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CAS No. : | 536-40-3 | MDL No. : | MFCD00007603 |
Formula : | C7H7ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PKBGHORNUFQAAW-UHFFFAOYSA-N |
M.W : | 170.60 | Pubchem ID : | 10816 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 42.35 |
TPSA : | 55.12 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) : | -6.5 cm/s |
Log Po/w (iLOGP) : | 1.44 |
Log Po/w (XLOGP3) : | 1.18 |
Log Po/w (WLOGP) : | 0.94 |
Log Po/w (MLOGP) : | 1.73 |
Log Po/w (SILICOS-IT) : | 0.84 |
Consensus Log Po/w : | 1.23 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.91 |
Solubility : | 2.09 mg/ml ; 0.0122 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.93 |
Solubility : | 1.99 mg/ml ; 0.0117 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.65 |
Solubility : | 0.383 mg/ml ; 0.00224 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.08 |
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 |
---|---|---|
91% | With hydrazine hydrate In ethanol; waterReflux | General procedure: Hydrazides (30–58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3–6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information). |
91.9% | With hydrazine hydrate In ethanol at 80℃; for 6 h; | (10.83 mmol) of ethyl 4-chlorobenzoate and 50 mL of absolute ethanol were added to a 100 mL round-bottomed flask and 1.08 g (21.67 mmol) of 80percent hydrazine hydrate was added. The temperature of the oil bath was 80Othe C heated under reflux for 6 h, the end of the reaction by TLC, the solvent was distilled off under reduced pressure, to the system was added 30 mL of purified water, extracted with dichloromethane, and finally as a white solid 1.7 g, yield 91.9percent, |
82% | With hydrazine hydrate In ethanolReflux | General procedure: Ethylbenzoates (11-15, 1.5g, 9.98 mmol)and ethyl-2-phenylacetates (16-20, 1.5g, 9.13 mmol)were dissolved in ethanol and then hydrazine-hydrate(99percent) was added and reux for 8-12h. Ethanol wasconcentrated and the resultant residue was pouredin ice cold water and stirred for 15 -20 min, the solidsthat were thrown out was fltered at the pump anddried to obtain the corresponding benzohydrazides(21-25) and 2-phenylacetohydrazides (26-30) in 80-82percent yield. |
79.3% | With hydrazine hydrate In ethanolReflux | General procedure: A solution of the isolated esters 2a–e (10mmol) in ethanol (20mL), hydrazine hydrate (97percent, 3mL) was added and heated under reflux for 5–8h. After cooling, the formed precipitate was filtered off, washed with water, dried, and crystallized from ethanol. |
79.3% | With hydrazine hydrate In ethanolReflux | General procedure: Hydrazine hydrate (97percent, 30 mmol, 1.5 mL) was added to a solutionof the isolated esters 2a–e (10 mmol) in ethanol (20 mL), and themixture was heated at reflux for 5–8 h. After cooling, the resultingprecipitate was filtered off, washed with water, dried, and crystallizedfrom ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | With hydrazine hydrate In ethanol for 5 h; Reflux | General procedure: A solution of hydrazine hydrate (20.00 mmol) in 2 mL EtOH was added dropwise to the ester 2 (5.00 mmol). The mixture was refluxed for 5 h and filtered, and the corresponding acid hydrazide 3 was obtained by washing the residue with ice water. |
92% | With hydrazine hydrate In methanolReflux | General procedure: Compound (2) (0.1 mol) was taken in a round-bottom flaskwith methanol (100 mL). Hydrazine hydrate (99percent) (0.15mol, 5.7 mL) was added drop wise with gentle stirring. Thereaction mixture was refluxed for 4–6 h. Excess of methanolwas distilled off under reduced pressure. The precipitatedhydrazide was dried and re-crystallized from methanol(Zamani and Faghihi 2003). |
88% | With hydrazine hydrate In water at 50 - 60℃; for 0.166667 h; | General procedure: Pathway A-Hydrazine hydrate 64percent (v/v) (30.0 mL, 0.33 mol) was heated up to 50-60 °C. The methyl ester previously isolated (0.01 mol) was added and the mixture was refluxed during 10 min. The cooling down was proceeded sequentially in a water bath, followed by ice bath and dry ice - ethanol bath. The solid was filtered and washed with cold water. Different conditions were needed to obtain 4-nitro-3-(trifluoromethyl)benzhydrazide (3d) and 4-nitrobenzhydrazide (3 h). Hydrazine hydrate 64percent (v/v) (30.0 mL, 0.33 mol) was cooled down in ice bath to -3 to 2 °C. The respective methyl ester (0.01 mol) was added and the mixture was stirred during 1 hour. The cooling down was proceeded in dry ice - ethanol bath. The solid was filtered and washed with cold water. Pathway B-each substituted benzoic acid (0.01 mol) was refluxed during 4 h in 20.0 mL (0.50 mol) of anhydrous methanol and 0.5 mL (1.0 mmol) of sulfuric acid. The reaction mixture was cooled down to room temperature. and the hydrazine hydrate 80percent (v/v) (10.0 mL, 0.11 mol) was added. The system was maintained into vigorously stirring for more 30 minutes. In the case of compounds with 4-nitro and 4-nitro-3-trifluoromethyl substituent groups attached in the benzene moiety, after the addition of hydrazine hydrate 80percent (v/v) at room temperature, the reaction mixture was cooled down in ice bath and maintained into stirring during 1 hour. After these periods, the mixture was maintained at cold temperature to give 3. |
82.4% | With hydrazine hydrate In ethanolReflux | General procedure: To a solution of the appropriate methyl benzoate ester (1.0 mmol) in ethanol (30 mL), hydrazine monohydrate (0.15 g, 3.0 mmol) was added. The reaction mixture was heated under reflux overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was washed with water (2 x 3 mL), and the obtained solid was filtered and dried to give benzohydrazide derivatives 3a-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: With thionyl chloride In methanol at 50℃; for 4 h; Cooling with ice Stage #2: With hydrazine hydrate In ethanol for 4 h; Reflux |
Dissolve 4-chlorobenzoic acid (3. 2g, 20mmol) in methanol (30mL) and slowly add 2mL of thionyl chloride in an ice bath. Heat at 50 ° C for 4h (15mLX3), spin-dried for use; the previous step in 30mL ethanol, 80percent hydrazine hydrate added 4mL, reflux reaction heating (15mLX3), the mixture was cooled to room temperature, 4h, cooling, precipitation of white solid, filter drying, a white solid 2. 5g, yield 74percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With silica gel; hydrazine In neat (no solvent) at 130℃; for 24 h; Inert atmosphere; Sealed tube | General procedure: These compounds were prepared using the standard procedure at 130°C for 20–24h. For each reaction, the crude product was adsorbed onto silica gel and purified on a 15cm×2.5cm silica gel column eluted with 80percent EtOAc in hexanes. The isolated yields are given in Table 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With hydrazine hydrate In ethanol for 30 h; Reflux | The methyl ester of indomethacin (0.01 mol) and hydrazine hydrate (99percent) (0.2 mol) in presence of absolute ethanol (50 mL) were refluxed for 30 h. The reaction mixture was concentrated by using rota vapor and poured in a beaker containing ice while stirring and kept for 4 h at room temperature.The solid was separated out by filtration. The product was dried and recrystallized from ethanol.The product was carefully checked by thin layer chromatography. Two compounds were isolated by column chromatography by using different fractions of n-hexane and ethyl acetate. The first compound was 2-(6-methoxy-2-methyl-1H-indol-3-yl) acetohydrazide compound (1) and was obtained as the major product. The second compound, 4-chlorobenzohydrazide (2) was obtained as minor product. Both the compounds were fully characterized by the spectral data. 2-(6-methoxy-2-methyl-1H-indol-3-yl) acetohydrazide (1). Color: white; Yield: 70percent; m.p.: 168–170 °C; UV max (Methanol) = 280 nm; 1H-NMR (500 MHz, DMSO-d6): δ = 2.38 (3H, s, CH3), 3.54 (2H, s,CH2), 3.80 (3H, s, OCH3), 4.26 (2H, s, NH2, D2O exchg.), 6.67 (1H, d, J = 8.5 Hz, Ar–H), 7.16 (2H, d,J = 7.5 Hz, Ar–H), 9.16 (1H, s, NH, D2O exchg.), 10.62 (1H, s, CONH, D2O exchg.); 13C-NMR (125 MHz,DMSO-d6): δ = 12.0 (CH3), 30.2 (CH2), 55.8 (OCH3), 101.1, 105.1, 109.8, 110.0, 111.7, 128.0, 129.3, 129.7,130.6, 134.3, 153.4, 170.8 (C=O); ms: m/z = 233.11 [M]+, 234.07 [M + 1]+; Analysis: C12H15N3O2 for,calcd. C 61.79, H 6.48, N 18.01percent; found C 61.58, H 6.46, N 18.05percent. 4-Chlorobenzohydrazide (2). Color: white; Yield: 20percent; m.p.: 148–150 °C; UV max (Methanol) = 230 nm;1H-NMR (500 MHz, DMSO-d6): δ = 4.53 (2H, s, NH2, D2O exchg.), 7.52 (2H, d, J = 8.5 Hz, Ar–H), 7.84(2H, d, J = 8.5 Hz, Ar–H), 9.87 (1H, s, CONH, D2O exchg.); 13C-NMR (125 MHz, DMSO-d6): δ = 128.86,129.32, 132.50, 136.25, 165.29; MS: m/z = 170.45 [M]+; Analysis: C7H7N2OCl for, calcd. C 49.28, H 4.14,N 16.42percent; found C 49.37, H 4.12, N 16.46percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With hydrazine monohydrate In methanol at 20℃; | 2.3. Synthesis of 4-chlorobenzohydrazide (2) Ethyl 4-chlorobenzoate (1; 9.8 mL, 0.05 mol) was taken in a250-mL round-bottom flask and 35 mL of hydrazine hydrate(80%) was added slowly on stirring and the mixture was furtherstirred for 5-6 h. Yellow precipitates were obtained onevaporation of solvent under vacuum. The precipitates werewashed with cold water and dried. The physical and spectroscopicdata of 2 is as follows:Yellow amorphous powder; Yield: 95%; M.P.: 164-166 C;IR (KBr, max, cm1): 3390, 3350 (N-H), 3030 (Ar-H), 2954 (CH),1673 (CO), 1613-1516 (Ar-CC); 1H-NMR (400 MHz,CDCl3, ppm): 7.49 (2H, d, J8.5 Hz, H-3,5), 8.10 (2H, d,J8.5 Hz, H-2,6); 13C-NMR (100 MHz, CD3OD): d 125.1 (C-3,5),128.9 (C-2,6), 131.0 (C-1), 134.9 (C-4), 168.9 (CO); HR-EI-MS(m/z): 170.0247. [M] calculated for C7H7ClN2O; 170.0238. |
93.2% | With hydrazine hydrate monohydrate In ethanol at 80℃; for 4h; Reflux; | |
91% | With hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate Reflux; | Synthesis of benzohydrazides General procedure: Hydrazides (30-58) were synthesized by one pot conventionalmethod24 Benzoic acid or its derivative (10 mmol) was dissolvedin ethanol (20 mL). Sulfuric acid (3 N, 2 mL) was added and thereaction contents were refluxed for six hours. The reaction wasmonitored with TLC. After the completion of the reaction, the reactionmixture was neutralized by adding solid NaHCO3, and filteredto remove excess of NaHCO3. In the neutralized reaction mixture which contains ethyl ester, hydrazine monohydrate (1.5 mL,3 mmol) was added and refluxed for 3-6 h to complete the reaction.Ethanol and unreacted hydrazine were removed by distillationupto 1/3 volume. The reaction contents were cooled, filteredand recrystallized from methanol to obtain the desired hydrazidecrystals (see Supporting information). |
91.9% | With hydrazine hydrate monohydrate In ethanol at 80℃; for 6h; | 1.2 (2) Preparation of 4-chlorobenzohydrazide (10.83 mmol) of ethyl 4-chlorobenzoate and 50 mL of absolute ethanol were added to a 100 mL round-bottomed flask and 1.08 g (21.67 mmol) of 80% hydrazine hydrate was added. The temperature of the oil bath was 80Othe C heated under reflux for 6 h, the end of the reaction by TLC, the solvent was distilled off under reduced pressure, to the system was added 30 mL of purified water, extracted with dichloromethane, and finally as a white solid 1.7 g, yield 91.9%, |
88% | With hydrazine hydrate monohydrate In ethanol for 4h; Reflux; | |
87% | With hydrazine hydrate monohydrate In ethanol for 6h; Heating; | |
82% | With hydrazine hydrate monohydrate In ethanol Reflux; | General method for the preparation of benzohydrazides ( 21-25 ) and 2-henylbenzohydrazides (26-30) General procedure: Ethylbenzoates (11-15, 1.5g, 9.98 mmol)and ethyl-2-phenylacetates (16-20, 1.5g, 9.13 mmol)were dissolved in ethanol and then hydrazine-hydrate(99%) was added and reux for 8-12h. Ethanol wasconcentrated and the resultant residue was pouredin ice cold water and stirred for 15 -20 min, the solidsthat were thrown out was fltered at the pump anddried to obtain the corresponding benzohydrazides(21-25) and 2-phenylacetohydrazides (26-30) in 80-82% yield. |
