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CAS No. : | 50890-83-0 | MDL No. : | MFCD00272569 |
Formula : | C9H8N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OVVDFORZEGKEJM-UHFFFAOYSA-N |
M.W : | 176.17 | Pubchem ID : | 689105 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 9 |
Fraction Csp3 : | 0.11 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.95 |
TPSA : | 55.12 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.36 cm/s |
Log Po/w (iLOGP) : | 1.41 |
Log Po/w (XLOGP3) : | 1.43 |
Log Po/w (WLOGP) : | 1.27 |
Log Po/w (MLOGP) : | 1.04 |
Log Po/w (SILICOS-IT) : | 0.78 |
Consensus Log Po/w : | 1.19 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -2.28 |
Solubility : | 0.926 mg/ml ; 0.00525 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.19 |
Solubility : | 1.13 mg/ml ; 0.00642 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.84 |
Solubility : | 2.52 mg/ml ; 0.0143 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.59 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride; | 1-Methyl-indazole-3-carbonyl chloride A stirred suspension of 1-methyl-indazole-3-carboxylic acid (0.68 g, 3.86 mol) in anhydrous ether (50 ml) was treated with thionyl chloride (0.28 ml, 3.84 mol) and a few drops of dimethylformamide. After stirring for one hour the solid dissolved. The solvent was evaporated to give 1-methyl-indazole-3-carbonyl chloride as a yellow solid (0.75 g, 100%). |
With thionyl chloride; In chloroform; | EXAMPLE 14 A stirred mixture of <strong>[50890-83-0]1-methyl-3-indazolylcarboxylic acid</strong> (0.31 g), thionyl chloride (2 ml) and chloroform (10 ml) was refluxed for 2 hours and the solvent was evaporated to give a residue of 1-methyl-3-indazolylcarbonyl chloride. | |
With thionyl chloride; In N,N-dimethyl-formamide; at 20℃; for 4h;Heating / reflux; | EXAMPLE 1; Preparation of l-Methyl-indazole-3-carbonyl chloride; Into an all glass reactor, charged chloroform (12L), followed by l-methyl-indazole-3- carboxylic acid (2Kg) and N,N-dimethylformamide (0.2L). Then slowly added thionyl chloride (4Kg) at room temperature. Raised the mass temperature to reach reflux condition and maintained at reflux condition for 4 hr. Checked the completion of the reaction by HPLC. Then distilled off chloroform and excess thionyl chloride completely under vaccum. Cooled the reaction to room temperature and added chloroform (5L) and again distilled off chloroform completely under vacuum. Repeated the operation one more time with fresh chloroform (5L). Cooled the reaction mass to room temperature. As the acid chloride is an unstable compound, dissolved the acid chloride in methylene chloride (40L) and kept the reaction mass under nitrogen atmosphere till proceed to next stage. A small sample was taken, triturated with n-hexane, quickly filtered under nitrogen atmosphere and dried under vacuum and checked IR and M.P. The IR spectrum showed a strong band at 1748 cm'1 and MP is 122C. |
With thionyl chloride; | Following the example described in EP 200444, at pages 4-5, 1-MICA is converted to its corresponding acid chloride with thionyl chloride using conventional methods. | |
With thionyl chloride; In chloroform; | EXAMPLE 14 A stirred mixture of <strong>[50890-83-0]1-methyl-3-indazolylcarboxylic acid</strong> (0.31 g), thionyl chloride (2 ml) and chloroform (10 ml) was refluxed for 2 hours and the solvent was evaporated to give a residue of 1-methyl-3-indazolylcarbonyl chloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With hydrogenchloride; sodium hydroxide; In tetrahydrofuran; | (Step 7) Synthesis of 1-methylindazole-3-carboxylic acid In THF (250 ml) was dissolved methyl 1-methylindazole-3-carboxylate (4.49 g, 23.6 mmol). To the resulting solution was added 0.25N NaOH (145 ml, 35.4 mmol), followed by stirring at room temperature for 24 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added 1N HCl (145 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water, and dried under reduced pressure to give 1-methylindazole-3-carboxylic acid (2.81 g, 68%) as a pale yellow solid. 