at room temperature was added concentrated hydrochloric acid (13.2 g, 0.136 mol), followed by dropwise addition of 50percent glyoxylic acid (17.1 g, 0.115 mol) over 20 minutes to form a thick precipitate. The reaction mixture was then stirred for 30 minutes. The product was isolated by filtration, washed with water, and then dissolved in ethyl acetate (400 mL). The resulting solution was dried (MgSO4) and concentrated under reduced pressure to afford the title product as a tan solid (20.5 g). 1H NMR (DMSO-d6) delta 12.45 (s, 1H), 10.7 (s, 1H), 7.59 (d, 1H), 7.54 (s, 1H), 7.40 (d, 1H), 7.23 (t, 1H), 6.98 (t, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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83% | In acetic acid; for 3h;Heating / reflux; | 8-Chloro-2,3,4,9-tetrahydro-lH-carbazole-3-carboxylic acid A mixture of 4-oxo-cyclohexanecarboxylic acid (3.1 g, 21.7 mmol) and 2- chlorophenylhydrazine hydrochloride (4.O g, 21.7 mmol) in glacial acetic acid (740 ml) is stirred at reflux for 3 h. The solvent is evaporated and water is added to the residue. The resulting precipitate is filtered off and dried under high vacuum to give the subtitle compound as a brownish solid (4.5 g) in 83% yield. XR (LC-5) 0.88 min; ESI-MS (positive ion): m/z 250.14 [M+Eta]+ (calcd 249.70 for C13Hi2NO2Cl). 1H-NMR (DMSO-^6): 1.75 (m, IH); 2.14 (m, IH); 2.62 (m, 5H); 6.90 (t, J=7.9 Hz, IH); 7.02 (d, J=7.3 Hz, IH); 7.30 (d, J=7.6 Hz, IH); 7.92 (br s, IH); 10.9 (br s, IH). |
83% | In acetic acid; for 3h;Reflux; | A mixture of 4-oxo-cyclohexanecarboxylic acid (3.1 g, 21.7 mmol) and 2-chlorophenylhydrazine hydrochloride (4.0 g, 21.7 mmol) in glacial acetic acid (740 ml) is stirred at reflux for 3 h. The solvent is evaporated and water is added to the residue. The resulting precipitate is filtered off and dried under high vacuum to give the subtitle compound as a brownish solid (4.5 g) in 83% yield. tR (LC-5) 0.88 min; ESI-MS (positive ion): m/z 250.14 [M+H]+ (calcd 249.70 for C13H12NO2Cl). 1H-NMR (DMSO-d6): 1.75 (m, 1H); 2.14 (m, 1H); 2.62 (m, 5H); 6.90 (t, J=7.9 Hz, 1H); 7.02 (d, J=7.3 Hz, 1H); 7.30 (d, J=7.6 Hz, 1H); 7.92 (br s, 1H); 10.9 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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43% | With hydrogenchloride; sulfuric acid; In ethanol; | EXAMPLE 112A Ethyl 7-chloro-3-methyl-1H-indole-2-carboxylate A mixture of 2-chlorophenylhydrazine hydrochloride (2.75 g, 15.38 mmol) and 2-oxo-butyric acid ethyl ester (2.0 g, 15.38 mmol) in ethanol (40 mL) was treated with concentrated H2SO4 (6 drops), heated to reflux for 2 hours, cooled to room temperature, treated with HCl gas for about 3 minutes, heated to reflux for 90 minutes, cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was recrystallized from ethanol to provide the desired product (1.56 g, 43%). MS (CI) m/e 238 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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12% | 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 30percent 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 0-5percent methanol in chloroform. (Note: In the case of 4-methoxyphenyl hydrazine hydrochloride 6d, schiff's base gets cyclized instantaneously without acid to afford 1d) | |
0.3724 g (18%) | In dichloromethane; water; acetone; trifluoroacetic acid; | Preparation 4 8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one <strong>[41052-75-9]2-Chlorophenylhydrazine hydrochloride</strong> (1.6885 g, 0.0094 mol) is added portion-wise to a solution of 1,3-cyclohexanedione (1.0316 g, 0.0092 mol) in water (17.4 mL). The mixture is allowed to stir for three days at room temperature. The solids are collected by filtration, washed with water and vacuum dried at 50° C. for 30 min and then overnight at room temperature to give the hydrazone. The hydrazone is then heated at reflux in trifluoroacetic acid (9 mL). After stirring overnight, the mixture is cooled and then partitioned between ice water and dichloromethane. The organic layer is washed with aq. sodium bicarbonate and the aqueous layer is backwashed with dichloromethane. The combined organic layers are then dried over sodium sulfate and concentrated to a foam. Product is precipitated from the foam by adding dichloromethane, methanol and acetone. After filtering the solids, the filtrate is concentrated to a foam and again more product is precipitated using acetone/dichloromethane (2/98). The solids are collected by filtration and the filtrate is chromatographed on silica gel (150 mL) using acetone/dichloromethane (2/98 and 4/96) to give product. All of the solids are combined and recrystallized from dichloromethane/methanol/hexane to give 0.3724 g (18percent) of a first crop and 0.1092 g (5percent) of a second crop of the title compound; mp >247° C.; MS (ESI-) for C12H10ClNO m/z 217.9 (M-H)-; IR (drift) 3155, 3142, 3105, 3080, 2943, 1633, 1613, 1473, 1174, 1139, 1071, 1015, 858, 791, 744 cm-1; 1H NMR (CDCl3) delta2.28, 2.61, 3.03, 7.22, 8.11, 8.60. Anal. Calcd for C12H10ClNO: C, 65.61; H, 4.59; N, 6.38. Found: C, 65.48; H, 4.62; N, 6.38. |
Yield | Reaction Conditions | Operation in experiment |
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70% | With hydrogenchloride; diphenylphosphoranyl azide; triethylamine; In ethanol; water; toluene; | REFERENTIAL PRODUCTION EXAMPLE 1 Preparation of 1-(2-chlorophenyl)-1,2,4-triazol-5-one 25 g of 2-chlorophenylhydrazine hydrochloride was dissolved in 230 ml of water. To the resulting solution, 29 g of an aqueous solution of 40percent of glyoxylic acid was added dropwise under ice-cooling. The resulting mixture was stirred for 2 hours at a temperature of 10 to 20° C. and the powder thus deposited was recovered by filtration under suction and then washed with water. The resulting powder was dried under reduced pressure in a desiccator to obtain 27.2 g of a brown powder. 27.2 g of the powder so obtained was suspended in 400 ml of toluene, and 14 g of triethylamine was added dropwise to the resulting suspension, followed by adding dropwise 37.8 g of diphenylphosphoryl azide to it. The resulting mixture was stirred under heating for 4 hours at 70 to 80° C. and further for 2 hours at 100° C. The resulting reaction solution was allowed to cool and then extracted with 760 ml of 1N aqueous potassium hydroxide solution under cooling with ice-water. The alkaline aqueous layer obtained as the extract solution was made acidic by adding 160 g of a concentrated hydrochloric acid portionwise. The crystals thus deposited were separated by filtration and washed with water. The resulting crystals were dissolved in a mixed solvent of toluene and ethanol, and the solution obtained was subjected to azeotropic distillation under reduced pressure to remove water therefrom. The crystals so obtained were recrystallized from ethyl acetate to obtain 19.1 g of the titled target compound (at a yield of 70percent). Melting point of 155 to 156° C. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium methylate; sodium acetate In methanol; water; acetic acid; ethyl acetate | 1.a Manufacture of 1-(2-chlorophenyl)-3-methoxycarbonyl-5-phenylpyrazole STR27 (a) 19.3 g (0.105 mol) of 2-chlorophenylhydrazine hydrochloride (97% strength) and 8.6 g (0.105 mol) of sodium acetate are added to a solution of 21.2 g (0.103 mol) of benzoylpyruvic acid methyl ester in 100 ml of glacial acetic acid. After the reaction mixture has been boiled under reflux for 2 hours, it is cooled to room temperature and then poured into ice-water. The resin formed is taken up in ethyl acetate and washed neutral with water and 1M soda solution. The organic phase is separated off, dried over sodium sulphate and concentrated in a rotary evaporator. The oil that remains is crystallized from diisopropyl ether. 17.6 g of title product having a melting point of 67°-70° are thus obtained. The benzoylpyruvic acid methyl ester required as starting material is prepared in the following manner: STR28 (b) A mixture of 75 ml (0.405 mol) of 30% sodium methoxide solution and 30 ml of methanol is cooled to 0°, and then 48 g (0.4 mol) of acetophenone are added slowly while stirring. A solution of 47.2 g (0.4 mol) of oxalic acid dimethyl ester in 100 ml of methanol is added dropwise to the mixture while stirring at 8°-10°. The reaction mixture becomes turbid and finally a thick yellow precipitate is formed which can hardly be stirred. Sufficient methanol is added to make it possible to stir the reaction mixture again. After stirring for a further 3 hours at room temperature, the whole is filtered with suction and the precipitate is washed with diethyl ether and subjected to suction until dry. The filter material is suspended in water and adjusted to pH 4 with glacial acetic acid while stirring and cooling whereupon the benzoylpyruvic acid methyl ester is formed. It is filtered off, washed with ice-water and dried over phosphorus pentoxide in an desiccator. 42 g of ester having a melting point of 56°-58° are obtained. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 8 8-Chloro-3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole Following the procedure given in Example 3 and using 7.05 g. of <strong>[40594-34-1]4-dimethylaminocyclohexanone</strong> and 8.95 g. of o-chlorophenylhydrazine hydrochloride there was obtained 4.9 g. of 8--chloro-3-(dimethylamino)-1,2,3,4-tetrahydrocarbazole which melted at 154-157C. (corr.). Test procedure 1b: active at 50 mg./kg. Test procedure 5: active at 100 mg./kg. (IP) Test procedure 7: active at 33.5 +- 6.5 mg./kg. |
Yield | Reaction Conditions | Operation in experiment |
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<strong>[41052-75-9]2-Chlorophenylhydrazine hydrochloride</strong> (1.0 g) suspended in 6.0 ml of diethyl ether was dropped into 5 ml of concentrated hydrochloric acid cooled at 0°C. After the reaction solution was stirred for 10 minutes, 462 mg of sodium nitrite dissolved in 2.0 ml of water was dropped into the reaction solution and the mixture was stirred for 2 hours together with raising the temperature up to room temperature. Water was added to the reaction solution, the mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with a saturated aqueous saline solution and dried over sodium sulfate. The solvent was evaporated in vacuo to give 506 mg of the title compound as a red oily crude product. |
Yield | Reaction Conditions | Operation in experiment |
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Step B: Ethyl 5-[4-(benzyloxy)phenyl]-l-(2-chlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate Ethyl 3-[4-(benzyloxy)phenyl]-2-methyl-3-oxopropanoate lithium salt or lithium-l-[4- (benzyloxy)phenyl]-4-ethoxy-2-methyl-3,4-dioxobut-l-en-l-olate (3.66 g, crude) and (2- chlorophenyl)hydrazine hydrochloride (1.30 g, 7.26 mmol) were mixed in ethanol (50 ml) and reacted at room temperature for 16 hours. The solvent was evaporated and the mixture was suspended in acetic acid (40 ml). The temperature was increased to 1000C and the reaction continued for 4 hours. The solvent was evaporated. Water and DCM were added. The phases separated and the organic phase washed with water and dried over MgSO4. The EPO <DP n="55"/>product was purified further by flash chromatography (SiO2, heptane/ethyl acetate, product came at 30percent ethyl acetate) (771 mg, 10percent for two steps).1H NMR (399.964 MHz) delta 7.50-7-25 (m, 9H), 7.10 (d, 2H), 6.90 (d, 2H), 5.01 (s, 2H),4.46 (q, 2H), 2.36 (s, 3H), 1.43 (t, 3H). MS m/z 447, 449 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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85% | Into a 500 mL flask was weighed 25.0 g (139.6 mmol) of 2-chlorophenylhydrazine hydrochloride, 27.4 g (153 mmol) of 4,4,4-trifluoro-1-furan-2-yl-butane-1,3-dione, and 200 mL of acetic acid. The resulting solution was heated at 80 °C for 18 h then was cooled and was washed into a separatory funnel with 1.0 M NaOH and ethyl acetate. The ethyl acetate was separated, washed with 1.0 M NaOH, brine, dried (Na2SO4), and was concentrated in vacuo. The residue was filtered through a short column of silica gel affording 1-(2- chlorophenyl)-5-furan-2-yl-3-trifluoromethyl-1H-pyrazole as a brown oil, yield: 37.31 g (85percent); MS (ES): 313 [M+H]+. | |
With sodium acetate; In acetic acid; | Step A Preparation of 1-(2-Chlorophenyl)-5-(2-furanyl)-3-(trifluoromethyl)-1H-pyrazole To a solution containing 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (30.0 g, 146 mmol) in glacial acetic acid (65 mL) was added sodium acetate (12.1 g, 148 mmol). The mixture was cooled to about 25° C., 2-chlorophenylhydrazine hydrochloride (25.6 g, 145 mmol) was added portionwise and, following a mild exotherm, the mixture was heated to 60° C. for 4 h, then cooled to 25° C. The mixture was diluted with dichloromethane (400 mL) and the organic phase was washed with water (3*250 mL), saturated aqueous sodium carbonate (2*250 mL) and brine, then dried over magnesium sulfate and evaporated under reduced pressure to yield 43.2 g of the title compound as a brown oil. 1H NMR (CDCl3): delta 7.6 (m, 5H), 6.9 (1H), 5.7 (d, 1H). | |
With sodium acetate; acetic acid; at 20 - 60℃; for 1h; | To a mixture of 12.96 g of 4 , 4 , 4-trifluoro-1- (2-furyl) - 1, 3-butanedione, 8.56 g of sodium acetate and 40 ml of acetic acid was added 11.26 g of 2-chlorophenylhydrazme hydrochloride at room temperature. The mixture was stirred at 6O0C for 1 hour, and concentrated under reduced pressure . After the reaction mixture was concentrated under reduced pressure and water was poured into the residue, the mixture was extracted with chloroform three times. The organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 18.43 g of 1- (2-chlorophenyl) -5- (2-furyl) -3-trifluoromethyl-lH-pyrazole of the formula: EPO <DP n="493"/>1- (2-Chlorophenyl) -5- (i2-furyl) -3-trifIuoromethyl-1H- pyrazole1H-NMR (CDCl3, TMS) delta (ppm) : 5.76 (IH, d, J=3Hz) , 6.31 (IH, dd, J=3Hz, 2Hz), 6.95 (IH, s), 7.40 (IH, d, J=2Hz), 7.43-7.59 (4H, m) . |