79.3% | With hydrazine hydrate monohydrate In ethanol Reflux; | 2 4.1.2 General procedure for the synthesis of substituted benzohydrazides 3a-e [58,59] General procedure: A solution of the isolated esters 2a-e (10mmol) in ethanol (20mL), hydrazine hydrate (97%, 3mL) was added and heated under reflux for 5-8h. After cooling, the formed precipitate was filtered off, washed with water, dried, and crystallized from ethanol. |
79.3% | With hydrazine hydrate monohydrate In ethanol Reflux; | 4.1.2. General procedure for the synthesis of substitutedbenzohydrazides 3a-e General procedure: Hydrazine hydrate (97%, 30 mmol, 1.5 mL) was added to a solutionof the isolated esters 2a-e (10 mmol) in ethanol (20 mL), and themixture was heated at reflux for 5-8 h. After cooling, the resultingprecipitate was filtered off, washed with water, dried, and crystallizedfrom ethanol. |
76% | With hydrazine hydrate monohydrate In methanol | |
75% | With hydrazine hydrate monohydrate Reflux; Alcoholic solution; | |
With ethanol; hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate Yield given; | ||
With hydrazine hydrate monohydrate In ethanol Heating; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine In ethanol; lithium hydroxide monohydrate for 3h; Heating; | ||
With hydrazine hydrate monohydrate In ethanol for 2h; Heating; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate for 8h; Heating; | ||
With hydrazine hydrate monohydrate In ethanol | ||
With hydrazine | ||
With hydrazine hydrate monohydrate for 8h; Reflux; | ||
With hydrazine hydrate monohydrate In ethanol for 8h; Reflux; | ||
With hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate Reflux; | ||
With hydrazine In lithium hydroxide monohydrate | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate for 0.05h; Microwave irradiation; | ||
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux; | ||
With hydrazine In ethanol for 16h; Reflux; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate for 0.05h; Microwave irradiation; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate In ethanol for 24h; Reflux; | General method for the synthesis of hydrazides General procedure: Substituted aromatic acid (0.01 mol) was dissolved in 20 ml absolute ethanol added 1 ml conc. H2SO4 and refluxed for 8 h. The two third volume of reaction mixture was removed under reduced pressure and then poured into crushed ice and neutralized with sodium bicarbonate to obtain esters. In the subsequent step equimolar quantity of substituted ester (0.005 mol) and hydrazine hydrate (0.25 ml, 0.005 mol) in ethanol was refluxed for 24 h with stirring. The two third volume of alcohol was removed under reduced pressure and the reaction mixture was poured into the crushed ice. The resultant precipitate was filtered, washed with water and dried. The solid was recrystallized from 25 ml of 90 % ethanol. The purity of the compounds was checked by TLC using toluene-ethyl acetate-formic acid (5:4:1) as mobile phase. | |
With hydrazine hydrate monohydrate | ||
With hydrazine monohydrate In ethanol Microwave irradiation; | ||
With hydrazine hydrate monohydrate for 2h; Reflux; | ||
With hydrazine hydrate monohydrate Microwave irradiation; Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux; | ||
With hydrazine monohydrate for 2h; Reflux; | ||
With hydrazine hydrate monohydrate In ethanol; lithium hydroxide monohydrate | ||
With hydrazine hydrate monohydrate for 6h; Reflux; | ||
With hydrazine hydrate monohydrate Reflux; | 4.3. General procedure for the synthesis of acid hydrazides (9a-s) General procedure: The 0.015 mol of ethyl aromatic esters (8a-s) and 0.02 mol of hydrazine hydrate were dissolved in absolute ethanol or methanol (20 mL) to reflux the reaction mixture for 3-6 h for complete hydrazinolysis of ethyl aromatic esters. The product obtained was isolated after cooling as a white or yellow solid and recrystallized from ethanol or methanol. | |
With hydrazine hydrate monohydrate at 80℃; | Preparation of acyl hydrazine B General procedure: At firstseveral different acyl hydrazines Bwere synthesized. To do this, we have started with corresponding carboxylicacid A in solvent EtOH (2 mL/mmol), 4 equivalents ofthionyl chloride (SOCl2) was added dropwise at room temperature andrefluxed with stirring for 5-12 h (monitored by TLC). SOCl2 and EtOHwas evaporated. Water was added to the crude mixture, extracted withdichloromethane (DCM) and dried with anhydrous Na2SO4.Solvent DCM was evaporated and the residue was dried at high vacuum whichprovided the ethyl ester of the corresponding carboxylic acid A.The ester was added dropwise to hydrazinehydrate (NH2NH2,H2O) (5mmol/1mmol of ethylcarboxylate) and heated at 80 °C for 5-20 hours (monitored by TLC) and allowedto stand for 12 hours. If solid appeared it was filtered and the residue wasdissolved in DCM and dried with anhydrous Na2SO4, DCM wasthen evaporated and the solid was dried at high vacuum. If solid was notobserved then the reaction mixture was extracted several occasions by DCM, andthe combined organic layer was dried with anhydrous Na2SO4. DCM was evaporated and residue was dried at high vacuum that leads usdifferent acyl hydrazine Bcorresponding to the starting carboxylic acid A. | |
With hydrazine hydrate monohydrate In ethanol Reflux; | 2.6. General synthetic procedure for compound II General procedure: A 5 mL absolute ethanol solution of hydrazine hydrate (80%) and Compound I (6 mmol) was refluxed for 4-6 h under severely stirring, the product being appeared as yellowish white solid. For purification of product, it was filtered and washed with 30 mL water and 30 mL ethanol pre-cooled by ice, and recrystallized from ethanol to yield the Compound II as white solid. 4-chlorobenzohydrazide (II-1): yield (91.3%). Melting point: 143.6-144.1 °C. ESI-MS (m/z, [M+H]+) = 171.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With hydrazine | |
95% | With hydrazine hydrate monohydrate In methanol for 0.0666667h; Microwave irradiation; | General procedure for synthesis of substituted acid hydrazide: General procedure: The benzoic acid hydrazides, 3a-h were prepared accordingto reported method in literature28,29 with some desirablemodifications. The ester (2a-h, 0.1 mol) dissolved inappropriate volume of methanol was transferred to a flaskwith a reflux condenser. Hydrazine hydrate (99%, 0.15 mol) was slowly added to the mixture and then kept on reflux forabout 5-6 h. The excess of solvent and hydrazine hydratewere distilled off. On addition of water the product separatedout which was washed several times with distilled water anddried. The product was recrystallized from 80% aqueous ethanoland melting points determined (Table 2).Microwave method: The same procedure as stated abovewas adopted using 100 ml methanol following the other conditionsof microwave in a microwave reactor at 350 Watt(power) for 3-5 min. Precipitation and separation of precipitatewas done as for conventional method (Table 2). |
93.4% | With hydrazine monohydrate In ethanol for 5h; Reflux; | 1 4.1.3 General procedure for synthesis of 4-substituted benzohydrazide 3a-3c General procedure: A solution of hydrazine hydrate (20.00 mmol) in 2 mL EtOH was added dropwise to the ester 2 (5.00 mmol). The mixture was refluxed for 5 h and filtered, and the corresponding acid hydrazide 3 was obtained by washing the residue with ice water. |
92% | With hydrazine monohydrate In methanol Reflux; | Synthesis of acid hydraz ide (3a-b) General procedure: Compound (2) (0.1 mol) was taken in a round-bottom flaskwith methanol (100 mL). Hydrazine hydrate (99%) (0.15mol, 5.7 mL) was added drop wise with gentle stirring. Thereaction mixture was refluxed for 4-6 h. Excess of methanolwas distilled off under reduced pressure. The precipitatedhydrazide was dried and re-crystallized from methanol(Zamani and Faghihi 2003). |
91.34% | With hydrazine hydrate monohydrate In ethanol Heating; | |
90% | With hydrazine hydrate monohydrate In methanol Reflux; | |
88% | With hydrazine hydrate monohydrate In lithium hydroxide monohydrate at 50 - 60℃; for 0.166667h; | 5.1.2. General procedure for the preparation of benzhydrazides (3) General procedure: Pathway A-Hydrazine hydrate 64% (v/v) (30.0 mL, 0.33 mol) was heated up to 50-60 °C. The methyl ester previously isolated (0.01 mol) was added and the mixture was refluxed during 10 min. The cooling down was proceeded sequentially in a water bath, followed by ice bath and dry ice - ethanol bath. The solid was filtered and washed with cold water. Different conditions were needed to obtain 4-nitro-3-(trifluoromethyl)benzhydrazide (3d) and 4-nitrobenzhydrazide (3 h). Hydrazine hydrate 64% (v/v) (30.0 mL, 0.33 mol) was cooled down in ice bath to -3 to 2 °C. The respective methyl ester (0.01 mol) was added and the mixture was stirred during 1 hour. The cooling down was proceeded in dry ice - ethanol bath. The solid was filtered and washed with cold water. Pathway B-each substituted benzoic acid (0.01 mol) was refluxed during 4 h in 20.0 mL (0.50 mol) of anhydrous methanol and 0.5 mL (1.0 mmol) of sulfuric acid. The reaction mixture was cooled down to room temperature. and the hydrazine hydrate 80% (v/v) (10.0 mL, 0.11 mol) was added. The system was maintained into vigorously stirring for more 30 minutes. In the case of compounds with 4-nitro and 4-nitro-3-trifluoromethyl substituent groups attached in the benzene moiety, after the addition of hydrazine hydrate 80% (v/v) at room temperature, the reaction mixture was cooled down in ice bath and maintained into stirring during 1 hour. After these periods, the mixture was maintained at cold temperature to give 3. |
88% | With hydrazine hydrate monohydrate In ethanol for 10h; Reflux; | |
84% | With hydrazine hydrate monohydrate In ethanol at 70℃; | |
82.4% | With hydrazine hydrate monohydrate In ethanol Reflux; | 4.2. Synthesis of benzohydrazide derivatives 3a-c [23] General procedure: To a solution of the appropriate methyl benzoate ester (1.0 mmol) in ethanol (30 mL), hydrazine monohydrate (0.15 g, 3.0 mmol) was added. The reaction mixture was heated under reflux overnight. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was washed with water (2 x 3 mL), and the obtained solid was filtered and dried to give benzohydrazide derivatives 3a-c. |
82% | With hydrazine In methanol for 12h; Reflux; | |
80% | With hydrazine hydrate monohydrate In ethanol for 8h; Reflux; | |
75% | With hydrazine hydrate monohydrate In ethanol for 18h; Reflux; | |
68% | With hydrazine hydrate monohydrate Ambient temperature; | |
64% | With hydrazine hydrate monohydrate In methanol at 60℃; for 1h; | 4-chlorobenzohydrazide (22) To a solution of methyl 4-chlorobenzoate (5.0 g, 29.3mmol) in MeOH (50 mL) was added N2H4.H20 (80%, 50 mL). The resulting solution was heated at 60 °C for 1 h. After concentration, the resulting solid was dissolved in EA (150 mL), washed with brine (2 x 50 mL), dried over Na2SO4 and concentrated to dryness to afford desired product 4-chlorobenzohydrazide 22 (3.2 g, 64%). ‘H NMR (300 MHz, DMSO-d6): ö 9.83 (s, 1H),7.85-7.81 (dd, 2h), 7.54-7.51 (dd, 2H), 4.50 (s,2H). LCMS (TOF-ESI) for C7H7C1N2O, Calculated for [M+Hj:; Found [M+ Hj:171. |
With hydrazine hydrate monohydrate In ethanol Heating; | ||
With hydrazine In lithium hydroxide monohydrate Heating; | ||
With hydrazine hydrate monohydrate for 0.5h; Heating; | ||
With hydrazine hydrate monohydrate In ethanol Heating; | ||
With hydrazine In lithium hydroxide monohydrate at 60℃; | ||
With hydrazine hydrate monohydrate for 0.166667h; Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate In ethanol for 10h; Reflux; Inert atmosphere; | ||
With hydrazine hydrate monohydrate Reflux; | ||
With hydrazine hydrate monohydrate at 80℃; for 2h; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate In methanol Reflux; | ||
