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CAS No. : | 98-71-5 | MDL No. : | MFCD00025097 |
Formula : | C6H8N2O3S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IOMZCWUHFGMSEJ-UHFFFAOYSA-N |
M.W : | 188.20 | Pubchem ID : | 66825 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 43.51 |
TPSA : | 100.8 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -10.66 cm/s |
Log Po/w (iLOGP) : | -0.19 |
Log Po/w (XLOGP3) : | -4.52 |
Log Po/w (WLOGP) : | 1.11 |
Log Po/w (MLOGP) : | 0.49 |
Log Po/w (SILICOS-IT) : | -1.24 |
Consensus Log Po/w : | -0.87 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | 1.6 |
Solubility : | 7540.0 mg/ml ; 40.1 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 3.02 |
Solubility : | 198000.0 mg/ml ; 1050.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -1.44 |
Solubility : | 6.8 mg/ml ; 0.0361 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.05 |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P280-P305+P351+P338-P304+P340-P405-P501 | UN#: | |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | |
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 |
---|---|---|
85% | Stage #1: 4-aminobenzene sulfonic acid With sulfuric acid; sodium carbonate; sodium nitrite In water at 5℃; Stage #2: With hydrogenchloride; sodium sulfite In water at 5℃; Reflux; | 1 Synthesis of p-Hydrazinobenzenesulfonic Acid 33 g of sodium carbonate was added to a suspension of 104 g (0.6 mol) of p-aminobenzenesulfonic acid in 400 mL of hot water. The solution was cooled to 5° C. in an ice-bath, and 70 g of concentrated sulfuric acid were added slowly under rapid stirring. A solution of 42 g of sodium nitrite in 100 mL of water was then added under cooling. A light yellow diazo-compound precipitate formed, which was filtered and washed with water, but not dried. (0113) The wet diazo-compound was added under stirring and cooling (5° C.) to a solution of 170 g of sodium sulfite in 500 mL of water. The solution, which turned orange, was stirred under cooling for 1 h, and then heated to reflux. Finally, 400 mL of concentrated hydrochloric acid were added. The solution turned yellow, and the product precipitated as a white solid. For complete decoloration, 1-2 g of powdered zinc were added. The reaction mixture was cooled overnight, and the precipitate was filtered, washed with water, and dried in an oven at 100° C. (0114) Yield: 96 g (85%), white powder; M.P.=286° C. (Lit.=285° C.); Rf: 0.95 (RP-18, water:MeOH 2:1). |
74% | Stage #1: 4-aminobenzene sulfonic acid With sulfuric acid; sodium carbonate; sodium nitrite In water at 12℃; Cooling with ice; Stage #2: With sodium sulfite In water at 5℃; Heating; Stage #3: With hydrogenchloride; zinc In water at 20℃; for 12h; | 7 Example 7. Preparation of phenylhydrazine-p-sulfuric acid (compound 7) Sulfanilic acid (52.0 g; 0.3 mole) and sodium carbonate (16.5 g; 0.06 mole) were dissolved in water (200 mL) on heating. The solution obtained was filtered off and concentrated sulphuric acid (35.0 g; 19.1 mL; 0.36 mole) was added thereto, with white precipitate being formed. To this slurry, on cooling with ice and stirring, the solution of sodium nitrite (21.0 g; 0.3 mole) in water (50 mL) was added dropwise at such a rate to maintain reaction temperature not higher than 12°C. The additional stirring was continued for 15 min. The obtained precipitate of diazo compound was collected by filtration and washed with small amount of ice water. To solution of sodium sulphite (84.8 g; 0.67 mole) in water (250 mL), under stirring and cooling with ice and salt, the crude diazo compound was added with portions at such a rate to maintain reaction temperature lower than 5°C. The mixture was additionally stirred for 1 h, then, heated to boiling and added dropwise the concentrated hydrochloric acid (200 mL), with precipitate being formed. |
Diazotization.Behandeln mit Na2SO3 und Spalten mit Salzsaeure; |
9 g | Stage #1: 4-aminobenzene sulfonic acid With sodium nitrite In sodium hydroxide Stage #2: With sulfuric acid at -5℃; for 0.333333h; | |
With hydrogenchloride; sulfuric acid; sodium carbonate; sodium sulfite; sodium nitrite In water | 1 p-Hydrazinobenzenesulfonic acid p-Hydrazinobenzenesulfonic acid 33 g of sodium carbonate was added to a suspension of 104 g (0.6 mol) of p-aminobenzenesulfonic acid in 400 mL of hot water. The solution was cooled to 5° C. in an ice-bath, and 70 g of concentrated sulfuric acid were added slowly under rapid stirring. A solution of 42 g of sodium nitrite in 100 mL of water was then added under cooling. A light yellow diazo-compound precipitate formed, which was filtered and ashed with water, but not dried. The wet diazo-compound was added under stirring and cooling (5° C.) to a solution of 170 g of sodium sulfite in 500 mL of water. The solution, which turned orange, was stirred under cooling for 1 h, and then heated to reflux. Finally, 400 mL of concentrated hydrochloric acid were added. The solution turned yellow, and the product precipitated as a white solid. | |
With hydrogenchloride; sulfuric acid; sodium carbonate; sodium sulfite; sodium nitrite In water | 1 p-Hydrazinobenzenesulfonic acid p-Hydrazinobenzenesulfonic acid 33 g of sodium carbonate was added to a suspension of 104 g (0.6 mol) of p-aminobenzenesulfonic acid in 400 mL of hot water. The solution was cooled to 5° C. in an ice-bath, and 70 g of concentrated sulfuric acid were added slowly under rapid stirring. A solution of 42 g of sodium nitrite in 100 mL of water was then added under cooling. A light yellow diazo-compound precipitate formed, which was filtered and washed with water, but not dried. The wet diazo-compound was added under stirring and cooling (5° C.) to a solution of 170 g of sodium sulfite in 500 mL of water. The solution, which turned orange, was stirred under cooling for 1 h, and then heated to reflux. Finally, 400 mL of concentrated hydrochloric acid were added. The solution turned yellow, and the product precipitated as a white solid. | |
With hydrogenchloride; sulfuric acid; sodium carbonate; sodium sulfite; sodium nitrite In water | 1 Synthesis of p-Hydrazinobenzenesulfonic acid Synthesis of p-Hydrazinobenzenesulfonic acid 33 g of sodium carbonate was added to a suspension of 104 g (0.6 mol) of p-aminobenzenesulfonic acid in 400 mL of hot water. The solution was cooled to 5° C. in an ice-bath, and 70 g of concentrated sulfuric acid were added slowly under rapid stirring. A solution of 42 g of sodium nitrite in 100 mL of water was then added under cooling. A light yellow diazo-compound precipitate formed, which was filtered and washed with water, but not dried. The wet diazo-compound was added under stirring and cooling (5° C.) to a solution of 170 g of sodium sulfite in 500 mL of water. The solution, which turned orange, was stirred under cooling for 1 h, and then heated to reflux. Finally, 400 mL of concentrated hydrochloric acid were added. The solution turned yellow, and the product precipitated as a white solid. | |
Stage #1: 4-aminobenzene sulfonic acid With hydrogenchloride; sodium nitrite at -10 - -5℃; Stage #2: With hydrogenchloride; tin(II) chloride hydrate at -10 - -5℃; | ||
With hydrogenchloride; sulfuric acid; sodium carbonate; sodium sulfite; sodium nitrite In water | 1 Synthesis of p-Hydrazinobenzenesulfonic Acid Synthesis of p-Hydrazinobenzenesulfonic Acid 33g of sodium carbonate was added to a suspension of 104g (0.6 mol) of p-aminobenzenesulfonic acid in 400 mL of hot water. The solution was cooled to 5° C. in an ice-bath, and 70g of concentrated sulfuric acid were added slowly under rapid stirring. A solution of 42g of sodium nitrite in 100 mL of water was then added under cooling. A light yellow diazo-compound precipitate formed, which was filtered and washed with water, but not dried. The wet diazo-compound was added under stirring and cooling (5° C.) to a solution of 170g of sodium sulfite in 500 mL of water. The solution, which turned orange, was stirred under cooling for 1 h, and then heated to reflux. Finally, 400 mL of concentrated hydrochloric acid were added. The solution turned yellow, and the product precipitated as a white solid. | |
Stage #1: 4-aminobenzene sulfonic acid With sodium nitrite In water at 0 - 5℃; Stage #2: With sodium sulphite-heptahydrate In water at 0 - 5℃; for 1h; | Technical grade 4-aminobenzenesulphonic acid (1) corresponding to 173g (1mol) of 100% purity added in 1500ml water in 3L beaker and also added 65g of Na2CO3 then given a mixing for complete dissolution. Then the solution is filtered off to remove undissolved particles and impurities. Then the made ice jacketed around the beaker to attain temperature 0-5°C. Then during continuous agitation, the addition of 400ml of HCl was made gradually. Then the ice flakes about 100g added to the solution to maintain temperature 0-5°C, and the addition of Sodium nitrite solution i.e. 73 g of NaNO2 in 150ml water was done dropwise in 15min at temperature 0-5°C. Then the congo-iodo paper was checked which was positive by giving blue coloration. Then the reaction mixture allowed for 1:30h for reaction completion. Afterwards, diazonium salt filtered off with filtration unit associated with vacuum pump [20]. Scheme 1 showed the synthesis of diazonium salt (2) of 4-aminobenzenesulphonic acid (1). 2.2.2 Reduction of diazonium salt (2) of 4-aminobenzenesulphonic acid (1) (0006) To a beaker of 3L, 565g of crystalline Na2SO3·7H2O had been added in 830ml water and made a clear solution of it. Solution of Sodium sulfite cooled in an ice bath to attain 0-5°C temperature. At that temperature moist paste of diazonium salt (2) added in one hour. Then the orange coloration appears in solution without turbidity. Then the stirring made continuously for 1h. Afterwards, the reaction solution was heated to boil-age with continuous stirring and 664 concentrated HCl was added in half an hour. The solution color lightens and finally very light yellow color appeared at the end of reaction. Reaction mixture cooled down over a period of overnight. Precipitate formation takes place and these are filtered off with sanction unit, washing of precipitates was done with cold water. Precipitates of 4-hydrazinylbenzenesulfonic acid (3) dried in an electric oven at 100°C. Purification was done by employing the method as described by Ref.[19]. % age yield=96% of the theoretical amount. Scheme 1 was represented the synthesis of 4-hydrazinylbenzenesulfonic acid (3). | |
Multi-step reaction with 2 steps 1.1: sodium carbonate; hydrogenchloride; sodium nitrite / water / 1.45 h / 0 - 5 °C 2.1: sodium sulphite-heptahydrate / water / 2 h / 0 - 5 °C 2.2: 0.5 h | ||
Multi-step reaction with 2 steps 1: sodium nitrite; sulfuric acid / water / 0 - 5 °C 2: sulfuric acid; sodium sulfite / 0 - 5 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: pyridine-2-carbonyl chloride With pyridine at 80℃; Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 2-furancarbonyl chloride With pyridine at 80℃; Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.5% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃; Stage #3: Tetrahydrothiopyran-4-one With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: 1-Methyl-4-piperidone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.6% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃; Stage #3: 1-Methyl-4-piperidone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: pyridine-2-carbonyl chloride With pyridine at 80℃; Stage #3: cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 2-furancarbonyl chloride With pyridine at 80℃; Stage #3: cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 2-furancarbonyl chloride With pyridine at 80℃; Stage #3: 5-ketohexanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 2-furancarbonyl chloride With pyridine at 80℃; Stage #3: 2-Pentanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 2-furancarbonyl chloride With pyridine at 80℃; Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 2-furancarbonyl chloride With pyridine at 80℃; Stage #3: 4-Phenyl-2-butanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 2-Thiophenecarbonyl chloride With pyridine at 80℃; Stage #3: cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.8% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃; Stage #3: cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-(dimethylamino)benzoyl chloride With pyridine at 80℃; Stage #3: cyclohexanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: 2-Pentanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: cycloactanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: 4-Phenyl-2-butanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-chloro-benzoyl chloride With pyridine at 80℃; Stage #3: 4-(4-hydroxyphenyl)-2-oxobutane With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃; Stage #3: 6-oxoheptanoic acid With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃; Stage #3: 4-Phenyl-2-butanone With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5% | Stage #1: 4-hydrazino-benzenesulfonic acid With polystyrene aldehyde resin; triethylamine In 1,2-dichloro-ethane at 45℃; Stage #2: 4-biphenyl-carboxylic acid chloride With pyridine at 80℃; Stage #3: 4-(4-hydroxyphenyl)-2-oxobutane With trifluoroacetic acid In 1,2-dichloro-ethane at 70℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With acetic acid for 3h; Reflux; | 1 [0123] In the above reaction, to a flask equipped with magnetic stirrer and reflux condenser were added acetic acid (5 mL), 3-methyl-2-butanone (1.67 mL), and p- hydrazinobenzenesulfonic acid (1 g), and the mixture heated to reflux for three hours, and then cooled until a pink solid precipitated as product. Compound 15 (1.24 g), was obtained as wine-colored crystals in a yield of 97%. 1H NMR (500MHz, DMSO): δ 7.78 (1H, s), 7.64 (d, 1H), 7.48 (d, 1H), 2.5 (s, 3H), 1.37 (s, 6H). |
