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CAS No. : | 1673-47-8 | MDL No. : | MFCD00014757 |
Formula : | C7H7ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PHRDZSRVSVNQRN-UHFFFAOYSA-N |
M.W : | 170.60 | Pubchem ID : | 74289 |
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) : | 0.78 |
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 : | 1.09 |
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 : | 1.2 |
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 |
---|---|---|
88% | 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). |
890 mg | With hydrazine hydrate In ethanolReflux | To a solution of 3-chlorobenzoic acid (1 g, 6.39 mmol) in ethanol (10 mL) was added cHCl (5 drops) and the mixture heated at reflux overnight. The solvents were evaporated to give the target compound as a white solid. This compound was then dissolved in ethanol (10 mL) and hydrazine hydrate (6.21 mL, 128 mmol) was added and the mixture heated at reflux overnight. Solvents were evaporated and the product was purified by flash chromatography using a gradient mixture of ethyl acetate and hexanes to give the desire compound as a yellow solid (890 mg, 81percent over 2 steps). 1H NMR (CDCl3), ä 7.41 (t, J = 7 Hz, 1H), 7.49 (d, J = 7 Hz, 1H), 7.73 (m, 1H), 7.86 (m, J = 4 Hz, 1H); MS m/z = 171.5, 173.5 (M + H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With dmap; hydrazine hydrate In methanol; ethanol; dichloromethane | 3-Chlorobenzhydrazide A mixture of 3-chlorobenzoic acid (0.5 g, 3.19 mmol), 1,3-diccyclohexylcarbodiimide (0.72 g, 3.51 mmol), 4-dimethylaminopyridine (0.04 g, 0.32 mmol) in ethanol was stirred at ambient temperature for 1.5 hour. The white solid was filtered off and the filtrate diluted with dichloromethane (100 mL). The organic solution was washed with 1N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in ethanol (15 mL) and treated with hydrazine monohydrate (0.46 mL, 9.58 mmol). The resulting clear solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated to dryness in vacuo. Silica gel chromatography of the residue, using 3percent methanol in dichloromethane, afforded 0.29 g (53percent) of 3-chlorobenzhydrazide as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrazine hydrate; In ethanol; water;Reflux; | 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). |
With hydrazine hydrate; at 80℃; | 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. | |
890 mg | With hydrazine hydrate; In ethanol;Reflux; | To a solution of 3-chlorobenzoic acid (1 g, 6.39 mmol) in ethanol (10 mL) was added cHCl (5 drops) and the mixture heated at reflux overnight. The solvents were evaporated to give the target compound as a white solid. This compound was then dissolved in ethanol (10 mL) and hydrazine hydrate (6.21 mL, 128 mmol) was added and the mixture heated at reflux overnight. Solvents were evaporated and the product was purified by flash chromatography using a gradient mixture of ethyl acetate and hexanes to give the desire compound as a yellow solid (890 mg, 81% over 2 steps). 1H NMR (CDCl3), ae 7.41 (t, J = 7 Hz, 1H), 7.49 (d, J = 7 Hz, 1H), 7.73 (m, 1H), 7.86 (m, J = 4 Hz, 1H); MS m/z = 171.5, 173.5 (M + H)+. |
With hydrazine hydrate; In ethanol;Reflux; | General procedure: Then, the corresponding ester was refluxed with 85% hydrazine monohydrate in ethanol to get hydrazide 1. | |
With hydrazine; In methanol; at 5 - 20℃; | General procedure: Amixture of ethyl esters (25 mmol, 3a-k) and methanol (20mL)was taken in 100 mLround bottom flask and cooled up to 5C. Hydrazine hydrate (80%, 0.05-0.07 mol) wasadded gradually to the reaction mixture and kept stirring for 4-6 h at room temperature.Some of the hydrazide products were formed at room temperature while some esters gotaltered on refluxing with continuous stirring. The reaction completion was monitored byTLC using n-hexane and ethyl acetate as solvent system. After completion of reaction, colddistilled water was added to acquire the precipitates. Precipitates of consequent aryl/aralkylacid hydrazides (3a-k) were filtered, washed with distilled water, and dried to follow thefurther reaction.17-19 | |
With hydrazine hydrate; In ethanol;Reflux; | General procedure: To a stirred solution of ethyl benzoate (3 mmol) derivatives in ethanol was added hydrazine-hydrate (5.44 mmol) and refluxed for 6-12 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain the respective benzohydrazide derivatives (4a-m)15,16. The yields of the products varied from 80-85 %. | |
With hydrazine hydrate; In ethanol; for 8h;Reflux; | General procedure: A mixture of benzoic acid (6.42 mmol), catalytic quantity of conc. H2SO4 in ethanol was heated to reflux for 10 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was washed with saturated NaHCO3 followed by water and brine solution. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain respective ethyl benzoates. To a stirred solution of ethyl benzoates (5 mmol) in ethanol was added hydrazine-hydrate (12.5 mmol) and refluxed for 8 h. The reaction mixture was diluted with ethyl acetate followed by water. The organic layer was dried over sodium sulphate, filtered and evaporated to obtain respective benzohydrazides 7a-k. | |
With hydrazine hydrate; In ethanol; for 6h;Reflux; | General procedure: The substituted ethyl benzoates (16-30) (0.01 mol)dissolved in dry ethanol (25 mL), hydrazine hydrate (99%,0.01 mol) was added and the mixture was reuxed for 6 h.The reaction mixture was cooled and the solid obtained wasltered and recrystallized from dilute ethanol or from water.Details of these compounds are available in SupplementaryInformation. | |
With hydrazine hydrate; In ethanol; for 5h;Reflux; | General procedure: 5mL of hydrazine monohydrate (80%) was added to a solution of intermediate 3 (5mmol) in ethanol (5mL). The reaction mixture was maintained under reflux for 5h. was then concentrated under reduced pressure and the resulting solid was collected by filtration, washed with cold water and dried to give the desired intermediate 4 as a white solid. | |
With hydrazine hydrate; In methanol;Reflux; | General procedure: The ethyl esters (0.15 mol; 2a-o) were taken in 250 mL round bottom flask.About 30 mL of methanol was added to the flask and homogenized by stirringat room temperature. Hydrazine hydrate (80%; 0.15 mol) was introduced to theflask drop wise and the reaction apparatus was refluxed for 5-6 hrs. Reactionprogress was confirmed by thin layer chromatography. n-Hexane and ethylacetate (3:2). At the end of reaction, excess of solvent was evaporated andresidue was poured into the ice cold water. Precipitates of acid hydrazides werefiltered, washed with water and dried. Re-crystallization of acid hydrazides wasperformed by using methanol. | |
With hydrazine; In ethanol;Reflux; | General procedure: The synthesized aryl/aralkyl esters (IIa-n)(3.5 mL) were diluted in 250 mL ethanol followed byaddition of 4.8 mL 80% hydrazine. Refluxing wascontinued for 4-6 h. After monitoring by TLC, icecold distilled H2O was poured to acquire the precipitatesof (IIIa-n), which were filtered and washed offwith cold distilled H2O [18, 19]. | |
With hydrazine hydrate; In ethanol;Reflux; | General procedure: Ethyl ester (Va-n) (0.04 mol) was refluxed with 80% N2H4 · H2O(7.2 mL) for 3-4 h in 20 mL EtOH in a round-bottom flask (100 mL). The reaction was monitored by TLC. At completion, excess ice-cold distilled water (60 mL) was added to get the precipitate, which was filtered, washed with distilled water, and dried to acquire title compounds (VIa-n) [18, 19]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With ammonium chloride In ethanol for 10h; Reflux; | 1 Preparation Example 1. Synthesis of Intermediates A1 to A5 SM1 (hydrazine compound; 1 eq), SM2 (triethyl orthoester; 1.1 eq) and ammonium chloride (3.5 eq) were added to an excess of ethanol, followed by heating to reflux in the combination described in Table 1 below. After 10 hours, the reaction was terminated and the temperature was stabilized at room temperature, followed by distillation under reduced pressure. Thereafter, the slurry was stirred through hexane and diethylether, filtered, and purified by column chromatography with hexane to prepare intermediates A1 to A5 of Table 1 below. |
In neat (no solvent) for 15h; Heating; | ||
at 120℃; for 12h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With hydrogenchloride | |
With hydrogenchloride In water | ||
With hydrogenchloride In methanol for 1h; Reflux; |
With hydrogenchloride In methanol; water for 1h; Reflux; | ||
With hydrogenchloride In water for 3h; Reflux; | ||
With hydrogenchloride In water for 3h; Reflux; | General Procedure for the Synthesis of Thiosemicarbazide (4a-t) General procedure: A suspension of hydrazide 3 (0.01 mol), potassium thiocyanate (0.02 mol), concentrated hydrochloric acid (10 mL) and water (50 mL) was refluxed for 3 h. The reaction mixture was allowed to cool to room temperature. The solid formed was collected by filtration, washed with water, dried and the crude thiosemicarbazide 4 was used as such for the next step. | |