With hydrazine hydrate monohydrate Reflux; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate In lithium hydroxide monohydrate at 75℃; for 0.166667h; | 4.1.2. General procedure for the synthesis of benzhydrazides (3a-o) General procedure: Hydrazine hydrate 64% (v/v) (30.0 mL, 0.33 mol) was heated up to 50-60 °C. The methyl ester 3 (0.01 mol) was added and the mixture was heated at reflux for 10 min. The cooling was performed sequentially in water bath, followed by ice bath and dry ice-ethanol bath. The precipitate was filtered and washed with cold water. | |
With hydrazine hydrate monohydrate In methanol Reflux; | 2.2.2. Synthesis of p-substituted benzoic hydrazides General procedure: Methyl benzoates were synthesized from their respective p-substituted benzoic acids, using excess dry methanol in the presence of H2SO4. para-Substituted benzoic hydrazides (2a-i) were prepared by reaction of the corresponding methyl benzoates (10 mmol) with hydrazine hydrate 99% (50 mmol) in methanol under reflux for 4-6 h. The excess solvent was removed under vacuum and the residue was filtered under suction, washed with water, and dried. The spectral and analytical data of benzoic hydrazide (2a) [26], 4-bromobenzoic hydrazide (2b) [27], 4-chlorobenzoic hydrazide (2c) [28], 4-fluorobenzoic hydrazide (2d) [26], 4-hydroxybenzoic hydrazide (2e) [29], 4-methoxybenzoic hydrazide (2f) [30], 4-methylbenzoic hydrazide (2g) [28], 4-nitrobenzoic hydrazide (2h) [28] and 4-aminobenzoic hydrazide (2i)[28] are in good agreement with literature values. | |
With hydrazine | ||
With hydrazine hydrate monohydrate In methanol Reflux; | 2.2.2. Synthesis of p-substituted benzoic hydrazides 2a-i General procedure: Methyl benzoates were synthesized from their respective p-substituted benzoic acids, using excess of dry methanol in presence of H2SO4. p-Substituted benzoic acid hydrazides (2a-i) were prepared by reaction of the corresponding methyl benzoates (10 mmol) with hydrazine hydrate 99% (50 mmol) in methanol under reflux for 4-6 h. The excess solvent was removed under vacuum and the residue was filtered under suction, washed with water and dried. The spectral and analytical data of benzoic hydrazide (2a) [35], 4-bromobenzoic hydrazide (2b) [36], 4-chlorobenzoic hydrazide (2c) [37], 4-fluorobenzoic hydrazide (2d) [35], 4-hydroxybenzoic hydrazide (2e) [38], 4-methoxybenzoic hydrazide (2f) [39], 4-methylbenzoic hydrazide (2g) [37], 4-nitrobenzoic hydrazide (2h) [37] and 4-aminobenzoic hydrazide (2i) [38] are in good agreement with literature values. | |
With hydrazine hydrate monohydrate Reflux; | ||
With hydrazine hydrate monohydrate at 80℃; for 2h; | ||
With hydrazine hydrate monohydrate In methanol Reflux; | ||
With hydrazine hydrate monohydrate In ethanol at 70℃; for 3h; | ||
With hydrazine hydrate monohydrate In methanol Reflux; | ||
With hydrazine hydrate monohydrate Reflux; | ||
With hydrazine hydrate monohydrate In ethanol for 6h; Reflux; | ||
With hydrazine hydrate monohydrate In lithium hydroxide monohydrate for 0.5h; Reflux; | 4.1.1. General procedure for the synthesis of benzhydrazides (2a-j) General procedure: Each substituted benzoic acid (1) (0.02 mol) was refluxed for 4 h in 20.0 mL (0.49 mol) of anhydrous methanol and 0.5 mL (0.01 mol) of sulphuric acid. The reaction mixture was cooled down to room temperature and the hydrazine hydrate 80% (v/v) (10.0 mL, 0.13 mol) was added. The system was maintained by vigorously stirring for more 30 min in reflux. In the case of compound with 4-nitro substituent group attached to the benzene moiety, after the addition of hydrazine hydrate 80% (v/v) at room temperature, the reaction mixture was cooled down in ice bath and maintained into stirring during 1 h. After this period, the mixture was maintained at low temperature to give 2.19,22 | |
With hydrazine hydrate monohydrate In methanol Reflux; | ||
With hydrazine hydrate monohydrate In methanol | ||
With hydrazine hydrate monohydrate In methanol for 5h; Reflux; | General procedure: Compounds 6a-t were synthesized from substituted benzoic acid via six steps according to the literature method as described. Various substituted benzoic acids 1a-t were treated with SOCl2 to give compounds 2a-t, which were reacted with CH3OH and EtN3 in CH2Cl2 at 0 to afford compounds 3a-t. Compounds 4a-t were prepared by the reaction of compounds 3a-t, hydrazine hydrate in CH3OH under reflux condition about 5h. Subsequently, compounds 5a-t were obtained by reaction of compounds 4a-t with CS2 and KOH in CH3OH. Compounds 6a-t were obtained by the cyclization reaction of compounds 5a-t in the presence of HCl at 0-5°C. | |
With hydrazine monohydrate In methanol | ||
With hydrazine hydrate monohydrate In ethanol for 16h; Reflux; | Synthesis of acid hydrazides (2-3) General procedure: A solution of substituted benzoic acid 1 (0.083 mol) in 20 ml methanol containing 2-3 ml of sulfuric acid was refluxed for 12 h (Scheme 1). The mixture was then allowed to cool at room temperature. A saturated solution of sodium bicarbonate was added to neutralize the mixture. Prepared ester was extracted by using dichloromethane (DCM). The DCM layer was dried using anhydrous sodium sulfate. The solvent was removed to dryness to afford ester which was used without further purification. To a solution of acid methyl ester in 15 ml of ethanol, 5 ml hydrazine hydrate was added and the resulting solution was refluxed for 16 h. Excess ethanol was distilled off and the concentrated solution was cooled to obtain acid hydrazide which was used without further purification. | |
With hydrazine monohydrate In methanol Reflux; | ||
With hydrazine hydrate monohydrate In methanol for 8h; Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate for 0.0833333h; Microwave irradiation; Inert atmosphere; | ||
With hydrazine hydrate monohydrate In methanol | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate for 5h; Reflux; | 10 To a solution of ester (5g, 29.4mmole), hydrazine hydrate (5.2m1, 102.9mmole, 3.Seq) was added dropwise. The mixture was refluxed for 5 hr, after completion of reaction the solid product (hydrazide) was formed and the excess solvent was removed under reduced pressure.To the slurry of hydrazide (5gm, 29 .3Ommole) in ethanolic potassium hydroxide (1.97gm, 35.l6mmole), carbon disulfide (2.14m1, 35.l6mmole) was added slowly followed by refluxfor 10 hrs. After completion of reaction solvent was evaporated. The reaction mixture was acidified with conc.H2S04. The precipitate was filtered, washed with water and dried. By using the above procedure the representative compounds viz., 45 ,46 etc were prepared. | |
With pyridine; hydrazine hydrate monohydrate In methanol Reflux; | ||
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate In methanol for 8h; Reflux; | General Procedure for the Synthesis of Acid Hydrazides (3a-t) General procedure: To a solution of methyl ester of aromatic carboxylic acid 2 (0.1 mol) in methanol (30 mL), hydrazine hydrate (0.2 mol) was added drop wise with stirring. The resulting mixture was allowed to reflux for 8 h. After the completion of the reaction as monitored by TLC, the excess methanol was distilled off under reduced pressure. The resulting acid hydrazide 3 was washed with cold water, dried and recrystallized from ethanol. | |
With hydrazine hydrate monohydrate In ethanol Reflux; | ||
With hydrazine hydrate monohydrate In ethanol for 10h; Reflux; | ||
With hydrazine hydrate monohydrate | ||
With hydrazine hydrate monohydrate In methanol | General procedure for the synthesis ofbenzohydrazides (3a-e) General procedure: The substituted benzoic acid (2.46 m mol)was reuxed with methanol in sulphuric acid for 4h.The ester formed reacts with hydrazine and getsconverted to benzohydrazides by hydrozinolysis22. | |
With hydrazine hydrate monohydrate In ethanol for 5h; Reflux; | ||
With hydrazine hydrate monohydrate at 80℃; for 5h; | 6.1; 7.1; 8.1 1) In a 100 ml round bottom flask,To a solution of 15.12 g (80.0 mmol) of methyl p-chlorobenzoateAnd hydrazine hydrate 30ml (excess) at 80 for 5h,After the reaction was completely cooled, the solid was precipitated at low temperature,Filter,Dried to give p-chlorobenzoyl hydrazide. | |
With hydrazine In lithium hydroxide monohydrate | ||
With hydrazine hydrate monohydrate In ethanol | ||
With hydrazine hydrate monohydrate In methanol at 65 - 67℃; for 9h; | ||
With hydrazine hydrate monohydrate In ethanol at 70℃; | ||
With hydrazine monohydrate In ethanol | ||
With hydrazine hydrate monohydrate Cooling with ice; Reflux; | General procedure for synthesis of hydrazides (5a-l)1 General procedure: Carboxylic acids (10 mmol) were refluxed for 1-2 h in methanol (5 mL) in presence of conc. H2SO4 (catalytic amount) with continuous stirring. The reaction was monitored by TLC till the acids were fully converted to the corresponding esters [Eluent: EtOAc/Hexanes (1:4)]. The reaction mixture was allowed to cool down to room temperature and hydrazine monohydrate 80% (40 mmol, 1.91 mL) was added slowly in an ice bath. The reaction was then warmed to room temperature and refluxed for another 1-2 h and followed by TLC till formation of hydrazide. The reaction mixture was kept at refrigerator till the product precipitated. All hydrazides were isolated in quantitative yields and in a pure form. There melting points were in full agreement with the literature melting points of the same compounds. | |
With hydrazine In ethanol for 4h; Reflux; | General procedure: Synthesis of triazoles: Substituted benzoic acid (0.01mol) in 0.2 mol of anhydrous methanol and 0.5 mL of conc. H2SO4 was added in a round bottom flask and then refluxed for 5 h. The resultant compound was confirmed by TLC (hexane:ethyl acetate) in the ratio 80:20 and then required compound was isolated by treating with NaOH. Then 0.01 mol of substituted methyl benzoate in 25 mL of ethanol was taken in a round bottom flask. The solution was refluxed for 4 h by adding 0.7 mL of 0.15 mol N2H4. The product was confirmed by TLC (hexane:ethyl acetate) in the ratio 80:20 and distilled off ethanol and it is cooled in ice water. The resultant compound was recrystallized with EtOH (78 % yield). | |
With hydrazine hydrate monohydrate In methanol at 85℃; for 14h; | ||
With hydrazine hydrate monohydrate In methanol at 45℃; for 5h; | 5.3.1. typical procedure for the synthesis of 1,3,4-oxadiazol-2(3H)-oneintermediates (18) General procedure: The substituted benzoic acid 15 (6 mmol) was dissolved in 20 mL MeOH, SOCl2 (1.4 g, 12 mmol) was added slowly in ice-bath, then themixture was heated at 45 °C for 5 h. Upon completion, the mixture was concentrated, the residue was re-dissolved in EtOAc and washed with NaHCO3 and brine. The organic layer was dried with Na2SO4 and concentrated to give the desired ester intermediate 16, which was used in the next step without further purification.The above ester 16 was dissolved in 15 mL MeOH, hydrazine hydrate(2 mL, 32 mmol), then the mixture was heated at 45 °C for 5 h.Upon completion, the mixture was concentrated, the residue was redissolved in EtOAc and washed with brine. The organic layer was concentrated and purified by silica gel affording the desired acylhydrazine intermediate 17 as a white solid in good yield.Add benzhydrazide 17 (2 mmol), CH2Cl2 (20 mL) and DIPEA(0.52 g, 4 mmol) to a round bottomed flask under N2 protection.Triphosgene (0.3 g, 1 mmol) dissolved in DCM (4 mL) Using a syringe,the triphosgene/DCM solution was added dropwise to the stirred solutionof hydrazide, and stirred at room temperature for 1 h. The reactionmixture was concentrated by rotary evaporation, the crudeproduct was purified by chromatography on silica (DCM/MeOH=100:1) affording the desired products 18 as white solid (about70% yield for three steps). Example 18-D3, 1H NMR (600 MHz,DMSO-d6) δ 12.66 (s, 1H), 7.80 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.6 Hz,2H). ESI-MS calcd for C8H4ClN2O2 [M-H]-, 195.0, found 195.2. | |