94% | With acetic acid for 14h; Reflux; | 2,3,3-Trimethylindolenine-5-sulfonic acid 2,3,3-Trimethylindolenine-5-sulfonic acid14-Hydrazinobenzenesulfonic acid (4.0 g, 20 mmol) and 3-methyl-2-butanone (1.8 g, 20mmol) were dissolved in acetic acid (15 mL). The solution was refluxed for 14 h, andthen allowed to stand to room temperature. A solidified product was obtained by addingethyl acetate and collected by filtration. The solid was washed with diethyl ether anddried under reduced pressure. (4.8 g, yield 94%). 1H NMR (270 MHz, DMSO): δ 7.77(d, 1H), 7.64 (dd, 1H), 7.45 (d, 1H), 2.40 (s, 3H), 1.33 (s, 6H). |
94% | With acetic acid at 120℃; | 8 2,3,3-Trimethyl-3H-indole-5-sulfonic acid 3 2,3,3-Trimethyl-3H-indole-5-sulfonic acid 3 The compound 3 (Scheme 2) was synthesized by conventional Fisher indole synthesis (IIIy and Funderburk 1968; Mujumdar, Ernst et al. 1993). Briefly, to a reacti-vial equipped with stir bar, acetic acid (3 mL), 3-methyl-2-butanone 2 (1.68 mL, 0.016 mol), and p-hydrazinobenzenesulfonic acid 1 (1 g, 0.0053 mol) were added. The mixture was heated to reflux and the reaction was monitored by TLC. Rf=0.67 (Silica, DCM-MeOH 3:1) The mixture was cooled to room temperature and then ether was added slowly until a pink solid separated. The precipitate collected by filtration and washed with ether (1.19 g, yield 94%). 1H NMR (400 MHz, MeOD) δ=7.79 (d, 1H, J=2.0 Hz, aromatic 4-H), 7.15 (dd, 1H, J=8.0 Hz, 2.0 Hz, aromatic 6-H), 7.41 (d, 1H, J=8.0 Hz, aromatic 7-H), 1.31 (s, 6H, C(CH3)2). Singlet for 2-methyl did not appear in MeOD. |
93.4% | With acetic acid for 3h; Heating; | |
91% | With sodium acetate; acetic acid at 130℃; Inert atmosphere; Schlenk technique; | |
90% | In acetic acid for 14h; Reflux; | |
89% | With acetic acid for 4h; Reflux; | 1.1 p-hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq, Aldrich) and 3-methyl-2-butanone (17.18 mL, 160 mmol, 3.02 eq, TCI) were added to acetic acid (30 mL), and the resulting mixture was heated under reflux for 4 hours. The reaction mixture was allowed to cool to ambient temperature and the resulting solid particles were filtered. The filtrate was washed with ethyl acetate two or three times and dried under reduced pressure (11.34 g, 89%). Rf=0.68 (RP-C18, acetonitrile/water 1:4 v/v). |
89% | With acetic acid for 4h; Reflux; | 1.1 17.18 mL (160 mmol, 3.02 eq) of p-hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq) and 3-methyl-2-butanone Acetic acid (30 mL), and the mixture was heated and refluxed for 4 hours. The mixture was cooled to room temperature, and the resulting solid particles were filtered. After washing with ethyl acetate two or three times, it was dried under reduced pressure. (11.34 g, 89%). |
89% | With acetic acid for 4h; Reflux; | 1.1 P-hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq, Aldrich) and 3-methyl-2-butanone (17.18 mL, 160 mmol, 3.02 eq, TCI) was added to 30 mL of acetic acid and the mixture was heated and refluxed for 4 hours. The mixture was cooled to room temperature, and the resulting solid particles were filtered. Washed with ethyl acetate two or three times, and then dried under reduced pressure. (11.34 g, 89%). |
89% | With acetic acid for 4h; Reflux; | 1.1 p-hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq, Aldrich) and 3-methyl-2-butanone (17.18 mL, 160 mmol, 3.02 eq, TCI) was added to 30 mL of acetic acid, and the mixture was heated to reflux for 4 hours. The mixture was cooled to room temperature, and the resulting solid particles were filtered. After washing with ethyl acetate two or three times, it was dried under reduced pressure. (11.34 g, 89%). |
89% | With acetic acid for 4h; Reflux; | 1.1 (1) Synthesis of Compound 4-1 p-hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq, Aldrich) and 3-methyl-2-butanone (17.18 mL, 160 mmol, 3.02 eq, TCI) was added to 30 mL of acetic acid, and the mixture was reacted by heating under reflux for 4 hours. The mixture was cooled to room temperature, and the resulting solid particles were filtered. After washing with ethyl acetate two or three times, it was dried under reduced pressure. (11.34 g, 89%). |
89% | With acetic acid for 4h; Reflux; | 1.1 1. Synthesis of Compound 1-1 Hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq, Aldrich) and 3-methyl-2-butanone (17.18 mL, 160 mmol, 3.02 eq, TCI) was added to 30 mL of acetic acid, and the mixture was reacted by heating under reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and the resulting solid particles were filtered. The residue was washed with ethyl acetate two or three times, and dried under reduced pressure to obtain 11.34 g (89%) of a solid substance. |
86% | With acetic acid at 120℃; for 3h; | 4.1; 12.1 Example 4. Synthesis of the compounds (32) and (42) of the present invention; [Show Image] (1) Synthesis of the indolenine compound (30); [Show Image] [Show Image] [Synthesis of the compound (27)]; As starting raw materials, 4-hydrazinobenzenesulfonic acid 0.5hydrate [compound(26)] (50.0 g, 0.253 mol), and 3-methyl-2-butanone (65.5 g, 0.759 mol) were used, which were subjected to stirring in acetic acid (200 mL) at 120°C for 3 hours. After completion of the reaction, the solvent was cooled, and was subjected to washing twice by the addition of diethyl ether (300 mL) to give the compound (27) (52.0 g, yield; 86%). Property data: Mass (nega=238); Example 12. Synthesis of the compound (43) of the present invention; [Show Image] (1) Synthesis of indolenine compound (30); [Show Image] [Show Image] [Synthesis of the compound (27)]; As starting raw materials, 4-hydrazinobenzene sulfonic acid 0.5hydrate (26) (50.0 g, 0.253mol) and 3-methyl-2-butanone (65.5 g, 0.759 mol) were used, which were subjected to stirring in acetic acid (200 mL) at 120°C for 3 hours. After completion of the reaction, the solvent was cooled, to be subjected to washing twice by the addition of diethyl ether (300 mL) to give the compound (27) (52.0 g, yield; 86%). Property data: Mass (nega=238) |
85% | With acetic acid for 14h; Reflux; | 2 2.2 Synthesis of 2,5-bis[2,3,3-trimethyl-3H-indole-5-sulfonic acid]-croconaine The synthetic route of 2,5-bis[2,3,3-trimethyl-3H-indole-5-sulfonic acid]-croconaine (TISC) was shown in Scheme 1. 4-Hydrazinobenzenesulfonic acid (2g, 10.627mmol) and 3-methyl-2-butanone (0.915g, 10.627mmol) were dissolved in acetic acid (30mL). The solution was refluxed for 14h, then allowed to cool to room temperature, and the precipitate was collected by filtration. The solid was washed with diethyl ether and was dried under reduced pressure to afford compound 1 as a pink solid [19] (2.16g, yield 85%). 1H NMR (300MHz, DMSO-d6): δ 7.64(d, 1H, J=1.5Hz), 7.56 (dd, 1H, J=7.9, 1.6Hz), 7.36 (d, 1H, J=8.0Hz), 2.23 (s, 3H), 1.25 (s, 6H). MS (ESI): m/z=240.00 [M+H]+, calcd m/z=239.06 for C11H13NO3S. |
83% | With sodium acetate In acetic acid at 110℃; Inert atmosphere; Sealed tube; | |
79% | With acetic acid for 4h; Reflux; | |
78% | With acetic acid at 120℃; for 4h; | |
75% | With acetic acid for 3h; Heating / reflux; | 1.1 1.1 Synthesis of 5-sulfo-2, 3, 3-trimethylindolenine (I) Conventional Fisher Indole synthesis was used as follows. In a 2-L three necked flask equipped with mechanical stirrer and reflux condenser was added acetic acid (300 mL), 3-methyl-2-butanone (168 mL, 1.59 mol) and p-hydrazinobenzenesulfonic acid (100 g, 0.53 mol). The mixture was heated to reflux for three hours and then cooled for several hours when pink solid separated. (93 g, 75%, mp. 290-95 °C). 1H NMR (D2O), δ, 1.4 (s, 6H C-(CH3)2); 6.5 (d, 1H, J = 7 Hz, 7-H); 7. 1 (dd, 1H, J = 7.0, 1.2 Hz, 6-H); 7.13 (s, 1H, 4-H). Singlet for 2-methyl is not seen in D2O, but it appears when nmr is recorded in DMSO d6. |
75% | In acetonitrile for 7h; Reflux; | The intermediate was synthesized following the report by Park et al. [29]. 5-Sulfo-2,3,3-trimethyl-3H-indole was synthesized by the reaction of 4-Hydrazino-benzenesulfonic acid hemihydrate 4 g (21.3 mmol) with 5 mL of 3-methyl-2-butanone in 20 mL acetonitrile under reflux for 7 h. Reaction monitoring was done by TLC and upon completion of reaction, solvent was evaporated and the crude was purified by column chromatography to give the product in 75 % yield. 2.5 g (10.4 mmol) of this compound was dissolved in 15 ml of acetonitrile and 2 equivalents of 1-Iodoethane (4 ml, 20.8 mmol) was added. The mixture was then refluxed for 12 h while monitoring the reaction progress by TLC. The solvent was evaporated under vacuum and ample diethyl ether was added for precipitation, which was filtered to get the titled compound as pinkish solid in 68 % yield (2.8 g). |
71.3% | In acetic acid at 0℃; for 15h; Reflux; | 11 A mixture of phenylhydrazine-p-sulphonic acid (compound 7) (11.3 g; 0.06 mole), 3-methyl-2-butanone (6.2 g; 7.72 mL; 0.072 mole), and glacial acetic acid (34 mL) was refluxed for 3 h, then, allowed to hold for 12 h at 0°C. The precipitate formed was collected by filtration, washed with acetone, and dried in a vacuum desiccator over P2O5. 5-Sulfo-2,3,3-trimethylindolenyne was obtained with yield 5.1 g (71.3%). 1H- NMR (D2O), δ (ppm): 1.28 (6H, s, C(CH3)2); 7.47-7.79 (3H, m, ArH) |
With acetic acid | ||
In acetic acid at 20℃; for 5h; Heating / reflux; | Preparation of 2,3,3-trimethylindole-5-sulfonic acid, potassium salt (1b) Preparation of 2,3,3-trimethylindole-5-sulfonic acid, potassium salt (1b) 18.2 g (0.12 mol) of p-hydrazinobenzenesulfonic acid and 14.8 g (0.17 mol) of isopropylmethylketone were stirred in 100 ML of glacial acetic acid at room temperature for 1 h.The mixture was then refluxed for 4 h.The mixture was cooled to room temperature, and the resulting pink solid precipitate was filtered and washed with ether. | |
64.5 g (87.5%) | With acetic acid In methanol | 7 Synthesis of an Activated Ester of Cy5 EXAMPLE 7 Synthesis of an Activated Ester of Cy5 To a 500 ml round bottomed flask equipped with a stir bar and reflux condenser was added AcOH (150 ml), p-hydrazinobenzenesulfonic acid (50.0 g, 0.255 mol), and 3-methyl-2-butanone (84 ml, 0.785 mmol). The flask was then heated in an oil bath at 115° C. to reflux for 3 h until all the starting material consumed (monitored by TLC, 1:1 MeOH:CH2 Cl2). The oil bath was removed and the flask was cooled to room temperature. The pink solid was collected via filtration with the acid of EtOAc. The solid was then dissolved in MeOH (800 ml) and air dried. Further drying in an oven at 40° C. under high vacuum overnight provided 64.5 g (87.5%) of the desired product, 2,3,3-trimethylindoleninium-5-sulfonate, potassium salt. TLC: Rf =0.875 (1:1 CH2 Cl2:MeOH). |
With potassium hydroxide In methanol; acetic acid; isopropyl alcohol | 3 3.1 5-Sulphonato-2,3,3-trimethylindolenine 3.1 5-Sulphonato-2,3,3-trimethylindolenine To a stirred solution of 4-hydrazinobenzene sulphonic acid (68 g, 361 mmol) in acetic acid (205 ml) at ambient temperature was added 3-methyl-2-butanone (88.44 g, 1027 mmol). The reaction was heated under reflux. After 3 hours the solution was cooled and the resulting pink precipitate was filtered, washed with acetic acid (50 ml) and dried. The product was redissolved in methanol (800 ml) and a solution of potassium hydroxide (20.4 g, 364 mmol) in isopropanol (200 ml) was added. The yellow solid obtained was filtered and dried (48 g, 56%); m/z (FAB+): 240. | |
With potassium hydroxide; acetic acid In methanol; dichloromethane; isopropyl alcohol | 1 Preparation of 2,3,3-Trimethylindoleninium-5-sulfonate, Potassium Salt (9) Example 1 Preparation of 2,3,3-Trimethylindoleninium-5-sulfonate, Potassium Salt (9) Referring now to Scheme 2, a 500-mL round bottomed flask was equipped with a stir bar, reflux condenser, acetic acid (150 mL), p-hydrazinobenzenesulfonic acid (8, 50.0 g, 0.266 mol), and 3-methyl-2-butanone (84 mL, 0.785 mmol). The flask was then heated in an oil bath at 115° C. to reflux for 3 hours until all the starting material was consumed (determined by monitoring using TLC, 1:1 MeOH:CH2Cl2). The reaction flask was then cooled to room temperature. A pink solid was collected via filtration with the aid of ethylacetate. The pink solid was then dissolved in MeOH (800 mL) and passed through a pad of filter paper to remove some solid impurities. Potassium hydroxide (15 g) in isopropylalcohol (200 mL) was then added to the filtrate and the solution was stirred. A yellow solid precipitated which was collected, washed with methanol (2*50 mL), followed by washing with diethyl ether (2*50 mL), and then air dried. The yellow solid was further dried in an oven at 40° C. under high vacuum overnight, which provided 64.5 g (87.5%) of compound 9. TLC:Rf=0.875 (1:1 CH2Cl2:MeOH). | |
With acetic acid for 3h; Heating / reflux; | 3.1 3.1 5-Sulphonato-2,3,3-trimethylindolenine To a stirred solution of 4-hydrazinobenzene sulphonic acid (68 g, 361 mmol) in acetic acid (205 ml) at ambient temperature was added 3-methyl-2-butanone (88.44 g, 1027 mmol). The reaction was heated under reflux. After 3 hours the solution was cooled and the resulting pink precipitate was filtered, washed with acetic acid (50 ml) and dried. The product was redissolved in methanol (800 ml) and a solution of potassium hydroxide (20.4 g, 364 mmol) in isopropanol (200 ml) was added. The yellow solid obtained was filtered and dried (48 g, 56%); m/z (FAB+): 240. | |