Yield | Reaction Conditions | Operation in experiment |
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With potassium acetate; In ethanol; at 20℃; for 30h; | Example 1B; Preparation of N-[2-(1-(2-chlorophenyl)hydrazono)ethyl-4-chlorophenyl]-trifluoromethanesulfonamide (Compound 149); <strong>[41052-75-9]2-Chlorophenylhydrazine hydrochloride</strong> (0.656 g, 3.66 mmol) was stirred with anhydrous potassium acetate (0.36 g, 3.66 mmol) in EtOH (20 mL). A solution of N-(2-acetyl-4-chlorophenyl)-trifluoromethanesulfonamide (1.00 g, 3.33 mmol) in EtOH (8 ml) was added and the reaction stirred at RT for 30 hours. The solvent was removed under vacuum and the residue partitioned between EtOAc and water. The organic phase washed with brine and dried (MgSO4). Removal of the solvent generated a slightly coloured solid (1.390 g). The crude product was recrystallized from DCM/PE to give 1.105 g of the product. The mother liquor was subjected to chromatography on a silica using 15percent DCM/PE to give more product (0.182 g). M.p. 137.5-139° C. 1H n.m.r (CDCl3) 12.58, 1H, s; 7.94, 1H, s br; 7.70, 1H, d, J8.8 Hz; 7.53, 1H, d, J2.1 Hz; 7.36-7.30, 4H, m; 6.94, 1H, m; 2.42, 3H, s. |
Yield | Reaction Conditions | Operation in experiment |
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41% | In acetic acid; at 60℃; for 0.25h; | 500 mg (0.00156 mol) of the intermediate compound (VI.1) are suspended in 8 ml 15 glacial acetic acid, combined with 400 mg (0.00223 mol) 2-chlorophenylhydrazine-hydrochloride. The mixture is stirred for 0.25 hours at 60° C., then cooled to ambient temperature. After the addition of 50 ml of water a precipitate is obtained. This is stirred for 5 minutes at 5° C., suction filtered and dried. Recrystallisation from methanol. Yield: 214 mg (=41percent of theoretical) of the intermediate compound (VIII.1) Mp: 255°-260° C. |
Yield | Reaction Conditions | Operation in experiment |
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52% | In ethanol; at 90 - 95℃; for 18h; | Example 10a Preparation of 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol <n="165"/>Into a 250 mL flask was weighed 5.01 g of 4,4,4-trifluoro-3-oxo-butyric acid ethyl ester, 4.88 g of 2-chlorophenylhydrazine hydrochloride, and 100 mL of ethanol. The resulting solution was heated at 90-95 °C for 18 h then was concentrated in vacuo to remove ethanol. The residue was washed into a separatory funnel with ethyl acetate and 1 M HCl. The ethyl acetate was separated, washed with brine, was dried, and concentrated in vacuo. The residue was partially purified by silica gel flash chromatography (Jones Flashmaster, 70 g Silica gel, gradient elution from 100percent hexanes to 20percent ethyl acetate over 30 minutes). Appropriate fractions were combined and concentrated and product was precipitated by addition of excess hexanes. The solid precipitate was collected by filtration and was dried under high vacuum to afford the intermediate 2-(2-Chlorophenyl)-5-trifluoromethyl-2H-pyrazol-3-ol as a tan powder, yield: 3.73 g (52percent). 1H NMR (DMSO-d6): delta 12.25(br s, 1H), 7.72(d, J= 8 Hz, 1H), 7.5-7.65(m, 3H), 5.94(s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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70% | With hydrogenchloride; In methanol; for 4h;Heating / reflux; | Preparation of 5-(5-bromo-thiophene-2-yl)- 1-(2-chloro-phenyl)-1H-pyrazole-3-olTo a solution of 3-(5-bromo-thiophen-2-yl-3-oxo-propionic acid methyl ester (2.0 g, 7.60 mmol) in 1.2 M HCl in MeOH (20 mL) was added 2-chlorophenylhydrazine hydrochloride (1.43 g, 7.98 mmol). The reaction mixture was heated to reflux for 4 hours and cooled off. The solvent was evaporated and the residue was purified by flash column chromatography with 10percent ethyl acetate in hexane. The product 5-(5-bromo-thiophene-2-yl)-1-(2-chloro- phenyl)-1H-pyrazole-3-ol was recovered as a white solid (1.89 g, 70percent yield. MS (ES): 355 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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44% | Dissolve sodium metal (1.5 g, 2.3 eq) in n-butanol (25 mL), then add 2- chlorophenylhydrazine hydrochloride (5.0 g, 1.0 eq. ) and stir 15 min. Add methyl, 3,3- dimethylacrylate (3.8 mL, 1.5 eq. ) dropwise, then heat the mixture to reflux. After 5 h., add H20 (100 mL) while the solution is still hot, then cool to RT and acidify to pH = 6 with 50percent aqueous acetic acid. Wash with IN NAOH, saturated NAHC03, and brine. Dry over NA2SO4, filter and concentrate. Purify the residue by column chromatography over silica gel to provide the title compound (44percent yield). MS (ES) 170.6 (M+1) + ; RF= 0.55 (1 : 1 EtOAc/hexanes). |
Yield | Reaction Conditions | Operation in experiment |
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[0237] 4-(4-Chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester lithium salt (10 g, 38.37 mmol) was dissolved in acetic acid (400 ml). After the solution was cooled to 10[deg.] C. with an ice-water bath, a concentrated aqueous solution of sodium nitrite (2.86 g, 40.29 mmol) was added dropwise, keeping the temperature between 10 and 15[deg.] C. The reaction mixture was stirred for another 45 minutes, and 2-chlorophenylhydrazine HCl salt (8.5 g, 46.04 mmol) was added in portions. Stirring was continued for 3 hours. Upon completion of the reaction, the reaction mixture was poured into 600 ml ice-cold water. A yellow solid precipitated and after 2 hours, it was collected, washed with water, and dried to give crude 4-(4-chlorophenyl)-2-[(2-chlorophenyl)hydrazono]-3-nitroso-4-oxobutyric acid ethyl ester which was used in the next step without further purification. | ||
[0140] A portion of 4-(4-chlorophenyl)-2-hydroxy-4-oxobut-2-enoic acid ethyl ester lithium salt obtained from the previous step (10 g, 38.37 mmol) was dissolved in acetic acid (400 ml). After the solution was cooled to 10° C. with an ice-water bath, a concentrated aqueous solution of sodium nitrite (2.86 g, 40.29 mmol) was added dropwise, keeping the temperature between 10° C. and 15° C. The reaction mixture was stirred for another 45 minutes, and 2-chlorophenylhydrazine HCl salt (8.5 g, 46.04 mmol) was added in portions. The reaction mixture was stirred for 3 hours and poured into ice-cold water (600 ml). A yellow solid precipitated out of solution and after 2 hours it was collected by filtration, washed with water, and dried to give crude 4-(4-chlorophenyl)-2-[(2-chlorophenyl)hydrazono]-3-ni- troso-4-oxobutyric acid ethyl ester which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A portion of the product from the previous step (10 g, 38.37 mmol) was dissolved in 400 ml acetic acid. After the solution was cooled to 10 C. with an ice-water bath, a concentrated aqueous solution of sodium nitrite (2.86 g, 40.29 mmol) was added dropwise, keeping