1H-NMR (DMSO-d6) delta: 4.15 (s, 3H), 7.32 (m, 1H), 7.48 (m, 1H), 7.75 (d, J=8.1Hz, 1H), 8.08 (d, J=8.1Hz, 1H), 12.96 (broad s, 1H). MS (ESI) m/z 177 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at -18℃; for 0.5h; | a) (1-Methyl-lH-indazol-3-yl) methanol; 1-Methyl-1H indazole-3-carboxylic acid (0.500 g, 2.84 mmol) was dissolved in dry THF and Et3N (0.435 mL, 3.12 mmol) was added. The mixture was stirred and cooled to-18C and isobutyl chloroformate (0.426 g, 3.12 mmol) was added dropwise. After 30 min the slurry was filtered and the filtrate was cooled again to-18C. Sodium borohydride (0.322 g, 8 : 51 mmol) was added plus a few drops of water. When foaming had subsided 8 mL of water was added, the cooling bath was removed and the reaction mixture was stirred for lh. The THF was evaporated and the residue was diluted with a few mL of water and extracted three times with EtOAc. The combined organic layer was washed with water, dried over Na2SO4, filtered and evaporated. The crude product was chromatographed on a pre-packed Si02-column (Isolute, 20 g) eluted with DCM: MeOH 95: 5. Yield: 0.320 g (70%). 'H NMR (500 MHz, CDC13) 8 7.80 (d, 1H), 7.39 (m, 1H), 7.32 (d, 1H), 7.15 (t, 1H), 5.01 (bd, 2H), 3.96 (s, 3H), 2.82 (bs, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | From n-hexane-ethyl acetate (1:1, v/v) elude fractions, 1-methylindazole-3-carboxylate (4.52 g, 73%) was obtained as a yellow solid. 1H-NMR (CDCl3) delta: 4.04 (s, 3H), 4.17 (s, 3H), 7.31-7.35 (m, 2H), 7.46 (d, J=4.4Hz, 1H), 8.22 (d, J=8.1Hz, 1H). MS (ESI) m/z 191 (M++1). | |
Examples of the indazole-3-carboxylic acids or their derivatives include the following: indazole-3-carboxylic acid, 1-methylindazole-3-carboxylic acid, 1-ethylindazole-3-carboxylic acid, 1-propylindazole-3-carboxylic acid, 1-isopropylindazole-3-carboxylic acid, 1-butylindazole-3-carboxylic acid, 1-isobutylindazole-3-carboxylic acid, 1-(sec-butyl)indazole-3-carboxylic acid, (S)-1-(sec-butyl)indazole-3-carboxylic acid, ... | ||
2.49 g (87%) | 1-Methylindazole-3-carboxylic acid Methyl-1-methylindazole-3-carboxylate (3.1 g, 0.016 mol) was stirred with a solution of sodium hydroxide (0.78 g, 0.02 mol) in tetrahydrofuran (100 ml) for 2 hours at room temperature, the solution evaporated and the yellow residue were dissolved in water. Acidification with methanesulfonic acid precipitated 1-methylindazole-3-carboxylic acid (2.19 g). A further crop (0.3 g) was obtained by extraction of the aqueous acid solution with a mixture of ether and methylene chloride. Total yield 2.49 g (87%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 4 Preparation of 1-methyl-N-(tetrahydro-1H-pyrrolizin7a(5H)-ylmethyl)-1H-indazole-3-carboxamide STR31 Following the procedure of example 1, 7a- Aminomethylhexahydro-1H-pyrrolizine is reacted with <strong>[50890-83-0]N-methylindazole-3-carboxylic acid</strong> [J. Medicinal Chemistry (1987) 30: 1535]to afford the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With CDI; In N,N-dimethyl-formamide; | (1) To a solution of 2.00 g (11.35 mmol) of <strong>[50890-83-0]1-methylindazole-3-carboxylic acid</strong> in 30 ml of DMF was added 1.84 g (11.35 mmol) of CDI at room temperature, and the mixture was stirred for 2 hours at the same temperature. To this solution was added a solution of 2.50 g (12.48 mmol) of cis-3-t-butoxycarbonylamino-4-methylpyrrolidine in 10 ml of DMF at room temperature, the mixture was stirred overnight at room temperature. After completion of the reaction, DMF was distilled off and concentrated residue was purified with silica gel column chromatography (methylene chloride:methanol=30:1). By crystalizing from ether, 2.26 g (76.1%) of cis--t-butoxycarbonylamino-4-methyl-l-(1-methylindazol-3-ylcarbonyl)pyrrolidine was obtained. m.p. 186-187 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With CDI; triethylamine; In ethanol; water; N,N-dimethyl-formamide; | EXAMPLE 11 3-Dimethylamino-(1-methylindazol-3-ylcarbonyl)pyrrolidine hydrochloride Into 3 ml of DMF was dissolved 491 mg (2.79 mmol) of 1-methylindazol-3-carboxylic acid, and to the solution was added 452 mg (2.79 mmol) of CDI and was stirred for 2 