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CAS No. : | 5446-18-4 | MDL No. : | MFCD00012929 |
Formula : | C6H7Cl3N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 213.49 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 11 |
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 : | 50.63 |
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) : | -5.32 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 3.22 |
Log Po/w (WLOGP) : | 2.89 |
Log Po/w (MLOGP) : | 2.88 |
Log Po/w (SILICOS-IT) : | 1.64 |
Consensus Log Po/w : | 2.13 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.53 |
Solubility : | 0.063 mg/ml ; 0.000295 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.69 |
Solubility : | 0.0434 mg/ml ; 0.000203 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.32 |
Solubility : | 0.102 mg/ml ; 0.00048 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.77 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | 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 |
---|---|---|
To a magnetically stirred solution of the above lithium salt (0.64g, 2.0 mmol) in 10 ml_ of ethanol was added <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.47g, 2.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 20 h. The precipitate was filtered, washed with ethanol and diethyl ether, and then dried under vacuum to give a light yellow solid. This solid was dissolved in acetic acid (7 ml_) and heated under reflux for 24 h. The reaction mixture was poured into cold water and extracted multiple times with ethyl acetate. The combined extracts were washed with water, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by flash column chromatography on silica gel gave the expected ester Int. J |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-(4-chlorobenzoyl)butanoic acid; p-H2NSO2-C6H4-CO-NH-CH2-resin With dmap; dacarbazine In dichloromethane at 20℃; for 96h; Stage #2: 2,4-dichlorophenyl hydrazine hydrochloride With zinc(II) chloride In acetic acid at 70℃; for 16h; Stage #3: With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine; cyanomethyl bromide at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol; for 14h;Reflux; | A stirred mixture of diketoester 2a or 2b (0.41 g, 1.39 mmol) and<strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> 3 or 4-methylbenzylhydrazine hydrochloride 4 (1.81 mmol) in EtOH(9 ml)was heated under reflux for 14 h. The mixturewas allowed tocool to room temperature, and the solvent was removed underreduced pressure to give a solid, which was purified by flashchromatography (petroleum ether/EtOAc, 8.5:1.5) to afford the titleproducts.6.1.4.1. Synthesis of Ethyl 8-chloro-1-(20,40-dichlorophenyl)-1,4,5,6-tetrahydrobenzo [6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate (5a)[13]. General Procedure A2 was used to convert 2a and 3 into thetitle product. Yellow solid; yield 80%; Rf 0.48 (petroleum ether/EtOAc, 8.5:1.5); mp 158e160 C (triturated with petroleum ether),IR 1724; 1H NMR (CDCl3) d 1.43 (t, 3H, J 7.2 Hz), 2.20e2.36 (m, 2H),2.66 (t, 2H, J 6.4 Hz), 3.10e3.30 (m, 2H), 4.45 (q, 2H, J 7.2 Hz),6.60 (d, 1H, J 8.4 Hz), 7.02 (dd, 1H, J 2.2 and 8.4 Hz), 7.31 (d, 1H,J 1.8 Hz), 7.37e7.42 (m, 2H), 7.54 (d, 1H, J 9.2 Hz). Anal.(C21H17Cl3N2O2) C, H, Cl, N. |
With acetic acid; for 8h; | 8-chloro-1-(2?-4?-dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7] cyclohepta[1,2-c]pyrazole-3-carboxylic acid was obtainedaccording to the synthesis described in Example 2.3 of US Patent Application 2010/0215741.7-chloro-2,3,4,5-tetrahydro-benzocycloheptan-1-one (12.84 mmoles) was reacted with metal sodium and diethyl oxalateto afford ethyl alpha-(7-chloro-1-oxo-2,3,4,5-tetrahydro-benzocyclohepten-2-yl)-alpha-oxo-acetate. 3.39 mmoles of this compoundwas refluxed with <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (3.90 mmoles) in 8 ml of glacial acetic acid for 8hours. At the end of the reaction the mixture was filtered. A residue was recovered that was washed with water and thenair dried to yield ethyl 8-chloro-1-(2?-4?-dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In ethanol; for 14h;Reflux; | A stirred mixture of diketoester 2a or 2b (0.41 g, 1.39 mmol) and<strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> 3 or 4-methylbenzylhydrazine hydrochloride 4 (1.81 mmol) in EtOH(9 ml)was heated under reflux for 14 h. The mixturewas allowed tocool to room temperature, and the solvent was removed underreduced pressure to give a solid, which was purified by flashchromatography (petroleum ether/EtOAc, 8.5:1.5) to afford the titleproducts. |
68% | With acetic acid; for 8h;Heating; Reflux; | 1.1b Preparation of ethyl 9-chloro-1-(2',4'-dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazol-3-carboxylate A mixture of the compound 1.1a (1.0 g corresponding to 3.39 mmoles) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.83 g corresponding to 3.90 mmoles) in 8 ml of glacial acetic acid was heated at reflux for 8 hours, then cooled at room temperature. A precipitate was formed that was filtered, washed with water and dried in the air to give 0.99 g (68% yield) of 9-chloro-1-(2',4'-dichlorophenyl)-1,4,5,6-tetrahydrobenzo [6,7]cyclohepta[1,2-c]pyrazol-3-ethyl carboxylate (compound 1.1b). Rf=0.43 (oil ligroin/AcOEt 9:1 v/v); IR (nujol) (lambda=cm-1) 170.9; 1H-NMR (CDCl3) delta 1.43 (t, 3H, J=7.0 Hz); 2.10-2.35 (m, 2H); 2.66 (t, 2H, J=6.8 Hz); 3.10-3.40 (m, 2H); 4.46 (q, 2H, J=7.2 Hz); 6.65 (s, 1H); 7.15-7.30 (m, 2H); 7.35-7.50 (m, 2H); 7.57: (d, 1H, J=9.0 Hz). Anal. calc. for C21H17Cl3N2O2: C, 57.89; H, 3.93; Cl, 24.41; N, 6.43. Found: C, 57.74; H, 3.92; Cl, 24.39; N, 6.41. |
68% | With acetic acid; for 8h;Reflux; | A mixture of the compound 1.1a (1.0 g corresponding to 3.39 mmoles) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.83 g corresponding to 3.90 mmoles) in 8 ml of glacial acetic acid was heated at reflux for 8 hours, then cooled at room temperature. A precipitate was formed that was filtered, washed with water and dried in the air to give 0.99 g (68% yield) of 9-chloro-1-(2',4'-dichlorophenyl)-1,4,5,6-tetrahydrobenzo [6,7]cyclohepta[1,2-c]pyrazol-3-ethyl carboxylate (compound 1.1b). Rf = 0.43 (oil ligroin/AcOEt 9:1 v/v); IR (nujol) (lambda= cm-1) 1709; 1H-NMR (CDCl3) delta 1.43 (t, 3H, J = 7.0 Hz); 2.10-2.35 (m, 2H); 2.66 (t, 2H, J = 6.8 Hz); 3.10-3.40 (m, 2H); 4.46 (q, 2H, J = 7.2 Hz); 6.65 (s, 1H); 7.15-7.30 (m, 2H); 7.35-7.50 (m, 2H); 7.57 (d, 1H, J = 9.0 Hz). Anal. calc. for C21H17Cl3N2O2: C, 57.89; H, 3.93; Cl, 24.41; N, 6.43. Found: C, 57.74; H, 3.92; Cl, 24.39; N, 6,41 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In ethanol; at 80℃;Inert atmosphere; | A stirred mixture of diketo ester 6 (4.57 g, 19.0 mmol, 1.0 equiv) and<strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (4.06 g, 19.0 mmol, 1.0equiv) in EtOH (130 mL) was heated at 80 C overnight. The mixturewas allowed to cool to r.t. and the solvent was removed under reducedpressure to give a red-orange solid that was purified by flashchromatography (hexane-EtOAc, 9:1) to afford 7 (4.56 g, 50%) as apale orange solid; mp 90-92 C; Rf = 0.60 (hexane-EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ethanol; for 8h;Reflux; | 1.6b Preparation of ethyl 7-chloro-1-(2',4'-dichlorophenyl)-6-methyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate A mixture of compound 1.6a (0.9 g, 3.05 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.72 g, 3.38 mmol) in ethyl alcohol (21 ml) was stirred at the reflux temperature for 8 hours. The solvent was then removed under reduced pressure and the crude ester was isolated. Purification of said compound by flash chromatography on silica gel, elution solvent petroleum ether/ethyl acetate (8.5/1.5 v/v) gave the compound ethyl 7-chloro-1-(2',4'-dichlorophenyl)-6-methyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate as a yellow solid (99% yield). |
99% | In ethanol; for 8h;Reflux; | A mixture of compound 1.6a (0.9 g, 3.05 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.72 g, 3.38 mmol) in ethyl alcohol (21 ml) was stirred at the reflux temperature for 8 hours. The solvent was then removed under reduced pressure and the crude ester was isolated. Purification of said compound by flash chromatography on silica gel, elution solvent petroleum ether/ethyl acetate (8.5/1.5 v/v) gave the compound ethyl 7-chloro-1-(2',4'-dichlorophenyl)-6-methyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate as a yellow solid (99% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate; Sodium metal (2 gram, 87 mmol) was dissolved in ethanol (80 ml). The resulting solution was added to a magnetically stirred solution of diethyl oxalate (6 gram, 41 mmol) and 1-(4-chlorophenyl)-2-(methylsulfanyl)ethanone (8.0 g, 40 mmol). The resulting mixture was reacted for 20 hours at room temperature and subsequently poured into aqueous hydrochloric acid (200 ml, 1 N). The resulting mixture was extracted twice with methyl-tert-butyl ether (MTBE) (200 ml), dried over MgSO4, filtered and concentrated. The resulting residue was dissolved in acetic acid (200 ml), 2,4-dichlorophenylhydrazine.HCl (8.6 gram, 40 mmol) was added and the resulting mixture was heated at 60 C. for 3 hours. The reaction mixture was allowed to attain room temperature, concentrated to approximately 50 ml and poured into water (200 ml), followed by extraction with MTBE (3 portions of 150 ml). The combined organic layers were washed with 5% aqueous NaHCO3, dried over MgSO4, filtered and concentrated. Further purification using column chromatography (silica gel, eluant: heptane/ethylacetate=90/10 (v/v)) gave ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylate (4.9 gram, 27% yield). Rf 0.4 (heptane/ethylacetate=90/10 (v/v)). 