With hydrazine hydrate monohydrate In ethanol at 90℃; | 44 General procedure E, Hydrazide Formation: General procedure: To a suspension of the methyl ester (1 eq) in EtOH (0.25-0.1M) was added hydrazine hydrate (3-5 eq) and the reaction mixture was heated at 90 °C overnight. The reaction mixture was cooled to rt often causing the product to crystallize out of solution. This solid was collected by removal of the supernatant. If the product did not crystallize, the solution was concentrated, and the crude product was sufficiently pure to use in subsequent steps. | |
With hydrazine monohydrate Reflux; | Synthesis of acid hydrazide derivatives (3) from esters (2) General procedure: One millimole of the corresponding ester was added insmall portion to a round bottom flask containing solution ofhydrazine hydrate (10 ml) and followed by stirring themixture under reflux conditions. When completion of thereaction was monitored by TLC, the media was poured ontoice bath and the resulting precipitation was isolated by filtration.The corresponding acid hydrazide was afforded andrecrystallized from ethanol and water. | |
With hydrazine monohydrate In methanol at 65℃; for 4h; | General Procedure 2: The Formation of Hydrazide General procedure: To a solution of esters (2a~2t, 1.0 equiv.), furan-2-carbonyl chloride (7a, 1.0 equiv.) orthiophene-2-carbonyl chloride (7b, 1.0 equiv.) in MeOH (2 mL/1 mmol) was added hydrazine hydrate(1 mL/1 mmol), then the mixture was allowed to reach 65 C and stirred for 4 h. After completion(monitored by TLC), the organic solvent was removed and extracted three times with ethyl acetate,the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to givethe corresponding hydrazides (3a~3t, 8a, or 8b) in high yields, which were taken up for the next stepwithout any purification. | |
With hydrazine | ||
With hydrazine hydrate monohydrate In methanol Reflux; Inert atmosphere; | 2.1.1. General procedure for the synthesis of hydrazides 2 General procedure: Hydrazine hydrate (5 mL, 40%) was added to a solution of requiredester (5.0 mmol) in methanol (20 mL). The solution was refluxed for12-24 h and monitored by TLC until starting material was completelyconsumed. After that, solvent was evaporated under reduced pressureand a small amount of water (5 mL) was added to precipitate the hydrazide,which was filtered and dried in vacuum to give a shiny white toyellow solid in excellent yields, without further purification. | |
With hydrazine hydrate monohydrate In methanol at 0℃; Reflux; | 4.1.1. General procedure for the preparation of hydrazides 8 General procedure: Carboxylic acids 1a-g (5 mmol) were heated under reflux in methanol(5 mL) for 2 h in presence of conc. H2SO4 (catalytic amount)with continuous stirring. The reaction was monitored by TLC till theacids were fully converted to the corresponding esters [Eluent: EtOAc/Hexanes (1:4)]. The reaction mixture was allowed to cool down to roomtemperature and hydrazine monohydrate 80% (20 mmol, 0.96 mL) wasadded slowly in an ice bath. The reaction was then warmed to roomtemperature and heated under reflux for another 1-2 h and followed byTLC till formation of hydrazide. The reaction mixture was kept at refrigeratortill the product precipitated. All hydrazides were isolated inquantitative yields and in a pure form. Their melting points were in fullagreement with the literature melting points of the same compounds. | |
With hydrazine hydrate monohydrate for 4h; Reflux; | 4.2.1. General procedure for the synthesis of hydrazides 2 General procedure: Hydrazides 2 were obtained in reaction of methyl esters 1 (1 mmol), which synthesized from corresponding acids [61], and hydrazine monohydrate (6 mmol) by heating under reflux for 4 h [62]. | |
With hydrazine hydrate monohydrate In methanol Reflux; | ||
With hydrazine hydrate monohydrate In ethanol for 10h; Inert atmosphere; Sealed tube; Reflux; | ||
With hydrazine monohydrate In methanol at 80℃; | 1-6 Under stirring conditions, 120mmol of hydrazine hydrate was dropped into 30mL (20mmol) of methanol solution (80), refluxed for 3~6h, cooled to room temperature under stirring conditions, a solid was precipitated, and the solid was obtained | |
With hydrazine hydrate monohydrate In methanol at 0 - 20℃; for 4h; | 4.3 General procedure for the synthesis of compounds 3a-3q General procedure: Compound 2a was dissolved in methanol and the mixture was cooled in an ice bath. Hydrazine hydrate (3 eq.) was added dropwise at 0°C. The resulting reaction mixture was stirred at room temperature for 4h. The reaction progress was monitored by TLC (MeOH/DCM=1:20) until it was completed. A crude solid 3a was obtained by filtering and washing with ice methanol, which was used to the next step without further purification. Preparation method of 3b∼3q was same as 3a. | |
With hydrazine hydrate monohydrate In ethanol Reflux; | Synthesis of benzohydrazide derivatives (4a-m) General procedure: Method A Methyl benzoate derivatives (2, 1 eq) and 85% hydrazine hydrate (10 eq) were dissolved in ethanol (45 mL). The mixture was refluxed overnight. After cooling, the solvent was removed in vacuo and the residue was separated on the Biotage SNAP Cartridge KP-Sil 100 g eluting with 0-60 % ethyl acetate/petroleum ether to afford compound 4. | |
With hydrazine hydrate monohydrate In ethanol at 60 - 70℃; | 4.2.2. General procedure for synthesis of aromatic hydrazide (3a-3r) General procedure: To a solution of substituted aromatic ester (1 mol) in ethanol,mixture of hydrazine hydrate (1.2 mol) in anhydrous ethanol was addeddropwise and refluxed at 60-70 C for 12-18 h. Upon completion of thereaction, excess of hydrazine hydrate was evaporated under vacuum andthe resulting mixture was allowed to cool, to yield the hydrazide derivatives[28]. | |
With hydrazine hydrate monohydrate In methanol for 3h; Reflux; | ||
With hydrazine In ethanol for 3h; Reflux; | ||
With hydrazine hydrate monohydrate In ethanol for 3h; Reflux; | ||
With hydrazine hydrate monohydrate In ethanol at 80℃; for 6h; | General procedure: The crude methyl ester (1 mmol) was dissolved in anhydrous methanol and hydrazine hydrate (1.5 mmol) was added. Then, the mixture was refluxed for about 6 h. After completion of the reaction as monitored by TLC, the mixture was cooled to room temperature. Upon cooling the precipitate, it was filtered and dried to give the aryl hydrazide product 3 | |
With hydrazine hydrate monohydrate In ethanol at 90℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: 4-chlorobenzoic acid With sulfuric acid In ethanol for 6h; Reflux; Stage #2: With hydrazine monohydrate; Sodium hydrogenocarbonate; glacial acetic acid Reflux; | |
90% | With hydrazine hydrate monohydrate for 0.0291667h; Microwave irradiation; | |
87% | With glacial acetic acid; acetylhydrazide for 0.0833333h; Microwave irradiation; |
74% | Stage #1: 4-chlorobenzoic acid With thionyl chloride In methanol at 50℃; for 4h; Cooling with ice; Stage #2: With hydrazine hydrate monohydrate In ethanol for 4h; Reflux; | 17 Preparation of 4-chlorobenzohydrazide: Dissolve 4-chlorobenzoic acid (3. 2g, 20mmol) in methanol (30mL) and slowly add 2mL of thionyl chloride in an ice bath. Heat at 50 ° C for 4h (15mLX3), spin-dried for use; the previous step in 30mL ethanol, 80% hydrazine hydrate added 4mL, reflux reaction heating (15mLX3), the mixture was cooled to room temperature, 4h, cooling, precipitation of white solid, filter drying, a white solid 2. 5g, yield 74%. |
With hydrazine hydrate monohydrate In methanol for 25h; Heating; | ||
Stage #1: 4-chlorobenzoic acid With thionyl chloride Stage #2: With hydrazine hydrate monohydrate; ethyl acetate | ||
Multi-step reaction with 2 steps 1: H2SO4 2: H2NNH2*H2O | ||
Multi-step reaction with 2 steps 1: H2SO4 / 3 h / Heating 2: NH2NH2*H2O / ethanol / 2 h / Heating | ||
Multi-step reaction with 2 steps 1: H2SO4 / Heating 2: hydrazine / ethanol; H2O / 3 h / Heating | ||
With hydrazine hydrate monohydrate In ethanol Acidic conditions; | 6.i The synthesis of bioactive/newer rings substituted title compounds involves the conversion of substituted title compounds involves the conversion of substituted-aromatic esters into their corresponding hydrazides | |
With hydrazine hydrate monohydrate Microwave irradiation; | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / Microwave irradiation 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 0.07 h / Microwave irradiation 2: hydrazine hydrate monohydrate / 0.05 h / Microwave irradiation | ||
Multi-step reaction with 2 steps 1: Reflux; Acidic conditions 2: hydrazine hydrate monohydrate / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride 2: hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine hydrate monohydrate / lithium hydroxide monohydrate / 0.17 h / 50 - 60 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine hydrate monohydrate / lithium hydroxide monohydrate / 0.17 h / 75 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 8 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 24 h / Reflux | ||
Multi-step reaction with 3 steps 1: thionyl chloride / Reflux 2: Reflux 3: hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine hydrate monohydrate / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / Microwave irradiation 2: hydrazine hydrate monohydrate / Microwave irradiation; Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 6 h / Reflux | ||
Stage #1: 4-chlorobenzoic acid With sulfuric acid In ethanol for 4h; Reflux; Stage #2: With hydrazine hydrate monohydrate In ethanol for 3h; Reflux; | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / 5 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 0.67 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 4 h / 80 °C / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine hydrate monohydrate / lithium hydroxide monohydrate / 0.5 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 20 °C 2: hydrazine hydrate monohydrate / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / ethanol; lithium hydroxide monohydrate | ||
Multi-step reaction with 2 steps 1: 8 h / Reflux 2: hydrazine hydrate monohydrate / 6 h / Reflux | ||
Multi-step reaction with 2 steps 1: hydrogenchloride / Reflux 2: hydrazine hydrate monohydrate / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / methanol | ||
Multi-step reaction with 3 steps 1: thionyl chloride / 5 h / Reflux 2: triethylamine / dichloromethane / 0 °C 3: hydrazine hydrate monohydrate / methanol / 5 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / Reflux 2: hydrazine monohydrate / ethanol / 5 h / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 20 °C / Reflux 2: hydrazine hydrate monohydrate / 80 °C | ||
With chloroformic acid ethyl ester; hydrazine hydrate monohydrate In dichloromethane at 0 - 5℃; | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 12 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 16 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine monohydrate / methanol / Reflux | ||
With thionyl chloride; hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 6 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 110 °C 2: hydrazine monohydrate / ethanol / 12 h / 100 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / Reflux 2: hydrazine hydrate monohydrate / methanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine monohydrate / methanol / 3 h / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: Reflux; Inert atmosphere 2: hydrazine hydrate monohydrate / 0.08 h / Microwave irradiation; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / methanol | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / ethanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 12 h / 70 - 80 °C / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
With sulfuric acid; hydrazine hydrate monohydrate In ethanol for 6h; Reflux; | General procedure for the preparation of acid hydrazides(10a-i) General procedure: The appropriate aromatic acids 9a-i (0.01 mol) were dissolved in absolute ethanol (10 ml). Hydrazine hydrate (0.02 mol, 1 ml) and few drops of conc. sulphuric acid were added. The reaction mixture was refluxed for 6 h. The resulting solid obtained was filtered, dried and crystallized from methanol. The completion of reaction was monitored by thin-layer chromatography and infrared spectrophotometer (Jha et al., 2010). (10a: naphthoxy acetic acidhydrazide; 10b: phenylacetic acid hydrazide; 10c: p-nitrobenzoic acid hydrazide; 10d: o-chlorobenzoic acid hydrazide; 10e: p-chlorobenzoic acid hydrazide; 10f: nicotinic acid hydrazide; 10g: phenoxyacetic acid hydrazide; 10h: 3,5-dinitrobenzoic acid hydrazide; 10i: salicylic acid hydrazide.) | |