With acetic acid for 3h; Heating / reflux; | 1.a EXAMPLE 1; Preparation of Cy3 Labeling Reagent; (a) Preparation of Compound I (2,3,3- Trimethylindolinium 5-Sulfone) P-Hydrazinobenzenesulfonic acid (250 g) was mixed with glacial acetic acid (750 ml) and 3-methyl-2- butanone (420 ml) and heated at reflux for 3 hr. The solution was poured into a 2 L beaker and allowed to cool overnight. The resultant suspension was filtered, washed with acetic acid and lyophylized to remove residual acetic acid. The resultant solid was dissolved in methanol (1.5 L) and a saturated solution of potassium hydroxide in 2-propanol (900 ml) was slowly added. The color of the solution turned progressively lighter as the potassium salt of 2,3,3-trimethylindolinium 5-sulfone precipitated. The precipitate was filtered by suction, washed with 2-propanol and lyophilized to dryness to give 238 g of Compound I. [0285] (b) Preparation of Compound II (1-Ethyl-2,3,3-Trimethylindolenineninium 5-Sulfone) [0286] A portion (78 g) of Compound I synthesized in step (a) was suspended in 1,2-dichlorobenzene (700 ml). Ethyl iodide (250 ml) was added and the mixture was heated at 90-100 C. for 12 hr while stirring. The mixture was poured into 3 L of a 1:1 mixture of ethylacetate/ether and stirred for 2 hours. The resulting precipitate was filtered, washed with a 1:1 mixture of ethylacetate/ether and air-dried to give 68 g of product, Compound II. [0287] (c) Preparation of Compound III (6-Bromohexanoyl Allyl Amide) [0288] 6-Bromohexanoic acid (20g) and N-hydroxysuccinimide (15 g) were dissolved in 200 ml of anhydrous dimethylformamide (DMF). Dicyclohexylcarbiimide (22 g) in anhydrous DMF (50 ml) was added and the mixture was left at room temperature overnight. The precipitated urea was removed by filtration and the DMF solution containing the product, N-hydroxysuccinimide-6-bromohexanoate, was cooled to -10 to -20° C. An equimolar amount of allylamine in H2O (11 ml) was first brought to pH 8-9 with glacial acetic acid and then added slowly with stirring to the active ester. Solid sodium bicarbonate (10 g) was added slowly to avoid excessive foaming and the mixture was left without covering until the temperature was raised to -10° C. in two hr. The mixture was poured into H2O (1 L) and the product was extracted twice with chloroform (300 ml). The extracts were washed once with 1 N HCl in H2O, once with 5% NaHCO3 (300 ml) and three times with 10% NaCl in water. The chloroform phase was dried by addition of solid MgSO4 and leaving it overnight under stirring. The chloroform was removed by evaporation under vacuum leaving a liquid that was used without any further purification for the next step. [0289] (d) Preparation of Compound IV (Addition of Linker Arm to Compound III) [0290] Compound I (11 g) from step (a) and Compound III (15 g) from step (c) were dissolved together in 1,2-dichlorobenzene (100 ml) and heated at 110° C. for 12 hours while stirring under argon. The mixture was slowly poured into ethylacetate a 1:1 mixture of ethylacetate/ether (700 ml) and after 30 minutes the solid precipitate was filtered, washed with a 1:1 mixture of ethylacetate/ether, air-dried and set aside. A glassy solid that was formed at the bottom of the flask was crushed in a mortar, triturated with a 1:1 mixture of ethylacetate/ether, filtered, washed with 2-propanol, dried in vacuum and combined with the precipitate from above to give Compound IV which was used without any further purification. [0291] (e) Synthesis of Cy3 Labeling Reagent (Compound V) [0292] A portion of Compound II (12 g) from step (b) and N,N'-diphenylformamidine (10 g) in acetic acid (60 ml) were heated at 100-110° C. for 90 min with stirring. During the reaction the absorption at 286 nm and 415 nm was measured. The ratio of 415/286 increased during the first 60 minutes then remained constant at 2.2 for the next 20 minutes. After 90 minutes, the hot mixture was poured slowly into 700 ml of a 1:1 mixture of ethylacetate/ether. The resultant solid precipitate was collected with a pressure filter funnel, washed with 1:1 mixture of ethylacetate/ether and dried by passing argon through the cake. The precipitate was collected from the pressure filter funnel and slowly added to a mixture of 6.5 g of Compound IV from step (d), 50 ml of pyridine and 50 ml of acetic anhydride. The progress of the reaction was monitored by the decrease of absorbance at 385 nm and an increase in absorbance at 550 nm. The reaction was carried out overnight under stirring at room temperature. The absorbance at 550 nm increased with time followed by a drop in absorbance as the product precipitated out of solution. At the end of the reaction, the brown precipitate was collected and put aside. The liquid portion was treated by the addition of a seven-fold volume of ethylacetate. The precipitate that formed was collected and combined with the first precipitate. Since pyridine would interfere with a later palladium catalyzed step, any remaining pyridine was removed by dissolving the combined precipitate in 100 ml of 0.5M Triethylammonium carbonate, pH 8.0 (TEAC). The TEAC was then removed by evaporation under vacuum leaving a solid pellet. This product (Compound V) was then dissolved in H2O and kept at -70° C. until ready to be used. | |
With acetic acid for 3h; Reflux; | 1 Phenylhyrazine-4-sulfonic acid is commercially available from a number of fine chemical suppliers. 5 g of Phenylhyrazine-4-sulfonic acid was treated with 3-methyl-2-butanone (15 mL) in acetic acid (AcOH, 20 mL) and refluxed for 3 h. On cooling, 2,3,3-trimethylindolenine-5-sulfonic acid precipitated out and was filtered, washed with a little diethyl ether and dried. The free base of was then formed by the addition of potassium hydroxide in 2-propanol. This was then refluxed with dimethylsulfate for 3 h to afford after removal of the solvent, the N-methyl compound. This was then treated with malonaldehyde bisphenylimine (0.3 equivalents) and refluxed in an acetic anhydride/pyridine mixture (4:1, 10 mL) for 1 h until a deep blue solution formed. The solvent was removed on a rotory evaporator and the crude dye was purified by flash chromatography on silica gel eluting with a gradient of methylene chloride and methanol (A=methylene chloride, B=methanol, gradient was 0 to 100% B over 30 minutes) to afford 0.4 g of the bis sulfonic acid. This was then refluxed with POCl3 for 2 h to form a key bis sulfonyl chloride intermediate that can also be used in its own right as a bifunctional sulfonyl chloride dye for labeling analytes or biomolecules that contain primary or secondary amines or alcohols and also phenols (Ar-OH). 200 mg of this compound was treated with an excess of ethylenediamine (1 g) in dimethylformamide for 5 minutes at 5° C. and the solvent was evaporated under vacuum. The residue was then acidified with trifluoroacetic acid (TFA) and subjected to flash chromatography on silica gel with a gradient of methylene chloride and methanol (A=methylene chloride, B=methanol, gradient was 0 to 100% B over 30 minutes) to afford 1 g of the bifunctional amino dye. | |
In acetic acid | 1 Synthesis of 2,3,3-trimethylindole-5-sulfonic acid 1a Synthesis of 2,3,3-trimethylindole-5-sulfonic acid 1a 18.2 g (0.12 mol) of p-hydrazinobenzenesulfonic acid and 14.8 g (0.17 mol) of isopropylmethylketone were stirred in 100 mL of glacial acetic acid at room temperature for 1 h. The mixture was then refluxed for 4 h. The mixture was cooled to room temperature, and the resulting pink solid precipitate was filtered and washed with ether. The precipitate was dissolved in methanol, and a concentrated solution of potassium hydroxide in 2-propanol was added until a yellow solid completely precipitated. | |
With acetic acid at 118℃; for 14h; | 1 4-hydrazinobenzenesulfonic acid and 3-methyl-2-butanone were added to a three-necked flask at a molar ratio of 1: 1,Dissolved in acetic acid, 118 ° C under reflux conditions 14h. After completion of the reaction, heating was stopped, and the mixture was cooled to room temperature, filtered with a Buchner funnel, washed with ether and dried under reduced pressure to obtain a pink solid.0.05 g of keto acid and 0.1685 g of 2,3,3-trimethyl-5-sulfonic acid-3H-1,Indole was added into a 100 mL three-neck flask, 30 mL of toluene and 30 mL of n-butanol were added, the condenser tube was connected,Stoke water separator, nitrogen, 105 heating reflux stirring 6 hours, the solution from red to deepBrown, the water generated in the reaction was separated by a water separator. After the end of the reaction, the heating was stopped and the solution was cooled toAt room temperature, the solvent was removed on a rotary evaporator under reduced pressure. Ethyl acetate to give a black powderend. The powder was placed in an evaporating dish, placed in an oven, and dried at 60 ° C. The resulting black powder was taken in two portions(Volume ratio V dichloromethane: V methanol = 4: 1) as the eluent, 300 mesh silica gelAs a stationary phase, column chromatography elution separation and purification, to get a black solid, 2,3,3-trimethyl-5-sulfonic acidYl-3H-indolidone cyanine dye. | |
With acetic acid In methanol at 117℃; for 5h; | 1.1 A solution of phenylhydrazine in sulfonic acid (5 g) was added to a methyl isopropyl ketone in methanol (8.55 / 15 ml)The solution was heated to 117 ° C and stirred for 5 h. The solvent was evaporated.Further, 50 ml of diethyl ether was added to the oily product to give a pink powder, i.e., compound (3).Then, the reddish brown powder (6 g) was added to a solution of sodium hydroxide (1.5 g) in methanol (10 ml) and isopropyl alcohol (10 ml)The solution was stirred at 82 ° C for 15 minutes, then cooled to room temperature and a large amount of compound was isolated for the next step. | |
With acetic acid for 10h; Reflux; Inert atmosphere; | ||
With acetic acid Reflux; | 1-2 Example 1 0.376 g of 4-hydrazinobenzenesulfonic acid(about 0.002 mol) and 0.258 g of isopentanone (about 0.003 mol) were added to a round bottom flask, 50 ml of glacial acetic acid was added, and glacial acetic acid was added. Stir under heating and reflux overnight, and the solution slowly changed from turbidity to clarification. And the color changes from light yellow to deep red. After the reaction is over, Heating and stirring were stopped, and the solvent was distilled off with a rotary evaporator. Using 200 ml of dichloromethane and 20 ml of methanol mixed solvent as eluent, Separation using a silica gel column, The separated product was suspended from the eluent by a rotary evaporator. Put the suspended product into an evaporating dish, After drying in an oven at 60 ° C, a yellow sulfonate oxime was obtained. | |
With acetic acid Reflux; | Compound 3 was synthetized from 4-Hydrazinobenzenesulfonic acid and 3-methyl-2-butanone, which cyclized to obtain 2,3,3-trimethyl indoline-5-sulfonic acid by Fisher method followed by potassium salinization. The detailed synthesis steps referred to reference | |
With acetic acid for 8h; Reflux; Inert atmosphere; | 1.1 (1) Synthesis of potassium N-ethyl-2,3,3-trimethylsulfonium-5-sulfonate (compound (II)) Add 10 mL of acetic acid to a 50 mL single-mouth bottle,Benzopyrene-4-sulfonic acid (2.000g, 0.010mol)And methyl isopropyl ketone 4.00 mL (0.037 mol),It was refluxed for 8 hours under a nitrogen atmosphere, at which time the solution turned dark red.After cooling to room temperature,The reaction solution was slowly dropped into ethyl acetate, and a pink solid precipitated in the solution;And washed several times with diethyl ether, dried in vacuum;Dissolving the dried pink powder described above with an appropriate amount of methanol,0.561 g of potassium hydroxide was dissolved in isopropanol to prepare a saturated solution.Then, a saturated solution of potassium hydroxide in isopropanol was added dropwise to the methanol solution.Obtained a yellow solid, centrifuged,It was washed 3-4 times with diethyl ether and dried in vacuo.Take another 50mL single-mouth bottle and add the above yellow solid, 20mL acetonitrile and ethyl bromide 1.49mL (0.020mol) to the bottle.Reflow under nitrogen for 24 hours,A red solid precipitated. After cooling to room temperature, suction filtration,It was washed with diethyl ether (3 × 10 mL) and dried in vacuo to give Compound (II). | |
With sodium acetate; acetic acid at 130℃; for 2h; | ||
With acetic acid for 10h; Reflux; | ||
With acetic acid at 120℃; for 6h; | 1.1 1. Take 4-hydrazinylbenzene-1-sulfonic acid10g,6g of methyl isopropyl ketone,70ml of acetic acid, heated and refluxed at 120 for 6h under constant stirring,It can be seen that the raw materials continue to dissolve and the solution turns brick red.After the reaction, the solution was spin-dried and washed with ether.Brick red solid 2,3,3-trimethyl-3H-indole-5-sulfonic acid can be obtained, | |
With sodium acetate; acetic acid for 8h; Reflux; | 1 Synthesis of 2,3,3-trimethyl-5-sulfoindole Dissolve p-sulfophenylhydrazine, 3-methyl-2-butanone, and anhydrous sodium acetate in a molar ratio of 1:1.1:1.5 in acetic acid, and react under reflux and stirring for 8 hours. The reaction solvent was removed by rotary evaporation, and then a mixed solution of water and methanol with a volume ratio of 9:1 was added to dissolve the remaining substances. The resultant was filtered, and then left open to crystallize at room temperature for 48 hours,The crystal 2,3,3-trimethyl-5-sulfoindole was obtained. | |
With acetic acid at 120℃; for 18h; Inert atmosphere; | 1 4-hydrazinebenzenesulfonic acid (1.6 g, 31.9 mmol), 3-methyl-2-butanone (2.10 ml, 90 mmol) and glacial acetic acid (50ml) were mixed and heated to 120 C under nitrogen atmosphere for 18 h. After precipitation in ethyl acetate, filter and collect the crude product as a pink solid, the resulting product (6.5 g, 25.4 mmol) was dissolved in methanol (50 mL). Under mild conditions, the dissolved liquid was added dropwise to a solution of potassium hydroxide (1.7g, 30 mmol) and isopropanol (20 ml), and the crude mixture was filtered and washed to obtain a brown solid, product 1, with a yield of 97%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-hydrazino-benzenesulfonic acid; (cis)-2-(3,4-diethoxybenzoyl)-1,2,3,6-tetrahydrobenzoic acid With triethylamine In propan-1-ol for 6h; Heating / reflux; Stage #2: With acetic acid for 2h; Heating / reflux; | A5 A5. (cis)-4-{4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzenesulfonic acid A5. (cis)-4-{4-(3,4-Diethoxyphenyl)-1-oxo-4a,5,8,8a-tetrahydro-1H-phthalazin-2-yl}benzenesulfonic acid A solution of 16 mmol of starting compound A4, 16 mmol of 4-hydrazino benzene sulfonic acid and 5 ml of triethyl amine in 100 ml of 1-propanol is refluxed for 6 h.. After evaporating the residue is dissolved in 100 ml of acetic acid and refluxed for 2 h.. After evaporating the residue is partitioned between 1N hydrochloric acid and ethyl acetate, The organic layer is dried over magnesium sulfate and evaporated.. Crystallisation from diethyl ether. M. p. 65-69° C. |