1H-NMR (CDCl3, 300 MHz) delta 1.44 (t, J=7 Hz, 3H), 2.32 (s, 3H), 4.46 (q, J=7, 2H), 7.10-7.45 (m, 7H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | To a magnetically stirred solution of Intermediate I(a) (3.5 g, 12.56 mmol) in 40 mL of ethanol was added <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (2.9 g, 13.82 mmol) in one portion at room temperature. The resultant mixture was stirred at room temperature for 20 hours. The precipitate thus formed was filtered, washed with ethanol and diethyl ether, and then dried under vacuum to give a light yellow solid (4.0 g, 74%). This solid was dissolved in acetic acid (30 mL) and heated under reflux for 24 hours. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The combined extracts were washed sequentially with water, a saturated sodium bicarbonate aqueous solution, and brine. The organic layer was then separated, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column chromatography on silica gel with n-hexane/ethyl acetate (9:1) to give Intermediate II(a), i.e., 1-(2,4-dichlorophenyl)-5-selenophene-2-yl-1H-pyrazole-3-carboxylic acid ethyl ester, as a white solid (3.0 g, 78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium carbonate; In ethanol; for 4h;Heating / reflux; | A mixture of 2, 4-dichlorophenyl hydrazine HYDROCHLORIDE (5. 0G, 23.4 MMOL) and diethylacetylene dicarboxylate (3.75 ML, 23.4 MMOL) in dry ethanol (50 ml) was treated with solid potassium carbonate (6.47 g, 46. 8 MMOL) and THERESULTING slurry mixture was heated at reflux for 4 hrs. The reaction mixture was cooled to room temperature and concentrated down to about 40 ml. A 1 N HCI (~100 ML) was added to the ethanol mixture to precipitate out the product. The pale tan solid product i-1a (6.79g, 96%) was isolated by filtration, washed with water and then dried in an oven overnight. 1H NMR (400 MHz, CDCl3) 8 7.53 (d, 1H), 7.48 (s, 1H), 7.35 (m, 1H), 7.31 (s, 1 H), 6.04 (s, 1 H), 4.43-4. 33 (m, 2H), 3.73 (s, 1 H), 1.40-1. 32 (m, 3H). (2: 1 enol : keto tautomers); MS (m/z) 301.1 (M+); HPLC (method A): retention time: 2.1 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In acetic acid; at 0 - 25℃; for 4h;Heating / reflux; | 4-(4-chlorophenyl)-2-oxo-3-butenoic acid obtained according to step a) (12.6 g, 60 mmoles), <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (12. 8 g, 60 mmoles) and glacial acetic acid (200 mL) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield). IR (KBr, cm-1) : 3200-2200,1668, 4,1458, 1251,4, 1104, 8. 1H NMR (CDCI3, a) : 3,3 (dd, 1H), 3,7 (dd, 1H), 5,9 (dd, 1H), 7,09-7, 25 (m, 7H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate; In ethanol; at 20℃; | An aqueous KOH (0.25 g in 4.4 mL water) solution was added to p-fluorobenzaldehyde Compound 10a (1.04 mL, 10 mMol) and the mixture was heated to 65 C. Cyclohexanone Compound 2a (1.03 mL, 10 mMol) was added dropwise over 10 min and the reaction mixture was refluxed for 5 hrs, then cooled to r.t. and stirred at r.t. overnight. The reaction mixture was acidified with 1N HCl (26 mL) and diluted with EtOAc. The organic layer was separated and washed with brine, then dried with anhydrous sodium sulfate and filtered. The solvent was evaporated to provide a crude product which was then purified by silica gel column (eluted with 6% EtOAc in hexane) to give 2-(4-fluoro-benzylidene)-cyclohexanone Compound 10b (1.1 g, 54%). Cyclohexanone Compound 10b (1.1 g, 5.4 mMol) in THF (5 mL) was added dropwise to a solution of lithium bis(trimethylsilyl)amide (5.4 mL of 1.0M solution in THF) in THF (10 mL) at -78 C. The mixture was stirred at -78 C. for 1 hr, then diethyl oxalate Compound 2b (0.732 mL, 5.4 mMol) in THF (5 mL) was added slowly at -78 C. The mixture was stirred at -78 C. for 1 hr, then stirred and allowed to warm to r.t. overnight. The mixture was concentrated, taken up in EtOAc (100 mL) and washed with 1N HCl (2×50 mL) and water (2×50 mL). The organic layer was separated, then dried with anhydrous sodium sulfate and filtered. The solvent was evaporated to provide a [3-(4-fluoro-benzylidene)-2-oxo-cyclohexyl]-oxo-acetic acid ethyl ester Compound 10c (1.4 g, 85%) as an orange oil which was used in the next step without further purification. Compound 10c (1.4 g, 4.62 mmol) was taken up in ethanol (30 mL), then anhydrous (2,4-dichloro-phenyl)-hydrazine hydrochloride Compound 10d (0.99 g, 4.62 mMol) and K2CO3 (1.28 g, 9.24 mMol) were added. The reaction mixture was stirred at r.t. overnight, then filtered and washed with ethanol (20 mL). The combined filtrate was concentrated and purified on a silica gel column (eluted with 20% EtOAc in hexane) to give 1-(2,4-Dichloro-phenyl)-7-(4-fluoro-benzylidene)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester Compound 10e (0.8 g, 39%). Ethyl ester Compound 10e (0.8 g, 1.8 mMol) was dissolved in THF (18 mL). Aqueous LiOH (lithium hydroxide) (0.26 g in 6 mL), then ethanol (2 mL) were added and the mixture was stirred at r.t. for 24 hrs, then concentrated, diluted with water (25 mL) and acidified to pH 4 using 1N HCl. The aqueous suspension was extracted with EtOAc (100 mL). The organic layer was separated and washed with brine, then dried over magnesium sulfate and filtered. The solvent was evaporated to provide an acid Compound 10f (0.74 g, 98%). The acid Compound 10f (0.74 g, 1.77 mMol) was taken up in CH2Cl2 (5 mL), then treated with thionyl chloride (1 mL, 14.1 mMol). The solution was heated to reflux for 3 hrs, the solvent was removed in vacuo to obtain the acid chloride Compound 10g (0.76 g, 99%). Compound 10g (0.044 g, 0.1 mMol) was added to a solution of commercially available 1-aminopiperidine Compound 10h (0.021 mL, 0.2 mMol) in CH2Cl2 (2 mL) and triethylamine (0.055 mL, 0.4 mMol). The suspension was stirred, then diluted and washed. The organic layer was dried, concentrated and purified on a silica gel column (eluted with 40% EtOAc in hexane) to provide Compound 297 (40 mg, 80.2%). MS m/z 499 (MH+); 1H NMR (CDCl3, 400 MHz) delta 7.57-7.41 (m, 4H), 7.07-6.92 (m, 4H), 5.89 (s, 1H), 3.09-3.00(m, 2H), 2.87-2.79 (m, 4H), 2.71-2.54 (m, 2H), 1.93-1.68 (m, 6H), 1.45-1.36 (m, 2H). Compound 297 (100 mg, 0.2 mMol) was dissolved in CH2Cl2 (2 mL) and a solution of 1N HCl in ether (1 mL) was added slowly. The mixture was stirred at r.t. for 1 hr, then concentrated and washed with ether (3×). The remaining ether was removed in vacuo to provide Compound 297 (95 mg, 89%) as a hydrochloride salt. MS m/z 499 (MH+); 1H NMR (CDCl3, 400 MHz) delta 9.33(s, 1H), 7.57(s, 1H), 7.46(s, 2H), 7.06-6.93 (m, 4H), 5.93 (s, 1H), 4.20-3.61(broad peak, 4H), 3.02-2.88 (m, 2H), 2.78-2.52 (m, 2H), 2.21-1.55 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In ethanol; at 20℃; for 2h;Heating / reflux; | A mixture is prepared consisting of the compound prepared in 1.1a (0.5g; 175 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.41 g; 1.93 mmol) in ethanol (11.67 ml). The mixtue is reacted at the reflux temperature for 2 hours, then cooled down to room temperature. After the solvent removal, a reddish solid is obtained. The raw solid was treated with oil ether and purified by flash chromatography (oil ether/ethyl acetate 9/1 on silica gel), obtaining 0.5 g (67% yield) of the ester 1.1b under the form of a light-coloured solid. Rf = 0.3 (oil ether/ethyl acetate 9/1 on silica gel); m.p.: 144C; IR (nujol) (lambda = cm-1) 3440 (OH as tautomer mixture), 1725 (COOEt), 1603 (C=O); 1H-NMR (CDCl3) delta 1.38-1.45 (t, 3H, J = 7.0 Hz); 2.90-3.0 (t, 2H, J = 10.0 Hz); 3.22-3.32 (t, 2H, J = 10.0 Hz); 4.4-4.5 (q, 2H, J = 7.0 Hz); 5.99 (s, 1H); 7.44-7.46 (d, 2H); 7.60 (s, 1H); Anal. calc. for C18H13Cl3N2O2S: C, 50.54; H, 3.06; Cl, 24.87; N, 6,55; S, 7.50. Found: C, 50.58; H, 2.88; Cl, 25.06; N, 6.78; S, 7.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.97% | A mixture formed of the compound obtained in the previous reaction (3.64 mmol, 1 eq) and 2.4-dichlorophenylhydrazine hydrochloride (4.00 mmol, 1,1 eq) in acetic acid (2 ml), was reacted at the reflux temperature for 1.5 hours. Then the mixture was cooled at room temperature, poured in water and the pH neutralized by adding a NaHCO3 solution. The aqueous phase is then extracted with ethyl ether, the ether phase washed with a saturated NaHCO3 solution, dried over Na2SO4 and concentrated by removing the solvent. A raw product was obtained which is purified by flash chromatography (oil ether/ethyl acetate 8/2 v/v) lastly isolating the ester in the form of a red-orange oil which tends to solidify (0.83 g, yield 54.97%). Rf 0.537 (oil ether/ethyl acetate 8/2, silica gel plates); m.p.: 91-92 C; IR (nujol) (lambda = cm-1) 1710 (C=O); 1H-NMR (CDCl3) delta 1.42 (t, 3H, J = 7.0 Hz); 2.42 (s, 3H); 4.44 (q, 2H, J = 7.0 Hz); 6.67 (d, 1H, J = 4.0 Hz); 6.82 (d, 1H, J = 4.0 Hz); 7.34-7.36 (m, 2H); 7.46-7.47 (m, 1H); Anal. calc. for C17H13Cl3N2O2S: C, 49.12; H, 3.15; Cl, 25.58; N, 6,74. Found: C, 49.54; H, 3.18; Cl, 25.76; N, 6.88. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.23% | A mixture formed of the compound isolated in the previous step (1.73 mmoles, 1 eq) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (1,90 mmol, 1,1 eq) in acetic acid (2 ml), was reacted at the reflux temperature for 1.5 hours and then cooled at room temperature. The reaction mixture was poured in H2O, neutralized with NaHCO3, then extracted with ethyl ether. The ether phase was washed with a saturated NaHCO3 solution, dried over Na2SO4, and the solvent removed under reduced pressure. A raw product is obtained from which by flash chromatography (oil ether/ethyl acetate 8/2) the ester is isolated in the form of a white-oranage solid (0.50 g, yield 67.23%). Rf 0.609 (oil ether/etyl acetate 8/2); m.p.: 91-92 C; IR (nujol) (lambda = cm-1) 1712 (C=O); 1H-NMR (CDCl3) delta 1.23 (t, 3H, J = 7.6 Hz); 1.42 (t, 3H, J = 7.0 Hz); 2.84 (q, 2H, J = 7.4 Hz); 4.45 (q, 2H, J = 7.4 Hz); 6.57 (d, 1H, J = 3.6 Hz); 6.81 (d, 1H, J = 3.8 Hz); 7.34-7.36 (m, 2H) ; 7.46-7.47 (m, 1H) ; Anal. calc. for C18H15Cl3N2O2S: C, 50.37; H, 3.53; Cl, 24.68; N, 6.50. Found: C, 50.31; H, 3.52; Cl, 24.75; N, 6.52. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydroxide; acetic anhydride; potassium carbonate; In water; | EXAMPLE 1 This example illustrates a process for preparing 4,5-dihydro-1-(2,4-dichlorophenyl)-3-methyl-1,2,4-triazol-5(1H)-one (1) from N-(2,4-dichlorophenyl)ethanehydrazonoyl chloride (A) in DMAC solvent A slurry of 101.4 grams (0.4751 mole) of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> in 600 mL of water was stirred, and a solution of 20.9 grams (0.5225 mole) of sodium hydroxide in 100 mL of water was slowly added. During the addition, the reaction mixture thickened. An additional 50 mL of water was added to aid fluidity. Upon completion of addition of the sodium hydroxide solution, an additional 70 mL of water was added. The reaction mixture was stirred for about 75 minutes, then it was extracted with three 300 mL portions of ethyl acetate. The extracts were combined and dried with magnesium sulfate. The mixture was filtered and the filtrate containing free 2,4-dichlorophenylhydrazine (1) was transferred to an appropriate reaction vessel. The stirred solution was cooled to about 10 C., and 58.2 grams (0.5701 mole) acetic anhydride was added dropwise. Upon completion of addition, gas chromatographic (GC) analysis of the reaction mixture indicated the reaction was about 99% complete. The cooling medium was removed, and a solution of 62.5 grams of potassium carbonate in 200 mL of water was added to the reaction mixture. The mixture was stirred for about five minutes and the organic layer was separated. The organic layer was concentrated under reduced pressure, yielding 102.0 grams (98% yield) of 1-acetyl-2-(2,4-dichlorophenyl)hydrazine (2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid In toluene at 55℃; for 4.5h; | 1.A Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-dichlorophenylhydrazine hydrochloride(12.6 g) is dissolved in 100 ml of toluene and this solution is placed under nitrogen; after stirring, 10 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 5 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 30 ml of water. The mixture is separated by settling out, the aqueous phase is discarded and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 10 ml of toluene and the expected product then crystallizes, m=10.2 g. ES-: [M-H]-=313.0. NMR (DMSO-d6 1H at 300 MHz): 1.26 ppm: t: 3H; 2.11 ppm: s: 3H; | |
102 g | With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Reflux; | 1.A A) Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Reflux; | 1.A A) Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride In toluene; trifluoroacetic acid at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene; trifluoroacetic acid at 20 - 75℃; | Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride In toluene; trifluoroacetic acid at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene; trifluoroacetic acid at 20 - 75℃; | Ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With acetic acid; for 4h;Heating / reflux; | A mixture of (E)-4-(5-chlorothiophen-2-yl) -2-oxo-3-butenoic acid (0.72 g, 3.3 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.71 g, 3.3 mmol) in 10.5 mL glacial acetic acid under nitrogen atmosphere was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature and poured into ice. The dark mixture was extracted with dichloromethane, washed with H2O, dried over Na2SO4 and evaporated to dryness to yield 1.35 g (?100% of the crude acid), which was purified by semi-preparative HPLC.1H NMR (400 MHz, CHLOROFORM-cQ delta ppm 3.39 (dd, J=17.88, 4.59 Hz, 1 H) 3.64 (dd, J=17.88, 11.92 Hz1 1 H) 6.11 (dd, J=11.92, 4.59 Hz, 1 H) 6.60 (d, J=3.78 Hz, 1 H) 6.61 (d, J=3.78 Hz, 1 H) 7.12 (dd, J=8.60, 2.15 Hz, 1 H) 7.25 (d, J=8.60 Hz, 1 H) 7.32 (d, J= 2.15 Hz, 1 H)MS (M+H)+: 375 |
100% | With acetic acid; for 4h;Heating / reflux; | Example 8 Preparation of 5-(5-Chloro-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid A mixture of (E)-4-(5-chlorothiophen-2-yl) -2-oxo-3-butenoic acid (0.72 g, 3.3 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.71 g, 3.3 mmol) in 10.5 mL glacial acetic acid under nitrogen atmosphere was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature and poured into ice. The dark mixture was extracted with dichloromethane, washed with H2O, dried over Na2SO4 and evaporated to dryness to yield 1.35 g (?100% of the crude acid), which was purified by semi-preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.39 (dd, J=17.88, 4.59 Hz, 1 H) 3.64 (dd, J=17.88, 11.92 Hz, 1 H) 6.11 (dd, J=11.92, 4.59 Hz, 1 H) 6.60 (d, J=3.78 Hz, 1 H) 6.61 (d, J=3.78 Hz, 1 H) 7.12 (dd, J=8.60, 2.15 Hz, 1 H) 7.25 (d, J=8.60 Hz, 1 H) 7.32 (d, J= 2.15 Hz, 1 H) MS (M+H)+: 375 |
100% | In acetic acid; for 4h;Heating / reflux; | A mixture of (E)-4-(5-chlorothiophen-2-yl) -2-oxo-3-butenoic acid (0.72 g, 3.3 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.71 g, 3.3 mmol) in 10.5 mL glacial acetic acid under nitrogen atmosphere was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature and poured into ice. The dark mixture was extracted with dichloromethane, washed with H2O, dried over Na2SO4 and evaporated to dryness to yield 1.35 g (?100% of the crude acid), which was purified by semi-preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.39 (dd, J=17.88, 4.59 Hz, 1 H) 3.64 (dd, J=17.88, 11.92 Hz, 1 H) 6.11 (dd, J=11.92, 4.59 Hz, 1 H) 6.60 (d, J=3.78 Hz, 1 H) 6.61 (d, J=3.78 Hz, 1 H) 7.12 (dd, J=8.60, 2.15 Hz, 1 H) 7.25 (d, J=8.60 Hz, 1H) 7.32 (d, J= 2.15 Hz, 1 H) MS (M+H)+: 375 |
In acetic acid; for 4h;Heating / reflux; | A mixture of (E)-4-(5-chlorothiophen-2-yl) -2-oxo-3-butenoic acid (0.72 g, 3.3 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.71 g, 3.3 mmol) in 10.5 mL glacial acetic acid under nitrogen atmosphere was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature and poured into ice. The dark mixture was extracted with dichloromethane, washed with H2O, dried over Na2SO4 and evaporated to dryness to yield 1.35 g (?100% of the crude acid), which was purified by semi-preparative HPLC. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.39 (dd, J=17.88, 4.59 Hz, 1 H) 3.64 (dd, J=17.88, 11.92 Hz, 1 H) 6.11 (dd, J=11.92, 4.59 Hz, 1 H) 6.60 (d, J=3.78 Hz, 1 H) 6.61 (d, J=3.78 Hz, 1 H) 7.12 (dd, J=8.60, 2.15 Hz, 1 H) 7.25 (d, J=8.60 Hz, 1 H) 7.32 (d, J= 2.15 Hz, 1 H) MS (M+H)+: 375 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.9% | With potassium carbonate; In ethanol; at 20℃; | Anhydrous (2,4-dichloro-phenyl)-hydrazine hydrochloride Compound 1d (1.06 g, 5 mmol) and K2CO3 (0.69 g, 5 mmol) were added to a solution of Compound 1c (1.67 g, 5 mmol) in ethanol (30 mL). The mixture was stirred at room temperature overnight, then filtered and washed with ethanol (20 mL). The filtrate was concentrated, dissolved in ethyl acetate (100 mL) and washed with 1N HCl (1×100 mL) and water (1×100 mL). The organic layer was dried over sodium sulfate, then concentrated and purified on silica gel column with 10% EtOAc/Hexane to give 5-(5-bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester Compound 1e (0.40 g, 16.9%), which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In ethanol; for 16h;Inert atmosphere; Reflux; | A mixture of 1,3-dicarbonyl 21 (1.2 g, 4.46 mmol) and 2,4-dichlorophenylhydrazineHCl (1.31 g, 6.14 mmol) in EtOH (20 mL) was heated at reflux for 16 h. The reactionmixture then was diluted with H2O (30 mL) and extracted with EtOAc (3 × 70 mL).The combined organic phases were dried over MgSO4, filtered, and concentrated invacuo. The resultant crude oil was then purified by flash chromatography (EtOAc-hexanes, 1:4-1:5) togive the product as a yellow solid (1.36 g, 81%). deltaC (400 MHz; CDCl3): 7.33 (m, 2H), 7.27 (m, 3H),7.06 (dt, J = 8.5 Hz, 2H), 4.42 (q, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.39 (t, J = 7.0, 3H); deltaC (100 MHz;CDCl3): 162.8, 143.0, 142.9, 136.1, 136.0, 135.0 133.1, 130.9, 130.8, 130.1, 128.9, 127.8, 127.1, 119.2,61.0, 14.5, 9.7. Spectroscopic and physical data were in good agreement with those previouslyreported.1 |