the temperature between 10 and 15 C. The reaction mixture was stirred for another 45 minutes, and 2-chlorophenylhydrazine HCl salt (8.5 g, 46.04 mmol) was added in portions. Stirring was continued for 3 hours. Upon completion of the reaction, the reaction mixture was poured into 600 ml ice-cold water. A yellow solid precipitated and after 2 hours it was collected, washed with water and dried to give crude 4-(4-chlorophenyl)-2-[(2-chlorophenyl)hydrazono]-3-nitroso4-oxobutyric acid ethyl ester which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Concentrated hydrochloric acid (30mmol, 2.5mL, 12M) was added to phenylaniline (10mmol) and the resulting white suspension was cooled to 0C, then appropriate amount of water was added to dissolve the white solid. Sodium nitrite (11mmol) in 10mL of water, precooled to 0C, was slowly added to the solution of phenylaniline hydrochloride. The temperature of the reaction was maintained at 0C for 0.5h. The diazonium salt solution was treated with a solution of stannous chloride hydrate (40mmol) in 15mL of concentrate hydrochloric acid (12M), then stirred for another 4hat 0C. A light brown solid which formed was collected by filtration, washed with little precooled ethyl alcohol and dichloromethane, the crude product was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
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62% | In methanol; at 20℃; | General procedure: Suitable indoline-2,3-dione 1a-c (1.0 mmol) was dissolved in methanol (5 mL) with gentle heating, then arylhydrazine (2.4 mmol) was slowly added with stirring at room temperature. After stirring overnight, the resulting precipitate was filtered and crystallized or the reaction mixture was evaporated to dryness and the residue suitably purified. |
Yield | Reaction Conditions | Operation in experiment |
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With acetic acid; at 100℃; for 16h; | A mixture of 250 mg of 11b, 110 mg of o-Cl-phenyl hydrazine hydrochloride and 3 ml of acetic acid was heated at 100° C. for 16 hr. The reaction mixture was cooled, diluted with 10 ml of water and neutralized by addition of cold conc. aq. NH4OH. The product was extracted into ethyl acetate. The organic extract was dried and concentrated and the crude product was purified by chromatography over silica gel, using a gradient of toluene/ethyl acetate as eluent, to provide 180 mg of 11e; MS-ESI: [M+H]+ 383.15.NMR (CDCl3) delta 1.42 (t, 3, CH3), 2.95-3.18 (2bm, 4, CH2CH2), 3.78 (s, 3, OCH3), 4.45 (q, 2, CH2) 6.25 and 6.45 and 6.50 (AB, 2, Ar-H), 6.83 (d, 1, Ar-H) 7.42-7.58, (m, 4, oClPhe-H). | |
A mixture of 250 mg of Hb, 110 mg of o-Cl-phenyl hydrazine hydrochloride and 3 ml of acetic acid was heated at 1000C for 16 hr. The reaction mixture was cooled, diluted with 10 ml of water and neutralized by addition of cold cone. aq. NH4OH. The product was extracted into ethyl acetate. The organic extract was dried and concentrated and the crude product was purified by chromatography over silica gel, using a gradient of toluene/ethyl acetate as eluent, to provide 180 mg of Hc; MS-ESI: [M+H]+ 383.15. NMR (CDCl3) delta 1.42 (t, 3, CH3), 2.95 -3.18 (2bm ,4, CH2CH2), 3.78 (s, 3, OCH3), 4.45 (q, 2, CH2) 6.25 and 6.45 and 6.50 (AB, 2, Ar-H), 6.83 (d, 1, Ar-H) 7.42- 7.58, (m, 4, oClPhe-H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With triethylamine; In ethanol; for 2h;Reflux; | Example 56 - Preparation of Cmpd 42; [ General Procedure 16][0282] General Procedure 16 was followed in the preparation of Cmpd 42.General Procedure 16Intermediate 35[0283] <strong>[41052-75-9]2-Chlorophenylhydrazine hydrochloride</strong> (122 mg, 0.68 mmol, 1 eq) and Et3N (95 mu, 0.68 mmol, 1 eq) was added to a solution of Intermediate 35 (100 mg, 0.68 mmol) in EtOH (3 mL). The resulting solution was heated to reflux and allowed to stir for 2 h. The solvent was then evaporated. The crude material was purified by column chromatography over silica gel (100-200 mesh) by using a gradient mixture of 0-70percent EtOAc-hexane as the eluent to afford Cmpd 42 (70 mg, 37percent). 1H NMR: (DMSO-d6) delta 8.56 (d, J= 4.4 Hz, 1H), 7.64-7.84 (m, 3H), 7.28-7.29 (m, 1H), 6.00 (s, 1H), 5.31 (s, 2H); MS: 271 [M + H]+, 273 [M + 2 + H]+; MP: 134-137 °C; TLC: EtOAc: Rf: 0.20. |
37% | With triethylamine; In ethanol; for 2h;Reflux; | General procedure: General Procedure 16 <strong>[41052-75-9]2-Chlorophenylhydrazine hydrochloride</strong> (122 mg, 0.68 mmol, 1 eq) and Et3N (95 muL. 0.68 mmol, 1 eq) was added to a solution of Intermediate 35 (100 mg, 0.68 mmol) in EtOH (3 mL). The resulting solution was heated to reflux and allowed to stir for 2 h. The solvent was then evaporated. The crude material was purified by column chromatography over silica gel (100-200 mesh) by using a gradient mixture of 0-70percent EtOAc-hexane as the eluent to afford Cmpd 42 (70 mg, 37percent). 1H NMR: (DMSO-d6) delta 8.56 (d, J= 4.4 Hz, 1H), 7.64-7.84 (m, 3H), 7.28-7.29 (m, 1H), 6.00 (s, 1H), 5.31 (s, 2H); MS: 271 [M+H]+, 273 [M+2 +H]+; MP: 134-137°C.; TLC: EtOAc: Rf: 0.20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; In 1,4-dioxane; at 20 - 80℃; for 4.33333h; | To a suspension of 2-chlorophenyl hydrazine hydrochloride (19.7g, 0.110 mol) in dioxane (190 mL) at RT was added cone. H2SO4 (8 mL, 0.150 mol) dropwise and the reaction mixture was stirred for 10 min. To this was added N-methyl-4-piperidone (17.53 g, 0.154 mol) and the reaction mixture was stirred at RT for 20 min, then heated at 80 °C for 4h. The reaction was monitored by TLC. The solvent was evaporated and pH adjusted to pH 8-9 with saturated sodium bicarbonate solution. The product was extracted with EtOAc(3x300mL). The combined organic layer was washed with water and brine, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by recrystallization (Ether/Hexane). The filtered solid was dried in vacuo to obtain 7.5 g of product as a brown solid. 1H NMR (CDC13, freebase) d (ppm): 8.10 (bs, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 7.0 (t, 1H), 3.62 (s, 2H), 2.90 (m, 2H), 2.82 (m, 2H), 2.38 (s, 3H). | |