Yield | Reaction Conditions | Operation in experiment |
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85% | Stage #1: 4-Sulfo-benzenediazonium; hydrogen sulfate With sodium sulfite In water Heating / reflux; Stage #2: With hydrogenchloride In water | 1 Preparation of 1-(ε-carboxypentyl)-2,3,3-trimethylindolenium-5-sulfonic acid potassium salt (1a); p-Hydrazinobenzenesulfonic acid The wet diazo-compound was added under stirring and cooling (5° C.) to a solution of 170 g of sodium sulfite in 500 ML of water.The solution, which turned orange, was stirred under cooling for 1 h, and then heated to reflux.Finally, 400 ML of concentrated hydrochloric acid were added.The solution turned yellow, and the product precipitated as a white solid.For complete decoloration, 1-2 g of powdered zinc were added.The reaction mixture was cooled overnight, and the precipitate was filtered, washed with water, and dried in an oven at 100° C. Yield: 96 g (85%), white powder; M.P.=286° C. (Lit.=285° C.); Rf: 0.95 (RP-18, water:MeOH 2:1). |
Yield | Reaction Conditions | Operation in experiment |
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40% | With acetic acid for 6 - 12h; Heating / reflux; | 5; 13.1 13.1 6-(2,3-dimethyl-5-sulfo-3H-indol-3-yl)hexanoic acid To a stirred solution of 4-hydrazinobenzenesulfonic acid (ALDRICH, LU,,. 25 g, 0.06 mol) in acetic acid (50 ml) was added 7-ACETYLOCTANOIC acid (16.7 g, 0.09 MOL). The reaction mixture was heated under reflux for 12 hrs. Acetic acid was removed under reduced pressure. The resulting solid was dissolved in methanol and reprecipitated with a saturated solution of potassium hydroxide in isopropanol. The solid was filtered, washed with isopropanol and dried, (8 g, 40%). The analytical sample was obtained by C18 reversed phase column chromatography using water/methanol mixture as solvent., m. p. 250 °C dec; IR v cm-1 = 2930,2597, and 1719. H NMR, D20, 6, 7.8-7. 9 (m, 2H, 4-H and 6-H of aromatic protons); 7.6 (d, J = 7Hz, 1H, 7-H of aromatic); 2.2 (T, J =7Hz, 2H,-CH2-COOH) ; 1.9-2. 1 (m, 2H, alkyl) ; 1.2-1. 6 (a singlet merged in a multiplet, 7H,-CH3 & (-CH2) 2) ; 0.6-0. 9 (m, 2H, alkyl.); 4-Hydrazinobenzenesulfonic acid (1.88g, 10mmol), 7-methyl-8-oxononanoic acid (2.8g, 15MMOL) and glacial acetic acid (10ml) were mixed and heated under reflux for 6hrs. The solvent was then evaporated under vacuum and the residue triturated with diethyl ether until a solid was obtained. This was dried under vacuum to give crude product, 3. 4G (100%). This was purified by preparative HPLC as required (RPC18. Water+0. 1%TFANo.MECN+0.1% TFA gradient). UVNis (Water+0.1% TFA): 274,229, 204NM. 1H-NMR (D20) 6 0.6-0. 9 (2H, broad M), 1.10- 1.25 (2H, broad m), 1.35-1. 50 (2H, m), 1.60 (3H, s), 2.10-2. 40 (2H, broad m + 2H, t), 7.77 (1 H, d), 7.97 (1 H, dd) and 8.06 (1 H, d) MS (MALDI-TOF) MH+ 340. |
In acetic acid at 140℃; for 5h; | 3.1 4-Hydrazinobenzenesulfonic acid (13.42 g, 71.4 mmol) was added to 7-methyl-8-oxononanoic acid (20 g, ·107 mmol) in a 1 l round bottomed flask, together with acetic acid (71 ml). The pink suspension was stirred at 140° C. for 5 hours. The reaction mixture was rotary evaporated to yield a red/brown oil. The oil was triturated with diethyl ether (4×50 ml) to produce a semi-solid sticky mass. This was dissolved in water (200 ml) and purified by flash chromatography. The product was eluted with 10% acetonitrile/water+0.1% TFA as a yellow band. HPLC analysis showed the yellow band to be of adequate purity and separated from the major impurity at 23.5 minutes. Yield 18 g. | |
12 Preparation of Compound 15 The Compound 15 is analogously synthesized from the Fisher reaction of 4-sulfophenylhydrazine with 7-methyl-8-oxo-nonanoic acid, followed by quaternization with 1,3-propanesultone utilizing a procedure as described in U.S. Pat. No. 7,465,810. |
23 g | With acetic acid for 5h; Reflux; | 1 EXAMPLE 1Preparation of 3-(5-carboxypentyl)-2,3-dimethyl-5-sulfoindolium,Inner Salt (Compound 1) 10104] The acetoacetate thus obtained is dissolved in 300 mL of methanol. A solution of lOg NaOH in 100 mL water is added. The mixture is heated at 50° C. overnight. The solution is reduced to .-50 mL, acidified to .-pH 1, and extracted with ethyl acetate. The organic layer is dried over Mg504 and evaporated to yield 13.5 g of 7-methyl-8-oxononanoic acid. The nonanoic acid is refluxed in 110 mL of acetic acid with 13.5 g of 4-hydrazinobenzenesulfonic acid for 5 hours. The acetic acid is evaporated and the product is purified on silicagel to yield 23 g of the product. |
3.1 g | With acetic acid for 8h; Reflux; | 4 Preparation of Compound 4 The mixture of 7-methyl-8-oxo-nonanoic acid (Compound 2, 4.2 g, 21.5 mmol) and 4-hydrazinobenzenesulfonic acid (4.23 g, 22.5 mol) in acetic acid (30 mL) is heated to reflux for 8 hours. After removal of the solvent, the residue is purified on silica gel to give Compound 4 (3.1 g). |
With acetic acid for 8h; Reflux; | 1.B B. Preparation of Compound 2 To prepare Compound 2 (shown below), Compound 1 (42 g) and 4-hydrazinobenzenesulfonic acid (43 g) in acetic acid (30 mL) was heated to reflux for 8 hours. After removal of the solvent, the residue was purified on silica gel to give Compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With acetic acid for 6h; Reflux; | 2.3 2,3-Dimethyl-3-(4-sulfobutyl)-3H-indole-5-sulfonic acid A mixture of 5-methyl-6-oxoheptane-1-sulfonic acid (1 g, 4.8 mmol), 4-hydrazinobenzenesulfonic acid (0.71 g, 3.8 mmol), and acetic acid (10 mL) was refluxed for 6 h. The solvent was removed under reduced pressure using a rotary evaporator and the residue was dried. The product was triturated with hot iso-propanol and the obtained precipitate was filtered and dried. Yield: 1.17 g (85%). λabs 260 nm. 1H NMR (200 MHz, DMSO-d6, ppm): δ 7.83 (1H, s, arom H), 7.53 (1H, d, J = 7.8 Hz, arom H), 7.54 (1H, d, J = 7.9 Hz, arom H), 2.58 (3H, s, 2-CH3), 2.36 (2H, t, J = 7.5 Hz, CH2SO3H), 2.09-1.86 (2H, m, CH2), 1.53-1.36 (2H, m, CH2), 1.43 (3H, s, 3-CH3), 0.88-0.47 (2H, m, CH2). |
With acetic acid for 6h; Heating / reflux; | 17.2 17.2 2,3-dimethyl-3-(4-sulfobutyl)-3H-indole-5-sulfonic acid 4-Hydrazinobenzenesulfonic acid (1.88g), 5-METHYL-6-OXOHEPTANESULFONIC acid (2.5g) and acetic acid (50MUT) were mixed and heated under reflux for 6hrs. The solvent was evaporated under vacuum, then the residue was triturated with 2- propanol to yield the crude product as a yellow solid. This was purified by HPLC as required (RPC18. WATER + 0. 1% TFA). 1H-NMR (D2O) No.0.8-1.0 (2H, m), 1.55-1. 65 (5H, =3H, s + 2H, m), 2.16 (1 H, ddd), 2.29 (1 H, ddd), 2.75 (2H, m), 2.81 (partially d- exchanged methyl singlet), 7.71 (1 H, d), 7.94 (1 H, d) and 8.01 (1 H, d). UV/Vis (WATER+0. 1% TFA): 269,229nm. MS (LCMS): MH+ 362. Acc. Mass: Found, 362.0729. MH+ = C14H2ONO6S2 requires 362.0732 (-0.8ppm). | |
With acetic acid for 6h; Heating / reflux; | 1.3 1.3 263-Dimethvl-3-(4-sulphobutel)-3H-indole-5-sulphonic acid; 4-Hydrazinobenzenesulphonic acid (7.5g), 5-methyl-6-oxoheptane-1- sulphonic acid (11.0g) and acetic acid (50mut) were heated under reflux under nitrogen for 6hrs, during which time all of the suspended solid dissolved. The solvent was then evaporated under vacuum and the residue triturated with 2- propanol at 80°C to give a light brown solid in suspension. The mixture was allowed to cool to ambient temperature, the solid collected by filtration, washed with 2-propanol and diethyl ether and dried under vacuum. The product was purified by HPLC, collecting the major peak detected at 270nm. (Phenomenex Jupiter 15, Cul 8 300A, 250x50mm. 100m1/min. 0.5g per run. Eluant isocratic water +0.1 % TFA). Product fractions were pooled and evaporated to give 11. 1g. |
Stage #1: 5-methyl-6-oxoheptane-1-sulphonic acid; 4-hydrazino-benzenesulfonic acid In acetic acid at 150℃; for 6h; Stage #2: With potassium hydroxide In methanol at 20℃; | 14.1 To hydrazinobenzene sulfonic acid (40 g) was added acetic acid (500 ml) and 5-methyl-6-oxoheptane-1-sulfonic acid (60 g). The mixture was heated to 150° C. for 6 hours and then cooled to room temperature. After filtration the volatiles were removed on a rotary evaporator to give a solid (110 g), 10 g of which was dissolved in methanol (1 L) and potassium hydroxide (38 g) in methanol (300 ml) added. The mixture was stirred for 1 hour and then stood overnight. The liquid layer was decanted off and the volatiles removed on a rotary evaporator to give the product as a pale yellow solid (80 g). | |
With acetic acid for 6h; Reflux; | ||
840 mg | With acetic acid for 16h; Reflux; | 2 Synthesis of 2,3-dimethyl-3-(4-sulfobutyl)-3H-5-indolesulfonic acid (IVd) A solution of 290 mg of NaOH in 3 ml water was added to the mixture of 710 mg (2.53 mmol) of 5-ethyloxycarbonyl-5-methyl-6-oxo-1-heptanesulfonic acid in 15 ml of methanol. The obtained mixture was stirred for 15 hours at 50° C. Methanol was removed by a rotary evaporator, residue was acidified to pH 1 and then solvent was removed until dry to yield 5-methyl-6-oxo-1-heptanesulfonic acid. The product thus obtained (940 mg, 4.5 mmol), 1.02 g (5.4 mmol) of 4-hydrazinobenzenesulfonic acid, and 15 ml of acetic acid was refluxing for 16 hours. The insoluble precipitate was filtered and the filtrate was evaporated. The obtained residue was column purified (RP-18, water) to yield 840 mg of the 2,3-dimethyl-3-(4-sulfobutyl)-3H-5-indolesulfonic acid (IVd). δH (200 MHz, DMSO-d6): 7.66 (1H, s, arom H), 7.6 (1H, d, 8.0 Hz, arom H), 7.4 (1H, d, 7.8 Hz arom H), 2.66 (2H, t, 6.8 Hz, CH2SO3H), 2.32 (3H, s, 2-CH3), 2.10-1.78 (2H, m, CH2), 1.53-1.26 (2H, m, C H2), 1.31 (3H, s, 3-C H3), 0.83-0.41 (2H, m, CH2). |
Yield | Reaction Conditions | Operation in experiment |
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90% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid for 4h; Reflux; Stage #2: With potassium hydroxide In methanol; propan-1-ol at 20℃; for 24h; | 1.1 Preparation Example 1 Preparation Example 1 (0140) (0141) Step 1: (0142) To p-hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq, Aldrich) and 3-methyl-2-butanone (17.18 mL, 160 mmol, 3.02 eq, TCI), 30 mL of acetic acid is added. Next, the reaction mixture is allowed to react by heating under reflux for 4 hours. After cooling the reaction mixture to room temperature, the resultant solid particles are filtered. Then, the resultant product is washed with ethyl acetate three times and dried under reduced pressure (11.34 g, 89%). (0143) Rf=0.68 (RP-C18, acetonitrile/water 1:4 v/v) (0144) Step 2: (0145) Potassium hydroxide (1.427 g, 25.4 mmol, 1.2 eq) is dissolved into 35 mL of propanol and the compound (5.073 g, 21.2 mmol, 1 eq) dissolved in 35 mL of methanol is added thereto. Next, the reaction mixture is agitated at room temperature for 24 hours and filtered to obtain the target compound (5.35 g, 90%). (0146) Rf=0.68 (RP-C18, acetonitrile/water 1:4 v/v) (0147) 1H NMR (300 MHz, D2O): δ 7.60 (s, 1H), 7.58 (d, 1H, J=8.32 Hz), 7.32 (d, 1H, J=7.99 Hz), 2.08 (s, 3H), 1.06 (s, 6H) |
82% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid for 4h; Reflux; Stage #2: With potassium hydroxide In methanol; propan-1-ol at 20℃; for 24h; | 1.1 Example 1.1 At room temperature, to a solution of p-hydrazinobenzenesulfonic acid (5.00 g, 26.6 mmol, 1.0 eq) in acetic acid, add 3-methyl-2-butanone (5.70 mL, 53.1 mmol, 2.0 eq) and reflux After 4h, the reaction was stopped, filtered, washed with ethyl acetate 3 times, the solid was dissolved in 30mL methanol, and slowly added dropwise to a solution of potassium hydroxide (1.50g, 26.6mmol, 1.0eq) dissolved in 30mL propanol, at room temperature Stir for 24h. After filtration, the target compound 1.1 (6.04 g, 21.8 mmol, Y=82%) was obtained. |
80% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid for 3h; Reflux; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol Cooling with ice; Sonication; | 1.1 (1) Synthesis of intermediate 2,3,3-trimethyl-3H-carboline-5-sulfonic acid potassium In a 1000 mL three-necked flask, 30 mL of glacial acetic acid, 17 mL (0.16 mol) of 3-methyl-2-butanone and 0.05 mol of p-nonylbenzene sulfonic acid were sequentially added.The mixture was heated at reflux for 3 h, the reaction was poured into a large amount of acetone, and a pink solid precipitated on standing in an ice bath. Filter and vacuum dry.The above pink solid was dissolved in 50 mL of methanol to obtain solution A, and 50 mL of isopropanol was dissolved in 2 g of KOH (0.036 mol) to obtain solution B. Solution A was slowly added dropwise to solution B under ultrasonic conditions.A large amount of a yellow solid precipitated, was filtered, and washed several times with diethyl ether to give a yellow solid of potassium 2,3,3-trimethyl-3H-carboline-5-sulfonate, which was vacuum-dried in 80% yield. |
77% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid In acetic acid at 105℃; for 2.33333h; Heating / reflux; Stage #2: With potassium acetate In methanol; acetic acid | 1.G 3.5 mol of phenylhydrazine-4-sulfonic acid and 1.9 L of acetic acid are heated at 105° C. Over the course of 30 min, 4.8 mol of 3-methyl-2-butanone are added dropwise. After 1 h 50 min, heating is removed and 4.2 mol of potassium acetate in 3.5 L of methanol are added. The mixture is further cooled in an ice bath and the precipitated solid is filtered off. It is washed with ethyl acetate. Yield: 77% |
75% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid In acetic acid for 3h; Reflux; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | |
75% | With acetic acid for 3h; Reflux; | |
74% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid In acetic acid for 5h; Reflux; Stage #2: With potassium acetate In isopropyl alcohol | |
71% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid at 20℃; for 5h; Reflux; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | 1 Synthesis of 2,3,3-trimethylindole-5-sulfonic acid, potassium salt (1a) 18.2 g (0.12 mol) of p-hydrazinobenzenesulfonic acid and 14.8 g (0.17 mol) of isopropylmethylketone were stirred in 100 mL of glacial acetic acid at room temperature for 1 h. The mixture was then refluxed for 4 h. The mixture was cooled to room temperature, and the resulting pink solid precipitate was filtered and washed with ether. (0116) The precipitate was dissolved in methanol, and a concentrated solution of potassium hydroxide in 2-propanol was added until a yellow solid completely precipitated. The precipitate was filtered, washed with ether, and dried in a desiccator over P2O5. (0117) Yield: 20.4 g (71%), off-white powder; M.P.=275° C.; Rf: 0.40 (silica gel, isopropanol:water:ammonia 9:0.5:1). |
62.6% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid at 110℃; for 3h; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | |
52% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid at 125℃; for 4h; Microwave irradiation; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol Microwave irradiation; | |
30% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With hydrogenchloride In ethanol; water Reflux; Stage #2: With potassium hydroxide In methanol; propan-1-ol at 20℃; for 12h; | 8.1 Synthesis of compound represented by Chemical Formula 52-a Hydrazinobenzenesulfonic acid (20 g, 106 mmol) and 3-methyl-2-butanone (27.48 g, 319 mmol) were added to 30 ml of a 6N hydrochloric acid aqueous solution and 60 ml of ethanol, And the mixture was refluxed and stirred. The mixture was cooled to room temperature, and the resulting solid was filtered. Washed with ethyl acetate and dried under reduced pressure. Potassium hydroxide (1.4 g, 25.4 mmol) was dissolved in propanol, And the filtered solid (5.1 g, 21.2 mmol) was dissolved in methanol (35 ml), and the mixture was stirred at room temperature for 12 hours. The solid was filtered and dried. Purification was performed using C18 reverse phase chromatography to obtain a compound represented by [Chemical Formula 52-a] (11.1 g, 30%). |
In acetic acid | 1 Preparation of 2,3,3-trimethylindole-5-sulfonic acid, potassium salt (1b) Preparation of 2,3,3-trimethylindole-5-sulfonic acid, potassium salt (1b) 18.2 g (0.12 mol) of p-hydrazinobenzenesulfonic acid and 14.8 g (0.17 mol) of isopropylmethylketone were stirred in 100 mL of glacial acetic acid at room temperature for 1 h. The mixture was then refluxed for 4 h. The mixture was cooled to room temperature, and the resulting pink solid precipitate was filtered and washed with ether. The precipitate was dissolved in methanol, and a concentrated solution of potassium hydroxide in 2-propanol was added until a yellow solid completely precipitated. | |
With potassium hydroxide In methanol; acetic acid; isopropyl alcohol | 1.a a) a) 2,3,3-Trimethyl-3H-indole-5-sulfonic acid, potassium salt (I) A mixture of p-hydrazinobenzenesulfonic acid (100 g, 0.53 mol) and 3-methyl-2-butanone (168 mL, 1.6 mol) in acetic acid (300 mL) is heated to reflux with mechanical stirring for 3 hours and the reaction mixture is cooled to room temperature, the stirring continued overnight, and filtered to give a pink solid which is then re-dissolved in methanol (750 mL) and precipitated by adding a saturated solution of potassium hydroxide in isopropanol (400 mL). The mixture is filtered and dried in a vacuum oven to give (I) as a yellow/brown cake which is crushed to a fine powder with a mortar and pestle. 1 H NMR (D2 O) δ 7.84 (s, 1H, aromatic 4-H), 7.80 (s, 1H, aromatic 6-H), 7.55 (d, 1H, aromatic 7-H), 2:33 (s, 3H, 2-methyl), 1.32 (s, 6H, 3,3-gem-dimethyl). | |
In acetic acid | 1 Synthesis of 2,3,3-trimethylindole-5-sulfonic acid, potassium salt (1a) Synthesis of 2,3,3-trimethylindole-5-sulfonic acid, potassium salt (1a) 18.2 g (0.12 mol) of p-hydrazinobenzenesulfonic acid and 14.8 g (0.17 mol) of isopropylmethylketone were stirred in 100 mL of glacial acetic acid at room temperature for 1 h. The mixture was then refluxed for 4 h. The mixture was cooled to room temperature, and the resulting pink solid precipitate was filtered and washed with ether. The precipitate was dissolved in methanol, and a concentrated solution of potassium hydroxide in 2-propanol was added until a yellow solid completely precipitated. | |
Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid for 4h; Reflux; Stage #2: With potassium hydroxide In methanol; propan-1-ol for 24h; | 1 P-hydrazinobenzenesulfonic acid (10 g, 53 mmol, 1 eq, Aldrich) and 3-methyl-2-butanone (17.18 mL, 160 mmol, 3.02 eq, TCI) was added to 30 mL of acetic acid, and the mixture was heated and refluxed for 4 hours.The mixture was cooled to room temperature, and the resulting solid particles were filtered.Washed three times with ethyl acetate and dried under reduced pressure (11.34 g, 89%). Potassium hydroxide (1.427 g, 25.4 mmol, 1.2 eq) was dissolved in 35 mL of propanol, and the compound (5.073 g, 21.2 mmol, 1 eq) obtained in the first step was dissolved in 35 mL of methanol and stirred at room temperature for 24 hours After filtration, the desired compound was obtained (5.35 g, 90%). | |
Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid In acetic acid at 120℃; for 18h; Stage #2: With potassium hydroxide In acetic acid; isopropyl alcohol | ||
Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid Stage #2: With potassium hydroxide | ||
Multi-step reaction with 2 steps 1: acetic acid / 18 h / 118 °C / Inert atmosphere 2: potassium hydroxide / isopropyl alcohol; methanol / 1 h / Inert atmosphere | ||
7.5 g | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid at 120℃; for 4h; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol for 1h; | Add 10 grams of 4-hydrazinobenzenesulfonic acid dissolved in 35 milliliters of glacial acetic acid into a 250 milliliter single-necked flask, then add 17 milliliters of methyl isopropyl ketone, and react at 120 degrees for 4 hours. The solid obtained by the reaction was filtered, washed three times with 50 ml of ethyl acetate, and dried under vacuum to obtain 9.4 g of a light pink solid. The obtained solid was dissolved in 100 ml of methanol, and 80 ml of isopropanol solution of 2.6 g of potassium hydroxide was slowly added dropwise. Stir for one hour and filter to obtain 7.5 g of yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1H-[1]benzazepin-2,5(3H,4H)-dione; 4-hydrazino-benzenesulfonic acid With sodium acetate In acetic acid at 133℃; for 1.25h; Sonographic reaction; Stage #2: With sulfuric acid In water; acetic acid at 20℃; for 1.25h; Sonographic reaction; | ||
Stage #1: 1H-[1]benzazepin-2,5(3H,4H)-dione; 4-hydrazino-benzenesulfonic acid With sodium acetate In acetic acid at 133℃; for 1.25h; Heating / reflux; Stage #2: With sulfuric acid at 20℃; for 1.25h; Heating / reflux; | Formulation 0.50 g Dihydro-1H-benz[b]azepine-2,5-dion (M=175.19 g mol-1=>2.85 mmol) 0.57 g 4-hydrazinobenzenesulphonic acid hemihydrate (98%; M=197.22 g mol-1-=>2.8528 mmol) 0.24 g Sodium acetate (98.5%, M=82.034 g mol-1=>2.88 mmol) 4.5 ml Acetic acid (99.8%; d=1.049 g cm-3) 250 μl H2SO4 (95-97%; d=1.84 g cm-3; M=98.079 g mol-1=>4.50 mmol) 0.79 g Sodium acetate (98.5%, M=82.03 g mold =>9.48 mmol) 325 ml Methanol (for analysis) 7.6 ml H2O Dihydro-1H-benz[b]azepine-2,5-dion and sodium acetate were charged into a 10 ml round flask and suspended in 3 ml of glacial acetic acid with the aid of ultrasound. 4-hydrazinobenzene sulphonic acid hemihydrate in solid form was added while stirring. The mixture was then subject to reflux under an argon protective gas atmosphere for 75 min at 133° C. oil-bath temperature. The educts almost completely dissolved. Then the still hot reaction mixture was filtered through a glass sintered strainer (P4), wherein rinsing took place with 1.5 ml of acetic acid. After cooling to room temperature 250 μl of sulphuric acid was added using a piston pipette while stirring. Already after a very brief ultrasound treatment, a fine, bright precipitate started to form. Now boiling occurred in a hot oil bath under reflux for a further 75 min. under argon. After cooling to room temperature, filtering took place in a glass sintered strainer, then washing with 3 ml of glacial acetic acid, then three times, each time with 5 ml of THF and finally three times, each time with 5 ml of diethyl ether. The product (about 1 g), which was dried under suction for some time and which according to experience contained some impurities which were difficult to identify, was dissolved in 300 ml of methanol with 7 ml of H2O. For this, a solution of three equivalents of sodium acetate was poured into 25 ml of methanol with 0.6 ml of H2O. The ensuing precipitate which formed was filtered off and discarded. The filtrate was centrifuged until dry and the residue suspended in 30 ml of dry methanol under ultrasound. After 10 min. of refluxing, the white product in the mixture which had cooled to room temperature was filtered off in a glass sintered strainer and washed three times with 5 ml of cold methanol each time and then three times with 5 ml of diethyl ether each time. Then drying took place in a vacuum. Yield: 0.62 g of white powder δH(400.13 MHz; d6-DMSO): 11.69[1H(N12); s]; 10.12[1H(N5); s]; 7.91[1H(C8); s]; 7.76[1H(C1); d; 3J(HC2)=7.5 Hz]; 7.51[1H(C10); d; 3J(HC11)=8.5 Hz]; 7.39[1H(C11); d; 3J(C10)=8.5 Hz]; 7.37[1H(C3); dd; 3J(HC2)=7.5 Hz; 3J(HC4)=7.5 Hz]; 7.28[1H(C2); dd; 3J(HC1)=7.5 Hz; 3J(HC3)=7.5 Hz;]; 7.27[1H(C4); d; 3J(HC3)=7.5 Hz]; 4.12[0.5H(OMeOH); s]; 3.49[2H(C7); s]; 3.18[1.5H(CMeOH); s]; δC(100.63 MHz; d6-DMSO): 172.27(C6); 140.67(C9); 138.15(C11a); 136.33(C12b); 134.12(C12a); 128.96(C3); 127.75(C1); 126.10(C7b); 124.57(C2); 123.62(C4a); 123.17(C4); 121.39(C10); 116.07(C8); 111.31(C11); 108.97(C7a); 49.35(CMeOH); 32.56(C7); δN(40.55 MHz; referred to NH4Cl; d6-DMSO): 108(N12); 117(N5); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In methanol; acetic acid; acetonitrile | 1 3-Methylureido-1-(p-sulfophenyl)-5-pyrazolone Triethylamine Salt EXAMPLE 1 3-Methylureido-1-(p-sulfophenyl)-5-pyrazolone Triethylamine Salt Into 30 ml of acetonitrile was dissolved 15.9 g of ethylβ-amino-β-ethoxy acrylate, and 6 g of methyl isocyanate was added thereto. The resulting mixture was allowed to stand at room temperature for 2 days. Into a mixed solution of 50 ml of methanol, 50 ml of triethylamine and 50 ml of glacial acetic acid there was dissolved 18.8 g of p-sulfophenyl hydrazine, into which was then slowly dropped the above solution in which the esterification reaction had been completed. The solution so obtained was allowed to stand at room temperature for 4 days, whereupon crystals precipitated. These crystals were combined and washed with acetonitrile and then recrystallized from ethanol; thus, 31 g of pale yellow plate-like crystals of the objective compound of a melting point of 248° to 250° C. was obtained. Elemental Analysis: Calculated for C11 H12 N4 O5 S.N(C2 H5)3: C, 49.38:; H, 6.58; N, 16.94. Found: C, 49.35; H, 6.72; N, 16.68. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine In methanol; acetic acid | 12 3-Methanesulfonylamino-1-(p-sulfophenyl)-5-pyrazolone Triethylamine Salt EXAMPLE 12 3-Methanesulfonylamino-1-(p-sulfophenyl)-5-pyrazolone Triethylamine Salt Into a mixed solution of 50 ml of methanol, 50 ml of triethylamine and 50 ml of glacial acetic acid there was dissolved 18.8 g of p-sulfophenyl hydrazine, to which was added 23.5 g of ethylβ-methanesulfonylamino-β-ethoxyacrylate. The resulting solution was allowed to stand at room temperature for one week. The crystals precipitated were collected and recrystallized from methanol; thus 29 g of plate-like crystals of the objective compound of a melting point of 236° to 238° C. was obtained. Analysis: Calculated for C10 H11 N3 O6 S2.N(C2 H5)3: C, 44.24; H, 6.03; N, 12.90. Found: C, 44.50; H, 6.25; N, 12.91. |
Yield | Reaction Conditions | Operation in experiment |
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82% | With hydrogenchloride; In ethanol; water; at 20℃; for 8h;Heating / reflux; | To a stirred suspension of p-hydrazino-benzenesulfonic acid (42 g, 0.223 mol) in ethanol (450 ml) 6N hydrochloric acid (74 ml, 0.446 mol) was added at room temperature, followed by addition of 4,4,4-trifluoro-l-(4-methyl-phenyl)-butane-l,3- dione (51.45 g, 0.223 mol). The obtained suspension was refluxed for 8 h, then concentrated in vacuo. The residue was dissolved in water (300 ml) and extracted with ethyl acetate (2 x 200 ml). The combined organic layers were washed with water (1 x 100 ml) and brine (1 x 100 ml), dried over MgSO4, decolorized, filtered and concentrated in vacuo. The obtained crystalline product was recrystallized from diisopropyl ether (300 ml) to yield 70.12 g (82 percent) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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65% | With acetic acid at 120℃; for 4h; | 1.1; 11.1 [Synthesis of the compound (5)]; In acetic acid (50 mL), the compound (3) (10.0 g, 0.051 mol) and the compound (4) (12.9 g, 0.066 mol) were subjected to refluxing under heating at 120°C for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure to be subjected to purification by using reversed phase column chromatography (elution liquid: water) to give the compound (5) (11.5 g, yield; 65%). Property data: IR (KBr) (cm-1): 3450, 1196; [Synthesis of the compound (5)]; In acetic acid (50 mL), the compound (3) (10.0 g, 0.051 mol) and the compound (4) (12.9 g, 0.066 mol) were subjected to refluxing under heating at 120°C for 4 hours. After completion of the reaction, the solvent was removed under reduced pressure to be subjected to purification by using reversed phase column chromatography (elution liquid: water) to give the compound (5) (11.5 g, yield; 65%). Property data: IR (KBr) (cm-1): 3450, 1196 |
65% | With acetic acid at 120℃; for 4h; | 1.1 Compound (3) (10.0 g, 0.051 mol) and compound (4) (12.9 g, 0.066 mol) in acetic acid (50 ml) were heated under reflux at 120° C. for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the product was purified by using reverse phase column chromatography (eluate: water) to obtain compound (5) (11.5 g, yield: 65%).Physical property data: IR (KBr) 3450, 1196 |