50% | In ethanol; for 16h;Reflux; | A stirred mixture of diketoester 11 (3.00 g, 11.17 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (12) (2.62 g, 12.28 mmol) in EtOH (90 mL) was heated under reflux for 16 h. The mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure to give a red-orange solid, which was purified by flash chromatography (petroleum ether/EtOAc, 9:1) to afford the analytically pure product as an orange solid (2.20 g, 50%). Rf = 0.29 (petroleum ether/EtOAc, 9:1); IR: nu = 1724; 1H NMR (CDCl3, 400 MHz) delta = 1.43 (t, 3H, J = 7.1 Hz), 2.33 (s, 3H), 4.45 (q, 2H, J = 7.2 Hz), 7.08 (bd, 2H, J = 8.5 Hz), 7.29 (dd, 1H, J = 2.2, 8.4 Hz), 7.30 (bd, 2H, J = 8.5 Hz), 7.35 (d, 1H, J = 8.4 Hz), 7.38 (d, 1H, J = 2.2 Hz); 13C NMR (CDCl3, 100 MHz) delta = 9.8, 14.6, 61.1, 119.2, 127.2, 127.9, 129.0, 130.2, 130.9, 131.0, 133.2, 135.1, 136.0, 136.1, 143.0, 143.1, 162.8; ESI-MS m/z: 408.1 [ESMS m/z: 409.1 (M + 1)] [38,47]. |
35% | In ethanol; for 16h;Reflux; | Part (b): Title compound: Ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- lH- pyrazole-3-carboxylate To solution of the intermediate compound obtained in part (a): ethyl 4-(4-chlorophenyl)-3- methyl-2,4-dioxobutanoate (23 g, 86 mmol) in ethanol (600 mL) was added (2,4- dichlorophenyl)hydrazine hydrochloride (20.10 g, 94 mmol) with continuous stirring. The resulting reaction mixture was heated and reflux for 16 h. The reaction mixture was cooled to room temperature. The solvent was removed from the reaction mixture to give a red-orange solid, which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, 9: 1) to afford the title compound. Yield: 20 g, 35 %; 1H NMR (300 MHz, CDC13): delta 1.43 (t, = 7.2 Hz, 3H, COOCH2CH3), 2.34 (s, 3Eta, pyrazole-CHj), 4.40 (q, = 7.2 Hz, 2H, COOCH2CH3), 7.08 (d, = 8.4 Hz, 2H, Ar-H), 7.27 - 7.39 (m, 5Eta, Ar-H); MS: m/z 411.9 [M + H]+. |
In ethanol; for 16h;Heating; | A stirred solution of ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (23 g,86 mmol) and (2,4-chlorophenyl)hydrazine hydrochloride (20.10 g, 94 mmol) in ethanol(600 mL) was heated for 16 h. The mixture was allowed to cool to room temperature, and the solvent was removed, which was purified by column chromatography (silica gel, petroleum ether in ethyl acetate, 9:1) to obtain the title compound.Yield: 35%; 1H NMR (300 MHz, CDCI3): 1.43 (t, J= 7.2 Hz, 3H, COOCH2CH3), 2.34(5, 3H, pyrazole-CH3), 4.40 (q, J = 7.2 Hz, 2H, COOCH2CH3), 7.08 (d, J = 8.4 Hz, 2H,Ar-I-n, 7.27-7.39 (m, 5H, Ar-I-n; MS: m/z41 1.9 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In ethanol; at -5 - 30℃; for 2h; | To a stirred suspension of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong>(19.4g, 0.09 mol) in 250 ml of ethanol, 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutyric acid ethyl ester lithium salt (25g, 0.091mol) was added at 28-30C. The reaction mass was cooled to 0 to -5C and stirred for 2 hours. After completion of the reaction, the precipitated solid was filtered, washed with chilled ethanol (50 ml) and dried under vacuum at 30-350C for 4 hours to give 21.5 g of 4-(4- chlorophenyl)-2-[(2,4-dichlorophenyl)-hydrazono]-3-methyl-4-oxo-butyric acid ethylester ( yield 55%) as pale yellow solid having purity of 97.51 % by high performance liquid chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With hydrogenchloride; In ethanol; water; at 20℃; for 3h;Heating / reflux; | c:5-(4-cvclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-l-H-pyrazole-3-carboxylic acid ethyl ester; To a stirred solution of 4-(4-cyclopropylphenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester (19.7 g, 0.072 mol) in ethanol (230 ml) <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (15.4 g, 0.072 mol) was added at ambient temperature, followed by addition of a mixture of cc. HCl (10 ml) and water (10 ml). The obtained suspension was refluxed for 3 h, then concentrated in vacuo. The residue was purified by column chromatography using dichloromethane as eluent. Yield: 9.3 g (31%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In acetic acid; for 4h;Heating / reflux; | A mixture of 4-(4-chlorophenyl)-3-methyl-2-oxo-but-3-enoic acid (0.72 g, 3.2 mmol) and <strong>[5446-18-4]2,4-dichlorophenyl hydrazine hydrochloride</strong> (0.68 g, 3.2 mmol) in glacial acetic acid (10.6 mL) was heated under nitrogen atmosphere to reflux for 4 h. The crude mixture was allowed to cool down to room temperature and poured into ice. The dark mixture was extracted with dichloromethane, washed with aq. NaCl, dried over Na2SO4, and evaporated to dryness to yield 1.18 g of crude product (100 % yield) as a mixture of two diastereomers. The ratio of the two diastereomers was determined by NMR spectroscopy to be 80:20. |
100% | In acetic acid; for 4h;Heating / reflux; | Preparation of 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid [Show Image] A mixture of 4-(4-chlorophenyl)-3-methyl-2-oxo-but-3-enoic acid (0.72 g, 3.2 mmol) and <strong>[5446-18-4]2,4-dichlorophenyl hydrazine hydrochloride</strong> (0.68 g, 3.2 mmol) in glacial acetic acid (10.6 mL) was heated under nitrogen atmosphere to reflux for 4 h. The crude mixture was allowed to cool down to room temperature and poured into ice. The dark mixture was extracted with dichloromethane, washed with aq. NaCl, dried over Na2SO4, and evaporated to dryness to yield 1.18 g of crude product (100 % yield) as a mixture of two diastereomers. The ratio of the two diastereomers was determined by NMR spectroscopy to be 80:20. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In acetic acid; at 25℃; for 4h;Heating / reflux; | 4-(4-chlorophenyl)-2-oxo-3-butenoic acid obtained according to step a) (12.6 g, 60 mmoles), <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (12.8 g, 60 mmoles) and glacial acetic acid (200 mL) were mixed under a nitrogen atmosphere and heated to reflux for 4 hours, cooled down to room temperature (approximately 25 C) and given into ice-water, whereby a sticky mass was obtained, which was extracted with methylene chloride. The combined methylene chloride fractions were washed with water, dried with sodium sulfate, filtered and evaporated to dryness to give a pale yellow solid (12.7 g, 57% of theoretical yield). IR (KBr, cm-1) : 3200-2200, 1668,4, 1458, 1251,4, 1104,8. 1H NMR (CDCl3, delta) : 3,3 (dd, 1H), 3,7 (dd, 1 H), 5,9 (dd, 1H), 7,09-7,25 (m, 7H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol; at 20℃; for 20h; | EXAMPLE 1 Preparation of 1-(2,4-dichloro-phenyl)-4-methyl-5-selenophen-2-yl-1H-pyrazole-3-carboxylic acid ethyl ester To a solution of lithium bis(trimethylsilyl)amide (17.6 mL, 1.0 M solution in THF 17.64 mmol) in diethyl ether (40 mL) was added under stirring a solution of 1-(selenophene-2-yl)-propan-1-one (3.0 g, 16.0 mmol) in dry diethyl ether (15 mL) at -78 C. After 45 min, diethyl oxalate (2.6 mL, 19.24 mmol) was added. The reaction mixture was allowed to warm to room temperature and then stirred for 16 h. The precipitate was filtered out, washed with dry diethyl ether, and dried under vacuum to afford lithium salt (3.0 g, 65%). To the above lithium salt (3.0 g, 10.2 mmol) in ethanol (40 mL) was added <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (2.4 g, 11.2 mmol) in one portion at room temperature. The resulting mixture was stirred at room temperature for 20 h. The precipitate was filtered, washed with diethyl ether, and then dried under vacuum to give a light yellow solid (3.2 g, 70%). The solid was dissolved in acetic acid (30 mL) and heated to reflux for 24 h. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, and evaporated. Purification by flash column chromatography on silica gel with n-hexane/ethyl acetate (9:1) gave the desired ester (2.4 g, 80%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(5-chloro-thiophen-2-yl)-propan-1-one With lithium hexamethyldisilazane In tetrahydrofuran; diethyl ether at -78℃; Inert atmosphere; Stage #2: oxalic acid diethyl ester In tetrahydrofuran; diethyl ether at -78 - 20℃; Stage #3: 2,4-dichlorophenyl hydrazine hydrochloride In ethanol at 20℃; for 22h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-(5-chloro-thiophen-2-yl)-propan-1-one; oxalic acid diethyl ester With lithium hexamethyldisilazane In tetrahydrofuran; diethyl ether at -78℃; Stage #2: 2,4-dichlorophenyl hydrazine hydrochloride In ethanol at 0 - 5℃; for 1h; Stage #3: With hydrogenchloride In isopropyl alcohol at 75 - 78℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-n-butanoylchlorobenzene With lithium hexamethyldisilazane In tetrahydrofuran; diethyl ether at -78℃; Inert atmosphere; Stage #2: oxalic acid diethyl ester In tetrahydrofuran; diethyl ether at -78 - 20℃; Inert atmosphere; Stage #3: 2,4-dichlorophenyl hydrazine hydrochloride In ethanol at 20℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | To acontinuously stirring solution of lithium salt B (1.0 g,3.64 mmol) in 15 ml of ethanol was added <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.777 g, 3.64 mmol) atroom temperature. The shaking was carried for 20 h till precipitate was obtained. The precipitate so obtained wasfiltered and washed with ethanol (10 ml) and dried undervacuum to give a pale yellow solid (1.1 g), which wasdissolved in acetic acid (10 ml) and refluxed for 24 h. Oncompletion of the reaction (TLC), the reaction mixture waspoured into cold water (20 ml) and then extracted withethyl acetate (3 9 15 ml). The combined extracts werewashed with water, saturated sodium bicarbonate solution,brine and then dried under vacuum to give the crudeproduct. It was then purified by column chromatography onsilica gel using ethyl acetate/petroleum ether (1:9) as elutionsystem to give the ester 3 (Kotagiri et al., 2007),(670 mg, 45 %,) pale yellow solid.mp 128-129C;1HNMR (CDCl3, 200 MHz): d 7.39 (d, J = 2.02 Hz, 1H),7.34 (d, J = 1.37 Hz, 1H), 7.33-7.28 (m, 3H), 7.08 (d,J = 8.59 Hz, 2H), 4.51-4.41 (q, J = 7.08 Hz, 2H), 2.34 (s,3H), 1.43 (t, J = 7.08 Hz, 3H); 13C NMR (CDCl3,100 MHz): d 162.7, 142.9, 136.0, 135.9, 135.0, 133.0,130.9, 130.7, 130.1, 128.9, 127.7, 127.0, 119.1, 60.9, 14.4,and 9.6.HRMS-ESI (m/z) Calcd. C19H15O2N2Cl3 ? H)?:409.0272 found: 409.0265. | |