With hydrogenchloride for 3h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In ethanol for 0.0833333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
In ethanol for 1h; Heating; Yield given; | ||
In ethanol Reflux; |
In toluene at 70℃; | 4.5.2. General procedure for the synthesis of 5-substituted-4-phenyl-4H-1,2,4-triazole-3-thiol (3f-3l) General procedure: Various substituted carboxylic acid hydrazides (25.0 mmol) andphenyl isothiocyanate (25.0 mmol) were dissolved in toluene (30 ml).The reaction mixture was heated for 1-2 h. After completion of thereaction, toluene was evaporated using a rotary evaporator. The resultingprecipitates were filtered, washed with water, and recrystallizedfrom ethanol. Recrystallized thiosemicarbazides 7 was further refluxedwith 4 N sodium hydroxide for 4-5 h. After completion of cyclization,reaction mixture was acidified with dilute hydrochloric acid (adjustedpH 5-6). The resulting precipitates of 1,2,4-triazole-3-thiols 3f-3l werecollected through filtration, washed with water and recrystallized fromethanol. | |
In dimethyl sulfoxide at 25℃; for 1h; | 2. General procedure for the synthesis of 2-amino-1,3,4-oxadiazole derivatives (3a-p, 4a-h) General procedure: A solution of benzoylhydrazine (0.20 g, 1.5 mmol) and phenylisothiocyanate (0.20 g, 1.5 mmol) in DMSO (3 mL) was stirred atroom temperature for 1 h. Then, KHSO4 (1.19 g, 8.75 mmol) wasdirectly added to the stirred solution at the room temperature andreacted for another 6 h. After the completion of the reactionmonitored by TLC, the solution was diluted with 30 mL water, andthe resulting precipitate was separated by filtration or extractedwith EA, concentrated and dried. The residue was purified by columnchromatography on silica gel with petroleum ether/ethyl acetateto afford the target product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium hydroxide In ethanol for 0.5h; | |
With potassium hydroxide | ||
With potassium hydroxide In methanol at 20℃; |
Stage #1: 3-chlorobenzhydrazide With potassium hydroxide In methanol for 0.25h; Stage #2: carbon disulfide at 20 - 25℃; for 3h; | ||
With potassium hydroxide In ethanol | ||
With potassium hydroxide In methanol at 20℃; 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 potassium hydroxide In ethanol at 20℃; | ||
With potassium hydroxide In ethanol for 10h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With aluminum oxide; potassium hydroxide In ethanol for 0.116667h; Microwave irradiation; | 10 General procedure for the synthesis of 5-substituted-1,3,4-oxadiazole-2-thione (1-12) General procedure: A mixture of respective hydrazide (10 mmol), potassiumhydroxide (0.56 g, 10 mmol) and alumina were finely ground in aglove box with a mortar and pestle. Then carbon disulfide(1.2 mL, 20 mmol) was added to this mixture in a Pyrex glass vial,which was placed in a screw-capped thick-walled Teflon vessel.Microwave-irradiation (MW domestic type oven 900W with a frequency2450 MHz, Dawlance, Pakistan) was applied for 7 min.After the completion of reaction (TLC analysis), ethanol was addedinto reaction mixture and filtered. Filtrate was evaporated; distilledwater was added to semi-solid material and acidified withhydrochloric acid to pH = 4. Precipitates so obtained were filteredand dried to afford off white solid compound 2a-r and then recrystallizedfrom ethanol:water (50:50) mixture. |
52% | With potassium hydroxide In ethanol for 3h; Heating; | |
With potassium hydroxide In ethanol at 85℃; for 3h; |
With potassium hydroxide In ethanol at 85℃; for 3h; | - Route B (R1 = aryl) General procedure: Note: hydrazine and carbon disulphide used during this procedure have to be handled withcaution.The carboxylic compound was first converted into its ethyl ester by refluxing in absoluteethanol in the presence of a few drops of H2SO4. The ester was then treated overnight withhydrazine hydrate (2 to 4 equiv.) without solvent at 120 °C. Evaporation of excess hydrazineyielded the corresponding hydrazide compound. The hydrazide, solubilized in absolute ethanol,was treated with CS2 (5 equiv.) in the presence of KOH (1.7 equiv.) at 85 °C for 3 h. Water wasadded and pH was adjusted to 2-3 with 1N HCl. The formed precipitate was collected byfiltration and washed with water, yielding the 1,3,4-oxadiazol-thione, which was used withoutfurther purification. Finally, the preceding compound was treated with hydrazine hydrate (10equiv.) in absolute ethanol at 100 °C overnight in a sealed tube. After evaporation of excesshydrazine, the residue was purified on a silica gel column to yield the final compound. | |
With potassium hydroxide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With agar at 20℃; for 0.15h; | |
88.3% | microwave irradiation; | |
88% | In ethanol for 0.0333333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
87.2% | at 20℃; for 0.15h; | |
86% | 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). |
In ethanol Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With agar at 20℃; for 0.133333h; | |
89.5% | microwave irradiation; | |
88.7% | at 20℃; for 0.133333h; |
88% | In ethanol for 0.0833333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
85% | 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). |
In ethanol for 0.0833333h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium hydroxide In ethanol for 20h; Reflux; | |
76% | With potassium hydroxide In ethanol for 14h; Reflux; | |
58% | In N,N-dimethyl-formamide at 40 - 70℃; Inert atmosphere; | 4.7 4.1.2. General procedure for synthesis of 5-substituted 1,3,4-oxadiazole-2-thiols General procedure: To a solution of acid hydrazide in anhydrous 5-15mL of DMF, carbon disulfide (2.5mL/mmol) was added at room temperature and under a nitrogen atmosphere. The reaction mixture was then heated to 40°C for 15min and then to 70°C for 4-8h until the reaction was completed. After completion, the reaction mixture was cooled to room temperature and poured dropwise into ice cold water. The solids formed were separated by filtration, washed with water and dried in vacuo. |
With potassium hydroxide In ethanol Heating; | ||
With potassium hydroxide In ethanol for 8h; Heating; | ||
With potassium hydroxide In ethanol | ||
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride In ethanol; water | ||
With potassium hydroxide In ethanol Reflux; | General Procedure for the Synthesis of 5-Substituted Aryl/aralkyl-1,3,4-oxadiazol-2-thiols (4a-k) General procedure: The aryl/aralkyl acid hydrazides (0.01 mol, 3a-k) were dissolved in ethanol(35-40 mL) followed by the addition of KOH (0.03 mol) and CS2 (0.01 mol) in 250 mLround bottom flask fitted with a reflux condenser. The reaction mixture was refluxedfor 3-6 h along with proper stirring and the progress of reaction was monitored byTLC. After completion of reaction, the reaction mixture was diluted with distilled H2O(70-75 mL) and acidified with dilute HCl (pH 2-3) to convert salt of oxadiazole into acidicform. Precipitates of corresponding 5-substituted-1,3,4-oxadiazole-2-thiols (4a-k) werefiltered, washed with distilled water, and dried. To get the pure product, precipitates wererecrystallized from methanol.17-19 | |
With potassium hydroxide In ethanol; water Reflux; | ||
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In ethanol Stage #2: With hydrogenchloride In water | ||
With potassium hydroxide In ethanol for 20h; Reflux; | ||
With potassium hydroxide In ethanol Reflux; | 2.4. Procedure for the synthesis of 5-substituted-1,3,4-oxadiazol-2-thiols (4a-o) General procedure: The aralkyl/aryl acid hydrazides (0.01 mol; 3a-o) were dissolved in 20 mLabsolute C2H5OH in a 250 mL of round bottom flask. Solid KOH (0.02 mol)and carbon disulphide (0.02 mol) were added to reaction flask. The reactioncontents were refluxed for 4-5 hrs with continuous stirring. H2S was evolvedduring the completion of reaction. Completion of reaction was confirmed bythin layer chromatography by using n-hexane and ethyl acetate (3:2) as mobilephase to develop a chromatogram. After confirmation, cold distilled water wasadded to the flask contents along with the addition of dilute HCl (pH 4-5).Precipitates of title compounds were filtered, washed with distilled waterand dried. To obtain the pure products, precipitates were recrystallized frommethanol. | |
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In ethanol Reflux; Stage #2: With hydrogenchloride | ||
With hydrazine hydrate; potassium hydroxide In ethanol Reflux; | General procedure for synthesis of 5-((un)substituted-phenyl)-1,3,4-oxadiazol-2-thiols (VIIa-n). General procedure: Solid KOH (0.03 mol) was dissolved in 25 mL EtOH on reflux in a 100 mL round-bottom flask. (Un)Substituted-benzohydrazide (VIa-n) (0.03 mol) was refluxed with CS2 (0.06 mol) in this basified EtOH for 5-6 h. The reaction was monitored by TLC. At completion, excess ice-cold distilled water (60 mL) wasadded to form homogeneous solution. pH was adjusted to 5-6 by pouring dilute HCl; precipitatethus formed was filtered, washed with distilled water and dried. The formed products (VIIa-n) were also re-crystallized from EtOH [18, 19]. | |