65% | In acetic acid at 120℃; for 4h; | 1.1 Synthesis of compound 5 Compound 3 (10.0 g, 0.051 mol) and compound 4 (12.9 g, 0.066 mol) in acetic acid (50 ml) were heated under reflux at 120°C for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the product was purified by using reverse phase column chromatography (eluate: water) to obtain compound 5 (11.5 g, yield: 65%). Property data: IR (KBr) (cm-1): 3450, 1196 |
Yield | Reaction Conditions | Operation in experiment |
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83% | Example 8. Preparation of 2,3-dimethyl-3-(4-carboxybutyl)-5-sulfoindolenyne, potassium salt (compound 8) A mixture of phenylhydrazine-p-sulphonic acid (compound 7) (1.8 g; 9.7 mmole), 6-methyl-7-oxooctane acid (compound 5) (2.0 g; 11.6 mmole), and glacial acetic acid (15 mL) was refluxed under stirring for 8 h, then an additional amount of acetic acid was added and treated with activated carbon. The solvent was removed and the residue was dissolved in methanol (10 mL). To solution obtained, there are added dropwise the solution of potassium hydroxide (600 mg; 10,56 mmole) in methanol (7 mL), isopropyl alcohol (15 mL), and diethyl ether (2 mL). The precipitate formed was collected by filtration and dried in vacuum desiccator over P2O5. 2,3-Dimethyl-3-(4-carboxybutyl)-5-sulfoindolenyne, potassium salt (compound 8) was obtained with yield of 3.47 g (83%), λmax 258 nm. Mass-spectrum (MALDI) (C15H19NO5S): found m/z 327.2, calculated m/z 325.38. 1H-NMR (D2O), δ (ppm): 0.45-0.7 (2H, m, CH2CH2CH2CH2COOH); 1.31 (3H, s, 3-CH3); 1.36 (2H, m, CH2CH2CH2CH2COOH); 1.88-2.14 (4H, m, CH2CH2CH2CH2COOH); 7.53 (1H, d, ArH), 7.8 (2H, m, ArH) |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 4-hydrazino-benzenesulfonic acid; acetophenone With sodium hydroxide In water at 100℃; Stage #2: With hydrogenchloride In water | 13.1 Example 13Preparation of (1r,4R)-4-(2-phenyl-1H-indole-5-sulfonamido)-N-((R)-1-phenylethyl)cyclohexanecarboxamide Step 1. Preparation of 4-{N'-[1-phenyl-eth-(E)-ylidene]-hydrazino}-benzenesulfonic acid; Sodium hydroxide (400 mg, 10 mmol) in 10 mL of water was added to a solution of 4-hydrazino-benzenesulfonic acid (1.88 g, 10 mmol) in 20 mL of water. Acetophenone (1.32 g, 11 mmol) was then added, and the mixture was heated to 100° C. overnight. The resulting mixture was then cooled and washed with ether. The pH of the aqueous solution was then adjusted to 4 with conc. HCl. Water was removed under vacuum, and methanol was added. The solution was filtered and concentrated to give product (680 mg) as a yellow solid (MS: (M+H)+=291.15). |
Yield | Reaction Conditions | Operation in experiment |
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With NaOH; acetic acid In methanol; water | 2 Synthesis of 2,3-dimethyl-3-(4-sulfobutyl)-3H-5-indolesulfonic acid (IVd) Synthesis of 2,3-dimethyl-3-(4-sulfobutyl)-3H-5-indolesulfonic acid (IVd) A solution of 290 mg of NaOH in 3 ml water was added to the mixture of 710 mg (2.53 mmol) of 5-ethyloxycarbonyl-5-methyl-6-oxo-1-heptanesulfonic acid in 15 ml of methanol. The obtained mixture was stirred for 15 hours at 50° C. Methanol was removed by a rotary evaporator, residue was acidified to pH 1 and then solvent was removed until dry to yield 5-methyl-6-oxo-1-heptanesulfonic acid. The product thus obtained (940 mg, 4.5 mmol), 1.02 g (5.4 mmol) of 4-hydrazinobenzenesulfonic acid, and 15 ml of acetic acid was refluxing for 16 hours. The insoluble precipitate was filtered and the filtrate was evaporated. The obtained residue was column purified (RP-18, water) to yield 840 mg of the 2,3-dimethyl-3-(4-sulfobutyl)-3H-5-indolesulfonic acid (IVd). δH (200 MHz, DMSO-d6): 7.66 (1H, s, arom H), 7.6 (1H, d, 8.0 Hz, arom H), 7.4 (1H, d, 7.8 Hz arom H), 2.66 (2H, t, 6.8 Hz, CH2SO3H), 2.32 (3H, s, 2-CH3), 2.10-1.78 (2H, m, CH2), 1.53-1.26 (2H, m, C H2), 1.31 (3H, s, 3-C H3), 0.83-0.41 (2H, m, CH2). |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 5-methyl-6-oxoheptane-1-sulphonic acid; 4-hydrazino-benzenesulfonic acid In acetic acid at 100℃; Stage #2: With sodium hydroxide In water at 75 - 80℃; for 10h; | 1.c Step (c): Compound 1.4-Hydrazinobenzene sulfonic acid (Alfa Aesar; 40 g) was suspended in acetic acid (1200 ml) and 5 -methyl-6-oxoheptane-l -sulfonic acid [from step (b); 72 g] was added. The reaction mass was heated to 100°C and maintained at 100°C for 10-12 hrs during which time the 4-hydrazinobenzenesulfonic acid completely dissolved. Qualitative HPLC analysis of the reaction mass showed less than 1.5% of 4-hydrazinobenzenesulfonic acid. The reaction mass was cooled to 40°C and undissolved material removed by filtration. The reaction mass was then concentrated at 60°C in vacuo until no further acetic acid distilled out. The residue was dissolved in methanol (80 ml) at 55 °C and 2-propanol (800 ml) was added at 55°C over a period of 30 min. The reaction mass was stirred at 55 °C for a period of 2 hrs. The product was filtered hot under a nitrogen atmosphere and dried under suction. The damp product was dissolved in distilled water (400 ml) at 30°C, and concentrated in vacuo to remove traces of 2-propanol. The pH of the reaction mass was adjusted to pH 8.0 to 8.5 using 10% w/v aqueous sodium hydroxide solution and the reaction mass was heated to 75- 80°C and stirred for 10 hrs. The reaction mass was concentrated at 60°C in vacuo until no further water distilled out. 2-Propanol (600 ml) was added to the residue and stirred for 30 min. The reaction mass was concentrated in vacuo at 60°C to dryness, giving Compound 1 as a fine powder. The product was dried for 12 hrs at 60°C in vacuo. Yield 61.2 g. | |
61.2 g | Stage #1: 5-methyl-6-oxoheptane-1-sulphonic acid; 4-hydrazino-benzenesulfonic acid With acetic acid at 100℃; Stage #2: With sodium hydroxide In water at 75 - 80℃; for 10h; | 1.c Step (c) Compound 1 4-Hydrazinobenzene sulfonic acid (Alfa Aesar; 40 g) was suspended in acetic acid (1200 ml) and 5-methyl-6-oxoheptane-1-sulfonic acid [from step (b); 72 g] was added. The reaction mass was heated to 100° C. and maintained at 100° C. for 10-12 hrs during which time the 4-hydrazinobenzenesulfonic acid completely dissolved. Qualitative HPLC analysis of the reaction mass showed less than 1.5% of 4-hydrazinobenzene-sulfonic acid. The reaction mass was cooled to 40° C. and undissolved material removed by filtration. The reaction mass was then concentrated at 60° C. in vacuo until no further acetic acid distilled out. The residue was dissolved in methanol (80 ml) at 55° C. and 2-propanol (800 ml) was added at 55° C. over a period of 30 min. The reaction mass was stirred at 55° C. for a period of 2 hrs. The product was filtered hot under a nitrogen atmosphere and dried under suction. The damp product was dissolved in distilled water (400 ml) at 30° C., and concentrated in vacuo to remove traces of 2-propanol. The pH of the reaction mass was adjusted to pH 8.0 to 8.5 using 10% w/v aqueous sodium hydroxide solution and the reaction mass was heated to 75-80° C. and stirred for 10 hrs. The reaction mass was concentrated at 60° C. in vacuo until no further water distilled out. 2-Propanol (600 ml) was added to the residue and stirred for 30 min. The reaction mass was concentrated in vacuo at 60° C. to dryness, giving Compound 1 as a fine powder. The product was dried for 12 hrs at 60° C. in vacuo. Yield 61.2 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.5% | Stage #1: 3-methyl-butan-2-one; 4-hydrazino-benzenesulfonic acid With acetic acid at 115℃; for 4h; Inert atmosphere; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | 1.3; 5; 6.3 0203] 1.3 2,3,3,-Trimethylindoleninium-5-sulfonate. To an oven dried 500-mL round bottomed flask equipped with a stirring bar, a reflux condenser and a nitrogen balloon was add p-hydrazinobenzenesulfonic acid hemihydrate (50.0 g, 0.253 mol), acetic acid (150 mL), and 3-methyl-2-butanone (84 mL, 0.785 mol). Heated the reaction mixture with stirring in an oil bath at 1 15 °C for 4 h. Monitored the reaction with TLC (2: 1 CH2Cl2:MeOH; starting material Rf = 0.42, product Rf = 0.69) until all starting material was consumed. Removed oil bath and cooled the reaction solution to ambient temperature. Slowly added EtOAc (-200 mL) and the resultant pink solid were collected via filtration with the aid of EtOAc (2 X 50 Attorney Docket No. 67191-5037WO mL). After brief drying the solid was dissolved in MeOH (700 mL). Added KOH (15 g) in iPrOH (200 mL) to the above solution and stirred. Collected the resultant yellow solid via filtration. Washed the solid with iPrOH (2 X 100 mL), EtOAc (3 X 100 mL) and air dried. Placed the solid in two amber bottles and dried in a desiccator under high vacuum overnight. There was obtained 48.8 g (69.5%) of the desired product as a potassium salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.4% | Stage #1: 4-methyl-5-oxohexane sulfonic acid; 4-hydrazino-benzenesulfonic acid With acetic acid at 115℃; for 30h; Inert atmosphere; Reflux; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol at 50℃; for 18h; | 1.49; 5 [0249] 1.49 2,3-Dimethyl-3-(3-sulfopropyl)indoleninium-5-sulfonate. To an oven dried 100-mL round bottomed flask equipped with a stirring bar, a reflux condenser and a nitrogen balloon was add p-hydrazinobenzenesulfonic acid hemihydrate (2.0 g, 0.010 mol), acetic acid (25 mL), and 4-methyl-5-oxo-l-hexanesulfonate (5.5 g, 0.028 mol). Heated the reaction mixture to reflux with stirring in an oil bath at 1 15 °C for 30 h. Removed the oil bath and cooled the reaction solution to ambient temperature. Solvent was evaporated off under reduced pressure to dryness. The residual crude product was triturated with MeOH/iPrOH (1 :5, 100 mL) and filtered. The solid was then dissolved in MeOH (400 mL) and filtered to remove the undissolved solid (starting material). The filtrate was poured into a beaker and to it was added KOH (1.19 g, 0.021 mol) in iPrOH (400 mL) and stirred. The resultant solid was collected, washed with iPrOH (2 x 20 mL), EtOAc (2 x 20 mL) and dried. Placed the solid in an amber bottle and dried in an oven at 50 °C under high vacuum for 18 h. There was obtained 2.94 g (68.4%) of the desired product as a potassium salt. |
Yield | Reaction Conditions | Operation in experiment |
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With sulfuric acid; acetic acid at 80 - 90℃; for 1h; | 1 2,3,4,5-Tetrahydro-1H-γ-carboline-8-sulfonic acids 12(1-4) (general method, scheme 12). A mixture of piperidone 10(1-4) (0.10 mol) and 4-hydrazinobenzenesulfonic acid 11 (18.8 g, 0.10 mol) in AcOH (200 ml) was boiled for 2 h. The precipitate formed after cooling the mixture was filtered off, washed with AcOH, i-PrOH, and hexane. It was dryed in the opened air. H2SO4 (50 ml) was added to suspension of the prepared product in AcOH (140 ml) and the resultant mixture was stirred at 80-90° C. for 1 h. After cooling the mixture was diluted with AcOH (200 ml) and poured into ether (1.5 l) at vigorous stirring. The solvent was decanted, the residue was twice washed with ether, treated with boiling methanol and left in freezer for night. Obtained precipitate of 2,3,4,5-tetrahydro-1H-γ-carboline-8-sulfonic acid 12(1-4) hydrosulfate was filtered off, washed with methanol, ether and dryed in vacuo. Compounds 12(1-4) were prepared as hydrosulfates, yield 59-74%: LCMS 2-methyl-2,3,4,5-tetrahydro-1H-γ-carboline-8-sulfonic acid 12(1) hydrosulfate-m/z: 267 (M+H)+; 2-benzyl-2,3,4,5-tetrahydro-1H-γ-carboline-8-sulfonic acid 12(2) hydrosulfate-m/z: 343 (M+H)+; 2-ethyloxycarbonyl-2,3,4,5-tetrahydro-1H-γ-carboline-8-sulfonic acid 12(3) hydrosulfate-m/z: 325 (M+H)+; 2-tert.-butyloxycarbonyl-2,3,4,5-tetrahydro-1H-γ-carboline-8-sulfonic acid 12(4) hydrosulfate-m/z: 353 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: 4-methyl-5-oxohexane sulfonic acid; 4-hydrazino-benzenesulfonic acid In acetic acid at 140℃; for 4h; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | 2 Example 2 Synthesis of 2,3-dimethyl-3-(3-sulfopropyl)-3H-indole-5-sulfonic acid di-potassium salt used to synthesize Example 3 compound 1 -(2-methoxy-ethyl)-2,3-dimethyl-5-sulfo-3-(3- sulfo-propyl)-3H-indolium andExample 4 compound 1 -[2-(2-methoxy-ethoxy)-ethyl]-2,3-dimethyl-5-sulfo-3-(3-sulfo-propyl)-3H-indolium andExample 5 compound 1-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl}-2,3-dimethyl-5-sulfo-3-(3-sulfo- propyl)-3H-indolium andExample 6 compound 1 -(5-carboxypentyl)-2,3-dimethyl-5-sulfo-3-(3-sulfopropyl)-3H-indoliumTen g (51 mmol) 4-hydrazino-benzene sulfonic acid and 9.85 g (51 mmol) 4-methyl-5- oxohexane sulfonic acid were dissolved in 50 ml acetic acid. The solution was heated at 140°C for 4 h. The solvent was evaporated in vacuum. The oily residue was dissolved in 20 ml methanol, then 50 ml of a saturated solution of KOH in 2-propanol was added to yield a yellow precipitate. The solid was filtered off and dried in vacuum. Yield 1 1 g, MS (ESI-): 172.5 [M]2" | |
11 g | Stage #1: 4-methyl-5-oxohexane sulfonic acid; 4-hydrazino-benzenesulfonic acid With acetic acid at 140℃; for 4h; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | 2 Ten g (51 mmol) 4-hydrazino-benzene sulfonic acid and 9.85 g (51 mmol) 4-methyl-5-oxohexane sulfonic acid were dissolved in 50 ml acetic acid. The solution was heated at 140° C. for 4 h. The solvent was evaporated in vacuum. The oily residue was dissolved in 20 ml methanol, then 50 ml of a saturated solution of KOH in 2-propanol was added to yield a yellow precipitate. The solid was filtered off and dried in vacuum. Yield 11 g, MS (ESI-): 172.5 [M]2- |