hours at room temperature. To this solution was added at room temperature a solution obtained by dissolving 423 mg (2.79 mmol) of 3-dimethylaminopyrrolidine hydrochloride into 8 ml of DMF, adding 1.0 ml (7.1 mmol) of triethylamine and stirring for 0.5 hour at room temperature. After the mixture was stirred for 2 hours at the same temperature, DMF was distilled off under reduced pressure and to the residue was added water, then the solution was extracted with methylene chloride. After washed with saturated saline solution and dried over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure to obtain pale orange oil. This was subjected to silica gel column chromatographic purification (methylene chloride:methanol=20:1 to 10:1) to obtain 565 mg (76.2%) of pale orange oil. This oil was dissolved with 5 ml of ethanol, was added with 0.7 ml of ethanol saturated with hydrogen chloride under cooling with ice. Deposited crystal was collected by filtration to obtain 528 mg of aimed compound. m.p. 278-281 C. (decompd.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.23 g (39%) | In tetrahydrofuran; | EXAMPLE 8 N-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)-1-methyl-1H-indazole-3-carboxamide A suspension of <strong>[50890-83-0]1-methyl-1H-indazole-3-carboxylic acid</strong> (1.76 g, 0.0101 mole) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 0.0115 mole). After a few minutes bubbling commenced and the solid dissolved, and, after a few more minutes, a precipitate formed. The suspension was diluted with anhydrous N,N-dimethylformamide (3 ml), stirred for two hours, then degassed over 15 minutes under a stream of nitrogen. A solution of the free base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.03 g, 0.013 mole) in anhydrous tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 18 hr and at 50 C. for 4 hr, then concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (2*30 ml) containing some 2-propanol). The combined organic solution was concentrated in vacuo, and the residual gum washed with water (50 ml) to remove most of the imidazole and then dried azeotropically with toluene. The gum was taken up in tetrahydrofuran and filtered through alumina (eluted with 20% methanol/tetrahydrofuran) and the concentrated filtrate was recrystallized from acetonitrile to afford 1.23 g (39%) of the title compound as a pale yellow solid; mp 147-149 C. Analysis: Calculated for C17 H22 N4 O2: C, 64.95; H, 7.05; N, 17.82. Found: C, 64.78; H, 7.06; N, 17.82. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With triethylamine; In dichloromethane; water; N,N-dimethyl-formamide; | (Step 1) Synthesis of methyl (3-Chloro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate To <strong>[50890-83-0]1-methylindazole-3-carboxylic acid</strong> (600 mg, 3.41 mmol) and DMF (27.0 ael, 0.34 mmol) was added methylene chloride (20 ml). Under stirring at room temperature, oxalyl chloride (0.36 ml, 4.09 mmol) was added dropwise to the resulting mixture. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 50 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (5 ml). The resulting solution was added to a solution of methyl 4-amino-3-chlorophenylacetate (680 mg, 3.41 mmol) and triethylamine (1.42 ml, 10.2 mmol) in methylene chloride (5 ml) under stirring at room temperature. The reaction mixture was heated under reflux at room temperature for 7 hours. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (2:1, v/v) eluate fractions, methyl (3-chloro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (1.08 g, 89%) was obtained as a yellow solid. 