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In ethanol at 80℃; Stage #2: With hydrogenchloride; water at 20℃; | ||
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In ethanol Stage #2: With hydrogenchloride In water | ||
With potassium hydroxide In ethanol; water at 95℃; for 16h; Inert atmosphere; | ||
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With sodium hydroxide Stage #2: With hydrogenchloride | ||
With potassium hydroxide In ethanol for 6h; Reflux; | ||
In N,N-dimethyl-formamide for 10h; Sonication; | 4.2.1. general procedure for the synthesis of 2-mercapto-1,3,4-oxadiazolederivatives (compounds 85-110) General procedure: Carbon disulfide (50 mmol 4.7 mL) was added dropwise to the suspension including carboxyhydrazides (compound 59-84, 50 mmol) in DMF (5 mL) processed to an ultrasonic bath for 10 h. Hydrogen sulfide emission was treated with a saturated solution of sodium bicarbonate.The reaction mixture was added to 20 g crushed ice containing excess of salt. The solid phase was filtered with Buchner funnel, washed with water, and dried to obtain compound 85-110, respectively. | |
With potassium hydroxide In ethanol for 7h; Reflux; | ||
With potassium hydroxide In ethanol for 12h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sulfuric acid In ethanol at 50℃; | 77 General Procedure Y The relevant hydrazide of formula II as described herein (2.4 mmol) was dissolved in EtOH (10 mL) and to it was added 2 drops of concentrated sulfuric acid, and the appropriate oxime of formula III as described herein (2 mmol). The reaction was heated at 50°C overnight, filtered, washed with EtOH and recrystallised from EtOH/water. General procedure Y was employed using 2.3 mmol of the relevant hydrazide to give the title compound colourless crystals (410 mg, 48% yield). 1H-NMR (DMSO-d6) : No. 12.80 (bs, 1H), 12.60 (s, 1H), 8.64 (s, 2H), 8.05 (bs, 1H), 7.93 (t, 1H), 7.83-7. 81 (m, 2H), 7.71-7. 68 (m, 2H), 7.59 (t, 1H). MS (M++H) m/z = 370. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 5-chlorobenzoic acid With sulfuric acid In ethanol for 6h; Reflux; Stage #2: With hydrazine monohydrate; Sodium hydrogenocarbonate; glacial acetic acid Reflux; | |
0.29 g (53%) | With 4-dimethylaminopyridine; hydrazine hydrate monohydrate In methanol; ethanol; dichloromethane | 3 3-Chlorobenzhydrazide 3-Chlorobenzhydrazide A mixture of 3-chlorobenzoic acid (0.5 g, 3.19 mmol), 1,3-diccyclohexylcarbodiimide (0.72 g, 3.51 mmol), 4-dimethylaminopyridine (0.04 g, 0.32 mmol) in ethanol was stirred at ambient temperature for 1.5 hour. The white solid was filtered off and the filtrate diluted with dichloromethane (100 mL). The organic solution was washed with 1N sodium hydrogen sulfate (100 mL), saturated sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was dissolved in ethanol (15 mL) and treated with hydrazine monohydrate (0.46 mL, 9.58 mmol). The resulting clear solution was stirred overnight at ambient temperature. The reaction mixture was then concentrated to dryness in vacuo. Silica gel chromatography of the residue, using 3% methanol in dichloromethane, afforded 0.29 g (53%) of 3-chlorobenzhydrazide as a white solid. |
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 / 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: thionyl chloride / Microwave irradiation 2: hydrazine hydrate monohydrate / Microwave irradiation; Reflux | ||
Multi-step reaction with 2 steps 1: Acidic conditions; 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 / 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: hydrogenchloride / lithium hydroxide monohydrate / Reflux 2: hydrazine monohydrate / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 12 h / 70 - 80 °C / Reflux 2: hydrazine hydrate monohydrate / ethanol / Reflux | ||
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 / lithium hydroxide monohydrate / 6 h / Reflux 2: hydrazine hydrate monohydrate / lithium hydroxide 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 3 steps 1: thionyl chloride / 2 h / Reflux 2: sulfuric acid / 4 h / Reflux 3: hydrazine hydrate monohydrate / ethanol / 9 h / Reflux | ||
Multi-step reaction with 2 steps 1: hydrogenchloride 2: hydrazine / ethanol / 5 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: 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 / 10 h / Reflux | ||
Stage #1: 5-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 / Reflux 2: hydrazine hydrate monohydrate / neat (no solvent) / 120 °C / Sealed tube | ||
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 / lithium hydroxide monohydrate; methanol / 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 / Heating 2: hydrazine hydrate monohydrate / ethanol / 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 / Reflux 2: hydrazine / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine monohydrate / Reflux | ||
With sulfuric acid; hydrazine hydrate monohydrate In methanol | ||
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 / 7 h / 80 °C 2: hydrazine / methanol / 7 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 85 °C 2: hydrazine hydrate monohydrate / methanol / 14 h / 85 °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 / ethanol / Reflux | ||
Multi-step reaction with 2 steps 1: thionyl chloride / 1 h / 40 °C 2: hydrazine monohydrate / methanol / 4 h / 65 °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 / 5 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 6 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / Reflux 2: hydrazine monohydrate / neat (no solvent) / 120 °C / Sealed tube | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 3 h / Reflux 2: hydrazine hydrate monohydrate | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 2 h / 78 °C 2: hydrazine hydrate monohydrate / ethanol / 6 h / 78 °C | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 8 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 8 h / Reflux | ||
Multi-step reaction with 2 steps 1: sulfuric acid / 24 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 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 / Reflux | ||
Multi-step reaction with 3 steps 1: thionyl chloride / 2 h / 75 °C 2: potassium carbonate / 4 h / 65 °C 3: hydrazine hydrate monohydrate / ethanol / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.67% | With hydrazine hydrate; In methanol; at 70℃; for 1h; | [0283] To a stirred solution of <strong>[2905-65-9]methyl 3-chlorobenzoate</strong> (600.00 mg, 3.53 mmol) in methanol (5.00 mL) was added Hydrazine Monohydrate (1.0 mL). The resulting solution was stirred for 1 h at 70C. The precipitated solids were collected by filtration and washed with ACN (2x2 mL) to give the title compound as a off-white solid (550 mg, 91.67%) MS m/z: 171 [M+H]+. |
With hydrazine hydrate; 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 0-5C. | |
With hydrazine hydrate; In ethanol; for 9h;Reflux; | General procedure: Substituted benzoic acid (1.0 mmol) was dissolved in thionylchloride and refluxed for 2 h, then the solvent was removed underreduced pressure to obtain the white solid. The white solid in methanol was added concentrated sulfuric acid (1 mL) and themixture was refluxed for 4 h, the solvent was removed to obtaincrude solid. The crude solid was extracted with ethyl acetate andwater. The solvents were evaporated to afford the pure product.Finally, the pure product was dissolved in ethanol, and the hydrazinehydrate was added. The mixture was refluxed for 9 h, and thesolvent was removed |
With hydrazine hydrate; In methanol; for 8h;Reflux; | 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;Reflux; | 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 hydrate; In methanol; at 65℃; for 4h; | 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 hydrate; In methanol;Reflux; Inert atmosphere; | 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; In methanol; at 80℃; for 4h; | General procedure: At the 250 cm3double-mouth bottle, 13.5 mmol of themethyl benzoate derivatives was added to 100 cm3of methanol,added 6.75 cm3of hydrazine hydrate (108 mmol) tothe reaction mixture slowly. After that warming to 80 Cand reflux for 4 h until the reaction was completed, thenconcentrated under reducing pressure to remove methanol,filtering and drying to get white solid 2. | |