11 g | Stage #1: 4-methyl-5-oxohexane sulfonic acid; 4-hydrazino-benzenesulfonic acid With acetic acid at 140℃; for 4h; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | 2 EXAMPLE 2 SYNTHESIS OF 2,3-DIMETHYL-3-(3-SULFOPROPYL)-3H-INDOLE-5-SULFONIC ACID DI-POTASSIUM SALT EXAMPLE 2 SYNTHESIS OF 2,3-DIMETHYL-3-(3-SULFOPROPYL)-3H-INDOLE-5-SULFONIC ACID DI-POTASSIUM SALT USED TO SYNTHESIZE EXAMPLE 3 COMPOUND 1-(2-METHOXY-ETHYL)-2,3-DIMETHYL-5-SULFO-3-(3-SULFO-PROPYL)-3H-INDOLIUM AND EXAMPLE 4 COMPOUND 1-[2-(2-METHOXY-ETHOXY)-ETHYL]-2,3-DIMETHYL-5-SULFO-3-(3-SULFO-PROPYL)-3H-INDOLIUM AND EXAMPLE 5 COMPOUND 1-{2-[2-(2-METHOXY-ETHOXY)-ETHOXY]-ETHYL}-2,3-DIMETHYL-5-SULFO-3-(3-SULFO-PROPYL)-3H-INDOLIUM AND EXAMPLE 6 COMPOUND 1-(5-CARBOXYPENTYL)-2,3-DIMETHYL-5-SULFO-3-(3-SULFOPROPYL)-3H-INDOLIUM Ten g (51 mmol) 4-hydrazino-benzene sulfonic acid and 9.85 g (51 mmol) 4-methyl-5-oxohexane sulfonic acid were dissolved in 50 ml acetic acid. The solution was heated at 140° C. for 4 h. The solvent was evaporated in vacuum. The oily residue was dissolved in 20 ml methanol, then 50 ml of a saturated solution of KOH in 2-propanol was added to yield a yellow precipitate. The solid was filtered off and dried in vacuum. Yield 11 g, MS (ESI-): 172.5 [M]2- |
11 g | Stage #1: 4-methyl-5-oxohexane sulfonic acid; 4-hydrazino-benzenesulfonic acid With acetic acid at 140℃; for 4h; Stage #2: With potassium hydroxide In methanol; isopropyl alcohol | 2 Ten g (51 mmol) 4-hydrazino-benzene sulfonic acid and 9.85 g (51 mmol) 4-methyl-5-oxohexane sulfonic acid were dissolved in 50 ml acetic acid. The solution was heated at 140° C. for four h. The solvent was evaporated in vacuum. The oily residue was dissolved in 20 ml methanol, then 50 ml of a saturated solution of KOR in 2-propanol was added to yield a yellow precipitate. The solid was filtered off and dried in vacuum. Yield 11 g, MS (ESI-): 172.5 [M]2 |
Yield | Reaction Conditions | Operation in experiment |
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82% | Stage #1: C35H44N2O5S3 With hydrogenchloride In methanol at 90℃; Stage #2: 4-hydrazino-benzenesulfonic acid In ethanol; water at 90℃; for 16h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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43% | Stage #1: C19H19N2O(1+)*CF3O3S(1-); 4-hydrazino-benzenesulfonic acid With pyridine In methanol for 75h; Inert atmosphere; Stage #2: With acetic acid at 100℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
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60 g | Stage #1: 5-methyl-6-oxoheptan-1-sulfonic acid sodium salt; 4-hydrazino-benzenesulfonic acid With acetic acid for 6h; Reflux; Stage #2: With potassium hydroxide In methanol for 3h; | 2 2,3-Dimethyl-3-(4-sulfobutyl)-3H-indole-5-sulfonic acid, dipotassium salt. 4-Hydrazinobenzenesulfonic acid (40g), 5-methyl-6-oxoheptane-l -sulfonic acid (from 3a; 60g) and acetic acid (500ml) were mixed and heated under reflux for 6hrs. The solvent was filtered, rotary evaporated and dried under vacuum. The solid was dissolved in methanol (lL). To this was added 2M methanolic potassium hydroxide (300ml). The mixture was stirred for 3 hours and then the volume of solvent reduced by 50% using rotary evaporation. The resulting precipitate was filtered, washed with methanol and dried under vacuum. Yield 60g. MS (LCMS) : MH+ 362. Acc. Mass: Found, 362.0729. MH+ = C14H2oN06S2 requires m/z 362.0732 (-0.8ppm). |
Yield | Reaction Conditions | Operation in experiment |
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23 g | In acetic acid for 4h; | 1 Synthesis of 3-(5-carboxypentyl)-2,3-dimethyl-5-sulfo-1-(3-sulfopropyl) indolium sodium salt (1d), (Scheme I) The nonanonic acid is refluxed in 110 mL of acetic acid with 13.5 g of 4-hydrazinobenzenesulfonic acid for 4 hours. The acetic acid is evaporated and the product is purified on silica gel to yield 23 g of the product (IVa). |
Yield | Reaction Conditions | Operation in experiment |
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13.7% | With acetic acid for 20h; Reflux; | 2 Synthesis of 3-(2-phosphonoethyl)-3H-5-indolenines 2,3-dimethyl-3-(2-diethylphosphonatethyl)-3H-5-indolesulfonic acid (1i) A mixture of 4.70 g (20 mmol) of diethyl 3-methyl-4-oxo-1-butylphosphonate, 3.75 g (20 mmol) of 4-hydrazinobenzenesulfonic acid (synthesis as described above), and 40 ml of acetic acid was refluxed for 20 hours. The insoluble precipitate was filtered and the filtrate was evaporated. The obtained residue was column purified (RP-18, water) to yield 1.27 g (13.7%) of title product as brown sludge oil. λabs 260 nm (water). δH (200 MHz, DMSO-d6): 7.69 (1H, s, arom H), 7.61 (1H, d, 8.2 Hz, arom H), 7.41 (1H, d, 8.2 Hz arom H), 3.99-3.78 (4H, m, POCH2), 2.30 (3H, s, 2-CH3), 2.23-1.84 (2H, m, CH2) 1.33 (3H, s, 3-C H3), 1.24-1.09 (6H, m, CH2CH3), 0.96-0.71 (2H, m, C H2). |
Yield | Reaction Conditions | Operation in experiment |
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60 g | Stage #1: 5-methyl-6-oxoheptane-1-sulphonic acid; 4-hydrazino-benzenesulfonic acid With acetic acid for 6h; Reflux; Stage #2: With potassium hydroxide In methanol for 3h; | 2 2,3-Dimethyl-3-(4-sulfobutyl)-3H-indole-5-sulfonic acid, dipotassium salt. 4-Hydrazinobenzenesulfonic acid (40g), 5-methyl-6-oxoheptane-1-sulfonic acid (from 3a; 60g) and acetic acid (500ml) were mixed and heated under reflux for 6hrs. The solvent was filtered, rotary evaporated and dried under vacuum. The solid was dissolved in methanol (lL). To this was added 2M methanolic potassium hydroxide (300ml). The mixture was stirred for 3 hours and then the volume of solvent reduced by 50% using rotary evaporation. The resulting precipitate was filtered, washed with methanol and dried under vacuum. Yield 60g. MS (LCMS) : MH+ 362. Acc. Mass: Found, 362.0729. MH+ = requires m/z 362.0732 (-0.8ppm |
60 g | Stage #1: 5-methyl-6-oxoheptane-1-sulphonic acid; 4-hydrazino-benzenesulfonic acid With acetic acid for 6h; Reflux; Stage #2: With potassium hydroxide In methanol for 3h; | 3.3b (3b) 2'3-Dimethyl-3-(4-sulfobutyl)-3H-indole-5-sulfonic acid , diootassium salt 4-Hydrazinobenzenesulfonic acid (40g), 5-methyl-6-oxoheptane-1 -sulfonic acid (from 3a; 60g) and acetic acid (500ml) were mixed and heated under reflux for 6 hours. The solvent was filtered, rotary evaporated and dried under vacuum. The solid was dissolved in methanol (1 L). To this was added 2M methanolic potassium hydroxide (300ml). The mixture was stirred for 3 hours and then the volume of solvent reduced by 50% using rotary evaporation. The resulting precipitate was filtered, washed with methanol and dried under vacuum. Yield 60g. MS (LCMS) : MH+ 362. Acc. Mass: Found, 362.0729. MFT = CMH2ONO6S2 requires m/z 362.0732 (-0.8ppm). |
Yield | Reaction Conditions | Operation in experiment |
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With acetic acid Reflux; | 61 EXAMPLE 61Preparation of Compound 83 10222] A mixture of 100 mg of 4-acetylcyclohexanecar- boxylic acid and 120mg of hydrazinobenzenesulfonic acid is refluxed in 5 mL of acetic acid to obtain the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
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With acetic acid for 3h; Reflux; | 62 EXAMPLE 62Preparation of Compound 84 10224] A mixture of 2-(4-carboxyphenyl)-butan-2-one and hydrazinobenzenesulfonic acid in acetic acid is refluxed for 3 hours to obtain the desired product. |
Yield | Reaction Conditions | Operation in experiment |
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9.7 g | With acetic acid for 8h; Reflux; | 5 Preparation of Compound 5 The mixture of methyl 7-methyl-8-oxo-nonanoate (Compound 3, 6.9 g, 34.4 mmol) and 4-hydrazinobenzenesulfonic acid (6.45 g, 32.7 rnol) in acetic acid (50 mL) is heated to reflux for 8 hours. After removal of the solvent, the residue is purified on silica gel to give Compound 5 (9.7 g). |
3 g | In acetic acid for 3h; Reflux; | 13 Example 13 Preparation of Compound No. 13 A mixture of p-hydrazinobenzenesulfonic acid (5 g), methyl 7-methyl-8-oxononanoate (6 g) (US patent application 2006/0121503 A1) in acetic acid (20 mL) was refluxed gently for 3 hours. After cooling down to room temperature, the mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel to give a reddish brown solid (3 g). The solid was mixed with NaOAc (1 equivalent) in MeOH (100 mL) and the resulting solution was stirred at room temperature for 30 minutes. The solution was concentrated to dryness under vacuum to give a reddish brown solid (3 g). |
Yield | Reaction Conditions | Operation in experiment |
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270 mg | In acetic acid Reflux; | 28 Example 28 Preparation of Compound No. 28 A mixture of p-hydrazinobenzenesulfonic acid (100 mg) and compound No. 27 (300 mg) in acetic acid (5 mL) was heated to reflux overnight. After cooling down to room temperature, the mixture was concentrated to dryness and the residue was purified by column chromatography on silica gel a pale brown solid (270 mg). The solid was mixed with NaOAc (1 equivalent) in MeOH (10 mL) and the resulting solution was stirred at room temperature for 30 minutes. The solution was concentrated to dryness under vacuum to give reddish brown solid (280 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With acetic acid In water at 60℃; for 3h; | Benzaldehyde (4-sulfophenyl)hydrazone (1). A mixture of 18.8 g (0.1mol) of (4-hydrazinobenzene)sulfonic acid, 40 mL of water, 10 mL of acetic acid, and 11.7 g (0.1 mol) of benzaldehyde was stirred at 60° for 3 h. The reaction product was precipitated with saturated aqueous sodium chloride and twice recrystallized from 70% ethanol. Yield 19 g (72%), mp243-246° (decomp.). 1 NMR spectrum, δ, ppm (J,Hz): 7.01 d (2, 2,6, J 8.6), 7.30 t (, 13, J 7.4Hz), 7.39 t (2, 12,14, J 7.6 Hz), 7.50 d (2, 3,5, J8.6), 7.65 d (2, 11,15, J 7.3), 7.88(1H, C9), 10.49 s(1H, NH). 13 NMR spectrum, δ, ppm: 111.10 (2,6),126.18 (11,15), 127.31 (3,5), 128.53 (13), 129.14(12,14), 136.13 (10), 137.56 (9), 139.11 (4), 145.85(1). Mass spectrum, m/z (Irel, %): 196 (16) [ - SO3]+,178 (100) [ - SO3 - NH3]+. Mcalc 31. Found, %: 49.38; H 4.87; N 8.45; S 10.42. C13H12N2O3S·2H2O. Calculated, %: 49.99; H 5.16; N 8.97; S 10.27. At 80° and 10 mm Hg the compound loses 11.2% of weight, which corresponds to the fraction of the water of crystallization. Found, %: 56.11; H 4.58; N 9.85;S 11.13. C13H12N2O3S. Calculated, %: 56.51; H4.38; N 10.14; S 11.60. The IR spectral data are listed in Table 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.3% | With acetic acid for 4h; Reflux; | 5.3 The compound of the above two steps (2.1 g, 12.3 mmol, 1 eq) and p-hydrazinobenzenesulfonic acid(2 g, 12.3 mmol, 1 eq, Aldrich) was dissolved in 16 mL of acetic acid and refluxed for 4 hours.After completion of the reaction, the reaction mixture was cooled to room temperature, and the resulting solid was filtered, washed with ethyl acetate three times, and dried under reduced pressure. The dried compound was purified by column chromatography (SiO2, isobutanol / n-propanol / water / ethyl acetate) to obtain the desired compound (790 mg, 20.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | Stage #1: 4-hydrazino-benzenesulfonic acid With sodium hydroxide In water at 45℃; for 0.5h; Stage #2: benzaldehyde In water at 55 - 60℃; for 3.5h; | 2.2.3. The preparation of 4-[(2Z)-2-benzylidenehydrazinyl] benzenesulfonic acid (5) The 198.75 g (1 mole) quantity (considering 95% pure) of 4-hydrazinylbenzenesulfonic acid (3) was measured accurately on analytical-balance and was added into a beaker of 3 L having 2508 ml H2O and 99.99 ml sodium hydroxide was transferred toaccomplish pH~10. The reaction mixture was heated on constantstirring at the temperature of 45 °Cfor 30 min to complete dissolution. Subsequently, the reaction mixture was cooled down toroom temperature and was sifted to confiscate contamination andun-dissolved materials. Then, the filtered reaction solution was transferred into the reactor of 3 L capacity and was heated up to the temperature of 55 - 60 °C. At that temperature, the condensationreaction was performed by the addition of 106.2 g (1 mol) of benzaldehyde (4) dropwise in 30 min on constant stirring and heating (55 - 60 °C) with constant mixing was provided to the reaction mixture until the reaction was completed. The reaction was completed in 3 h and the precipitation of the required product was accomplished through salting out and acidification process at pH~2.5 at room temperature (30 C). The 20% of NaCl of the totalvolume of the solution and 25 ml HCl were employed for precipitation.Afterwards, the precipitates was filtrated off at ambienttemperature and the filtered cake of the productwas dried out in an electric-oven at the temperature of 60 °C until constant weight obtained. The percentage yield was 97% of the theoretical amountand the product was 4-[(2Z)-2-benzylidenehydrazinyl] benzenesulfonic acid (5) which was coupler reagent used for the prepartionof formazan dyes (18-23) through the azo-coupling reaction. Thisproduct (5) was purified through the procedure of [20,21] and theprepartion of 4-[(2Z)-2-benzylidenehydrazinyl] benzene sulfonicacid (5) was denoted in Scheme 1. |
96% | With 1-deoxy-1-(methylamino)-D-glucitol In ethanol; water at 20℃; for 0.5h; | |