General Method 2.Step 1 : Preparation of compound 2-B.; [0279] To a suspension of 2-chlorophenyl hydrazine hydrochloride (2-A) (19.7 g, 0.110 mol) in dioxane (190 mL) is dropwise added cone. H2S04 (8 mL, 0.150 mol). After stirring for 10 min, N-methyl-4-piperidone (17.53 g, 0.154 mol) is added into the reaction mixture and stirring continued at RT for 20 min. The reaction mixture is then stirred at 80 °C for 4 h. The progress of reaction is monitored by TLC. The solvent is removed under reduced pressure and the pH of the residue adjusted to pH 8-9 by addition of saturated sodium bicarbonate solution. The aqueous layer is extracted with EtOAc (3x300 mL). The combined organic layer is washed with water, followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which is purified by re-crystallization (Ether/Hexane) to yield compound 2-B as a brown solid (7.5g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With triethylamine; In ethanol; at 80℃; for 2h;Inert atmosphere; | General procedure: A mixture of phenylhydrazine (0.50 mmol), ethyl 3-oxo-2-(trifluoromethyl)butanoate (0.50 mmol), and EtOH (3.0 mL) in an Ar atmosphere was stirred for 2 h at 80 °C (process A). NEt3 (0.75 mmol) was subsequently added to the mixture and was further stirred for 1 h at 80 °C (process B). After cooling to room temperature, the product was extracted to ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of NaCl, dried with Na2SO4, and then concentrated under vacuo. The product was isolated using silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1,3-bis(3-sulfopropyl)-1H-imidazol-3-ium trifluoromethanesulfonate; In water; at 100℃; for 0.333333h;Microwave irradiation; Green chemistry; | General procedure: Cyclohexanone (0.91 g, 10.0 mmol) was mixed with [(HSO3- p)2im][CF3SO3] (0.5 mmol) in water (15 mL), and phenylhydrazine hydrochloride (1.44 g, 10.0 mmol) was added. The mixture was then stirred at 100 8C for about 15 min under microwave irradiation. Reaction progress was monitored by GC?MS. After completion, the reaction mixture was cooled to room temperature, and 1,2,3,4-tetrahydrocarbazole was obtained by filtration. The remaining mixture of [(HSO3-p)2im][CF3SO3]/H2O was reused directly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; at 60℃; for 24h;Reflux; | General procedure: To a stirred solution of aryl hydrazine hydrochloride (10 mmol) and Et3N (1.52 g, 15 mmol) in EtOH (30 mL) at 60 oC, ethyl acetoacetate (1.30 g, 10 mmol) was added and stirred at reflux for 24h. After the reaction was completed, the solvent was removed under reduced pressure. The crude salt was solved in EtOAc/H2O 30:70 and stirred for 2h. Then the organic phase was separated, dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure after filtration. After recrystallization from EtOH, pure pyrazolones were obtained as white or pink solid.The pyrazolones were solved in Ac2O (20 mL) and stirred at room temperature for 12h. After the reaction was completed, the solution was diluted with H2O (200 mL) and stirred for another 2h. Then the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic phases were washed with H2O (2×100 mL), dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure after filtration. The residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate 10:1-6:1) to afford the desired products 1 in 54-83percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 mg | With acetic acid; In ethanol; at 120℃; for 6h; | Intermediate A (500 mg, 1.18 mmol) and <strong>[41052-75-9](2-chlorophenyl)-hydrazine hydrochloride</strong> (0.42 mg, 2.36 mmol) in a 3:1 mixture of acetic acid and ethanol (12 mL) was stirred at 120°C for 1 h. The reaction mixture was allowed to cool to rt. (2-Chlorophenyl)-hydrazine hydrochloride (0.42 mg, 2.36 mmol) was added. The mixture was refluxed for 5 h at 120°C, allowed to cool to rt, and concentrated. The residue was neutralized to pH 7 and the product was extracted with EtOAc. The organic layer was dried (Na2S04), filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate, 92:8) to provide 120 mg of the title compound. tR: 7.30 min (HPLC 2); ESI-MS: 528 [M+H]+(LC-MS 2); Rf= 0.32 (hexane/EtOAc, 1 : 1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In ethanol; dichloromethane; at 25℃; | General procedure: To a solution of 4-chloro-2,6-bis(trifluoromethyl)pyrimidine-5-carbonitrile (I-34; 1.88 mmol, 1 equiv) in CH2Cl2 (2 mL) was added an appropriate solution of hydrazine (2.01 mmol, 1.07 equiv) dissolved in EtOH (2-5 mL). When hydrazine hydrochlorides were used, triethylamine (2.01 mmol, 1.07 equiv) was added dropwise to the mixture. The mixture was stirred at ambient temperature from 30 min to 24 h. The solvents were removed under a stream of nitrogen (N2). The residue was dissolved in CH2Cl2 and the mixture was washed with H20. The organic layer was dried, filtered and concentrated. Purification by column chromatography gave the 4,6-bis(trifluoromethyl)-2H-pyrazolo[3,4-(i]pyrimidin-3-amines. Compounds 193 - 195 in Table 1 were made in accordance with the procedures disclose in Example 23. | |
With triethylamine; In ethanol; dichloromethane; at 20℃; | General procedure: To a solution of 4-chloro-2,6-bis(trifluoromethyl)pyrimidine-5-carbonitrile (1-34; 1.88 mmol, 1 equiv) in CH2Cl2 (2 mL) was added an appropriate solution of hydrazine (2.01 mmol, 1.07 equiv) dissolved in EtOH (2-5 mL). When hydrazine hydrochlorides were used, triethylamine (2.01 mmol, 1.07 equiv) was added dropwise to the mixture. The mixture was stirred at ambient temperature from 30 min to 24 h. The solvents were removed under a stream of nitrogen (N2). The residue was dissolved in CH2Cl2 and the mixture was washed with H2O. The organic layer was dried, filtered and concentrated. Purification by column chromatography gave the 4,6-bis(trifluoromethyl)-2H-pyrazolo[3,4-d]pyrimidin-3-amines. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; | General procedure: To a 50 mL round-bottomed flask was added 1 (97percent, 500 mg, 2.74mmol), 4-methoxyphenylhydrazine hydrochloride (2a; 456 mg,2.61 mmol), and DMF (10 mL). The reaction was allowed to stir undera N2 atmosphere at r.t. for 1 h. Ice (5 g) was added with stirring,followed by a solution of NaHCO3 (330 mg, 3.9 mmol) in H2O (5mL). The resultant precipitate was filtered, washed with H2O, anddried at 40-50 °C under vacuum overnight to obtain 3a; yield: 678mg (87percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere; | General procedure: A mixture of the enone derivative (2 mmol) and the corresponding phenylhydrazine hydrochloride (3 mmol) in 15 mL of anhydrous DMF was heated to 85 °C for 5 h under argon atmosphere. The reaction solution was cooled to room temperature and partitioned between 50 mL of diethyl ether and 20 mL of water. The organic layer was separated and washed with three 20 mL-portions of water. The aqueous layers were combined and extracted with three 20 mL-portions of diethyl ether. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using column chromatography or used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere; | General procedure: A mixture of the enone derivative (2 mmol) and the corresponding phenylhydrazine hydrochloride (3 mmol) in 15 mL of anhydrous DMF was heated to 85 °C for 5 h under argon atmosphere. The reaction solution was cooled to room temperature and partitioned between 50 mL of diethyl ether and 20 mL of water. The organic layer was separated and washed with three 20 mL-portions of water. The aqueous layers were combined and extracted with three 20 mL-portions of diethyl ether. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using column chromatography or used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere; | General procedure: A mixture of the enone derivative (2 mmol) and the corresponding phenylhydrazine hydrochloride (3 mmol) in 15 mL of anhydrous DMF was heated to 85 °C for 5 h under argon atmosphere. The reaction solution was cooled to room temperature and partitioned between 50 mL of diethyl ether and 20 mL of water. The organic layer was separated and washed with three 20 mL-portions of water. The aqueous layers were combined and extracted with three 20 mL-portions of diethyl ether. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using column chromatography or used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere; | General procedure: A mixture of the enone derivative (2 mmol) and the corresponding phenylhydrazine hydrochloride (3 mmol) in 15 mL of anhydrous DMF was heated to 85 °C for 5 h under argon atmosphere. The reaction solution was cooled to room temperature and partitioned between 50 mL of diethyl ether and 20 mL of water. The organic layer was separated and washed with three 20 mL-portions of water. The aqueous layers were combined and extracted with three 20 mL-portions of diethyl ether. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using column chromatography or used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | In N,N-dimethyl-formamide; at 85℃; for 5h;Inert atmosphere; | General procedure: A mixture of the enone derivative (2 mmol) and the corresponding phenylhydrazine hydrochloride (3 mmol) in 15 mL of anhydrous DMF was heated to 85 °C for 5 h under argon atmosphere. The reaction solution was cooled to room temperature and partitioned between 50 mL of diethyl ether and 20 mL of water. The organic layer was separated and washed with three 20 mL-portions of water. The aqueous layers were combined and extracted with three 20 mL-portions of diethyl ether. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified using column chromatography or used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Acidic conditions; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2% | 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 percent), dppf (6 mol percent), 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 |
---|---|---|
74.2% | 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 percent), dppf (6 mol percent), 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 |
---|---|---|
39% | With hydrogenchloride; In ethanol; water; at 20℃; | 5.2.1 1-(2-Chlorophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one (1) The reaction of <strong>[41052-75-9]1-<strong>[41052-75-9](2-chlorophenyl)hydrazine hydrochloride</strong></strong> (71.6 mg, 0.40 mmol) with 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (72.9 mg, 0.40 mmol) in ethanol (1.2 mL) at room temperature overnight, by a procedure similar to that for 20 using concd HCl (0.40 mL) instead of H2SO4 and the crude product was purified by flash chromatography on silica gel eluting with EtOAc/hexane (4:1), gave 1-(2-chlorophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one 1 (45.2 mg, 39percent) as a powder. 1H NMR (CD3OD, 400 MHz) delta 7.68 (d, J = 7.6 Hz, 1H), 7.60-7.52 (m, 3H), 2.54 (s, 2H), 2.47 (s, 3H), 2.40 (s, 2H), 1.09 (s, 6H); HRMS calcd for C16H18ClN2O (M+H) 289.1108, found 289.1117. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With potassium carbonate In N,N-dimethyl-formamide for 16h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With sulfuric acid; In ethanol; water; at 79℃; for 14h;Inert atmosphere; | General procedure: A mixture oflithium salt of ethyl 4-(4-chlorophenyl)-3-methyl-4-oxydo-2-oxobuten-3-oate (B, 1.0 g, 3.6 mmol), ethanol (25 ml),2,4-dichlorophenyl hydrazine hydrochloride (0.777 g,3.6 mmol), and 50 percent sulfuric acid (10 ml) was refluxed for6 h. After the reaction was complete (TLC), ethanol wasremoved under reduced pressure, and again, a second installmentof 50 percent sulfuric acid (20 ml) was added, followedby refluxing for 8 h. The reaction mixture wascooled to room temperature (35°C) and was poured ontocrushed ice, stirred for 15 min, filtered and washed withwater (20 ml). The wet solid so obtained was stirred withwater (30 ml), and the pH was adjusted to[10 with 20 percentdil. NaOH. This aqueous layer was washed with petroleumether. The aqueous layer was separated, cooled to 0°C, andpH was adjusted to 2.0 by concentrated hydrochloric acid.Solid so obtained was filtered, washed with water (100 ml)and dried to afford 2 (Kotagiri et al., 2007), (0.923 mg,65 percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sodium acetate; In ethanol; for 1h;Reflux; | General procedure: A mixture of 2 mmol of compound 1, 4 mmol of arylhydrazine hydrochloride, and 4 mmol of sodium acetate was refluxed in 25 mL of ethanol. After cooling the reaction mixture, the formed colorless precipitate was separated on a glass frit filter, washed with small amount of ethanol, water, and dried in a vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33% | To a solution of compound 5 (10 mmol) in 20 mL MeOH in 100 mL round flask, substituted phenylhydrazine hydrochloride 6 (1 equiv) was added. The reaction mixture was allowed to stir at room temperature for 1 .5-2 h until TLC detected the reaction was complete (eluting with (0361) DCM:MeOH = 10:1 ). MeOH was removed to afford a dark brown solid and the mixture was then refluxed for 2 h with 20 mL 10percent H2S04 until TLC detected the reaction complete (eluting with DCM:MeOH = 10:1 ). After cooling to room temperature, the reaction mixture was extracted with ethylacetate (1 0 mL x 4). The organic phases were combined and dried over anhydrous Na2S04. After concentrating in vacuum, compound 7a was obtained by column chromatography, which after recrystallization (0.85 g, 33percent) had an ee value: 99.3percent. Analogous conditions produced 7b with an ee value of 99.3percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.5% | 15 g of <strong>[41052-75-9]o-chlorophenylhydrazine hydrochloride</strong> was dissolved5percent potassium carbonate in a dilute solution of 240 g,And extracted with 500 mL of dichloromethane 2 to 3 times,And 11 g of trimethyl orthoacetic acid was added to the extracted organic substance100mL methanol, stirring reflux 1 ~ 2h,Then cooled to 20 ~ 30 ,Then add 8g potassium cyanate stirring 30 ~ 40min, the final temperature dropped to 0 ~ 2 ,Dropping 6 g of glacial acetic acid,And the mixture was stirred at 20 to 30 ° C for 18 to 20 hours,9g1- give o-chlorophenyl-3-methyl -1H-1,2,4- triazole-5-one,The yield of 1-o-chlorophenyl-3-methyl-1H-1,2,4-triazol-5-one was 51.5percent based on <strong>[41052-75-9]o-chlorophenylhydrazine hydrochloride</strong>. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In ethanol; water; at 50℃; for 5h;Green chemistry; | A mixture of 179.5 g of 2-chlorophenylhydrazine hydrochloride and 127 g of ethyl pyruvate in ethanol at 1275 mlEthanol and 265 ml of water in a mixed solvent, refluxed at a temperature of about 50 ° C. After 5 hours the reaction was monitored, the solvent was removed and recrystallized from 70percent aqueous ethanol. The crystals were filtered and dried to give pale yellow crystals of 2-chlorobenzene Hydrazine pyruvate phenylhydrazone 199.7 g, yield 83percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With hydrogenchloride; In water; at 20℃; for 16h;Darkness; | To a solution of hydrochloricacid (12 mL, 0.25 M, 3 mmol) was added potassium thiocyanate (0.291 g, 3 mmol) and 2-chlorophenylhydrazine hydrochloride (3 mmol). 3-pentanone (3 mmol) was added to the solution dropwise. 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 2-(2-chlorophenyl)-5,5-diethyl-1,2,4-triazolidine-3-thione as a tan solid (m.p = 178 °C, 54percent). 1H ( 400 MHz, CDCh) 8 8.29 (brs, 1H),7.58 (dt, J1=2, 12=6.4, 1H), 7.48 (dt, J1=2, 12=6.4, 1H), 7.36-7.31 (m, 2H), 1.89-1.73 (m, 4H), 1.022 (t, J=7.2, 6H) ppm;13C NMR (100 MHz, DMSO-d6) 8 177.9, 137.0, 132.5, 131.1, 129.9, 129.5,127.5, 80.9, 28.0, 7.7 ppm; IR Vmax (cm-1) 3156, 2971, 1488, 1402, 908, 767; HRMS (ESI) calcdfor C12H16ClN3S [M+Ht 270.08262, found 270.08252. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | To a suspension of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}ethanimidate (Example 2A, 4.00 g, 10.6 mmol) in dioxane (110 ml) at room temperature were added successively pyridine (1.8 ml; 23 mmol) and methyl 3-chloro-3-oxopropanoate (1.2 ml, 12 mmol). After stirring for 10 min at room temperature, <strong>[41052-75-9](2-chlorophenyl)hydrazine hydrochloride</strong> (1 : 1) (2.08 g, 11.6 mmol) was added and the resulting mixture was heated to 100C for 4 h. The volatiles were removed at a rotary evaporator. The residue was dissolved in ethyl acetate. This organic phase was washed twice with hydrochloric acid 1M, then with a saturated aqueous solution of sodium bicarbonate and with brine, dried over sodium sulfate and evaporated at a rotary evaporator. The residue was dried in high vacuum, giving the title compound (2.26 g; 97 percent purity; 36percent of th.). LC-MS (Method 2): Rt = 1.89 min; MS(ESIpos): m/z = 571 [M+H]+ 'H-NMR (400 MHz, DMSO-d6): _ [ppm] =3.49 (s, 3H), 3.80 - 3.90 (m, 3H), 3.97 - 4.04-[(m, 1H), 4.22- 4.38 (m, 1H), 5.08 (s, 2H), 6.90 (d, 1H), 7.52- 7.66 (m, 5H), 7.71- 7.79 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acetic acid at 70℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | General procedure: A solution of N-Boc amino acid (0.25 g, 1.43 mmol, 1 equiv.), HOBt (2 equiv.) and DCC (1.2 equiv.)was dissolved in THF (7.5 mL), cooled to 0 C and stirred for 15 min. The solution was treatedwith N-Aryl/Alkyl hydrazine * (1.2 equiv.) before warming to room temperature and stirring fora further 1.5 h. The mixture was then poured into sat. aq. NH4Cl (20 mL) before separating andextracting the aqueous layer with EtOAc (40 mL). The organic layer was further washed with sat.aq. NaHCO3 (20 mL) and then brine (20 mL). The combined organic layers were dried over MgSO4,filtered, concentrated and dried in vacuo. Flash chromatography (DCM/EtOH/NH3 [600:8:1], [400:8:1],[200:8:1]) afforded the desired N-Boc amino acid hydrazides. * When the hydrazine hydrochlorides were used, Et3N (1.2 equiv.) is added to neutralise the salt |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | Methyl 2- { 3-(4-chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro- 1 H1,2,4-triazol-1-yl}ethanimidate (Example 2A, 150 mg, 396 pmol) was dissolved in THF (3.0 ml) and cooled to 0C.N,N-diisopropylethylamine (280 p1, 1.6 mmol) and (tert-butylamino)(oxo)acetylchloride (77.8 mg, 475 pmol, Org Lett. 2014, 16(2 1), 5682-5685) were added and stirred for 1 h at roomtemperature. The reaction mixture was cooled to 0C and <strong>[41052-75-9](2-chlorophenyl)hydrazine hydrochloride</strong> (1:1) (78.0 mg, 436 pmol) was added.The reaction mixture was stirred for 1 h at roomtemperature and 1 h at 120C in a sealed vial under microwave irradiation. A solution of lithium hydroxide (100 mg, 4.2 mmol) in water (2.0 ml) was added and stirred for 30 mm at roomtemperature.The crude product was purified by preparative HPLC (Method 4) affording 163 mg (69% of th.) of the title compound.LC-MS (Method 2): R = 2.15 mm; MS (ESIpos): mlz = 598 [M+H]?H-NMR (400 MHz, DMSO-d6) oe [ppm]: 1.281 (16.00), 5.138 (1.64), 5.142 (1.64), 6.881 (0.71), 6.897 (0.71), 7.566 (0.86), 7.570 (0.89), 7.616 (1.19), 7.637 (1.68), 7.652 (0.68), 7.743 (1.75),7.765 (1.26), 8.085 (0.90). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Under argon, a solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-4,5-dihydro-lH-l,2,4-triazol-l-yl}ethanimidate (Example 2A, 10 g, 26.40 mmol) in 200 ml anhydrous THF was treated at 0C with 5.1 ml (29.1 mmol) /V,/V-diisopropylefhylamine and 2.67 ml (29.0 mmol) methyl chlorooxoacetate and stirred at 0C for 30 min. 5.2 g (29.1 mmol) of <strong>[41052-75-9](2-chlorophenyl)hydrazine hydrochloride</strong> was added, followed by 5.1 ml (29.1 mmol) of N,N- diisopropylethylamine. The resulting mixture was stirred 1 h at room temperature, followed by 1 h at 120C in the microwave and evaporated. The residue was retaken in ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with a saturated sodium chloride solution, dried over magnesium sulfate and purified by flash chromatography (silica gel, cyclohexane/ethyl acetate eluent) affording 10.6 g (70% of th.) of the title compound. LC-MS (Method 2): Rt = 1.95 min; MS (ESIpos): m/z = 557.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.7% | A solution of l-(dimethylamino)cyclopropanecarboxylic acid (150 mg, 1.16 mmol) in tetrahydrofuran (3.0 ml, 37 mmol) was treated with DCC (240 mg, 1.16 mmol) and HOBt (178 mg, 1.16 mmol) and stirred 30 min at room temperature. The solid was filtered off, rinsed with dichloromethane (5 ml) and the filtrate evaporated. The residue was retaken in 1,4-dioxane (4 ml), methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H- l,2,4-triazol-1-yl}ethanimidate (Example 2A; 400 mg, 1.06 mmol) and N,N-diisopropylethylamine (370 mu, 2.1 mmol) were added and the resulting mixture was stirred overnight at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1: 1) (208 mg, 1.16 mmol) was added and the resulting mixture was stirred 2 h at room temperature and overnight at reflux temperature. The reaction mixture was evaporated and the residue purified by preparative HPLC (Method 4) followed by a preparative TLC affording 4.3 mg (0.7% of th.) of the title compound.LC-MS (Method 2): Rt = 1.92 min; MS (ESIpos): m/z = 582 [M+H]+-NMR (400 MHz, DMSO-d6) delta [ppm]: 7.90-7.39 (m, 8H), 6.87 (d, 1H), 5.16-4.93 (m, 2H), 4.38-4.19 (m, 1H), 4.11-3.69 (m, 2H), 2.06-1.84 (m, 6H), 1.06-0.82 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,33-trifluoro-2-hydroxypropyl]-4,5- dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 956 mg, 2.53 mmol) in 1,4-dioxane (30 ml) was treated with Nu,Nu-diisopropylethylamine and with a solution of 3-tert-butoxy-2-(l,3-dioxo- l,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 