With hydrazine hydrate; In ethanol;Reflux; | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at -15 - 20℃; | 21.21a Example 21; 2-chloro-4-((1R,2S)-1-(5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile; Intermediate 21a; 3-chloro-N'-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide; (2R,3S)-2-(3-chloro-4-cyano-2-ethylphenylamino)-3-hydroxybutanoic acid (800 mg, 2.98 mmol), 3-Chlorobenzhydrazide (508 mg, 2.98 mmol) and anhydrous THF (40 mL) were placed in a 100 mL round bottomed flask and the mixture was cooled to -15° C. 1-Hydroxybenzotriazole hydrate (403 mg, 2.98 mmol) was added to the mixture together with N-(3-Dimethylaminopropyl)-N-ethylcarbodimide HCl (857 mg, 4.47 mmol) at -15° C. followed by triethylamine (0.62 mL, 4.47 mmol). The reaction mixture was maintained at -15° C. and stirred for 1 h after which, stirring continued overnight while the mixture slowly warmed to room temperature. Water (40 mL) was added to the reaction mixture followed by citric acid (4 g) while stirring. EtOAc (60 mL) was then added to the mixture and the phases were partitioned. The organic phase was then washed with saturated aqueous sodium bicarbonate (40 mL) and the organic phase dried (Na2SO4). EtOAc was removed under vacuum and replaced by chloroform (60 mL). The insoluble hydrazide was then separated from the mixture by filtration and dried under reduced pressure to furnish a white solid (855 mg, 68%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.7 (br s, 2H), 7.96 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.46-7.7 (m, 2H), 6.64 (d, J=8.6 Hz, 1H), 5.3 (d, J=7 Hz, 1H), 4.19-4.03 (m, 1H), 3.98-3.87 (m, 1H), 2.35 (s, 3H) and 1.26 (d, J=6.35 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate monohydrate In ethanol at 80℃; | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 0 °C 2: hydrazine hydrate monohydrate / methanol / 5 h / Reflux | ||
Multi-step reaction with 2 steps 1: triethylamine / diethyl ether 2: acetonitrile; dimethyl sulfoxide; lithium hydroxide monohydrate / 25 °C |
Multi-step reaction with 2 steps 1: sulfuric acid / 4 h / Reflux 2: hydrazine hydrate monohydrate / ethanol / 9 h / Reflux | ||
With hydrazine hydrate monohydrate In dichloromethane at 0 - 20℃; for 12h; | ||
With hydrazine hydrate monohydrate In dichloromethane at 20℃; | General procedure: Method B Substituted benzoyl chloride (3, 1 eq) and 85% hydrazine hydrate (2 eq) were dissolved in dichloromethane (25 mL). The mixture was stirred at room temperature overnight. The progress was monitored by TLC and the terminated by addition of water. The mixture was extracted with dichloromethane, washed with water and dried over anhydrous Na2SO4. After filtration, 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. | |
Multi-step reaction with 2 steps 1: sulfuric acid / 5 h / 60 °C 2: hydrazine hydrate monohydrate / 12 h / 80 °C | ||
Multi-step reaction with 2 steps 1: potassium carbonate / 4 h / 65 °C 2: hydrazine hydrate monohydrate / ethanol / 90 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In ethanol for 0.0333333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
96% | 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). |
In ethanol for 0.0833333h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In ethanol for 0.0833333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
86% | 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 |
---|---|---|
90% | In ethanol for 0.0333333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
85% | 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 |
---|---|---|
94% | 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). |
93% | In ethanol for 0.0333333h; Reflux; | 4.1.2. General procedure for the synthesis of 1-[(3-chlorophenyl)carbonyl]-4-substituted-thiosemicarbazides (1-11) General procedure: A solution of 0.01 mol of 3-chlorobenzoic acid hydrazide and equimolar amount of appropriate isothiocyanate in 25 ml of anhydrous EtOH was heated under reflux for 2 min (for compounds 2, 6, 8-10) or for 5 min (in the case of compounds 1, 3-5, 7, 11). Next, the solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and crystallized from EtOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In methanol at 20℃; Stage #2: With hydrazine hydrate In water Reflux; Stage #3: With hydrogenchloride In water | |
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In ethanol at 20℃; Stage #2: With hydrazine hydrate In water Reflux; | ||
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In ethanol at 0 - 5℃; for 2h; Stage #2: With hydrazine hydrate In ethanol for 4h; Reflux; Stage #3: With hydrogenchloride In ethanol; water at 20℃; | 4.1.2. General procedure for the synthesis of 4-amino-5-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones (A-D) General procedure: Solid potassium hydroxide (0.015 mol) and appropriate aryl hydrazide (benzhydrazide - for A, 2-chlorobenzhydrazide - for B, 3-chlorobenzhydrazide - for C, 4-chlorobenzhydrazide - for D) (0.01 mol) were dissolved in anhydrous ethanol (25 mL) and the resulted solution was cooled to 0-5 °C. Then carbon disulfide (CS2, 1 mL) was added dropwise and the reaction mixture was stirred for 2 min. The precipitated solid of potassium dithiocarbazinate was filtered off, washed with diethyl ether and dried. Thus obtained (in quantitative yield) potassium salt was used in the next step without further purification. A solution of potassium dithiocarbazinate and 80% hydrazine hydrate (10 mL) was refluxed for 4 h, cooled to room temperature, diluted with water (50 mL) and acidified with 3 M HCl. The resulting solids of compounds A-D were filtered, dried and crystallized from anhydrous ethanol. Physicochemical/spectral properties of compounds A-D were described earlier [16], [17], [18], [19], [20], [21] and [22]. |
Stage #1: carbon disulfide; 3-chlorobenzhydrazide With potassium hydroxide In methanol at 20℃; for 24h; Stage #2: With hydrazine hydrate Reflux; | General synthetic procedure for the key intermediates 2 General procedure: The hydrazide 1 was stirred with KOH in absolute methanol and carbon disulfide (CS2) was slowly added. The mixture was stirred 24h at room temperature and the white solid was precipitated, dried. The solid was refluxed with 85% hydrazine monohydrate to obtain the intermediate 2. The crude product was purified by silica gel column chromatography DCM/methanol (40:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In methanol for 2h; Reflux; | |
With acetic acid at 20℃; for 0.25h; | General procedure, exemplified by 1-phenyl-1,3-dihydroisobenzofuran (5a) General procedure: (i) The benzoylhydrazine (1 mmol) was added to a solution of the salicylaldehyde (1 mmol) in 5 mL acetic acid at room temperature. The mixture was stirred for 15 min and then was poured into 15 mL cold water. The resulting solid was filtered, washed with water and dried under vacuum. (ii) The obtained solid (1 mmol) was dissolved in 10 mL THF at room temperature. The solution was cooled to 0°C and lead tetraacetate (1 mmol) was added under nitrogen. The mixture was stirred 4 h at 0°C and then the solvent was removed under reduced pressure. Ethyl acetate was added to the residue and filtered over celite. The solvent was removed under reduced pressure and the residue was purified by column chromatography to obtain the 2-benzoylbenzaldehyde as a white solid. (iii) The 2-benzoylbenzaldehyde (1 mmol) was dissolved in 10 mL methanol at room temperature. NaBH4 (0.5 mmol) was added to the solution followed by 1 drop of pyridine and then the mixture was stirred 5 h at room temperature. The solvent was removed under reduced pressure and 0.5 mL hydrochloric acid was added to the residue. The mixture was extracted three times with ethyl acetate. The combined organic phase was distilled under reduced pressure. The residue was used without further purification. The residue was dissolved in 10 mL toluene and p-toluenesulfonic acid (0.1 mmol) was added. The resulting mixture was stirred 3 h under reflux. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel to give compound 5a. | |
1.39 g | With hydrogenchloride In ethanol; water at 20℃; for 16h; | 2 SYNTHESIS EXAMPLE 2 SYNTHESIS EXAMPLE 2 Preparation of (0314) (0315) 1.15 g of 3-chlorobenzhydrazide are suspended in 35 mL of ethanol and stirred at room temperature for 10 minutes. After addition of 0.93 g of salicylaldehyde and 1 mL of concentrated hydrochloric acid the resulting yellow solution is stirred for 16 hours at room temperature. A colorless precipitate is filtrated off, washed with 10 mL of water and dried at 100° C. in the vacuum yielding 1.39 g of the desired product as a colorless powder. Melting point: 201.8° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With copper(I) oxide; caesium carbonate In 1,4-dioxane; N,N-dimethyl-formamide at 90℃; for 6h; Inert atmosphere; | |