Stage #1: 4-hydrazino-benzenesulfonic acid With sodium hydroxide In water at 45℃; for 0.5h; Stage #2: benzaldehyde at 55 - 60℃; for 3h; | 2.2.3 Synthesis of 4-[(2Z)-2-benzylidenehydrazinyl] benzene sulfonic acid (5) To a beaker of 3L, quantity 198.75g (1mol) of 4-hydrazinylbenzenesulfonic acid (3) weighed on analytical balance by considering it 95% pure and dissolved it by the addition of 2508ml of water as well as 99.99ml of NaOH added to attain pH∼10, heated with continuous stirring for 30min at 45°C. Afterwards, cool down and filter it to remove impure and undissolved materials. Solution was shifted in 3L reactor and heated to 55-60°C. Condensation reaction was done by the drop-wise addition of benzaldehyde (4) 106.2g (1mol) in 30min at 55°C with continuous stirring. Stirring plus heating continue till complete reaction. Reaction completed in 3h. Then the precipitation achieved by acidification as well as salting out process at pH∼2.5at room temperature which is done by employing the 25ml HCl and 20% of NaCl of the total volume of the solution. After, filtration was done through filtration unit at ambient temperature. Filtered cake was dried in electric oven at 60°C. % age yield was 97% of the theoretical amount. 4-[(2Z)-2-benzylidenehydrazinyl] benzene sulfonic acid (5) was that coupler reagent which was employed for the synthesis of formazan dyes by the azo coupling reaction. This product (5) was purified by following the method as described by Refs.[20,21]. Scheme 1 exhibited the synthesis of 4-[(2Z)-2-benzylidenehydrazinyl] benzene sulfonic acid (5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | Stage #1: 4-sulfobenzenediazonium With sodium sulphite-heptahydrate In water at 0 - 5℃; for 2h; Stage #2: With hydrogenchloride In water for 0.5h; | 2.2.2. The preparation of 4-hydrazinylbenzenesulfonic acid (3) For the reduction of diazonium salt, 565 g of crystalline Na2SO37H2O was added into a beaker of 3 L containing 830 ml of water and provided the stirring until a clear solution of it was not achieved. The Sodium sulfite solution was cooled in an ice bath to accomplish 0 - 5 °C temperature and on this temperature, the diazonium salt wet paste (2)was transferred into the beaker of Sodium sulfite solution in 1 h and orange coloration was started to appear in reaction solution without turbidity. Afterwards, a constant stirring was provided to the reaction solution for 1 h. Subsequently, the reaction solution was heated to boil-age on constant stirring and 664 ml of concentrated HCl was added in 30 min. The color of reaction solution was become lightens and lastly very light yellow color was seemed at the end of reaction. The reaction mixture was cooled down to room temperature over a period of over-night and after the formation of precipitate formation, reaction mixture was sifted through sanction unit, and cold water was employed to wash the precipitates. The precipitates of 4-hydrazinyl benzenesulfonicacid (3) dried out in an electric-oven at the temperature of 100 °C. Further purification of the 4-hydrazinylbenzenesulfonic acid (3) was performed following the method [19]. The percentage yield of the product was 96% of the calculated amount. The preparation of 4-hydrazinylbenzenesulfonic acid (3) was denoted in Scheme 1. |
95% | With sulfuric acid; sodium sulfite at 0 - 5℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.7 g | With sodium acetate; acetic acid for 4h; Reflux; | 1.4 1.4 Synthesis of Compound 31 Weigh 5g of 4-mercaptobenzenesulfonic acid, 3.2g of 3-methyl-2-butanone, and 4.4g of sodium acetate into a 100mL single-mouth bottle.After 25 mL of acetic acid, it was heated to reflux for 4 h. Rotate the solvent,The red crystal product was separated by column chromatography to obtain 5.7 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 3-Bromophthalide With hydrogenchloride In water for 2h; Reflux; Stage #2: 4-hydrazino-benzenesulfonic acid In water at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: rac-methyl 6-methyl-7-oxooctanoate; 4-hydrazino-benzenesulfonic acid With acetic acid for 4h; Reflux; Stage #2: With sodium carbonate In methanol at 20℃; for 15h; | 6 Sodium 3-(5-methoxy-5-oxopentyl)-2,3-dimethyl-3H-indole5-sulfonate (12). Methyl 6- methyl-7-oxooctanoate (1.86 g, 10 mmol) was added to a stirred solution of p- hydrazinobenzenesulfonic acid (2.24 g, 10 mmol) in acetic acid (6 mL). The solution was heated to reflux for 4 h, then cooled to room temperature. The solvents were evaporated. Na2C03 (1.06 g, 10 mmol) was added to the residue dissolved in methanol (15 mL). The resulting mixture was stirred at room temperature for 15 h. The solvents were evaporated, and the residue was purified by reverse phase column chromatography to provide 12 (2.72 g, 7.6 mmol, 76%). NMR (400 MHz, CD3OD): δ 7.84-7.80 (m, 2H), 7.46 (d, 1H, J= 7.8 Hz), 3.57 (s, 3H), 2.28 (s, 3H), 2.16 (dt, 2H, J = 7.4, 2.3 Hz), 2.04-1.84 (m, 2H), 1.50-1.41 (m, 2H), 1.34 (s, 3H), 0.74-0.56(m, 2H). LC-MS (ESI) 340 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With toluene-4-sulfonic acid In ethanol at 80℃; | 1 Preparation of CN-sensor In a 100 mL round bottom flask,Add 5 mmol of o-hydroxynaphthaldehyde, 6 mmol p-hydrazinobenzenesulfonic acid, 0.17 g of p-toluenesulfonic acid, 30 mL of solvent ethanol were stirred under reflux at 80 ° C overnight, and the reaction solution was brownish yellow; after the solution was cooled, suction filtration, washing with water, and drying to obtain a yellow product X 1.42 g, yield 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In water; at 60℃; for 2h; | 25.0 g of 2-sulfobenzaldehyde sodium salt (manufactured by Tokyo Chemical Industry Co., Ltd.) and 22.6 g of p-hydrazinobenzene sulfonic acid 0.5 hydrate (manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in 250 mL of RO water, and 11.8 g of sodium acetate was added thereto. The mixture was heated and stirred in a water bath at 60 C. for 2 hours. After completion of the heating and stirring, the solvent was removed. The residue thus obtained was washed with methanol, and then a precipitate was separated by filtration. The precipitate thus obtained was dried, and thus hydrazone compound 7 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With acetic acid at 118℃; for 18h; Inert atmosphere; | 1.1-1 Example 1-1 Preparation of Ammonium 2,3,3-trimethyl-3H-indole-5-sulfonate (3NH 4) A 1 L round bottom flask equipped with an oil bath, stirrer bar, reflux condenser, rubber septum and nitrogen injector was prepared. Then, after nitrogen injection, 4-hydrazinobenzenesulfonic acid (1) (60 g, 319 mmol) was weighed and placed in the reaction flask. Glacial acetic acid (AcOH) (300 mL) was measured in a graduated cylinder and added to the reaction flask. Then, 3-methyl-2-butanone (2) (3-methyl-2-butanone) (45 mL, 418 mmol) was added through a 50 mL syringe. The flask was stirred under nitrogen atmosphere for 18 hours while heating to reflux (118 ± 3 ° C.). After 18 hours, heating was stopped and the oil bath was removed and cooled to room temperature. At this time, the solution in the flask was dark red. A 3 L flask was prepared on the stirrer and EA 2 L was added to the flask. The solution in the reaction flask was slowly poured into the 3L flask and a pink precipitate formed. After vigorous stirring for at least 30 minutes, the pink solid was filtered using a Buchner funnel. And the precipitate was washed with EA 500mL. The filtered precipitate was dried in a vacuum desiccator for 24 hours (overnight). Then ammonium 2,3,3-trimethyl-3H-indole-5-sulfonate (3NH4) as a light pink solid (Ammonium 2,3,3-Trimethyl-3H-indole-5-sulfonate) (65 g, 80 % yield) was obtained and no further purification was performed. |
80% | With acetic acid at 118℃; for 18h; Inert atmosphere; | 1.1-1 Example 1-1: Preparation of ammonium 2,3,3-trimethyl-3H-indole-5-sulfonate (3NH 4) A 1 L round bottom flask equipped with an oil bath, stirrer bar, reflux condenser, rubber septum and nitrogen injector was prepared. Then, after nitrogen injection, 4-hydrazinobenzenesulfonic acid (1) (60 g, 319 mmol) was weighed and placed in a reaction flask. Glacial acetic acid (AcOH) (300 mL) was measured in a graduated cylinder and added to the reaction flask. Then, 3-methyl-2-butanone (2) (3-methyl-2-butanone) (45 mL, 418 mmol) was added through a 50 mL syringe. The flask was stirred for 18 hours under a nitrogen atmosphere while heating to reflux temperature (118 ± 3 ° C.). After 18 hours, heating was stopped and the oil bath was removed and cooled to room temperature. At this time, the solution in the flask was dark red. A 3 L flask was prepared on a stirrer, and 2 L of EA was added to the flask. The solution in the reaction flask was slowly poured into the 3L flask, and a pink precipitate formed. After vigorous stirring for at least 30 minutes, the pink solid was filtered using a Buchner funnel. Then, the precipitate was washed with 500 mL of EA. The filtered precipitate was dried in a vacuum desiccator for 24 hours (overnight). Then, ammonium 2,3,3-trimethyl-3H-indole-5-sulfonate (3NH4) as a light pink solid (Ammonium 2,3,3-Trimethyl-3H-indole-5-sulfonate) (65 g, 80 % yield), and no further purification was performed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: ethanol; C10H16O4; 4-hydrazino-benzenesulfonic acid With hydrogenchloride for 12h; Reflux; Stage #2: With potassium hydroxide In methanol; propan-1-ol at 20℃; for 12h; | 1.2; 3.2 (2) Synthesis of the Compound Represented by Formula 1-b The compound represented by Formula 1-b was synthesized by Reaction 1-2. p-Hydrazinobenzenesulfonic acid (20 g, 106 mmol) and the compound represented by Formula 1-a (59.4 g, 319 mmol), which was synthesized by Reaction 1-1, were added to a mixture of a 6 N solution of hydrochloric acid (30 mL) and ethanol (60 mL). The resulting mixture was stirred under reflux for 12 h. The reaction mixture was cooled to room temperature and the resulting solid was filtered. The solid was washed with ethyl acetate and dried under reduced pressure. A solution of the solid (5.1 g, 21.2 mmol) in 35 mL of methanol was added dropwise to a solution of potassium hydroxide (1.4 g, 25.4 mmol) in 35 mL of propanol. Thereafter, the resulting solution was stirred at room temperature for 12 h. The solid was filtered, dried, and purified by C18 reverse-phase chromatography using water/methanol (11.1 g, 30%). LC-MS: m/z=404.86[M+] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate at 100℃; Overall yield = 78 percent; | Ethyl benzoylformate (1.1 equiv, 1.96 g, 0.011 mol) was added to a suspension of 4-hydrazinobenzenesulfonic acid hemihydrate (1 equiv, 1.88 g, 0.01 mol) in water (5 mL) at 100 °C. Heating was stopped once all the solids were dissolved. Then sodium bicarbonate was added until the pH of the solution turned 7 followed by the addition of sodium chloride to precipitate the product. Overall yield: 78% (Z/E=8/2)after reversed-phase column chromatography (water: ethanol=1: 1).1-Z 1H NMR (500 MHz, D2O) 7.68 (d, J = 8.7 Hz, 2H), 7.61 (d, J = 6.5 Hz, 2H), 7.43 - 7.35 (m, 3H), 7.32(d, J = 7.2 Hz, 2H), 4.31 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (126 MHz, D2O) δ163.19, 144.94, 135.79, 135.40, 130.09, 128.37, 128.16, 127.99, 126.87, 113.63, 62.06, 13.17. m.p. 96.0- 96.7 °C. High Res ESI-MS: C16H15N2O5S-: 347.0705 (calculated: 347.0702).1-E 1H NMR (500 MHz, D2O) δ 7.64 (d, J = 8.9 Hz, 2H), 7.58 - 7.38 (m, 3H), 7.37 - 7.31 (m, 2H), 7.19 (d,J = 8.9 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (126 MHz, D2O) δ 166.17,144.96, 135.93, 135.66, 130.17, 129.67, 129.50, 129.11, 126.90, 114.03, 62.73, 13.35. High Res ESI-MS:C16H15N2O5S-: 347.0703 (calculated: 347.0702). The melting point is not reported because of thermalrelaxation when heating above 120 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; tetrabutylammomium bromide / dichloromethane / 15 h / 20 °C 4.2: 4 h / -78 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; tetrabutylammomium bromide / dichloromethane / 15 h / 20 °C 4.2: 4 h / -78 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; water / 60 °C 5.2: 0.25 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; tetrabutylammomium bromide / dichloromethane / 15 h / 20 °C 4.2: 4 h / -78 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; water / 60 °C 5.2: 0.25 h / 20 °C 6.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; tetrabutylammomium bromide / dichloromethane / 15 h / 20 °C 4.2: 4 h / -78 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; water / 60 °C 5.2: 0.25 h / 20 °C 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere; Sealed tube 6.2: 1 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 8 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; tetrabutylammomium bromide / dichloromethane / 15 h / 20 °C 4.2: 4 h / -78 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; water / 60 °C 5.2: 0.25 h / 20 °C 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere; Sealed tube 6.2: 1 h / 20 °C 7.1: trifluoroacetic acid / 0.08 h / 60 °C 8.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 9 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; tetrabutylammomium bromide / dichloromethane / 15 h / 20 °C 4.2: 4 h / -78 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; water / 60 °C 5.2: 0.25 h / 20 °C 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere; Sealed tube 6.2: 1 h / 20 °C 7.1: trifluoroacetic acid / 0.08 h / 60 °C 8.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 20 °C / Inert atmosphere 9.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: acetic acid / 1.5 h / 130 °C 1.2: 15 h 2.1: potassium hydrogencarbonate; potassium iodide / acetonitrile / 48 h / 85 °C 3.1: acetic anhydride; triethylamine / methanol / 15 h / 20 °C 4.1: tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride; tetrabutylammomium bromide / dichloromethane / 15 h / 20 °C 4.2: 4 h / -78 °C / Inert atmosphere 5.1: hydrogenchloride / methanol; water / 60 °C 5.2: 0.25 h / 20 °C 6.1: N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere; Sealed tube 6.2: 1 h / 20 °C 7.1: trifluoroacetic acid / 0.08 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: rac-methyl 6-methyl-7-oxooctanoate; 4-hydrazino-benzenesulfonic acid With acetic acid at 130℃; for 1.5h; Stage #2: With potassium carbonate In methanol for 15h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5 g | With acetic acid at 130℃; for 6h; Inert atmosphere; Sealed tube; | Preparation of sodium 2,3,3-trimethyl-1-(4-sulfonatobutyl)-3H-indol-1-ium-5-sulfonate (105) A mixture of 4-hydrazinobenzenesulfonic acid (6 g, 31.9 mmol, 1 equiv), NaOAc (5 g, 63.8 mmol, 2.0 equiv), and 3-methyl-2-butanone (8 g, 92.9 mmol, 2.95 equiv) in glacial acetic acid (36 mL) was heated at 130° C. under a nitrogen atmosphere in a sealed tube. The crude product was filtered, washed with methyl tert-butyl ether, and collected 103 after precipitation as a brown solid (5 g, 98% purity); mp 292 to 293° C. |
Tags: 98-71-5 synthesis path| 98-71-5 SDS| 98-71-5 COA| 98-71-5 purity| 98-71-5 application| 98-71-5 NMR| 98-71-5 COA| 98-71-5 structure
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Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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