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine / methanol / 5 - 20 °C | ||
Multi-step reaction with 2 steps 1: thionyl chloride 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 8 - 12 h / Reflux 2: hydrazine / ethanol / 12 h / Cooling with ice | ||
Multi-step reaction with 2 steps 1: sulfuric acid / lithium hydroxide monohydrate / 6 h / Reflux 2: hydrazine hydrate monohydrate / lithium hydroxide monohydrate; ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 20 °C 2: hydrazine hydrate monohydrate / tetrahydrofuran / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 10 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: Acidic conditions 2: hydrazine hydrate monohydrate / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 3 h / 70 °C 2: H4N2*5H2O / ethanol / 6 h / 70 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / ethanol | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / methanol | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine hydrate monohydrate / 5 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate; pyridine / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 10 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 8 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 6 h / Reflux | ||
Multi-step reaction with 2 steps 1: glycerol-based sulfonic acid functionalized carbon catalyst / 6 h / Reflux; Green chemistry 2: hydrazine hydrate monohydrate / methanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 20 °C 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 5 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 6 h / 80 °C | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 2 h / 20 °C 2: hydrazine hydrate monohydrate / 20 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 5 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 10 h / Reflux | ||
Stage #1: 4-chlorobenzoic acid With sulfuric acid In ethanol Stage #2: With hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 10 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 10 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine hydrate monohydrate / methanol | ||
Multi-step reaction with 2 steps 1: sulfuric acid 2: hydrazine hydrate monohydrate / ethanol | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / neat (no solvent) / 120 °C / Sealed tube | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / lithium hydroxide monohydrate / 12 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / 5 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 6 h / Reflux 2: hydrazine monohydrate / methanol / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / Reflux 2: hydrazine monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Inert atmosphere 2: hydrazine / ethanol / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / 65 - 67 °C 2: hydrazine hydrate monohydrate / methanol / 9 h / 65 - 67 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine monohydrate / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / ethanol / 70 °C | ||
With sulfuric acid; hydrazine hydrate monohydrate In methanol | ||
Stage #1: 4-chlorobenzoic acid at 210℃; for 2h; Stage #2: With sulfuric acid In methanol Reflux; Stage #3: With hydrazine hydrate monohydrate In ethanol Reflux; | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine hydrate monohydrate / Cooling with ice; Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | at 200℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate monohydrate In methanol for 0.5h; Heating; | ||
With hydrazine hydrate monohydrate In methanol | 4.2.3. Synthesis of substitutedbenzoyl hydrazides (III) General procedure: The substituted phenyl benzoate (II) (0.01 mol)was reacted withhydrazine hydrate (0.02 mol) in methanol. The mixture wasrefluxed and monitored by TLC. The crude product was washedwith water and recrystallized from ethanol [12,20]. | |
With hydrazine hydrate monohydrate |
With hydrazine hydrate monohydrate In methanol | Synthesis of the substituted hydrazide derivatives (iii). General procedure: Firstly 4-substituted aroyl chloride (10 mmol)was reacted with phenol (10 mmol in 100 mL of 10% sodium hydroxide solution) to form 4-substituted phenyl benzoate. The crude product was washed with water and recrystallized from ethanol. Then the 4-substituted phenyl benzoate (5 mmol) was reacted with hydrazine hydrate (10 mmol) in methanol. The mixture was refluxed and monitored by TLC. The crude product was washed with water and recrystallized from ethanol [54]. | |
With hydrazine monohydrate In methanol for 0.5h; Reflux; | Synthesis of substituted benzoic acid hydrazide (5a-m) General procedure: 0.05 mol of substituted benzaldehyde in 3 mL of methanol is mixed with 0.1 mol of 99% hydrazine hydrate, the rinsing isrefluxed for 30 min, the mixture is allowed to cool once the product formed, and the precipitated solid is filtered off. Theproduct obtained is purified by washing with plenty of water and crystallizing from ethanol [27, 28]. | |
With hydrazine monohydrate In methanol for 0.5h; Reflux; | Synthesis of substituted benzoic acid hydrazide (5a-m) General procedure: 0.05 mol of substituted benzaldehyde in 3 mL of methanol is mixed with 0.1 mol of 99% hydrazine hydrate, the rinsing isrefluxed for 30 min, the mixture is allowed to cool once the product formed, and the precipitated solid is filtered off. Theproduct obtained is purified by washing with plenty of water and crystallizing from ethanol [27, 28]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 2 percent HCl / 3 h / Heating 2: 4 percent aq. NaOH / 4 h / Heating | ||
Multi-step reaction with 2 steps 1: HCl(conc) / methanol / 4 h / Heating 2: aq. NaOH / 4 h / Heating | ||
Multi-step reaction with 2 steps 1: 70 percent / conc. HCl / H2O / 3 h / Heating 2: 70 percent / 10percent KOH / 3 h / Heating |
Multi-step reaction with 2 steps 1: hydrogenchloride / water 2: sodium hydroxide / Reflux | ||
Multi-step reaction with 2 steps 1: ethanol / Reflux 2: sodium hydroxide / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: hydrogenchloride / 3 h / Reflux 2: sodium hydroxide / 3 h / Reflux | ||
Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol / Reflux 2: sodium hydroxide / water / Reflux | ||
Multi-step reaction with 2 steps 1: hydrogenchloride / water; ethanol / Reflux 2: sodium hydroxide / water / 4 h / 100 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 18h; | A. 4-Chloro-benzoic acid N'-(4-amino-3-nitro-benzoyl)-hydrazide; To 4-Chloro-benzoic acid hydrazide (5.0 g, 29 mmol) and 4-Amino-3-nitro- benzoic acid (5.3 g, 29 mmol) in DMF (100 mL) was added HOBT (3.9 g, 29 mmol), and EDCI (5.5 g, 29 mmol), followed by triethylamine (12.1 mL, 87 mmol). The mixture was stirred at ambient temperature for 18 hours. Water (50 mL) was added to the reaction mixture. The precipitate was collected by filtration, washed with water, and dried under vacuum to provide the title compound as a yellow solid. 1H NMR(DMSO-cf6, 400MHz) delta ppm 7.08 (d, J=8.97 Hz, 1 H) 7.61 (m, 2 H) 7.82 - 7.97 (m, 5 H) 8.66 (d,J=2.15 Hz, 1 H) 10.52 (s, 1 H) 10.57 (s, 1 H; (M+H)+ = 335.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.2% | In ethanol at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In ethanol at 80℃; | 3.2. General experimental procedure for synthesis of compounds 1-25 General procedure: The reaction mixture containing 4-chlorophenyl hydrazide(0.5 mmol) and aryl isothiocyanate (0.5 mmol) in absolute ethanol(10 mL) was refluxed at 80 °C for 20-30 min and monitored throughTLC. Precipitates were appeared in the reaction mixture which werefiltered and washed with hot hexane then cold ethanol [37]. Productwas dried in vacuum and collected. All compounds 1-25 were characterizedby spectroscopic techniques such as EI-MS and 1H NMR.Spectral data of all compounds are as follows. |
In acetonitrile at 20℃; for 18h; | 41.a A mixture of 4-chlorobenzohydrazide 32 (0.5 g, 2.93 mmol) and isonicotinohydrazide 1 (0.5 g,2.93 mmol) in acetonitrile was stirred at ambient temperature for 18 hours, concentrated to dryness, and 20 mL of 10% K2CO3(aq.) was added. The resulting mixture was stirred under reflux for 6 hours. The clear solution was cooled to ambient temperature, washed with ether, and acidified with IN HCl. The solid was collected, washed with H2O and ether, and dried to afford compound 34 (0.74 g). Yield: 80%.1H-NMR (300 MHz, DMSO-(I6) δ (ppm): 7.65-7.58 (m, 2 H), 7.56-7.50 (m, 2 H), 7.38-7.28 (m,4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | In methanol Inert atmosphere; Reflux; | |
72% | In ethanol at 80℃; | 3.2. General experimental procedure for synthesis of compounds 1-25 General procedure: The reaction mixture containing 4-chlorophenyl hydrazide(0.5 mmol) and aryl isothiocyanate (0.5 mmol) in absolute ethanol(10 mL) was refluxed at 80 °C for 20-30 min and monitored throughTLC. Precipitates were appeared in the reaction mixture which werefiltered and washed with hot hexane then cold ethanol [37]. Productwas dried in vacuum and collected. All compounds 1-25 were characterizedby spectroscopic techniques such as EI-MS and 1H NMR.Spectral data of all compounds are as follows. |
In methanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.75% | With acetic acid In ethanol for 5h; Reflux; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In tetrahydrofuran at 50℃; for 2h; | 1A 2-[(4-Chlorophenyl)carbonyl]-N-(prop-2-ene-1-yl)hydrazinecarboxamide Example 1A 2-[(4-Chlorophenyl)carbonyl]-N-(prop-2-ene-1-yl)hydrazinecarboxamide An amount of 5.00 g (29.3 mmol) of 4-chlorobenzenecarbohydrazide was suspended in dry tetrahydrofuran (150 ml) at 50° C. and then 2.63 ml (29.9 mmol) of allyl isocyanate in solution in 110 ml of dry tetrahydrofuran were added dropwise. The starting material underwent temporary complete dissolution, and then a fine precipitate was produced. The mixture was stirred at 50° C. for 2 hours. After cooling to room temperature it was admixed with diethyl ether. The colourless solid was isolated by suction filtration, washed with diethyl ether and dried in a high vacuum. This gave 7.42 g (100% of theory) of the target compound. HPLC [Method 1] Rt=3.45 min LC-MS [Method 3] Rt=1.51 min; MS [ESIpos]: m/z=254 (M+H)+ 1H NMR (400 MHz, DMSO-d6): δ=3.60-3.70 (m, 2H), 5.01 (dd, 1H), 5.14 (dd, 1H), 5.72-5.86 (m, 1H), 6.70 (s, 1H), 7.56 (d, 2H), 7.85-7.95 (m, 3H), 10.21 (s, 1H). |
100% | In tetrahydrofuran at 50℃; for 2h; | 11.A 2-[(4-Chlorophenyl)carbonyl]-N-(prop-2-en-1-yl)hydrazinecarboxamide Example 11A 2-[(4-Chlorophenyl)carbonyl]-N-(prop-2-en-1-yl)hydrazinecarboxamide At 50° C., 5.00 g (29.3 mmol) of 4-chlorobenzohydrazide were suspended in 150 ml of dry THF. 2.63 ml (29.9 mmol) of allyl isocyanate, dissolved in 110 ml of dry THF, were then added dropwise. Initially, all of the starting material dissolved, and then a fine precipitate formed. The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, diethyl ether was added. The colorless solid was filtered off with suction, washed with diethyl ether and dried under high vacuum. This gave 7.42 g (100% of theory) of the target compound. LC/MS [Method 5]: Rt=1.51 min; MS [ESIpos]: m/z=254 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): δ=3.60-3.70 (m, 2H), 5.01 (dd, 1H), 5.14 (dd, 1H), 5.72-5.86 (m, 1H), 6.70 (s, 1H), 7.56 (d, 2H), 7.85-7.95 (m, 3H), 10.21 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate In butan-1-ol at 160℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In propan-1-ol for 24h; Reflux; | 4.2. Procedure for the synthesis of 3-[1-(acyl-hydrazono)-ethyl]-4-hydroxy-2H-1-benzopyran-2-ones (4) General procedure: The appropriate hydrazide (3, 1 mmol) was added to a solution of 3-acetyl-4-hydroxy-coumarin 2 (1 mmol) in n-propanol (15-20 mL). The mixture was refluxed for 24 h and cooled to rt. The resulting precipitate was collected by filtration, dried in vacuum, and recrystallized from n-propanol to give the 3-[1-(acyl-hydrazono)ethyl]-4-hydroxy-coumarins (4a-i) as solids in very good yields. The yields of formation of the new compounds 4 as well as their melting points are presented in refPreviewPlaceHolderTable 1. |