61A, 860 mg, 2.78 mmol) in dioxane (8 ml) and stirred 30 min at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1 : 1) (497 mg, 2.78 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) followed by flash chromatography (silica gel, eluent cyclohexane/ethyl acetate) affording 840 mg (44% of th.) of the title compound which has racemized under the reaction conditions.LC-MS (Method 1): Rt = 1.25 min; MS (ESIpos): m/z = 744 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | A solution of methyl 2- {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3, 3, 3-trifluoro-2-hydroxypropyl] -4,5- dihydro- lH-l,2,4-triazol-1-yl}ethanimidate (Example 2A, 313 mg, 826 muiotaetaomicron) in tetrahydrofurane (7.9 ml) was treated with N,N-diisopropylethylamine (580 mu, 3.3 mmol) and with a solution of 2- (l,3-dioxo-l,3-dihydro-2H-isoindol-2-yl)propanoyl chloride (Example 62A, 216 mg, 909 muiotaetaomicron) in tetrahydrofurane (4 ml) and stirred 45 min at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1: 1) (163 mg, 909 muiotaetaomicron) was added. The resulting mixture was stirred 2 h at room temperature followed by 2 h at 130C under microwave irradiation and evaporated. The residue was purified by preparative HPLC (Method 4) affording 315 mg (56% of th.) of the title compound.LC-MS (Method 1): Rt = 1.09 min; MS (ESIpos): m/z = 672 [M+H]+-NMR (400 MHz, DMSO-d6) delta [ppm]: 7.92-6.72 (m, 13H), 5.67-5.41 (m, 1H), 5.28-4.94 (m, 2H), 4.44-4.18 (m, 1H), 4.09-3.67 (m, 2H), 1.89-1.60 (m, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,33-trifluoro-2-hydroxypropyl]-4,5- dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2 A, 480 mg, 1.27 mmol) in 1,4-dioxane (13 ml) was treated with N,N-diisopropylethylamine (550 mu, 3.2 mmol) and 5-oxo-D-prolyl chloride (206 mg, 1.39 mmol) and stirred 1 h at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1 : 1) (250 mg, 1.39 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 125 mg (16% of th.) of the title compound.LC-MS (Method 1): Rt = 0.94 min; MS (ESIpos): m/z = 582 [M+H]+-NMR (400 MHz, DMSO-d6) delta [ppm]: 8.06 (br s, 1H), 7.89-7.47 (m, 8H), 6.90 (d, 1H), 5.09 (s, 2H), 4.62-4.19 (m, 2H), 4.14-3.72 (m, 2H), 2.39-1.96 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | A solution of methyl 2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5- dihydro-1H-l,2,4-triazol-1-yl}ethanimidate (Example 2 A, 480 mg, 1.27 mmol) in 1,4-dioxane (13 ml) was treated with N,N-diisopropylethylamine (550 mu, 3.2 mmol) and 5-oxo-1-prolyl chloride (206 mg, 1.39 mmol) and stirred 1 h at room temperature. (2-Chlorophenyl)hydrazine hydrochloride (1 : 1) (250 mg, 1.39 mmol) was added. The resulting mixture was stirred 1.5 h at room temperature followed by overnight at reflux temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 113 mg (15% of th.) of the title compound.LC-MS (Method 1): Rt = 0.95 min; MS (ESIpos): m/z = 582 [M+H]+-NMR (400 MHz, DMSO-d6) delta [ppm]: 8.07 (br s, 1H), 7.80-7.53 (m, 8H), 6.88 (d, 1H), 5.15- 5.01 (m, 2H), 4.58-4.44 (m, 1H), 4.38 - 4.18 (m, 1H), 4.07-3.76 (m, 2H), 2.38-1.83 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With oxygen; potassium acetate; copper(I) bromide; In acetone; at 20℃; for 12h;Schlenk technique; | General procedure: Under the oxygen atmosphere, a Schlenk tube (35 mL) equipped with a magnetic bar was loaded with the NH-sulfoximine 1 (0.5 mmo), arylhydrazine chloride (2.0 equiv.), Cu(OAc)2 (20 mol%), KOAc (2.0 equiv.) in dry acetone (4.0 mL). Then the mixture was allowed to stir at room temperature for 12 h. After the completion of the reaction, as monitored by TLC analysis, the mixture was filtered through a short celite pad and washed with dichloromethane (15 mL 3). The filtrate was concentrated, and the oily crude product was puried by column chromatography using silica gel (200-300 mesh) as stationary phase and a mixture of n-hexaneand ethyl acetate (2:1) as eluent to give the corresponding arylated products 3 or 5 (Rf = ca.0.3 otherwise noted). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With [2,2]bipyridinyl; nickel(II) acetate tetrahydrate; nickel; sodium carbonate; In dimethyl sulfoxide; for 0.5h;Sonication; Green chemistry; | General procedure: The reaction of dipheyldiselenide (0.125 mmol) and 4-chloropheylhydrazinehydrochloride (0.25 mmol) was carried out in DMSO in presence of sodium carbonate (0.3 mmol), metal salt (0.05 mmol)and 2,2-Bipyridine ligand (0.1 mmol) in an ultrasonic bath as a modelreaction (Scheme 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.46% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 6h; | 500 mg of compound A4 (3.05 mmol) was dissolved in 5 mL of DCM. 643.12 mg of EDCI (3.35 mmol), 489.04 mg of HOBt (3.05 mmol), 1004.6 muL of DIEA (6.09 mmol), and 654.26 mg of B3 (3.65 mmol) were dissolved in 5 mL of DCM while stirring at room temperature. Slowly add dropwise, and the reaction is complete at room temperature for 6h. The reaction solution was added with water, extracted with ethyl acetate three times, washed with saturated brine, dried and concentrated to obtain the crude compound 8. The column chromatography gave 223.5 mg of a pale yellow product with a yield of 25.46%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: triethylamine / ethanol / 2 h / 80 °C 2: sodium hydroxide; water / ethanol / 1 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.3% | at 85℃; for 12h; | 4.1.1. 5-methyl-1-(4-((N-methylsulfiiamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylic acid (12a) General procedure: Step 2. To a solution of 8a (118 mg, 1 mmol) and 4-hydrazino-N-methylbenzenemethanesulfonamide hydrochloride (9, 252 mg, 1 mmol) in anhydrous ethanol (10 mL) was stirred at 85 °C overnight. The reaction was allowed to cool to room temperature and concentrated. The crude material was purified by Isolera Biotage LPLC (PE/EA = 30%) to give a mixture of methyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (10a) and ethyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (11a) as a white solid. |
72.3% | at 85℃; for 12h; | 4.1.1. 5-methyl-1-(4-((N-methylsulfiiamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylic acid (12a) General procedure: Step 2. To a solution of 8a (118 mg, 1 mmol) and 4-hydrazino-N-methylbenzenemethanesulfonamide hydrochloride (9, 252 mg, 1 mmol) in anhydrous ethanol (10 mL) was stirred at 85 °C overnight. The reaction was allowed to cool to room temperature and concentrated. The crude material was purified by Isolera Biotage LPLC (PE/EA = 30%) to give a mixture of methyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (10a) and ethyl 5-methyl-1-(4-((N-methylsulflamoyl)methyl)phenyl)-1H-pyrazole-3-carboxylate (11a) as a white solid. |
Tags: 41052-75-9 synthesis path| 41052-75-9 SDS| 41052-75-9 COA| 41052-75-9 purity| 41052-75-9 application| 41052-75-9 NMR| 41052-75-9 COA| 41052-75-9 structure
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