Example 9; Synthesis of 5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (3a)To a solution of the lithium salt 2a (2.60 g, 9.47 mmol) in ethanol (35 mL) was added <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (2.2 g, 10.30 mmol) in one portion at room temperature. The resulting mixture was stirred at the same temperature for 20 h. After the reaction was complete, the precipitate was collected by filtration, washed with ethanol and diethyl ether, and dried under vacuum to give a light-yellow solid. This crude solid, without purification, was dissolved in acetic acid (30 mL) and heated to reflux for 24 h. The reaction mixture was poured into ice water and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined extracts were washed with water, saturated aqueous sodium bicarbonate, and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the crude residue by flash chromatography on silica gel with hexanes/ethyl acetate (9:1) gave the ester 3a (1.9 g, 49% over two steps) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In ethanol; for 1.5h;Reflux; | 1.9c Preparation of (Z)-ethyl 2-(2-(2,4-dichlorophenyl)-hydrazone)-2-(3-hydroxy-6-methylbenzofuran-2-yl)acetate A solution in absolute ethanol (1.15 ml) of the compound obtained in Ex. 1.9b (1.07 g; 4.31 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (1.20 g; 5.60 mmol) was prepared. The solution was reacted at the reflux temperature for 1.5 hours, then cooled to room temperature and poured on ice. The resulting precipitate was filtered under reduced pressure, then air dried to obtain 1.37 g (78% yield) of a solid residue corresponding to (Z)-ethyl 2-(2-(2,4-dichlorophenyl)hydrazone)-2-(3-hydroxy-6-methylbenzofuran-2-yl)acetate. Rf=0.42 (oil ether/ethyl, acetate 9.5/0.5 v/v on silica gel); m.p.: 190-192 C.; IR (nujol) (lambda=cm-1) 3423 (OH as tautomer mixture), 1619 (COOEt); 1H-NMR (CDCl3) delta 0.83 (t, J=7.4 Hz, 3H), 2.46 (s, 3H), 4.07 (q, J=7.0 Hz, 2H), 6.93 (d, J=0.8 Hz), 7.35 (s, 2H), 7.60 (d, J=8.6 Hz, 2H), 12.80 (s, 1H); API-ESI calc. for 407.25, found 407.10. |
78% | In ethanol; for 1.5h;Reflux; | A solution in absolute ethanol (1.15 ml) of the compound obtained in Ex. 1.9b (1.07g; 4.31 mmol)and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (1.20 g; 5.60 mmol) was prepared. The solution was reacted at the reflux temperature for 1.5 hours, then cooled to room temperature and poured on ice. The resulting precipitate was filtered under reduced pressure, then air dried to obtain 1.37 g (78% yield) of a solid residue corresponding to (Z)-ethyl 2-(2-(2,4-dichlorophenyl)hydrazone)-2-(3-hydroxy-6-methylbenzofuran-2-yl)acetate. Rf=0.42 (oil ether/ethyl acetate 9.5/0.5 v/v on silica gel); m.p.: 190-192 C; IR (nujol) (lambda = cm-1) 3423 (OH as tautomer mixture), 1619 (COOEt); 1H-NMR (CDCl3) delta 0.83 (t, J=7.4 Hz, 3H), 2.46 (s, 3H), 4.07 (q, J=7.0 Hz, 2H), 6.93 (d, J=0.8 Hz), 7.35 (s, 2H), 7.60 (d, J=8.6 Hz, 2H), 12.80 (s, 1H); API-ESI calc. for 407.25, found 407.10 |
78% | In ethanol; for 1.5h;Reflux; | A solution in absolute ethanol (1.15 ml) of the compound obtained in Ex. 1.9b (1.07g; 4.31 mmol)and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (1.20 g; 5.60 mmol) was prepared. The solution was reacted at the reflux temperature for 1.5 hours, then cooled to room temperature and poured on ice. The resulting precipitate was filtered under reduced pressure, then air dried to obtain 1.37 g (78% yield) of a solid residue corresponding to (Z)-ethyl 2-(2-(2,4-dichlorophenyl)hydrazone)-2-(3-hydroxy-6-methylbenzofuran-2-yl)acetate. Rf=0.42 (oil ether/ethyl acetate 9.5/0.5 v/v on silica gel); m.p.: 190-192 C; IR (nujol) (lambda = cm-1) 3423 (OH as tautomer mixture), 1619 (COOEt); 1H-NMR (CDCl3) delta 0.83 (t, J=7.4 Hz, 3H), 2.46 (s, 3H), 4.07 (q, J=7.0 Hz, 2H), 6.93 (d, J=0.8 Hz), 7.35 (s, 2H), 7.60 (d, J=8.6 Hz, 2H), 12.80 (s, 1H); API-ESI calc. for 407.25, found 407.10 |
78% | In ethanol; for 1.5h;Reflux; | (Z)-ethyl 2-(2-(2,4-dichlorophenyl)hydrazone)-2-(3-hydroxy-6-methylbenzofuran-2-yl)acetate was obtained according tothe synthesis described in Example 1.9c of US Patent Application 2010/0215741. A solution of the compound obtainedin Ex. 22b (1.07g; 4.31 mmol) and <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (1.20 g; 5.60 mmol) in absolute ethanol(1.15 ml) was prepared. The solution was reacted under reflux conditions for 1.5 hours, then cooled to room temperatureand poured on ice. A precipitate was formed that was filtered under reduced pressure, then air dried to obtain 1.37 g(78% yield) of a solid residue corresponding to (Z)-ethyl 2-(2-(2,4-dichlorophenyl)hydrazone)-2-(3-hydroxy-6-methylbenzofuran-2-yl)acetate. Rf=0.42 (eluent oil ether/ethyl acetate 9.5/0.5 v/v on silica gel); m.p.: 190-192C; IR (nujol) (lambda= cm-1) 3423 (OH as tautomer mixture), 1619 (COOEt); 1H-NMR (CDCl3) delta 0.83 (t, J=7.4 Hz, 3H), 2.46 (s, 3H), 4.07 (q,J=7.0 Hz, 2H), 5.28 (br s, 1H), 6.96 - 6.92 (m, 2H), 7.34 - 7.21 (m, 2H), 7.62 - 7.57 (m, 2H), 12.80 (br s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.5% | In ethanol; for 1.5h;Heating; Reflux; | 1.5d Preparation of the Compound ethyl 8-chloro-1-(2',4'-dichlorophenyl)-4,5-dihydrobenzo-1H-6oxa-cyclohepta[1,2-c]-pyrazol-3-carboxylate 1 eq of the diketoester obtained in example 1.5c and 1.1 eq of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> in 50 ml of ethanol were heated at reflux for 90 minutes. The reaction solvent was then removed under vacuum and the obtained residue purified by flash chromatography (oil ligroin/EtOAc 9:1). The compound ethyl 8-chloro-1-(2',4'-dichlorophenyl)-4,5-dihydrobenzo-1H-6oxa-cyclo-hepta[1,2-c]pyrazol-3-carboxylate was thus obtained as an orange solid (47.5% yield). Rf=0.32 (oil ligroin/EtOAc 9:1); m.p. 130-131 C.; IR (nujol) (lambda=cm-1) 1712 (CO); 1H-NMR (CDCl3) delta 1.42 (t, 3H, J=7.0 Hz)., 3.44 (qu, 2H, J=5.4 Hz), 4.35-4.51 (m, 4H), 6.65 (d, 1H, J=8.6 Hz), 6.81 (d, 1H, J=8.6 Hz), 7.14 (s, 1H) 7.39-7.44 (m, 2H), 7.49 (s, 1H); Anal. Calc. for C20H15Cl3N2O2: C, 54.88; H, 24.30; Cl, 6.40; N, 3.45. Found: C, 54.80; H, 24.26; Cl, 6.39; N, 3.44. |
47.5% | In ethanol; for 1.5h;Reflux; | 1 eq of the diketoester obtained in example 1.5c and 1.1 eq of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> in 50 ml of ethanol were heated at reflux for 90 minutes. The reaction solvent was then removed under vacuum and the obtained residue purified by flash chromatography (oil ligroin/EtOAc 9:1). The compound ethyl 8-chloro-1-(2',4'-dichlorophenyl)-4,5-dihydrobenzo-1H-6oxa-cyclo-hepta[1,2-c]pyrazol-3-carboxylate was thus obtained as an orange solid (47.5% yield). Rf = 0.32 (oil ligroin/EtOAc 9:1); m.p. 130-131 C; IR (nujol) (lambda= cm-1) 1712 (CO); 1H-NMR (CDCl3) delta 1.42 (t, 3H, J = 7.0 Hz), 3.44 (qu, 2H, J = 5.4 Hz), 4.35-4.51 (m, 4H), 6.65 (d, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 8.6 Hz), 7.14 (s, 1H) 7.39-7.44 (m, 2H), 7.49 (s, 1H); Anal. Calc. for C20H15Cl3N2O2: C, 54.88; H, 24.30; Cl, 6.40; N, 3.45. Found: C, 54.80; H, 24.26; Cl, 6.39; N, 3.44 |
47.5% | In ethanol; for 1.5h;Reflux; | 1 eq of the diketoester obtained in example 1.5c and 1.1 eq of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> in 50 ml of ethanol were heated at reflux for 90 minutes. The reaction solvent was then removed under vacuum and the obtained residue purified by flash chromatography (oil ligroin/EtOAc 9:1). The compound ethyl 8-chloro-1-(2',4'-dichlorophenyl)-4,5-dihydrobenzo-1H-6oxa-cyclo-hepta[1,2-c]pyrazol-3-carboxylate was thus obtained as an orange solid (47.5% yield). Rf = 0.32 (oil ligroin/EtOAc 9:1); m.p. 130-131 C; IR (nujol) (lambda= cm-1) 1712 (CO); 1H-NMR (CDCl3) delta 1.42 (t, 3H, J = 7.0 Hz), 3.44 (qu, 2H, J = 5.4 Hz), 4.35-4.51 (m, 4H), 6.65 (d, 1H, J = 8.6 Hz), 6.81 (d, 1H, J = 8.6 Hz), 7.14 (s, 1H) 7.39-7.44 (m, 2H), 7.49 (s, 1H); Anal. Calc. for C20H15Cl3N2O2: C, 54.88; H, 24.30; Cl, 6.40; N, 3.45. Found: C, 54.80; H, 24.26; Cl, 6.39; N, 3.44 |