98% | In propan-1-ol for 24h; Reflux; | Synthesis of 3-[1-(Acyl-hydrazono)ethyl]-4-hydroxycoumarins (2a-l) General procedure: To a solution of 3-acetyl-4-hydroxy-coumarin 1 (1 mmol) in n-propanol (15-20 mL) was added the appropriate hydrazide (1 mmol). The mixture was refluxed for 24 h and cooled at room temperature. The precipitate was collected by filtration and dried to give the 3-[1-(acyl-hydrazono)ethyl]-4-hydroxycoumarin (2a-l) as solid and was then recrystallized from n-propanol in very good yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In ethanol; at 60℃; for 16h; | Example 8Preparation of 4-chlorobenzoic acid [1-(2-chloro-6-hydroxyphenyl)-methylidene]-hydrazide (Compound 70) A suspension of <strong>[18362-30-6]2-chloro-6-hydroxybenzaldehyde</strong> (0.10 g, 0.64 mmol) and 4-chlorobenzoic acid hydrazide (0.10 g, 0.61 mmol) in EtOH (3 mL) was agitated and heated to 60° C. for 16 h. The reaction mixture was cooled to room temperature and H2O (1-2 mL) was added portionwise to precipitate the product. The solid was collected via suction filtration and rinsed with ethanol to furnish the title compound as an off-white solid (0.18 g, 95percent): mp 273-277° C.; 1H NMR (400 MHz, DMSO-d6) delta 12.53 (s, 1H), 12.51 (s, 1H), 9.04 (s, 1H), 8.03-7.95 (m, 2H), 7.71-7.63 (m, 2H), 7.34 (t, J=8.2 Hz, 1H), 7.07 (dd, J=7.9, 0.9 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H); ESIMS m/z 309 ([M+H]+), 307 ([M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tetrahydrofuran;Reflux; | General procedure: Tripod (1) (0.106 g, 0.24 mmol) was added to a solution of benzoic hydrazide (2a) (0.109 g, 0.8 mmol) in tetrahydrofuran (75 mL) and the reaction mixture was stirred under reflux for 15-18 h. The solvent was removed by evaporation under reduced pressure. The residue was filtered under suction and washed several times withhot tetrahydrofuran. The resulting solid (3a) was dried in vacuo at 40 C for 4 h. The same general procedure was followed for the compounds 3b-i. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sulfuric acid; In methanol; water; acetic acid; for 1h;Reflux; | General procedure: The twenty-two substituted-benzhydrazides (1a-v) described in this study were available to be used since they were recently synthesized and reported elsewhere.35,37 An equimolar mixture of 5-nitrofuran-2-carbaldehyde (0.05 mol) and benzhydrazides (1a-v) in water, sulfuric acid, acetic acid, and methanol, (8:7:8:20 v/v) was heated under reflux during 1 h. After cooling down, the mixture was poured into cold water to give 2a-v. |
67% | With sulfuric acid; acetic acid; In methanol; water; for 1h;Reflux; | General procedure: compounds were synthesized by refluxing 5-nitro-2-furaldehyde 98% (5 mmol) and hydrazides (b) (5 mmol) in water, sulfuric acid, acetic acid, and methanol (8:7:8:20 v/v) for 1 h. After cooling, the mixture was poured into cold water to precipitate, and recrystallized from acetonitrile [33]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: trimethylsilyl isothiocyanate; 4-chlorobenzoic acid hydrazide In ethanol Reflux; Stage #2: With sulfuric acid In ethanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99.8% | With acetic acid In methanol for 0.5h; Reflux; | |
84% | With acetic acid In ethanol at 20℃; for 12h; | 2.2. General procedure for the synthesis of compounds 1-10 General procedure: In a 25-mL Erlenmeyer flask, 1 mmol of 4-chloroben zohydrazide or 4-chlorophenyl hydrazine, 1 mmol of aldehyde derivatives (4-hydroxybenzaldehyde, 5chloro-2-hydroxyben zaldehyde, 4-hydroxy-3,5-dimethoxybenzaldehyde, 2-hydroxy- 1-naphthaldehyde, or 4-hydroxy-3-methoxybenzaldehyde), and 3 drops of acetic acid were dissolved in 5 ml of ethanol. The reaction mixture was stirred for 12 h at room temperature. After completion of the reaction monitored using TLC, the residue obtained was filtered, washed with ethanol, and dried on air, to afford the pure product. |
81% | With acetic acid at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With sulfuric acid; acetic acid; In methanol; water; for 1h;Reflux; | General procedure: Compounds of series I were synthesized by refluxing <strong>[92-55-7]5-nitro-2-furaldehyde diacetate</strong> 98% (5 mmol) and benzhydrazides (3) (5 mmol) in water, sulphuric acid, acetic acid, and methanol (8:7:8:20 v/v) for 1 h. After cooling, the mixture was poured into cold water to precipitate the azomethine derivatives 20(see structural elucidation of the compounds of series I in Supplementary data, p. S2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol;Reflux; | General procedure: General procedure: A mixture of 8 (1mmol) and aromatic acid hydrazide was refluxed in absolute ethanol for 3-4h. After the completion of the reaction the solid precipitated was filtered off, washed with cold ethanol, dried and recrystallized from ethanol which afforded the pure products 9a-9g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol for 0.25h; Reflux; | |
90% | In ethanol for 0.0833333h; Reflux; | 3.1.1. General Procedure for the Synthesis of Thiosemicarbazide Derivatives (1-18) General procedure: A solution of 0.01 mol of 3-chlorobenzhydrazide or 4-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 mL of anhydrous ethanol (EtOH) was heated under reflux for 5 min. Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether and crystallized from EtOH. Information on already known compounds may be retrieved in the Chemical Abstract Service database (CAS numbers are given below). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With trichlorophosphate at 20℃; for 3h; Reflux; | 4-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-2,6-di-tert-butylphenol (5e). General procedure: To a mixture of (0.31 g, 1.24 mmol) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 1.24 mmolearyl acid hydrazide in a 50 mL round bottom flask, 5 mL of phosphorus oxychloride was added in a fewportions at room temperature. The mixture was refluxed for 3 h with stirring on water bath 80-90 °C.After cooling, the mixture poured onto 100 mL crushed ice and stirred for 15 min. Sodium bicarbonatewas added in a few portions until the pH was around to 7-8. The precipitate was filtered, washed withwater and dried then purified either by column chromatography or by crystallization from suitable solvent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | With acetic acid; In ethanol; at 70℃; for 5h; | General procedure: The Compound I (0.79 mmol)was dissolved in 10 mL of absolute ethanol. Then the mixture of R2-CHO (0.66 mmol), 10 mL acetic acid and 3 mL absolute ethanol was added dropwise at 70 °C. The mixture was refluxed for 5 h. The solvent was evaporated. The crude product was purified by flash chromatography (neutral Al2O3). 4-[N,N-di(4-tolyl)amino]benzaldehyde 4-chlorobenzoylhydrazone (III-1): yield (91.3percent). Melting point: 114.2-117.6 °C. IR(KBr, cm-1): 3446 (gamma -NH-), 3090, 3027, 2920, 1654, 1598, 1564, 1506, 1273, 817. 1H NMR (CDCl3, 400 MHz, ppm): 7.79(d, 1H, J = 6.8 Hz), 7.71-7.69(q, 1H), 7.55-7.52(q, 2H), 7.49(s, 1H, -N=CH-), 7.43(d, 2H, J = 7.6 Hz), 7.26(s, 1H), 7.10(d, 4H, J 8.0 Hz), 7.01(d, 4H, J = 8.0 Hz), 6.94(d, 2H, J = 8.4 Hz), 2.33(s, 6H, -CH3). 13C NMR (CDCl3, 100 MHz, ppm): 153.8, 144.3, 139.3, 133.8, 130.9, 130.1, 129.1, 128.8, 125.6, 122.2, 120.2, 20.9. HR-ESIMS (m/z, [M + H]+) calcd. for C28H25ON3Cl+ 454.1681, found 454.1679. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In water at 90℃; for 2h; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With silica gel; hydrazine In neat (no solvent) at 130℃; for 24h; Inert atmosphere; Sealed tube; | 2 Conversion of benzamides to benzhydrazides General procedure: These compounds were prepared using the standard procedure at 130°C for 20-24h. For each reaction, the crude product was adsorbed onto silica gel and purified on a 15cm×2.5cm silica gel column eluted with 80% EtOAc in hexanes. The isolated yields are given in Table 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol; for 1h;Reflux; | General procedure: To a stirred solution of compound 3 (100mg, 0.40 mmol) in ethanol was added corresponding benzohydrazides (4a-m) (1.0 mmol) and refluxed for 1 h. The reaction mass was washed with pet ether, filtered and dried undervacuum to obtain the pure hydrazone compounds. Yields ofthe products varied between 78 and 88 %. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine In ethyl acetate at 160℃; Sealed tube; Inert atmosphere; Microwave irradiation; | 19 General procedure for two steps synthesis of 1,3,4-oxadiazole derivatives 8-17 (Method A) and general procedure for one-step synthesis of 1,3,4-oxadiazole derivatives 8-28 (Method B) General procedure: Method B; To a stirred solution of acrylic acid (200mg, 1 eq) and substituted hydrazide (1 eq) in dry ethyl acetate (5-10mL) were added dropwise T3P (3 eq, 50% solution in EtOAc) and triethylamine (5 eq). The reaction vessel was sealed under argon atmosphere and the mixture was heated under microwave conditions at 160°C for 20min to 30min. The completion of reaction was confirmed by TLC. The mixture was cooled to room temperature. The organic layer was washed twice with 1N HCl, once with H2O and once with brine. The organic layer was dried under Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (cyclohexan/EtOAc or DCM/Methanol) to afford the desired 1,3,4-oxadiazole derivative.; 4.1.2.19 2-[(E)-2-(5-bromothiophen-2-yl)ethenyl]-5-(4-chlorophenyl)-1,3,4-oxadiazole 24 1H NMR (DMSO-d6, 250 MHz): δ = 8.04 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 16.2 Hz, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 3.9 Hz, 1H), 7.27 (d, J = 3.8 Hz, 1H), 7.00 (d, J = 16.2 Hz, 1H); 13C NMR (DMSO-d6, 101 MHz): δ = 164.31, 163.09, 141.87, 137.32, 132.45, 131.86, 131.76, 130.14, 128.94, 122.72, 115.35, 109.43; LC/MS (ESI): 366.74 [M+H]+ and isotopic peak: 368.72; purity = 95%; HRMS (TOF, ESI+) cald for C14H9N2OSClBr (M + H)+ 366.9307, found 366.9306; yellow powder. Yield = 38%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic acid In methanol at 60 - 70℃; for 2h; | Hot methanolic solutions of 4-chlorobenzhydrazide (2.49mmol, 500mg) and 1,1,1-trifluoryl-2,4-pentanedione (2.49 mmol, 0.4ml) and acetic acid were added and refluxed for 2h at 60-70°C. The obtained yellow reaction mixture was evaporated and the white colored crystalline product obtained was washed with petroleum ether and dried. L1=Yield: 85%, White solid. m.p.: 90°C. Anal calc. For C12H10ClF3N2O2: C: 47.00, H: 3.29, N: 9.13. Found: C: 46.97, H: 3.28, N: 9.15. UV-Vis (methanol): λmax (MeOH)/nm (ε,dm-3mol-1cm-1) 210(67,000), 240(35,666). FT-IR (KBr, νmax/cm-1): 1662.64 (C=O), 1643.35 (C=N), 3360 (NH). 1H NMR (400MHz, CDCl3): δH, ppm 2.053 (3H, s, CH3), 7.396, 7.417, 7.839, 7.860 (Ar-H, 4H), 3.113, 3.160, 3.278, 3.325 (CH2 protons, 2H)·13C NMR (100MHz, CDCl3): δC ppm 15.86 (CH3), 46.89 (CH2), 92.49, 92.89 (CF3), 122.07, 124.93, 128.31, 131.48, 131.79 (Ar C), 138.59 (Ar C- Cl), 155.23 (C=N), 170.01 (C=O) GC-MS Calc. for C12H10ClF3N2O2: 306.6 Found: 306.14. Chromatogram: RT- 16.38min, Purity: 99.19%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With acetic acid In ethanol for 4h; Reflux; | General procedure for the synthesis of N'-((1-(substituted)-1H-indol-3-yl)methylene)hydrazides (18a-v) General procedure: Indole-3-aldehyde 16 (1 mmol) and the correspondingalkyl/aryl acid hydrazide 17 (1.05 mmol) were refluxed in ethanol (5 mL) in the presence of glacial acetic acid(0.3 mL) for 4 h. On cooling the reaction mixture to roomtemperature, the crude product was precipitated, filteredand dried. Further recrystallization of the crude products inethanol allowed to obtain pure products in 85-95 % yields. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trichlorophosphate; In toluene; at 100℃; for 2h; | General procedure: A mixture of benzoylhydrazine 23 (0.68 g, 5 mmol), 3-<strong>[590-92-1]bromopropionic acid</strong> (1.2 g, 7.5 mmol), POCl3 (4 mL) in toluene (20 mL) was stirred at 100 C for 2 h. After cooling to room temperature, the mixture was poured into ice water slowly, and extracted with ethyl acetate (20 mL* 3). The organic layer was combined, dried over Na2SO4, and concentrated to afford crude 2-(2-bromoethyl)-5-phenyl-1,3,4- oxadiazole 19o as a yellow solid in 41% of yield. This crude product was used without purification. Following the same procedure for the synthesis of 17a, targetcompound 17o was obtained using crude 2-(2-bromoethyl)-5-phenyl-1,3,4-oxadiazole 19o as halide. | |