With copper(I) oxide; caesium carbonate In 1,4-dioxane; N,N-dimethyl-formamide at 90℃; for 6h; Sealed tube; Inert atmosphere; Schlenk technique; | Preparation of 3-aryl-1,2,4-Benzotriazines General procedure: To a 15 mL general branch reaction vial was added Cu2O (14 mg, 0.1 mmol), Cs2CO3 (0.65 g, 2 mmol), 2-iodoaniline (0.22 g, 1 mmol) and benzohydrazide (0.20 g, 1.5 mmol). The Schlenk tube was sealed and then evacuated and backfilled with nitrogen (3 cycles). Following, 2 mL DMF and 2 mL dioxane were added to the reaction tube. The reaction was stirred at 90 °C under N2 for 6 h. After cooling to room temperature, 10 mL H2O was added to the reaction mixture and it was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated brine(2×10mL), dried over anhydrous Na2SO4. After the solvent was evaporated in vacuo, the residues were purified by column chromatography, eluting with petroleum ether/EtOAc (v/v, 20/1) to afford the pure 3-phenyl-1,2,4-benzotriazine (1a, 0.125 g, 60% yield) as a yellow solid, m.p. 119-121 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With acetic acid In ethanol Reflux; regioselective reaction; | 1.3 Synthesis of compounds 6a-m and 7a-j General procedure: To a mixture of 2 or 3 (61.5mg, 0.25mmol) and the corresponding hydrazides or hydrazines (0.25mmol) in EtOH (5 mL), two drops of AcOH was added. Then the above mixture was heated at reflux. When the reaction was complete according to TLC analysis, the mixture was concentrated in vacuo, and purified by PTLC or recrystallization to afford 6a-m and 7a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With acetic acid In ethanol Reflux; regioselective reaction; | 1.3 Synthesis of compounds 6a-m and 7a-j General procedure: To a mixture of 2 or 3 (61.5mg, 0.25mmol) and the corresponding hydrazides or hydrazines (0.25mmol) in EtOH (5 mL), two drops of AcOH was added. Then the above mixture was heated at reflux. When the reaction was complete according to TLC analysis, the mixture was concentrated in vacuo, and purified by PTLC or recrystallization to afford 6a-m and 7a-j. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 2.15 4.2.15 (3-Oxo-1,2-benzisothiazol-3(2H)-2-yl)-acetic acid 2′-(3-fluorobenzoyl)hydrazide (6a) General procedure: To a stirred solution of compound 2 (0.58 g; 2 mmol) in dry DMF (6 mL) was added EDCI (0.46 g; 2.4 mmol), followed by m-fluorobenzhydrazide (0.31 g; 2 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was taken up in ethyl acetate (50 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified using flash chromatography (silica gel/ethyl acetate/hexanes) to give pure compound 6a, as a white solid (0.27 g; 32% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 2.15 4.2.15 (3-Oxo-1,2-benzisothiazol-3(2H)-2-yl)-acetic acid 2′-(3-fluorobenzoyl)hydrazide (6a) General procedure: To a stirred solution of compound 2 (0.58 g; 2 mmol) in dry DMF (6 mL) was added EDCI (0.46 g; 2.4 mmol), followed by m-fluorobenzhydrazide (0.31 g; 2 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was taken up in ethyl acetate (50 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified using flash chromatography (silica gel/ethyl acetate/hexanes) to give pure compound 6a, as a white solid (0.27 g; 32% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 2.15 4.2.15 (3-Oxo-1,2-benzisothiazol-3(2H)-2-yl)-acetic acid 2′-(3-fluorobenzoyl)hydrazide (6a) General procedure: To a stirred solution of compound 2 (0.58 g; 2 mmol) in dry DMF (6 mL) was added EDCI (0.46 g; 2.4 mmol), followed by m-fluorobenzhydrazide (0.31 g; 2 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was taken up in ethyl acetate (50 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified using flash chromatography (silica gel/ethyl acetate/hexanes) to give pure compound 6a, as a white solid (0.27 g; 32% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; | 2.15 4.2.15 (3-Oxo-1,2-benzisothiazol-3(2H)-2-yl)-acetic acid 2′-(3-fluorobenzoyl)hydrazide (6a) General procedure: To a stirred solution of compound 2 (0.58 g; 2 mmol) in dry DMF (6 mL) was added EDCI (0.46 g; 2.4 mmol), followed by m-fluorobenzhydrazide (0.31 g; 2 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was removed and the residue was taken up in ethyl acetate (50 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified using flash chromatography (silica gel/ethyl acetate/hexanes) to give pure compound 6a, as a white solid (0.27 g; 32% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In ethanol for 0.0333333h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
In ethanol for 0.0833333h; Reflux; | ||
In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In ethanol for 0.0333333h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
In ethanol for 0.0833333h; Reflux; | ||
In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In ethanol for 0.166667h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
In ethanol for 0.0833333h; Reflux; | ||
In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With acetic acid In ethanol; acetic acid Reflux; | |
87% | With acetic acid In ethanol Reflux; | 2 preparation method of compound 2 is as follows: Weigh the compound of formula a-1 (0.5 mmol, prepared as above),m-Chlorobenzoyl hydrazide (0.5 mmol) in a 50 mL flask,And adding 5mL of absolute ethanol to dissolve, adding (1 to 2 drops) of glacial acetic acid, and refluxing the reaction.After the reaction lasted for several minutes (5-10 min), a large amount of solids began to be produced, and the TLC was traced to the completion of the reaction; the room temperature was allowed to completely crystallize, and the crude product was obtained by vacuum filtration.The crude product was washed several times with frozen (-20 ° C) anhydrous ethanol to give a pure compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In ethanol for 0.0333333h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
88% | 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). |
In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In ethanol for 0.0333333h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
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). |
In ethanol |
In ethanol for 0.0833333h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | 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). |
85% | In ethanol for 0.0333333h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | 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). |
78% | In ethanol for 0.0333333h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | 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). |
80% | In ethanol for 0.166667h; Reflux; | 2.1.1. Synthesis of the Investigated Compounds General procedure: A synthesis pathway to compounds 1-16 is presented in Scheme 1. A solution of 0.01 mol of 3-chlorobenzhydrazide and equimolar amount of appropriate aryl isothiocyanate in 25 ml of anhydrous EtOH were heated under reflux for 2 - 10 min (details are given below). Next, the ethanolic solution was cooled and the solid formed was filtered off, washed with diethyl ether, dried, and recrystallized from EtOH. Reaction yields ranged from 74 to 96%. Structure of the synthesized compounds was corroborated by 1H NMR and IR spectra. The spectral data fully confirm the structures suggested for compounds 1-16. The 1H NMR spectra of the obtained compounds showed the signals of aromatic protons in the range of 6.89-8.01 ppm while the signals of the proton linked to N1-N2 and N3 nitrogens were shown at 9.46-10.76 ppm. |
In ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With acetic acid In ethanol Reflux; | Synthesis of piperine-based hydrazone derivatives (6a-p) General procedure: A mixture of 5 (80.8 mg, 0.4 mmol), hydrazides or hydrazines (0.4 mmol), and two drops of HOAc in EtOH (5 mL) was refluxed. When the reaction was complete checked by TLC after 1-3 h, the resulting reaction mixture was cooled to room temperature until no more precipitate was observed. The crude solid was collected by ltration, and washed with cooled ethanol and petroleum ether to afford 6a-p in 33-86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In water at 50 - 60℃; for 2h; | 3 General procedure General procedure: A solution of 1 (5.2 mmol) in water (60 mL) was added dropwise(over 1-2 h) under vigorous stirring to a solution of hydrazide2 (5.2 mmol) in water (60 mL) heated to 50-60° C. The mixture was stirred for additional 2 h, and then cooled on an ice bath untilthe complete precipitation of the white solid. After filtration, the solid was successively washed with cold water and cold diethylether (or 2-propanol). The hydrazones have been used in the nextstep without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With Al3+-K10 montmorillonite clay In neat (no solvent) at 55℃; for 0.25h; Microwave irradiation; | General procedure for 1,3,4-oxadiazole synthesis General procedure: A 5 mL microwave vial was charged with acidhydrazide (100 mg, 1 eq), trimethyl orthoester (2 eq) and Al3+-K10 clay (75 mg). The resulting mixture was kept under microwave irradiation maintaining the temperature at 55 °C for 15 min (Microwave irradiations were performed on CEM-discover model No. 908010). The reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with ethyl acetate stirred well, filtered, washed well with ethyl acetate. Filtrate was evaporated under reduced pressure to obtain highly pure product. In some cases, products were purified by column chromatography using 60-120 mesh silica with 20-100 % ethyl acetate in pet ether as eluting solvents. The catalyst recovered by filtration was reused for another 5 more times. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With Al3+-K10 montmorillonite clay In neat (no solvent) at 55℃; for 0.25h; Microwave irradiation; | General procedure for 1,3,4-oxadiazole synthesis General procedure: A 5 mL microwave vial was charged with acidhydrazide (100 mg, 1 eq), trimethyl orthoester (2 eq) and Al3+-K10 clay (75 mg). The resulting mixture was kept under microwave irradiation maintaining the temperature at 55 °C for 15 min (Microwave irradiations were performed on CEM-discover model No. 908010). The reaction was monitored by TLC. After completion of the reaction, reaction mixture was diluted with ethyl acetate stirred well, filtered, washed well with ethyl acetate. Filtrate was evaporated under reduced pressure to obtain highly pure product. In some cases, products were purified by column chromatography using 60-120 mesh silica with 20-100 % ethyl acetate in pet ether as eluting solvents. The catalyst recovered by filtration was reused for another 5 more times. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With phosphotungstic acid In N,N-dimethyl-formamide at 60℃; for 4h; | 3.6.1. Brevenal Derivatives General procedure: In a typical reaction, brevenal was dissolved in DMF and the hydrazide (2 eq) was added, followed by addition of a catalytic amount of tungstophosphoric acid. The reaction mixture was heated at 60 °C for 4 h. The solvents were evaporated under vacuum and the residue was taken up in methanol. The mixture was filtered through a 0.2 μm nylon filter and subjected to purification by HPLC. Desired products were positively identified by HRMS mass spectrometry and NMR. Spectroscopic data collected for all compounds can be found in the supplementary data document. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate In butan-1-ol at 150℃; | 15 Synthesis of escitalopram triazoles General procedure: The triazoles of escitalopram (60-88) were synthesized byfollowing a reported method for triazole formation.25 A mixtureof a benzohydrazide (33 mmol), escitalopram (59-oxalate,10 mmol) and K2CO3 (0.5 mmol) in n-butanol (2 mL) was heatedat 150 C for 5-6 h. The reaction was monitored with TLC. Afterthe completion of the reaction, the solvent was removed underreduced pressure. Finally, the triazole derivatives of escitalopram(60-88) were purified with column chromatography using solventsystem CH3OH/CH3Cl = 60:40 and finally with preparative thinlayer chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In methanol at 20℃; for 0.5h; | Synthesis of 1: To a solution of 2-hydroxy-5-methoxybenzaldehyde (0.152g, 1.0 mmol) in absolute MeOH (20 mL), 3-chlorobenzohydrazide (0.171g, 1.0 mmol) was added. The mixture was stirred at room temperature for30 min and the solvent was partially concentrated at reduced pressure. Thecolorless precipitate of the compound was isolated by filtration, and washedwith methanol. Single crystals suitable for X-ray diffraction were obtainedby recrystallization of the product in methanol. Yield, 76%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | 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 |
---|---|---|
32% | 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; | 3 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.; 4.1.2.3 2-[(E)-2-(5-bromothiophen-2-yl)ethenyl]-5-(3-chlorophenyl)-1,3,4-oxadiazole 8 1H NMR (DMSO-d6, 400 MHz): δ = 8.16 (t, J = 1.9 Hz, 1H), 8.11 (dt, J = 7.7 Hz and J = 1.3 Hz, 1H), 7.99 (d, J = 16.1 Hz, 1H), 7.79 (ddd, J = 8.1 Hz and J = 2.1 Hz and J = 1.2 Hz, 1H), 7.72 (t, J = 7.9 Hz, 1H), 7.49 (d, J = 4.0 Hz, 1H), 7.38 (d, J = 3.9 Hz, 1H), 7.12 (d, J = 16.2 Hz, 1H); 13C NMR (DMSO-d6, 101 MHz): δ = 164.40, 162.62, 141.82, 134.58, 132.41, 132.29, 131.97, 131.93, 131.83, 126.63, 125.75, 125.71, 115.38, 109.27; LC/MS (ESI): 368.95 [M+H]+ and isotopic peak: 370.94; HRMS (TOF, ESI+) cald for C14H9N2OSClBr (M + H)+ 366.9307, found 366.9306; beige powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In methanol at 20℃; for 0.5h; | Synthesis of H2L'. 3Methylsalicylaldehyde(1.0 mmol, 0.14 g) and 3chlorobenzohydrazide(1.0 mmol, 0.17 g) were dissolved in methanol (30 mL)with stirring. The mixture was stirred for about 30 minat room temperature to give colorless solution. The solution was left still in air to slow evaporate of most ofthe solvent, to give crystalline product of H2L. Theproduct was isolated by filtration and washed with coldmethanol. The yield was 81%.Selected IR data (KBr; ν, cm-1): 3228 (N-H), 1645(C=O), 1613 (C=N). For C15H13ClN2O2 anal. calcd., %: C, 62.40; H, 4.54; N, 9.70. Found, %: C, 62.23; H, 4.65; N, 9.82. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In dichloromethane at 20℃; | 2.3 2.1.2. General method of synthesis of benzohydrazide derivatives.(5a -5g) General procedure: Substituted benzohydrazide (1 mmol) and isatin (1 mmol) indichloromethane were refluxed for 10e12 h at room temperature,then the reaction mixture was concentrated under reduced pressure,recrystallized from ethanol to give benzohydrazide derivatives5a-5g. |
With trifluorormethanesulfonic acid In tetrahydrofuran Reflux; Green chemistry; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16h; | 191A Example 191A tert-butyl 4-(3-{ [2-(3-chlorobenzoyl)hydrazino]carbonyl}-5-oxo-4,5-dihydropyrazolo[l,5-a]pyrimidin- 7-yl)piperidine- 1 -carboxylate -[l-(te^butoxycarbonyl)piperidin-4-yl]-5-oxo-4,5-dm^ acid (150 mg, 0.42 mmol) and 3-chlorobenzohydrazide (105 mg, 0.6 mmol) were dissolved in N,N- Dimethylformamide (1,5 ml). N,N-Diisopropylethylamin (0.22 ml, 1.24 mmol) and N- [(Dimethylamino)(3H-[l,2,3]triazolo[4,5-b]pyridin-3-yloxy)methyliden]-N-methyl-methanaminium- hexalluorophosphate (266 mg, 0.62 mmol) were added and the mixture was stirred for 16h at RT. The mixture was purified via reverse phase HPLC (gradient acetonitrile/water with 0.01 % trinuoroacetic acid) which afforded the title compound (97 mg, 45% of theory). LC-MS (Method 5B): Rt = 0.88 min, MS (ESIPos): m z = 515.4 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 6h; | 3-Chloro-benzoic acid N′-[1-(5,6,7,8,-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidine-4-yl)-pyrrolidine-2-carbonyl]-hydrazide (9a) To a solution of 1-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d] pyrimidine-4-yl)-pyrolidine-2-carboxylic acid 6 (1 g,0.0033 mmol) in DMF (5 ml) was added EDC.HCl(0.950 g, 0.0050 mol) and 3-chloro-benzoic acid hydrazide (0.561 g, 0.0033 mol) followed by the HOBt (0.443 g,0.0033 mol). The reaction mixture was stirred for 6 h andquenched with water (50 ml); the off-white color solid thatcame out was filtered, dried, and washed with diethyl etherto give compound 9a (1.3 g, yield = 87 %); m.p. = 115-117°C; IR (KBr) νmax 3228, 3064, 2935, 1716, 1647, 1531,1446, 1323, 1236, 1138, 964, 742 cm-1; 1H NMR (DMSOd6,400 MHz) δ 10.45 (s, 1H, -NH-NH-), 10.05 (s, 1H, -NH-NH-), 8.26 (s, 1H, pyrimidine-H), 7.88 (d, 1H, J =1.6 Hz, Ar-H), 7.81 (d, 1H, J = 8 Hz, Ar-H), 7.62-7.64 (m,1H, Ar-H), 7.50-7.54 (m, 1H, Ar-H), 4.95 (t, 1H, J = 8 Hz,-N-CH-CO-), 3.90-3.94 (m, 1H, -CH2-CH2-CH2-),3.65-3.69 (m,1H, -CH2-CH2-CH2-), 3.11-3.15 (m, 2H,-CH2-CH2-CH2-), 2.33-2.40 (m, 2H, -CH2-CH2-CH2-),1.95-2.02 (m, 4H, -CH2-CH2-CH2-), 1.74-1.79 (m, 4H, -CH2-CH2-CH2-); 13C NMR (DMSO-d6, 100 MHz) δ 23.3,23.8, 25.3, 25.8, 28.6, 28.6, 52.4, 62.9, 115.9, 116.1, 122.8,124.9, 127.7, 131.8, 132.5, 134.3, 135.2 151.4, 158.7,164.3, 167.1, 170.2; ES-MS: m/z 455.3 (M+H)+; anal.calcd. for C22H22ClN5O2S: C, 57.95; H, 4.86; N, 15.36;found: C, 57.93; H, 4.84; N, 15.33. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride In ethanol at 50 - 60℃; | General procedure for synthesis of target compounds 4a-l, 5a-g and 6a-g General procedure: A mixture of compound 3 (3 mmol) with aminoguanidine hicarbonate (3 mmol) in refluxing ethanol (20 mL) in the presence of 5 drops of concentrated hydrochloric acid at 50-60 °C for 8-12 h afforded 4a-l in 60%-75% yields. The key intermediates 3 (3 mmol) reacted with isonicotinic acid hydrazide or substituted benzoyl hydrazine (3 mmol) in the presence of catalytic amounts of hydrochloric acid (5 drops) in ethanol (20 mL) to provide target compounds in series 5a-g or 6a-g in 75%-85% yields.22 The solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography with dichloromethane: methanol (50:1). The yield, melting point and spectra data of each compound are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With hydrogenchloride In ethanol at 50 - 60℃; | General procedure for synthesis of target compounds 4a-l, 5a-g and 6a-g General procedure: A mixture of compound 3 (3 mmol) with aminoguanidine hicarbonate (3 mmol) in refluxing ethanol (20 mL) in the presence of 5 drops of concentrated hydrochloric acid at 50-60 °C for 8-12 h afforded 4a-l in 60%-75% yields. The key intermediates 3 (3 mmol) reacted with isonicotinic acid hydrazide or substituted benzoyl hydrazine (3 mmol) in the presence of catalytic amounts of hydrochloric acid (5 drops) in ethanol (20 mL) to provide target compounds in series 5a-g or 6a-g in 75%-85% yields.22 The solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography with dichloromethane: methanol (50:1). The yield, melting point and spectra data of each compound are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride In ethanol at 50 - 60℃; | General procedure for synthesis of target compounds 4a-l, 5a-g and 6a-g General procedure: A mixture of compound 3 (3 mmol) with aminoguanidine hicarbonate (3 mmol) in refluxing ethanol (20 mL) in the presence of 5 drops of concentrated hydrochloric acid at 50-60 °C for 8-12 h afforded 4a-l in 60%-75% yields. The key intermediates 3 (3 mmol) reacted with isonicotinic acid hydrazide or substituted benzoyl hydrazine (3 mmol) in the presence of catalytic amounts of hydrochloric acid (5 drops) in ethanol (20 mL) to provide target compounds in series 5a-g or 6a-g in 75%-85% yields.22 The solution was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography with dichloromethane: methanol (50:1). The yield, melting point and spectra data of each compound are given below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With hydrogenchloride In ethanol for 2h; Reflux; | General procedure for the synthesis of N-acylhydrazones 3a-s. General procedure: N-acylhydrazones 3a-s were prepared by HCl catalyzed condensation of acid hydrazides 1a-i with the selected aromatic and aliphatic aldehydes 2a-h in ethanol according to the procedure described in the literature.82 The resulting precipitate was isolated by filtration, washed with EtOH and then recrystallized from EtOH to afford the pure N-acylhydrazone 3a-s. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With hydrogenchloride In ethanol for 2h; Reflux; | General procedure for the one-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazoles 4a-s. General procedure: To a stirred solutionof acid hydrazide 1a-i (2.50 mmol) and aldehyde 2a-h (2.50 mmol) in dry toluene (30 mL) were added p-TsOH(0.01 g, 0.05 mmol) and DDQ (0.57 g, 2.50 mmol). The mixture was stirred at reflux until the starting materialwas completely consumed (monitored by TLC, 3 h) and then cooled down to room temperature. Afterfiltration and evaporation of solvent from the filtrate, the resulting residue was purified by silica gel columnchromatography (benzene/EtOAc, 3:1 v/v), affording the pure 1,3,4-oxadiazole derivative 4a-s. |
Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol / 2 h / Reflux 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone / toluene / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With hydrogenchloride In ethanol for 2h; Reflux; | General procedure for the synthesis of N-acylhydrazones 3a-s. General procedure: N-acylhydrazones 3a-s were prepared by HCl catalyzed condensation of acid hydrazides 1a-i with the selected aromatic and aliphatic aldehydes 2a-h in ethanol according to the procedure described in the literature.82 The resulting precipitate was isolated by filtration, washed with EtOH and then recrystallized from EtOH to afford the pure N-acylhydrazone 3a-s. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With hydrogenchloride In ethanol for 2h; Reflux; | General procedure for the one-pot synthesis of 2,5-disubstituted 1,3,4-oxadiazoles 4a-s. General procedure: To a stirred solutionof acid hydrazide 1a-i (2.50 mmol) and aldehyde 2a-h (2.50 mmol) in dry toluene (30 mL) were added p-TsOH(0.01 g, 0.05 mmol) and DDQ (0.57 g, 2.50 mmol). The mixture was stirred at reflux until the starting materialwas completely consumed (monitored by TLC, 3 h) and then cooled down to room temperature. Afterfiltration and evaporation of solvent from the filtrate, the resulting residue was purified by silica gel columnchromatography (benzene/EtOAc, 3:1 v/v), affording the pure 1,3,4-oxadiazole derivative 4a-s. |
Multi-step reaction with 2 steps 1: hydrogenchloride / ethanol / 2 h / Reflux 2: 2,3-dicyano-5,6-dichloro-p-benzoquinone / toluene / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxylic acid; 3-chlorobenzhydrazide With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate In N,N-dimethyl-formamide for 0.333333h; Stage #2: With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 1h; | 4.4.1 General procedure General procedure: 5-(Aroylhydrazinocarbonyl)escitalopram (58-84) were synthesized by the coupling reaction conditions mostly used in peptide synthesis [19]. 5-Carboxyescitalopram (3, 0.001mmol) and benzohydrazide (31, 0.001mmol) were dissolved in DMF (15mL). After five minutes stirring, HBTU (0.0012mmol) was incorporated and stirred for 20min. Then DIEA (0.002mmol) was added and stirred for 1h. Saturated solution of NH4Cl (1×10mL) was added into the reaction mixture and extracted with ethyl acetate (3×10mL). The ethyl acetate layer was washed with solution of NaHCO3 (5%, 2×10mL) followed by brine (1×10mL) and dried over anhydrous MgSO4 overnight. After the removal of ethyl acetate under reduced pressure, the residue was purified using column chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With acetic acid In ethanol for 3h; | 4 5.5 General procedure for preparation of target compounds A, B, and C 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 |
---|---|---|
79% | 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 |
---|---|---|
79% | In methanol at 60℃; for 2h; | 2.1. Synthesis of ligands General procedure: The L1-L5 ligands were prepared using published methods [26]. Briefly, 10 mL of 2-hydroxy-1-naphthaldehyde (1.72 g, 10 mmol) in methanol (MeOH) was added dropwise with stirring to 10 mL of benzoylhydrazine (1.36 g, 10 mmol) or its derivatives in MeOH. The mixture was then refluxed for 2 h at 60 °C, and the ligands were precipitated and filtered to obtain the L1-L5 white-colored ligands. All ligands were characterized by elemental analysis, infrared spectral analysis, and electrospray ionization-mass spectrometry (ESI-MS; Supporting Information, Figs. S1-S10). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 2,2,2-Trifluoroacetophenone; 3-chlorobenzhydrazide With toluene-4-sulfonic acid In 1,4-dioxane Reflux; Stage #2: ethyl 2-bromomethyl-2-propenoate With tin In 1,4-dioxane Reflux; | 5-Trifluoromethyl-5-aryl-3-methylidenepyrrolidin-2-ones (4); General Procedure General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.1% | With acetic acid In ethanol at 20℃; for 2h; | General method of synthesis of N'-(1-(3-methylbut-2-en-1-yl)-2-oxoindolin-3-ylidene) hydrazine derivatives (S1-S20) General procedure: To intermediate B (0.5 mmol, 109.5 mg) in ethanol (5 mL), substituted benzoyl hydrazine or phenylhydrazine (0.5 mmol) was added. Then 200 μL glacial acetic acid was dripped in. After 2 h, the mixture was filtered and dried. The target compounds S1-S20 was then obtained through silica column (PE:EA = 4:1 v/v). In some cases, ultrasonic vibration can contribute to precipitation. No cis-trans isomerism was found during reaction and NMR data indicated all this series were trans configuration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With dipotassium peroxodisulfate; copper(l) iodide at 120℃; | 1 Example 1: Add 0.2 mM 33-chlorobenzohydrazideto 0.05 mmol of cuprous iodide in a 25 mL tube.0.2 mmol of potassium persulfate, and DMF (N,N-dimethylformamide) was added as a solvent.Stir at 120 °C.After the TLC (thin layer chromatography) detection reaction, the reaction solution was cooled to room temperature, and the reaction solution was filtered.Extraction, the filtrate is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography.The target product 2-(3-chlorophenyl)-1,3,4-oxadiazole is obtained.The column chromatography eluate used was a petroleum ether:ethyl acetate mixture of 3:1 by volume.The yield was 74%. |
74% | With dipotassium peroxodisulfate; copper(l) iodide In neat liquid at 120℃; for 1h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With acetic acid In ethanol Reflux; | 5 preparation method of compound 5 is as follows: Weigh the compound of formula a-2 (0.5 mmol, prepared as above),M-chlorobenzoic acid hydrazide(0.5 mmol) was dissolved in a 50 mL flask, and 5 mL of absolute ethanol was added thereto, and glacial acetic acid (1 to 2 drops) was added dropwise thereto, followed by refluxing.After the reaction lasted for several minutes (5-10 min), a large amount of solids began to be produced, and the TLC was traced to the completion of the reaction; the room temperature was allowed to completely crystallize, and the crude product was obtained by vacuum filtration, and the crude product was frozen (-20 ° C). The ethanol was washed several times to obtain a pure product of Compound 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic acid In ethanol Reflux; | 15 preparation method of compound 15 is as follows: Weigh the compound of formula a-4 (0.5 mmol, prepared as above), m-chlorobenzoic acid hydrazide (0.5 mmol) in a 50 mL flask, add 5 mL of absolute ethanol to dissolve it, and add (1 to 2 drops) of glacial acetic acid. After the reflux reaction, the reaction began to produce a large amount of solids after several minutes (5-10 min), and the TLC was traced to the completion of the reaction; the room temperature was allowed to complete crystallization, and the crude product was obtained by vacuum filtration, and the crude product was frozen (-20 ° C). The anhydrous ethanol was washed several times to obtain a pure product of Compound 15. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With acetic acid In ethanol Reflux; | 22 preparation method of compound 22 is as follows: Weigh the compound of formula a-5 (0.5 mmol, prepared as above),m-Chlorobenzoyl hydrazide (0.5 mmol) in a 50 mL flask,And adding 5mL of absolute ethanol to dissolve, adding (1 to 2 drops) of glacial acetic acid, and refluxing the reaction.After the reaction lasted for several minutes (5-10 min), a large amount of solids began to be produced, and the TLC was traced to the completion of the reaction; the room temperature was allowed to completely crystallize, and the crude product was obtained by vacuum filtration, and the crude product was frozen (-20 ° C). The ethanol was washed several times to obtain a pure product of Compound 22. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.35% | Stage #1: N'-(3-carboxylic acid phenyl)uracil-5-sulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Stage #2: 3-chlorobenzhydrazide In N,N-dimethyl-formamide | 19 Preparation of c. N'-phenyl-3-(uracil-5-carboxamido)benzoylhydrazide (A1): General procedure: Add N-(3-formic acid phenyl)uracil-5-sulfonamide to a 100 ml reaction flask at 0 °C(2.50 g, 8.07 mmol) was dissolved in 20 ml of DMF, and HOBT (1.25 g, 9.68 mmol) and EDCI (1.75 g, 9.68 mmol) were added. After reacting for 1 hour, the reaction was continued at room temperature for 2 h, and phenylhydrazine hydrochloride was added. (1.25g, 9.68mmol); after the reaction is completed, the reaction solution is slowly poured into water, a solid is precipitated, and the pH of the solution is adjusted to 2-3 with 10% diluted hydrochloric acid, and the solid is obtained by suction filtration, and washed with a saturated Na2CO3 solution. White solid powder, dried The target compound was 2.55 g, yield: 79.10%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63.35% | Stage #1: N'-(2-carboxylic acid phenyl)uracil-5-sulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Stage #2: 3-chlorobenzhydrazide In N,N-dimethyl-formamide | 24 c.Preparation of N'-phenyl-2-(uracil-5-carboxamido)benzoylhydrazide (A9): General procedure: Add in a 100ml reaction flask at 0 ° CN-(2-formic acid phenyl)uracil-5-sulfonamide(2.50g, 8.07mmol) dissolved in 20ml of DMF, addedHOBT (1.25 g, 9.68 mmol) and EDCI (1.75 g, 9.68 mmol),After reacting for 1 hour, the reaction was continued at room temperature for 2 h, and phenylhydrazine hydrochloride was added.(1.25 g, 9.68 mmol); after the reaction is completed, the reaction solution is slowly poured into water.Precipitate the solid, adjust the pH of the solution to 2-3 with 10% dilute hydrochloric acid, and filter to obtain a solid.Wash with saturated Na2CO3 solution to obtain a light brown solid powder.The target compound was dried to 2.40 g, yield: 74.45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64.18% | Stage #1: N'-(4-carboxylic acid phenyl)uracil-5-sulfonamide With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃; for 3h; Stage #2: 3-chlorobenzhydrazide In N,N-dimethyl-formamide | 29 Preparation of c. N'-phenyl-4-(uracil-5-carboxamido)benzoylhydrazide (A13): General procedure: At 0 ° C, atAdd N-(3-formic acid phenyl)uracil-5-sulfonamide to 100 ml reaction flask(2.50 g, 8.07 mmol) was dissolved in 20 ml of DMF and added to HOBT (1.25 g, 9.68 mmol)And EDCI (1.75g, 9.68mmol), after 1 hour of reaction, continue to react at room temperature2h, phenylhydrazine hydrochloride (1.25g, 9.68mmol) was added;After the reaction is completed, the reaction solution is slowly poured into water to precipitate a solid.Adjust the pH of the solution to 2-3 with 10% dilute hydrochloric acid, and filter to obtain a solid.Washing with a saturated Na2CO3 solution gave a white solid powder. The target compound was dried to 2.45 g, yield: 76.00%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate Reflux; | ||
With sodium hydroxide In acetonitrile at 0℃; for 1h; | 4.1.4. General synthetic procedure for intermediates 5a-e General procedure: To the slurry of benzoylhydrazide (1 equiv) in acetonitrile (20 mL)were added simultaneously choroacetylchloride (1.2 equiv) and 50%sodium hydroxide (1.2 equiv) while maintaining temperature below 0°C. After 1 h, the resulting slurry was filtered and the solid was washedwith water (2×5 mL). The filter cake was dried to provide the intermediates5a-e as white solid. | |
In ethyl acetate Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.5% | With acetic acid In ethanol at 20℃; for 2h; | General method of synthesis of N'-(1-(cyclopropylmethyl)-2-oxoindolin-3-ylidene) hydrazine derivatives (H1-H20, I1-I30) General procedure: To intermediate B (0.5 mmol) in ethanol (5 mL), substituted benzoyl hydrazine (or phenylhydrazine, thiosemicarbazide) (0.5 mmol) was added. Then 200 μL glacial acetic acid was dripped in. After 2 h, the mixture was filtered and dried. The target compounds H1-H20 and I1-I30 were then obtained through silica column (PE:EA = 4:1 v/v). In some cases, ultrasonic vibration could contribute to precipitation. No cis-trans isomerism was found during reaction and NMR data indicated all this series were trans configuration. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.9% | 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 |
---|---|---|
80% | With triethylamine In acetonitrile for 8h; | 4.1.3 General procedure for synthesis of compounds 24a,b General procedure: A mixture of 4-(2-chloroacetamido)benzoyl chloride 19 (2mmol) and proper acid hydrazides 23a,b, namely, 2-chlorobenzohydrazide and 3-chlorobenzohdrazide (2mmol) was allowed to stir in acetonitrile (50mL) in the presence of triethylamine (1mL) for 8h. The reaction mixture was poured onto water and acidified with HCl. The precipitated solids were collected by filtration, dried, and crystallized from ethanol to give the diamide products, 24a,b, respectively. |
80% | With triethylamine In acetonitrile at 20℃; for 8h; | |
With triethylamine In acetonitrile at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In N,N-dimethyl-formamide at 120℃; for 72h; | 2-(3-chlorophenyl)[1 ,2,4]triazolo[1 ,5-c]quinazolin-5(6H)-one Methyl (2-cyanophenyl)carbamate (1.60 g, 9.08 mmol) and 3-chlorobenzohydrazide (CAS 1673- 47-8, 1.55 g, 9.08 mmol) were stirred in N,N-dimethylformamide (30 mL) at 120 °C for 72 hours. Water was added to the mixture, precipitated product was filtered off, washed with water and dried under reduced pressure at 50 °C to give 2.38 g (88 % yield, 96 % purity) of the title compound.UPLC2-MS (short basic, 2-98%): Rt = 0.74 min., MS (ESIpos): m/z = 297 (M+H)+1H-NMR (400 MHz, DMSO-d6): d [ppm] = 7.39 (t, 1H), 7.43 (d, 1 H), 7.56-7.62 (m, 2H), 7.67- 7.72 (m, 1H), 8.13-8.18 (m, 2H), 8.21 (d, 1 H), 12.34 (br s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With acetic acid In ethanol Reflux; | 4.3. General procedures for the synthesis of coumarin-isatin hybrids (Spf-1 - Spf-10) General procedure: 1-(2-hydroxy-3-((2-oxo-2H-chromen-4-yl)oxy)propyl)indoline-2,3-dione (1.0 mmol; 0.365 g) was added into dry ethanol (25 mL) and kepton stirring at reflux until a clear solution was formed. Acid hydrazide(1.2 mmol) was added to this clear solution and the mixture was stirred for 15 min. Glacial acetic acid (2-3 drops) was added into the mixtureand it was refluxed for 5-7 h. Yellow-colored precipitates were formed,the reaction mixture was cooled, filtered and the product was washedwith dry and cold ethanol. (Scheme 1) The formation of the pure compoundwas confirmed by TLC, FTIR, NMR spectroscopy, and HRMS analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With acetic acid In methanol at 70℃; for 48h; | 1 Preparation of compound II-9 Using the compound limonin as the starting material,Add to 50ml eggplant-shaped bottle one by oneLimonin, 0.4011g,20ml methanol,0.200ml of glacial acetic acid,3-chlorobenzoyl hydrazide0.2147g, stirred at 70°C for 48h.TLC detects that the reaction is complete,After cooling, the solvent was evaporated under reduced pressure.Dichloromethane for crude product: methanol (100:1)Column chromatography,A white solid of II-9 is obtained,0.2853g, yield 54%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.63% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2h; | 4.2 Step 2: N-(3-chlorobenzoyl)-6-oxo-1H-pyridazine-3-carbohydrazide [0276] To a stirred solution of 3-chlorobenzohydrazide (500.00 mg, 2.93 mmol) in DMF(5.00 mL) were added 6-oxo-1H-pyridazine-3-carboxylic acid (451.66 mg, 3.22 mmol), HATU(1.33 g, 3.52 mmol) and DIEA (1.14 g, 8.79 mmol). The reaction mixture was stirred for 2 h at room temperature. The resulting mixture was diluted with water (10 mL). The precipitated solids were collected by filtration and washed with ACN (3x3 mL) to give the title compound as a white solid (400 mg, 46.63%) MS m/z: 293 [M+H]+. |
Tags: 1673-47-8 synthesis path| 1673-47-8 SDS| 1673-47-8 COA| 1673-47-8 purity| 1673-47-8 application| 1673-47-8 NMR| 1673-47-8 COA| 1673-47-8 structure
[ 14062-80-7 ]
4-Chloro-N,N-dimethylbenzamide
Similarity: 0.77
[ 1016768-00-5 ]
4-Chloro-2-fluorobenzohydrazide
Similarity: 0.75
[ 1185303-65-4 ]
(4-Chlorobenzyl)hydrazine dihydrochloride
Similarity: 0.76
[ 1016768-00-5 ]
4-Chloro-2-fluorobenzohydrazide
Similarity: 0.75
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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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