for 1.5h;Reflux; | 1 eq of the diketoester and 1.1 eq of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> in 50 ml of ethanol were heated at refluxfor 90 minutes. The reaction solvent was then removed under vacuum and the residue was purified by flash chromatography(eluent oil ligroin/ethyl acetate 9/1 v/v). The compound ethyl 8-chloro-1-(2?,4?-dichlorophenyl)-4,5-dihydrobenzo-1H-oxa-cyclohepta[1,2-c]pyrazole-3-carboxylate was isolated as an orange solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of hexamethyldisilazane (HMDS) (92.6 mL, 443 mmol) in diethyl ether (2 L) was added 15% n-butyllithium in hexane (200 mL, 443 mmol) at -20 C and stirred for 30 min. The reaction mixture was cooled to -78 C and to it was added 4-chloropropiophenone (50 g, 295 mmol) in ether (500 mL) and stirred for 45 min at -78 C. The cooling bath was removed and the reaction mixture was allowed to warm up to -20 C and stirred until the reaction mixture turned into a clear solution. The reaction mixture was cooled again to -78 C and diethyl oxalate (80.4 mL, 591 mmol) was added to it. The reaction mixture was slowly warmed up to room temperature over 4 h and stirred for additional 16 h. The yellow colored solid was filtrated and washed with ether and dried under vacuum to give 57 g of lithium salt of 4-(4-chloro-phenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester. This solid was added to a solution of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (44.5 g, 208 mmol) in ethanol (1.2 L) and stirred at room temperature for 16 h. The precipitated solid was filtered, washed with ethanol and dried under vacuum. This solid was dissolved in acetic acid (1 L) and refluxed for 16 h. The reaction mixture was cooled and slowly poured into cold water. The separated solid was filtered, washed with water and dried to give 24 g of the pyrazole ester which was dissolved in methanol (50 mL). To this solution was added a solution of potassium hydroxide (1.6 g, 28.4 mmol) in water (10 mL) and the mixture was refluxed for 3 h. The solvent was evaporated under vacuum and the residue was poured into crushed ice and acidified with 6N HCl (pH ~2). The separated solid was filtered, washed with water and dried under vacuum to give the desired compound (4.1 g) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-n-butanoylchlorobenzene; imidazol-1-yl-oxo-acetic acid ethyl ester With lithium hexamethyldisilazane In tert-butyl methyl ether at -20 - 20℃; Stage #2: 2,4-dichlorophenyl hydrazine hydrochloride In ethanol for 16h; Reflux; Stage #3: With acetic acid for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In ethanol; at 90℃; for 3h; | Reference Example 44 ethyl 3-[1-(2,4-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]benzoate A mixture of <strong>[55304-73-9]2,6-dichloropyridine-3-carbaldehyde</strong> (800 mg, 4.55 mmol), 2,4-dichlorophenylhydrazine hydrochloride (1.07 g, 5.00 mmol) and ethanol (16 ml) was stirred at 90C for 3 hr, and the reaction solution was concentrated. Diethyl ether was added to the residue and 2,6-dichloro-3-[(E)-[(2,4-dichlorophenyl)hydrazono]methyl]pyridine (1.49 g, yield 98%) was collected by filtration to give a solid. A mixture of the compound (1.49 g), sodium tert-butoxide (641 mg, 6.67 mmol), tris(dibenzylideneacetone)dipalladium(O) (81.5 mg, 0.089 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropyl-1,1'-biphenyl (127 mg, 0.267 mmol) and 1,4-dioxane (20 ml) was stirred in a microwave reactor (Initiator (trade name), Biotage AB) at 120C for 30 min. Water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane = 1:19) to give 6-chloro-1-(2,4-dichlorophenyl)-1H-pyrazolo[3,4-b]pyridine (339 mg, yield 26%) as a solid. To a solution of the compound (365 mg), [3-(ethoxycarbonyl)-phenyl]boronic acid (261 mg, 1.34 mmol) and 2 N aqueous sodium carbonate solution (2.4 ml) in 1,2-dimethoxyethane (12 ml) was added under a nitrogen atmosphere tetrakis(triphenylphosphine)palladium(O) (170 mg, 0.147 mmol) at room temperature, and the mixture was stirred overnight at 100C. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane= 1:9) to give the title compound (321 mg, yield 64%) as an oil. 1H-NMR (CDCl3) delta: 1.43 (3H, t, J = 7.2 Hz), 4.36 - 4.46 (2H, m), 7.44 (1H, dd, J = 8.6, 2.4 Hz), 7.51 - 7.62 (2H, m), 7.66 (1H, d, J = 2.4 Hz), 7.78 (1H, d, J = 8.6 Hz), 8.10 (1H, dd, J = 7.7, 1.1 Hz), 8.17 - 8.34 (3H, m), 8.70 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: dissolve the substituted anline (3 mmol) in HCl aq (6 M) at -5 C,and slowly added an aqueous solution of NaNO2 (0.23 g, 3.3 mmol).The mixture was stirred for further 0.5 h, a solution of SnCl2 (1.7 g,7.5 mmol) dissolved in concentrated HCl was added dropwise, then the resulting mixture was moved to room temperature and stirred for further1 h. The muddy mixture was filtered out, washed with a small amount of HCl solution and dried in vacuum. This desired phenylhydrazine hydrochloride intermediate was used directly without additional purification.To a solution of substituted benzyl halide 3 mmol in EtOH was added the hydrazine hydrate 30 mmol, and the mixture was stirred atroom temperature overnight till the reaction was completed monitored by TLC. The reaction mixture was concentrated to dryness, and redissolvedin a little EtOH, then added an aqueous HCl (12 M) andstirred for a while at 0 C. The resulting precipitate was collected byfiltration and dried. This desired benzylhydrazine hydrochloride intermediatewas used directly without additional purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: triethylamine / toluene / 12 h / 20 °C 2.1: toluene-4-sulfonic acid / toluene / 12 h / Reflux 3.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 20 °C / Cooling with ice 4.1: triethylamine / dichloromethane / 1 h / 10 - 20 °C 4.2: pH 1 | ||
Multi-step reaction with 3 steps 2.1: propionic acid / 16 h / Heating / reflux 2.2: 20 h / 140 - 145 °C 3.1: hydrogenchloride / water; isopropyl alcohol / 9.08 h / 10 - 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.4% | Intermediate l ib2,4-Dichloro-7,8, -tetrahydrocyclohepta[b]indol-6(5H)-oneCycloheptane-l,2-dione (1 g, 7.9 mmol) was dissolved in MeOH (25 mL) and (2,4-dichlorophenyl) hydrazine hydrochloride (1.86 g, 8.7 mmol) in AcOH-HCl (3.5: 1, 45 mL) was added and heated to 60 C for 18 h. MeOH was removed in vacuo, the reaction mixture was basified with aqueous NaHC03 (pH-8) and then extracted with EtOAc (3 x 25mL), The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to give the crude product which was purified by silica gel chromato graph [EtOAc-hexane (9: 1) as eluant] to give the title compound (0.2 g, 9.4%). 1H NMR (200 MHz, CDC13, delta in ppm) 9.0 (br s, 1H), 7.54 (d, J= 1.6 Hz, 1H), 7.33 (d, J= 1.8 Hz, 1H), 3.11 (t, J= 12.0 Hz, 2H), 2.90 (t, J= 11.8 Hz, 2H), 2.13-2.20 (m, 4H). |
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 |
---|---|---|
86% | 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 |
---|---|---|
Stage #1: 1-(2,4-dimethyl-phenyl)-propan-1-one; oxalic acid diethyl ester With sodium methylate; lithium chloride In tetrahydrofuran at 0 - 20℃; for 3h; Stage #2: 2,4-dichlorophenyl hydrazine hydrochloride With trifluoroacetic acid In ethanol for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: lithium chloride; sodium methylate / tetrahydrofuran / 3 h / 0 - 20 °C 1.2: 12 h / Reflux 2.1: sodium hydroxide / ethanol; water / 4 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With anhydrous Sodium acetate In ethanol for 1h; Reflux; | ||
Stage #1: 2,4-dichlorophenyl hydrazine hydrochloride With anhydrous Sodium acetate In ethanol for 0.333333h; Reflux; Stage #2: Ethoxymethylenemalononitrile In ethanol for 1h; Reflux; | ||
Stage #1: 2,4-dichlorophenyl hydrazine hydrochloride With anhydrous Sodium acetate In ethanol for 0.333333h; Stage #2: Ethoxymethylenemalononitrile In ethanol for 1h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With triethylamine; In ethanol; toluene; for 4h;Reflux; | 2,4-Dichlorophenylhydrazine hydrochloride (21.3 g, 0.1 mol) was dissolved in 200 ml of ethanol, triethylamine (10.1 g, 0.1 mol) was added, and a toluene solution of 50% ethyl glyoxylate was added dropwise. (40.8g, 0.2mol), after 30min addition, the reaction was stirred at reflux for 4h, the solvent was evaporated under reduced pressure, and then recrystallized from anhydrous ethanol to give ethyl 2-[2-(2,4-dichlorophenyl)hydrazin-1-ylidene]acetate 16.1 g, yield: 62%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With piperidine; In ethanol; at 20℃; for 24.25h;Reflux; | General procedure: To a solution of alpha,beta-insaturated ketone (1 equiv) in EtOH, piperidine (1 mL) and hydrazine were added dropwise. The mixture was stirred at rt for 15 min, and then refluxed for 24 h. EtOH was removed in vacuo, and the residue was purified by flash chromatography (eluent n-hexane/EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With piperidine; In ethanol; at 20℃; for 24.25h;Reflux; | General procedure: To a solution of alpha,beta-insaturated ketone (1 equiv) in EtOH, piperidine (1 mL) and hydrazine were added dropwise. The mixture was stirred at rt for 15 min, and then refluxed for 24 h. EtOH was removed in vacuo, and the residue was purified by flash chromatography (eluent n-hexane/EtOAc). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | 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 |
---|---|---|
90% | With acetic acid; In methanol; water; at 20℃; for 18h;Inert atmosphere; | To a solution of 4'-methylacetophenone (0.5 g, 3.73 mmol) in 8 mL of acetic acid and 5 mL of water/MeOH, <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> (0.8 g, 3.73 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with an additional 30 mL of water and subsequently filtered. The solid was dried in vacuo to afford 0.98 g of beige solid 1c (90% yield): mp 122.7 C. 1H NMR (CDCl3) delta 7.71 (t, 2H), 7.61 (d, 2H), 7.29 (s, 1H), 7.021(d, 3H), 2.38 (s, 3H), 2.28 (s, 3H). |