With trichlorophosphate; at 80℃; for 6h; | Dissolve 3-<strong>[590-92-1]bromopropionic acid</strong> (0.468, 3) in 5 mL of phosphorous oxychloride and add 4-chlorobenzohydrazide (0.47 g, 3 mmol) in oil bath at 80 C for 6 h, The reaction solution was slowly poured into ice water, and the sodium hydroxide solution was adjusted to pH 7-8. The mixture was extracted with methylene chloride (20 mLX3). The combined organic layers were dried over anhydrous sodium sulfate and dried to dryness to give a yellow solid. Rate of 36%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In ethanol at 30℃; | 1 General procedure C for synthesis of 2,3,4-trihydroxybenzylidene)hydrazide derivatives 10A-B General procedure: 2,3,4-trihydroxybenzaldehyde (1.5 equiv) and synthesized hydrazides (9A-T) were dissolved in anhydrous ethanol (10 mL) and stirred at 30 °C for overnight. The reaction monitored by TLC (thin layer chromatography). The crude reaction mixture was concentrated under vacuum and the product was obtained as yellow solid. The remained benzaldehyde was washed out by ethyl ether. (Yield 80-85%). |
65.3% | In methanol at 20℃; for 12h; Inert atmosphere; | 2.1.2. General procedure for the synthesis of hydrazides 3a-3z General procedure: 2,3,4-Trihydroxybenzaldehyde (0.55 g, 3.6 mmol) was added to asolution of hydrazides (3.0 mmol) in methanol (20 mL). The solutionwas stirred for 12 h under room temperature, which was then filteredand finally recrystallized from ethanol, to give the target hydrazonederivatives as white to gray powdered solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 24h; Sealed tube; Irradiation; | General procedure for synthesis of 2,5-diaryl 1,3,4-oxadiazoles and reuse of the catalyst: General procedure: A sealed tube equipped with a magnetic stir bar was charged with acylhydrazine 1 (0.5 mmol), α-keto acid 2 (0.5 mmol), K2CO3 (1 mmol), PANI-g-C3N4-TiO2 (40 mg) and DMF (5.0 mL). The mixture was then irradiated with a 14 W CFL and stirred at room temperature (25 °C) for 24 h. The distance of the reaction vial from the light is about 5 centimeters. After reaction, the mixture was diluted with EtOAc (10 mL) and H2O (5 mL), and the solid catalyst was recovered by centrifugation. The aqueous phase was extracted with EtOAc (5 mL × 3). The collected organic extracts were dried on Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography on silica gel using a mixture of PE/EA (20:1) to give the pure product 3. |
84% | With tetrabutylammonium acetate In methanol at 20℃; for 3h; Electrochemical reaction; Inert atmosphere; | |
81% | With tert.-butylhydroperoxide; sodium carbonate; potassium iodide In 1,4-dioxane at 120℃; for 5h; Sealed tube; | 2.Experimental Procedures General procedure: In a 35 mL sealed tube, a solution of 3 mL of 1,4-dioxane, acyhydrazines 1 (0.5mmol), α-ketoacids 2 (0.5 mmol) , Na2CO3 (0.6 mmol), KI (0.05 mmol) and TBHP (2.0 mmol) was sequentially added. The reaction mixture was stirred at 120 °C for 5 h and then cooled to room temperature. Then, the mixture extracted with ethyl acetate (2 × 10 mL), and the organic layer was combined and dried with anhydrous Na2SO4. After removal of the solvent under reduced pressure, the residue was separated by flash column chromatography to afford the pure product 3 (PE:EA = 20:1). |
72% | With Eosin Y In N,N-dimethyl-formamide at 45℃; for 12h; Sealed tube; Irradiation; | Experimental Procedures for the Synthesis of 3aa-3ak, 3ba-3ga, 5a-5k. General procedure: In sealed tube, a solution of 3 mL solvent (DMSO or DMF) of hydrazines 1 (0.5mmol), diketones 2 or 4 (0.5mmol), K2CO3 (1mmol), eosin Y (0.025mmol) was sequentially added. The reaction mixture was stirred under incandescent light (0.4 Wcm-2) irradiation at 45 °C for 24 h. Then, the mixture extracted with ethyl acetate (3 × 10 mL), and the organic layer was combined and dried with anhydrous Na2SO4. After removal of the solvent under reduced pressure, the residue was separated by flash column chromatography to afford the pure product 3 or 5 (PE: EA = 20:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The derivatives of the minimal pharmacophore (compounds 21-46) were synthesized on Knorramide MBHA resin. Each reaction was carried out by using 100 mg Knorr amide MBHA resin. The tripeptoid Nlys-Nlys-Nmea linker was incorporated by using standard submonomer synthesisprotocol discussed above. The beads were then bromoacylated by using bromoacetic and DIC asdiscussed before. The bromoacylated beads were then treated with 2mL (for 100 mg beads)NH2NHDdz (1M in NMP) at 37 C overnight (~15h). The beads were extensively washed withDMF followed by DCM and incubated with DCM for 5 min. The N-terminus was then protectedwith alloc by using allyl chloroformate (5 equiv.) in presence of DIEA (10 equiv.) for 3h in DCM.The beads were then washed with DCM and the Ddz protecting group was removed by using 1%TFA in presence of 2.5% TIPS in DCM for 10 mins (5 times). The beads were then washed withDCM followed by 1% DIEA in DCM and then incubated with 1% DIEA in DCM for 5 mins. Thebeads were then washed with DCM and treated with p-nitrophenyl chloroformate (5 equiv.) andDIEA (7 equiv.) at 37 C for 3h (twice). The beads were washed with DCM followed by DMF andthen treated with different amine nucleophiles (2M) in presence of 2M DIEA in NMP at 60 C for24h. The beads were washed with DMF followed by DCM and incubated with DCM for 5 min andthen treated with Pd(PPh3)4 (0.25 equiv.) and phenylsilane (5 equiv.) in DCM for 15 min at roomtemperature (3 times) to deprotect the alloc group. Once the alloc group was deprotected otherpeptoid and azapeptoid residues were incorporated by using standard submonomer synthesis protocol discussed above. Finally, the oxadiazolone ring of 1 was synthesized on resin as discussedabove. Each compound was then purified by using reverse phase HPLC. The purity of thecompounds was 50-60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In ethanol at 20℃; | General synthetic procedure for compounds 7a-q General procedure: To a stirred solution of 2H-chromene-3-carbaldehydes (2 mmol) 3a-c in 10-20 ml abs. ethanol appropriate hydrazide 6a-f (2 mmol) was added. The reaction mixture was vigorously stirred at room temperature for 15 min until TLC showed reaction completion. After 15 min - 2 h the clusters of yellow crystalline compounds 7a-q deposited from the solution. Upon filtration the crystals were washed with aqueous ethanol and recrystallized from EtOH to give TLC pure crystals. 4-Chloro-N'-[(E)-2H-chromen-3-ylmethylidene]benzohydrazide 7a. Yield 68%, 0.424 g;yellow crystals; m.p. 190-192.°C. FTIR (ATR) cm-1: 3378, 3195, 3031, 1653, 1623, 1592,1565. 1H NMR (DMSO-d6, 600 MHz, ppm) δ: 5.055 (s, 2H,H-2), 6.835 (d, J = 8.3 Hz, 1H,H-8), 6.929 (dt, J =0.9, 7.4 Hz, 1H, H-6), 6.955 (s, 1H,H-4), 7.18 - 7.21 (m, 2H, H-7 and H-5), 7.569 (d, J =8.5 Hz, 2H, H-3’ and H-5’), 7.857 (d, J =8.5 Hz, 2H, H-2’ and H-6’), 8.110(s, 1H, H-9), 11.970 (s, 1H, NH). 13C-NMR (DMSO-d6, 150 MHz, ppm) δ: 64.35 (C-2),116.23 (C-8), 122.29 (C-4a), 122.50 (C-6), 128.50 (C-5), 129.30 (C-2’ and C-6’), 129.50 (C-3), 129.89 (C-4), 130.10 (C-3’ and C-5’), 131.31 (C-7), 132.23 (C-1’),137.47 (C-4’), 147.70(C-9), 154.63 (C-8a), 163.26 (C-10). HRMS (ESI) m/z: found 313.07384 [M+H]+; calcd:313.073832 [M+H]+. |
68% | In ethanol at 20℃; | General synthetic procedure for compounds (4a-c) and(8a-d) General procedure: The compounds were prepared by an established procedure(Angelova et al. 2016b, 2017). An appropriate hydrazide3a-d (2 mmol) was added to a stirred solution of4-chlorocoumarin-3-carbaldehyde 2 or 2H-chromene-3-carbaldehydes (2 mmol) 7: in 10-20 mL anhydr. ethanol.The reaction mixture was vigorously stirred at room temperaturefor 15 min. After 15 min to 1 h the clusters ofyellow crystalline compounds 4a-c and 8a-d depositedfrom the solution. Upon filtration the crystals were washedwith aqueous ethanol to give TLC pure crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol at 20℃; Overall yield = 69%; Overall yield = 0.45 g; | General synthetic procedure for compounds 7a-q General procedure: To a stirred solution of 2H-chromene-3-carbaldehydes (2 mmol) 3a-c in 10-20 ml abs. ethanol appropriate hydrazide 6a-f (2 mmol) was added. The reaction mixture was vigorously stirred at room temperature for 15 min until TLC showed reaction completion. After 15 min - 2 h the clusters of yellow crystalline compounds 7a-q deposited from the solution. Upon filtration the crystals were washed with aqueous ethanol and recrystallized from EtOH to give TLC pure crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With acetic acid; In ethanol; for 3h; | General procedure: Appropriate substituted benzoyl hydrazine 4 (1 equiv) was added to a solution of intermediate 2 (1mmol) in ethanol (10mL). The reaction mixture was stirred for 3h at reflux under the condition of the presence of acetic acid as catalyzer, then poured into cold water and the resulting solid was collected by filtrated, washed with EtOH (10mL), and dried in the atmospheric pressure to give the desired title compounds A, B, and C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70%; 20% | With hydrazine hydrate; In ethanol; for 30h;Reflux; | The methyl ester of indomethacin (0.01 mol) and hydrazine hydrate (99%) (0.2 mol) in presence of absolute ethanol (50 mL) were refluxed for 30 h. The reaction mixture was concentrated by using rota vapor and poured in a beaker containing ice while stirring and kept for 4 h at room temperature.The solid was separated out by filtration. The product was dried and recrystallized from ethanol.The product was carefully checked by thin layer chromatography. Two compounds were isolated by column chromatography by using different fractions of n-hexane and ethyl acetate. The first compound was 2-(6-methoxy-2-methyl-1H-indol-3-yl) acetohydrazide compound (1) and was obtained as the major product. The second compound, 4-chlorobenzohydrazide (2) was obtained as minor product. Both the compounds were fully characterized by the spectral data. 2-(6-methoxy-2-methyl-1H-indol-3-yl) acetohydrazide (1). Color: white; Yield: 70%; m.p.: 168-170 C; UV max (Methanol) = 280 nm; 1H-NMR (500 MHz, DMSO-d6): delta = 2.38 (3H, s, CH3), 3.54 (2H, s,CH2), 3.80 (3H, s, OCH3), 4.26 (2H, s, NH2, D2O exchg.), 6.67 (1H, d, J = 8.5 Hz, Ar-H), 7.16 (2H, d,J = 7.5 Hz, Ar-H), 9.16 (1H, s, NH, D2O exchg.), 10.62 (1H, s, CONH, D2O exchg.); 13C-NMR (125 MHz,DMSO-d6): delta = 12.0 (CH3), 30.2 (CH2), 55.8 (OCH3), 101.1, 105.1, 109.8, 110.0, 111.7, 128.0, 129.3, 129.7,130.6, 134.3, 153.4, 170.8 (C=O); ms: m/z = 233.11 [M]+, 234.07 [M + 1]+; Analysis: C12H15N3O2 for,calcd. C 61.79, H 6.48, N 18.01%; found C 61.58, H 6.46, N 18.05%. 4-Chlorobenzohydrazide (2). Color: white; Yield: 20%; m.p.: 148-150 C; UV max (Methanol) = 230 nm;1H-NMR (500 MHz, DMSO-d6): delta = 4.53 (2H, s, NH2, D2O exchg.), 7.52 (2H, d, J = 8.5 Hz, Ar-H), 7.84(2H, d, J = 8.5 Hz, Ar-H), 9.87 (1H, s, CONH, D2O exchg.); 13C-NMR (125 MHz, DMSO-d6): delta = 128.86,129.32, 132.50, 136.25, 165.29; MS: m/z = 170.45 [M]+; Analysis: C7H7N2OCl for, calcd. C 49.28, H 4.14,N 16.42%; found C 49.37, H 4.12, N 16.46%. |
With hydrazine hydrate; In ethanol; for 30h;Reflux; | The methyl ester of indomethacin (0.01 mol) and hydrazine hydrate (99%) (0.2 mol) were refluxed in absolute ethanol (50 mL) for 30 hours. The mixture was concentrated, cooled and poured in crushed ice in small portions while stirring, and kept for 3-4 hours at room temperature. The solid separated out was filtered, dried and crystallized from ethanol. The product was carefully checked by thin layer chromatography, and two compounds were isolated by column chromatography by using different fractions of n-hexane and ethyl acetate. The first compound was 2-(6-methoxy-2-methyl-1H-indol-3-yl) acetohydrazide (Compound 1), and was obtained as the major product. The second compound, a minor product, was 4-chlorobenzohydrazide (Compound 2). Both compounds were fully characterized by the spectral data and are further described below. (0039) Data obtained for 2-(6-methoxy-2-methyl-1H-indol-3-yl) acetohydrazide (Compound 1) are as follows: Color: white; Yield: 70%; M.p.: 168-170 C.; UV lambda max (Methanol)=280 nm; 1H NMR (500 MHz, DMSO-d6): delta=2.38 (3H, s, CH3), 3.54 (2H, s, CH2), 3.80 (3H, s, OCH3), 4.26 (2H, s, NH2, D2O exchg.), 6.67 (1H, d, J=8.5 Hz, Ar-H), 7.16 (2H, d, J=7.5 Hz, Ar-H), 9.16 (1H, s, NH, D2O exchg.), 10.62 (1H, s, CONH, D2O exchg.); 13C NMR (125 MHz, DMSO-d6): delta=12.0, 30.24, 55.88, 101.15, 105.12, 109.88, 110.04, 111.27, 128.90, 129.34, 129.75, 130.65, 134.31, 153.49, 170.89; MS: m/z=233.11 [M]+, 234.07 [M+1]+; Analysis: C12H15N3O2 for, calcd. C, 61.79; H, 6.48; N, 18.01%. found C, 61.58; H, 6.46; N, 18.05%. (0040) Data obtained for 4-Chlorobenzohydrazide (Compound 2) are as follows: Color: white; Yield: 20%; M.p.: 148-150 C.; UV Amax (Methanol)=230 nm; 1H NMR (500 MHz, DMSO-d6): delta=4.53 (2H, s, NH2, D2O exchg.), 7.52 (2H, d, J=8.5 Hz, Ar-H), 7.84 (2H, d, J=8.5 Hz, Ar-H), 9.87 (1H, s, CONH, D2O exchg.); 13C NMR (125 MHz, DMSO-d6): delta=128.86, 129.32, 132.50, 136.25, 165.29; MS: m/z=170.45 [M]+; Analysis: C7H7N2OCl for, calcd. C, 49.28; H, 4.14; N, 16.42%. found C, 49.37; H, 4.12; N, 16.46%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With trichlorophosphate for 20h; Reflux; | 2.2.7. General Method for Preparation of Compound 14a-c,16 General procedure: A mixture of compound 1 (0.80 g, 4 mmol) and the appropriateacid hydrazide 13a-c, 15 (4 mmol) in phosphorous oxychloride (25 ml) was refluxed for 20 h. then it was poured over crushed ice, neutralized using 10% sodium carbonate solution, filtered and dried. The formed precipitate was purified by column chromatography on silica gel, using pet ether/EOAt (75/25, v/v). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In ethanol at 80℃; | 3.2. General experimental procedure for synthesis of compounds 1-25 General procedure: The reaction mixture containing 4-chlorophenyl hydrazide(0.5 mmol) and aryl isothiocyanate (0.5 mmol) in absolute ethanol(10 mL) was refluxed at 80 °C for 20-30 min and monitored throughTLC. Precipitates were appeared in the reaction mixture which werefiltered and washed with hot hexane then cold ethanol [37]. Productwas dried in vacuum and collected. All compounds 1-25 were characterizedby spectroscopic techniques such as EI-MS and 1H NMR.Spectral data of all compounds are as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In ethanol; at 80℃; | General procedure: The reaction mixture containing 4-chlorophenyl hydrazide(0.5 mmol) and aryl isothiocyanate (0.5 mmol) in absolute ethanol(10 mL) was refluxed at 80 C for 20-30 min and monitored throughTLC. Precipitates were appeared in the reaction mixture which werefiltered and washed with hot hexane then cold ethanol [37]. Productwas dried in vacuum and collected. All compounds 1-25 were characterizedby spectroscopic techniques such as EI-MS and 1H NMR.Spectral data of all compounds are as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In ethanol at 80℃; | 3.2. General experimental procedure for synthesis of compounds 1-25 General procedure: The reaction mixture containing 4-chlorophenyl hydrazide(0.5 mmol) and aryl isothiocyanate (0.5 mmol) in absolute ethanol(10 mL) was refluxed at 80 °C for 20-30 min and monitored throughTLC. Precipitates were appeared in the reaction mixture which werefiltered and washed with hot hexane then cold ethanol [37]. Productwas dried in vacuum and collected. All compounds 1-25 were characterizedby spectroscopic techniques such as EI-MS and 1H NMR.Spectral data of all compounds are as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In ethanol at 80℃; | 3.2. General experimental procedure for synthesis of compounds 1-25 General procedure: The reaction mixture containing 4-chlorophenyl hydrazide(0.5 mmol) and aryl isothiocyanate (0.5 mmol) in absolute ethanol(10 mL) was refluxed at 80 °C for 20-30 min and monitored throughTLC. Precipitates were appeared in the reaction mixture which werefiltered and washed with hot hexane then cold ethanol [37]. Productwas dried in vacuum and collected. All compounds 1-25 were characterizedby spectroscopic techniques such as EI-MS and 1H NMR.Spectral data of all compounds are as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In ethanol at 80℃; | 3.2. General experimental procedure for synthesis of compounds 1-25 General procedure: The reaction mixture containing 4-chlorophenyl hydrazide(0.5 mmol) and aryl isothiocyanate (0.5 mmol) in absolute ethanol(10 mL) was refluxed at 80 °C for 20-30 min and monitored throughTLC. Precipitates were appeared in the reaction mixture which werefiltered and washed with hot hexane then cold ethanol [37]. Productwas dried in vacuum and collected. All compounds 1-25 were characterizedby spectroscopic techniques such as EI-MS and 1H NMR.Spectral data of all compounds are as follows. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | In ethanol; for 5.0h;Reflux; | General procedure: To a stirred solution of compound 3 (100 mg, 0.30 mmol) in ethanol was added corresponding benzohydrazides (1.0 mmol) and refluxed for 5 h. The reaction medium was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure, to obtain the pure compounds. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-chlorobenzoic acid hydrazide With pyridine In acetonitrile for 0.166667h; Stage #2: 3-chlorosulfonyl-4-chlorobenzoyl chloride In acetonitrile at 20℃; for 1h; | 1.4. General procedure 3 (GP3): Synthesis of compounds 2a-e General procedure: A mixture of ArCONHNH2 7 (3 mmol), pyridine (3 mmol) and acetonitrile (10 mL) was added dropwise over 15 min to a solution of the substituted benzoyl chloride 10 (3.05 mmol) in anhydrous acetonitrile (5 mL) at room temperature with vigorous stirring. The mixture was incubated for 1 h under the same conditions. The product was isolated by addition of cold water (100 mL), the precipitate was collected by filtration and was dissolved in 20 mL toluene containing phosphorus oxychloride (0.1 ml) at boiling temperature. After the solution was cooled to room temperature, 0.56 ml phosphorus oxychloride (6 mmol) was slowly added. The reaction mixture was refluxed for 6 h. The hot solution was gently decanted from the oily residue, and the solvent was exchanged for acetonitrile. To the resulting solution of the sulfonyl chloride 12 was added 25% aqueous ammonia to yield a pH of 8-9. The mixture was stirred at 50 °C for 2 h. After cooling, the mixture was poured into 50 mL of ice water. A precipitate formed and was collected by filtration, washed with water and dried at 50 °C. The product was purified by subsequent recrystallization from a mixture of DMF-ethanol-water (3:1:1) to give the title compounds 2a-e. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With titanium tetrachloride at 110℃; for 1.5h; | General procedure for the synthesis of 1,3,4-oxadiazole derivatives (2a-2o) General procedure: To a 10mL three-necked round bottle was charged with benzoylhydrazine (0.30 g,2.2 mmol), TiCl4 (0.83 g, 4.4 mmol) and DMA (3 mL, 32.1 mmol). The resulting solutionwas warmed to 110 C and stirred at this temperature for 1.5 h. When the reaction wascompleted, 50mL water was added and the resulting mixture was extracted with 50mLethyl acetate three times. The combined organic layer was successively washed withH2O (50 mL) and then brine (50 mL), then dried over anhydrous Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified by column chromatographyon silica gel with petroleum ether and ethyl acetate to give the title products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; methanol; for 52h;Reflux; | An appropriate 4-halogenobenzohydrazide (1 mmol) was dissolved in 7 mL of a mixture of THF with MeOH (1:1, v/v), followed by addition of <strong>[2631-77-8]3,5-diiodosalicylaldehyde</strong> (411.3 mg, 1.1 mmol). After a complete dissolution, sodium cyanoborohydride (100 mg; 1.6 mmol) and glacial acetic acid (100 µL) were added. The mixture was heated under reflux for 4 h and then let stir for 48 h at room temperature. After this time, the reaction mixture was diluted with distilled water and let stir for 30 min. Then, the mixture was evaporated to dryness and suspended in a small volume of MeOH. After additional 2 h, the resulted precipitate was filtered off and dried to provide pure product. 4-Chloro-N′-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 4c. White solid; yield 68%; mp 256.5-259C. IR (ATR): 3227 (N-H), 1656 (CO-NH) cm-1. 1H NMR (500 MHz, THF-d8): δ 11.41 (1H, s, OH), 8.33 (1H, s, CONH), 8.04 (1H, d, J=2.0Hz, H4), 7.91 (2H, d, J=8.1Hz, H2, H6), 7.63 (1H, d, J=2.1Hz, H6), 7.52 (2H, d, J=8.2Hz, H3, H5), 4.12 (1H, s, NH), 2.59 (2H, s, CH2). 13C NMR (126 MHz, THF): δ 162.79, 158.66, 148.33, 148.01, 139.91, 130.14, 129.81, 129.55, 121.12, 87.51, 80.69, 51.93. Anal. Calcd for C14H11ClI2N2O2 (528.51): C 31.82, H 2.10, N 5.30, found: C 31.88, H 2.12, N 5.25. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol for 2h; Heating; | 2.1.2.1 Synthesis of hydrazide-hydrazones 1 and 2 General procedure: Briefly, 4-substituted benzohydrazides (1 mmol) were treated with 2- or 4-hydroxy-3,5-diiodobenzaldehyde (for hydrazones 1 and 2, respectively; 1.1 mmol; 411.3 mg) in boiling methanol for 2 h. The hydrazide-hydrazones spontaneously precipitated were crystallized from MeOH if necessary.29 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium phosphate; water-d2 In acetonitrile at 100℃; for 1h; Sealed tube; Inert atmosphere; | 2. General procedure for the synthesis of 3 General procedure: Anhydrous CH3CN (2 mL) was added to a mixture of ClCF2COONa 2a (0.3 mmol, 1.5 equiv) and hydrazides 1 (0.2 mmol, 1 equiv) in the presence of K3PO4 (0.3 mmol, 1.5 equiv) and D2O (4 mmol, 20equiv). Then the sealed tube was stirred at 100 °C under N2 for 1 h. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatograph (silica gel, petroleum ether:EtOAc = 2:1, v/v) to give the desired product 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With acetic acid In ethanol at 20℃; for 12h; | 2.2. General procedure for the synthesis of compounds 1-10 General procedure: In a 25-mL Erlenmeyer flask, 1 mmol of 4-chloroben zohydrazide or 4-chlorophenyl hydrazine, 1 mmol of aldehyde derivatives (4-hydroxybenzaldehyde, 5chloro-2-hydroxyben zaldehyde, 4-hydroxy-3,5-dimethoxybenzaldehyde, 2-hydroxy- 1-naphthaldehyde, or 4-hydroxy-3-methoxybenzaldehyde), and 3 drops of acetic acid were dissolved in 5 ml of ethanol. The reaction mixture was stirred for 12 h at room temperature. After completion of the reaction monitored using TLC, the residue obtained was filtered, washed with ethanol, and dried on air, to afford the pure product. |
Tags: 536-40-3 synthesis path| 536-40-3 SDS| 536-40-3 COA| 536-40-3 purity| 536-40-3 application| 536-40-3 NMR| 536-40-3 COA| 536-40-3 structure
[ 14062-80-7 ]
4-Chloro-N,N-dimethylbenzamide
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[ 1016768-00-5 ]
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[ 1185303-65-4 ]
(4-Chlorobenzyl)hydrazine dihydrochloride
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[ 1016768-00-5 ]
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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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