90% | With acetic acid; In methanol; water; at 20℃; for 18h; | To a solution of 4'- methylacetophenone (0.5 g, 3.73 mmol) in 8 mL of acetic acid and 5 mL of water/MeOH, 2,4- dichlorophenylhydrazine hydrochloride (0.8 g, 3.73 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with an additional 30 mL of water and subsequently filtered and the solid was dried in vacuo to afford 0.98 g of beige solid lc (90% yield): mp 122.7 C. NMR (CDC13) delta 7.71 (t, 2H), 7.61 (d, 2H), 7.29 (s, 1H), 7.021(d, 3H), 2.38 (s, 3H), 2.28 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With acetic acid; at 110℃; for 8h; | General procedure: To a stirred mixture of diketoester 9,10 (3.17mmol) and the requisite phenyl hydrazine hydrochloride (1.2 equiv) in AcOH (6mL) was heated under reflux for 8h. The reaction was allowed to cool to room temperature and poured onto ice-water. The precipitate was filtered, washed with water and air-dried to yield the analytically pure esters. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With acetic acid; at 110℃; for 8h; | General procedure: To a stirred mixture of diketoester 9,10 (3.17mmol) and the requisite phenyl hydrazine hydrochloride (1.2 equiv) in AcOH (6mL) was heated under reflux for 8h. The reaction was allowed to cool to room temperature and poured onto ice-water. The precipitate was filtered, washed with water and air-dried to yield the analytically pure esters. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With hydrogenchloride; In ethanol; water; for 5h;Reflux; | 5.2.21 1-(2,4-Dichlorophenyl)-3-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one (22) The reaction of 1-(2,4-dichlorophenyl)hydrazine hydrochloride (85.4 mg, 0.40 mmol) with 2-acetyl -1,3-cyclohexanedione (61.7 mg, 0.40 mmol) in ethanol (1.2 mL) under reflux for 5 h, by a procedure similar to that for 20 using concd HCl (0.40 mL) instead of H2SO4, gave 1-(2,4-dichlorophenyl)-3-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one 22 (49.9 mg, 42%) as a powder. 1H NMR (CD3OD, 300 MHz) δ 7.78 (d, J = 2.1 Hz, 1H), 7.59-7.52 (m, 2H), 2.88-2.69 (m, 2H), 2.56-2.49 (m, 2H), 2.46 (s, 2H), 2.37 (s, 1H), 2.19-2.12 (m, 2H); HRMS calcd for C14H13Cl2N2O (M+H) 295.0405, found 295.0403. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With hydrogenchloride In ethanol; water for 5h; Reflux; | 18 1-(2,5-Dichlorophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one (17) 5.2.18 1-(2,4-Dichlorophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one (18) The reaction of 1-(2,4-chlorophenyl)hydrazine hydrochloride (85.4 mg, 0.40 mmol) with 2-acetyl-5,5-dimethyl-1,3-cyclohexanedione (72.9 mg, 0.40 mmol) in ethanol (1.2 mL) under reflux for 5 h, by a procedure similar to that for 20 using concd HCl (0.40 mL) instead of H2SO4, gave 1-(2,4-dichlorophenyl)-3,6,6-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one 18 (62.1 mg, 48%) as a powder. 1H NMR (CDCl3, 400 MHz) δ 7.58 (d, J = 2.0 Hz, 1H), 7.42-7.35 (m, 2H), 2.53 (s, 3H), 2.49 (s, 2H), 2.38 (s, 2H), 1.10 (s, 6H); HRMS calcd for C16H17Cl2N2O (M+H) 323.0718, found 479.1360. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With sulfuric acid; In ethanol; for 5h;Reflux; | 5.3.5 1-(2,4-Dichlorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one (26) The reaction of 1-(2,4-dichlorophenyl)hydrazine hydrochloride (85.4 mg, 0.40 mmol) with <strong>[893842-26-7]5,5-dimethyl-2-(trifluoroacetyl)cyclohexane-1,3-dione</strong> 25a (94.5 mg, 0.40 mmol) in ethanol (1.2 mL) under reflux for 5 h, by a procedure similar to that for 20, gave 1-(2,4-dichlorophenyl)-6,6-dimethyl-3-(trifluoromethyl)-1,5,6,7-tetrahydro-4H-indazol-4-one 26 (71.5 mg, 47%) as a powder. 1H NMR (CD3OD, 400 MHz) delta 7.83 (d, J = 1.2 Hz, 1H), 7.61 (dd, J = 1.2, 1.2 Hz, 2H), 2.63 (s, 2H), 2.48 (s, 2H), 1.11 (s, 6H); HRMS calcd for C16H14Cl2F3N2O (M+H) 377.0435, found 377.0442. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With sodium hydroxide; In ethanol; at 20℃; | 5.3.6 3-Cyclopropyl-1-(2,4-dichlorophenyl)-6,6-dimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one (27) The reaction of 1-(2,4-dichlorophenyl)hydrazine hydrochloride (234.9 mg, 1.1 mmol) with 2-(cyclopropylcarbonyl)-5,5-dimethylcyclohexane-1,3-dione 25b (199.9 mg, 0.96 mmol) in ethanol (5.0 mL) at room temperature overnight, by a procedure similar to that for 20 using NaOH (44.0 mg, 1.1 mmol) instead of H2SO4, gave 3-cyclopropyl-1-(2,4-dichlorophenyl)-6,6-dimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one 27 (36.2 mg, 11%) as a powder. 1H NMR (CDCl3, 400 MHz) delta 7.55 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 2.0, 8.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 2.62-2.58 (m, 1H), 2.45 (s, 2H), 2.40 (s, 2H), 1.10 (s, 6H), 1.03-1.00 (m, 4H); HRMS calcd for C18H19Cl2N2O (M+H) 349.0874, found 349.0875. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With acetic acid; at 20℃; for 20h;Reflux; | 3.8 g of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> are added to an acetic acid (32 mL) solution of 1-(6-oxo-5,6-dehydro-4H-cyclopenta [b]thiophen-5-yl)pentan-1,2-dione (3.9 g; 16 mmoles) prepared in example 1d. It is left under stirring for 4 hours at room temperature and then the reaction mixture is heated under reflux for 16 hours. At the end, after cooling to room temperature, the reaction mixture is diluted with water (50 mL). The precipitate formed is filtered, washed with water and anhydrified. 3.7 g of ethyl 1-(2',4'-dichlorophenyl)-1,4-dehydro-thieno[3',2':4,5]cyclopenta[1,2-c] pyrazol-3-carboxylate are obtained (yellow solid; yield 60%). Rf=0.63 (ligroin/ethyl acetate 8/2 volume/volume); 1H NMR (CDCl3) delta (ppm): 7.61 (d, 1H, ArH), 7.58 (d, 1H, ArH), 7.43 (dd, 1H, ArH), 7.30 (d, 1H, ArH), 7.13 (d, 1H, ArH), 4.47 (q, 2H, OCH2), 3.73 (s, 2H, CH2), 1.44 (t, 3H, CH3); 13C NMR (CDCl3) delta (ppm): 167.3, 155.0, 149.2, 139.4, 136.2, 135.4, 132.0, 130.8, 130.6, 130.2, 129.3, 128.3, 123.5, 28.5; FT-IR (film) numax: 2976.4, 2926.6, 1727.5, 1262.7, 1175.8, 1102.7 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With triethylamine; In ethanol; at 25℃;Inert atmosphere; | General procedure: A mixture of appropriate aldehyde 2 (0.30 mmol), hydrazine salt (0.30 mmol), and Et3N (30 mg, 0.30 mmol) in EtOH (20 mL) was stirred at 25 C overnight under N2. (In the case of hydrazine, the free base was used and the reaction was performed without addition ofEt3N.) The solvent was removed and the residue was crystallized from EtOH. The filter cake was collected and dried. An additional portion of the product obtained from the filtrate by evaporation of the solvent was purified by chromatography (silica gel). The two portions of pure product 3 were combined for subsequent use. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With sulfuric acid; In ethanol; water; at 79℃; for 14h;Inert atmosphere; | 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),<strong>[5446-18-4]2,4-dichlorophenyl hydrazine hydrochloride</strong> (0.777 g,3.6 mmol), and 50 % 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 % sulfuric acid (20 ml) was added, followedby refluxing for 8 h. The reaction mixture wascooled to room temperature (35C) 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 %dil. NaOH. This aqueous layer was washed with petroleumether. The aqueous layer was separated, cooled to 0C, 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 %), Off white solid, mp 208-209C; 1H NMR (CDCl3, 400 MHz): d 7.44-7.41 (m, 1H), 7.35 (d, J = 1.89 Hz,1H), 7.33-7.28 (m, 3H), 7.09 (d, J = 8.47 Hz, 2H), 2.36 (s,3H); 13C NMR (CDCl3, 100 MHz): d 166.4, 143.3, 136.2,135.6, 135.1, 133.5, 130.8, 130.5, 129.8, 128.9, 127.8,127.7, 126.7, 119.6, 9.6; HRMS-ESI (m/z) Calcd.C17H11O2N2Cl3Na: 402.9778 found: 402.9781. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | 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),<strong>[5446-18-4]2,4-dichlorophenyl hydrazine hydrochloride</strong> (0.777 g,3.6 mmol), and 50 % 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 % sulfuric acid (20 ml) was added, followedby refluxing for 8 h. The reaction mixture wascooled to room temperature (35C) 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 %dil. NaOH. This aqueous layer was washed with petroleumether. The aqueous layer was separated, cooled to 0C, 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 %) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In ethanol; for 3h;Reflux; | A stirred solution of <strong>[5814-38-0]ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate</strong> (23 g, 90 mmol) and (2,4-dichlorophenyl)hydrazine hydrochloride (21 .21 g, 99 mmol) in ethanol (690 mL) was ref luxed for 3 h. The reaction mixture was allow to cool to room temperature and solvent was removed to give a red-orange solid, which was purified by column chromatography (silica gel, 0 - 9 % ethyl acetate in petroleum ether) to obtain the title compound.Yield: 49%; 1H NMR (300 MHz, DMSO-c13): 1.29 (t, J= 7.0 Hz, 3H, COOCH2CH3),4.40 (q, J= 7.2 Hz, 2H, COOCH2CH3), 7.21 -7.31 (m, 3H, pyrazole and Ar-I-n, 7.44 (d,J= 8.7 Hz, Ar-I-n, 7.66 (dd, J= 2.1 Hz, 8.4 Hz, 1H, Ar-I-n, 7.81 (d, J= 8.7 Hz, Ar-I-n, 7.88 (d, J= 2.1 Hz, Ar-I-n; MS: m/z419.0 [M + Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With sulfuric acid; In water; at 100℃; for 2h; | 2,4-Dichlorophenyl)hydrazine hydrochloride (5.0 g, 23.5 mmol) was suspended in 4% aqueous sulphuric acid (150 mL) and 4-amino butyraldehyde diethyl acetal (4.53 g, 28.mmol, 1.2 eq) was added to the suspension. The reaction mixture was heated to 100 C and monitored by LCMS. The reaction was complete after 2 h. The reaction mixture was then cooled to RT and the pH was adjusted to 10-12 with aqueous NaOH (1N, 90 mL). The aqueous layer was extracted with CH2Cl2 (2 × 250 mL). The combined organic layers were dried over anhydrous Na2SO4 filtered and concentrated to obtain 4 g of 2-(5,7-dichloro-1H-indol-3-yl)ethan-1-amine as a semi-solid. To this was added ethanolic HCl (150 mL) until the pH of the solution was 2-3. The solution was then concentrated under vacuum to remove to obtain 2-(5, 7-dichloro-1H-indol-3-yl) ethan-1-amine hydrochloride (4.5 g, 84%).LCMS: 228.02 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.8% | In ethanol; water;Reflux; | 1,1,3,3-tetramethoxypropane (16.4 g, 0.1 mol) was added to a suspension of <strong>[5446-18-4]2,4-dichlorophenyl hydrazine hydrochloride</strong> (21.35 g, 0.1 mol) in 95% ethanol aqueous solution (100 mL) and the resulting mixture was heated to reflux for 3-5 h. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol, and then poured into sodium carbonate solution. The water phase was extracted with ethyl acetate (3*100 mL), the organic phases were emerged, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether=1:10, as an eluent) to get 18.06 g 1-(2,4-dichlorophenyl)-1H-pyrazole as yellow solid with yield of 84.8%. |
84.8% | In ethanol; water;Reflux; | Take 21 · 35g (0 · lmol) of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> with16.4 g (0 · lmol) 1,1,3,3-tetramethoxypropane in 250 ml three-necked flask, 100 ml of a 95% aqueous ethanol solution was used as the solvent and the temperature was raised to reflux for 3-5 hours.After the TLC monitoring reaction was completed, most of the ethanol was distilled off under reduced pressure. The aqueous solution was added to the residue, and the aqueous phase was extracted with (3? 100 ml) of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and dissolved. The residue was subjected to column chromatography (eluent: ethyl acetate and petroleum ether in a volume ratio of 1:10) to give 18.06 g of a yellow solid in 84.8% yield. |
84.8% | In ethanol; water;Reflux; | Taking 21.35 g (0.1 muM) phenyl-dichloride jing hydrochloride with 2, 4 - 16.4 g (0.1 muM) 1, 1, 3, 3 - tetramethoxy propane in 250 ml three-mouth bottle, 100 ml 95% ethanol aqueous solution as the solvent, heating to reflux reaction for 3 - 5 hours. TLC monitoring after the reaction, reducing pressure and most of the ethanol, to the remnants in the fluid adds sodium carbonate aqueous solution, the aqueous phase is (3 × 100 ml) ethyl acetate extraction, the combined organic phase, anhydrous magnesium sulfate drying, filtering, desolvation. The residue column chromatography (eluting agent is ethyl acetate with petroleum ether, the volume ratio of 1:10) to separate the yellow solid 18.06 g, yield 84.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With toluene-4-sulfonic acid; In ethanol; at 78℃; for 5h; | General procedure: The 1,3,5-tris-beta-enaminone 1 (1 mmol), hydrochloride hydrazines 2-4 (3.6 mmol), and p-toluenesulfonic acid (0.6 mmol) were dissolved in dry ethanol (5 mL) in a round-bottom flask equipped witha stir bar. The reaction mixture was stirred at 78 C in a pre-heated oil bath for 5 h. Afterwards,the ethanol was evaporated under reduced pressure and 1,3,5-tris(pirazolyl)benzenes were isolatedwith chloroform (10 mL) and washed with distillated water (3 x 10 mL). The organic phase was driedwith anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With acetic acid; In ethanol; at 60℃; for 3.5h; | (2,4-Dichlorophenyl)hydrazine hydrochloride (2.08 g, 9.76 mmol) and AcOH(3.55 mL, 62.10 mmol) were added to a solution of methyl 5-(4-methoxyphenyl)-2,4-dioxopentanoate (2.22 g, 8.87 mmol) in EtOH (35 mL), the mixture waswarmed up to 60 00 and stirred at this temperature for 3.5 h. The reaction mixture was allowed to cool down to rt and the solvent was concentrated off. The residue was poured into EtOAc (100 mL), washed with brine (100 mL) and with NaHCO3 (saturated aqueous solution, 100 mL). The organic layer was dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residuewas purified by flash chromatography on Si02 (10-24% EtOAc/hexanes), to afford the title compound (orange oil, 2.84 g, 82% yield).HPLC-MS (Method A): Ret, 10.52 mm; ESl-MS mlz: 391 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | 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 |
---|---|---|
80% | With potassium carbonate; at 90℃; for 1.5h;Inert atmosphere; Molecular sieve; | General procedure: To a stirred solution of the carbonyl com.p.ound (1.0 mmol) in DMPU (5 mL) were addedpowdered 4 A molecular sieves (30 wt % relative to the carbonyl substrate), ArNHNH2.HCl (3.0 mmolfor 5, 2.0 mmol for 6), and K2CO3 (3.0 mmol for 5, 2.0 mmol for 6). For 5, all reagents were placed inthe flask and heated to 90 C; for 6, the hydrazone was allowed to form at 90 C (1.5 h) before K2CO3was added. The reaction was stirred at 90 C for the time indicated in Table 2. Workup was performedas described in Method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In N,N-dimethyl-formamide; at 50℃; for 2h;Inert atmosphere; | General procedure: To a stirred solution of the carbonyl compound (1.0 mmol) in DMF (5 mL) at 50 C (oil bath)was added ArNHNH2.HCl (3.0 mmol for 5, 2.0 mmol for 6) and the solution was stirred until TLC(20% EtOAc in hexanes) indicated complete conversion (roughly 2 h). The crude reaction mixture wasadded to water and extracted with EtOAc (2 Chi 15 mL). The combined organic layers were washedwith water and saturated aq NaCl, dried (MgSO4), filtered, and concentrated under vacuum to givethe crude hydrazones. The crude products were stirred with 20% ether/pentane for 1 h, filtered anddried to give arylhydrazones 9 and 10. Characterization data for these materials are given in the ESI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In N,N-dimethyl-formamide; at 50℃; for 2h;Inert atmosphere; | General procedure: To a stirred solution of the carbonyl compound (1.0 mmol) in DMF (5 mL) at 50 C (oil bath)was added ArNHNH2.HCl (3.0 mmol for 5, 2.0 mmol for 6) and the solution was stirred until TLC(20% EtOAc in hexanes) indicated complete conversion (roughly 2 h). The crude reaction mixture wasadded to water and extracted with EtOAc (2 Chi 15 mL). The combined organic layers were washedwith water and saturated aq NaCl, dried (MgSO4), filtered, and concentrated under vacuum to givethe crude hydrazones. The crude products were stirred with 20% ether/pentane for 1 h, filtered anddried to give arylhydrazones 9 and 10. Characterization data for these materials are given in the ESI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With acetic acid at 70℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | 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 |
---|---|---|
46% | With boron tribromide; dimethyl sulfoxide; at 80℃; for 1h; | General procedure: A 30-mL of round-bottomed flask was placed in ice. Arylhydrazine (0.5 mmol), CPME (or CH2Cl2) 0.2 mL was added. Then 2.4 equiv. of boron bromide (BBr3) was added gently. DMSO 0.2 mL was added in dropwise through a syringe. The mixture was then placed in hot plate (80oC), stirred in 1 hour under air. The yield of product was determined by 1H NMR (1,3,5 trioxane, CDCl3). The crude product was purified by liquid extraction with CH2Cl2 wash by sat. NaHCO3, dried over Na2SO4, column chromatography (Hexane 100% or Hexane: EtOAc =20:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). | ||
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene at 20 - 75℃; | Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
102 g | Stage #1: diethyl 3-methyl-2-oxo-succinate; 2,4-dichlorophenyl hydrazine hydrochloride With trifluoroacetic acid In toluene at 55℃; for 4.5h; Inert atmosphere; Stage #2: With water monomer In toluene at 20 - 75℃; | Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-oxo-4,5-dihydro-1H-pyrazole-3-carboxylate 2,4-Dichlorophenylhydrazine hydrochloride (126 g) is dissolved in 11 of toluene and this solution is placed under nitrogen; after stirring, 100 g of diethyl 2-methyl-3-oxosuccinate (Sigma) are added and the mixture is then heated and 50 ml of TFA are added at 55° C. The mixture is left at the reflux of the solvent for 4 and a half hours, with stirring. The mixture is allowed to return to ambient temperature and is then heated to 75° C. and the reaction medium is hydrolyzed with 300 ml of water. The mixture is separated by settling out, the aqueous phase is discarded, and the organic phase is then evaporated in order to eliminate the residual TFA. The organic phase is taken up with 100 ml of toluene and the expected product then crystallizes (102 g). |
Tags: 5446-18-4 synthesis path| 5446-18-4 SDS| 5446-18-4 COA| 5446-18-4 purity| 5446-18-4 application| 5446-18-4 NMR| 5446-18-4 COA| 5446-18-4 structure
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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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