1H-NMR (CDCl3) delta: 3.61 (s, 2H), 3.72 (s, 3H), 4.18 (s, 3H), 7.24 (dd, J=8.6,2.0Hz, 1H), 7.34 (m, 1H), 7.38 (d, J=2.0Hz, 1H), 7.45-7.50 (m, 2H), 8.41 (d, J=8.0Hz, 1H), 8.61 (d, J=8.6Hz, 1H), 9.47 (broad s, 1H). MS (LCMS) m/z 358 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With triethylamine; In N,N-dimethyl-formamide; benzene; | (Step 8) Synthesis of ethyl (5-chloro-2-fluoro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate In benzene (30 ml), oxalyl chloride (0.54 ml, 6.24 mmol) was added dropwise to 1-methylindazolyl-3-carboxylic acid (1.00 g, 5.68 mmol) and DMF (44.0 ael, 0.57 mmol) under stirring at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour. A solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (1.31 g, 5.68 mmol) and triethylamine (4.74 ml, 34.0 mmol) in benzene (5.0 ml), which solution had been prepared in advance, was added to the reaction mixture. The resulting mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (3:1, v/v) eluate fractions, (5-chloro-2-fluoro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (1.40 g, 63%) was obtained as a colorless solid. 1H-NMR (CDCl3) delta: 1.28 (t, J=7.1Hz, 3H), 3.62 (s, 2H), 4.17 (s, 3H), 4.18 (q, J=7.1Hz, 2H), 7.33-7.39 (m, 2H), 7.44-7.50 (m, 2H), 8.38 (d, J=8.3Hz, 1H), 8.53 (d, J=11.9Hz, 1H), 9.50 (broad s, 1H). MS (ESI) m/z 390 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | Calcium oxide (7.0 g, 0.124 mole, 2 molar equiv.) was added to technical methanol (150 ml) under nitrogen atmosphere and the mixture was heated under reflux for 2 hours. Indazole-3-carboxylic acid (10 g, 0.062 mole) was then added and the mixture was heated under reflux for 2 hours. lodomethane (26.3 g, 11.55 ml, 0.185 mole, 3 equiv.) in methanol (20 ml) was then added dropwise under reflux for 2 hours and the reflux was continued for a further 24 hours (the composition of the reaction mixture by HPLC was: 95.07% 1-MICA, 0.46% 2-MICA, and 4.47% ICA). The mixture was kept at room temperature overnight (the composition of the reaction mixture by HPLC was: 98.87% 1-MICA, 0.50% 2-MICA, and 0.63% ICA). Water (100 ml) and conc. hydrochloric acid were added to the mixture to produce pH of about 4. The mixture was filtered and the methanol was removed under reduced pressure from the filtrate. The residuary suspension was stirred vigorously for 6 hours with a control of pH of about 4. The solid product was collected by filtration, washed with water (3 x 30 ml), and dried in oven at 50C overnight to obtain crude 1-MICA (10.8 g, 99% yield, purity by HPLC: 99.82%). The crude 1-MICA was treated by slurry in water (50 ml) at room temperature for 4 hours. The solid product was collected by filtration, washed with water (3 x 30 ml), and dried oven at 50C overnight to give pure 1-MICA (9.1 g, 83.8% yield, purity by HPLC: 99.91%). | |
With hydrogenchloride; sodium chloride; sodium hydrogencarbonate; In dimethyl sulfoxide; mineral oil; | 1(b) 1-Methyl-indazole-3-carboxylic acid A solution of 15.7 g of indazole-3-carboxylic acid [prepared as described in step (a)] in 200 ml of dimethylsulphoxide was added to a suspension of 11 g of sodium hydrogencarbonate (a 55% dispersion in mineral oil) in 70 ml of dimethylsulphoxide. The resulting mixture was stirred at room temperature for 1 hour. 16.6 g of methyl iodide were then added to the mixture, and the mixture was stirred for a further 2 hours at room temperature. At the end of this time, the reaction mixture was poured into ice water, and then made acidic by the addition of a 1 N aqueous solution of hydrochloric acid. The mixture was then extracted with ethyl acetate and, after the ethyl acetate layer had been washed with a saturated aqueous solution of sodium chloride, it was dried over anhydrous sodium sulphate. The solvent was then removed by distillation under reduced pressure, and the residue was recrystallized from ethanol to give 11.9 g of the title compound, melting at 212-213C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methyl isobutyl ketone (MIBK); at -5 - 25℃;Product distribution / selectivity; | Example (1) Preparation of Granisetron hydrochloride; 10OmL of methyl isobutyl ketone (MIBK), 8.6g of triethylamine and 1Og of 1- methyl indazole-3-carboxylic acid were placed in a 25OmL RBF. The reaction mass was stirred and treated with 7.4g of ethyl chloro formate at O0C to (-) 50C to get a mixed anhydride and then condensed with 8.75g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 100 mL of water was added, organic layer separated and distilled to 8 volumes of MIBK, cooled the reaction mass and treated with 10.3g of IPA/HC1 (~ 20%) to get 1Og of Granisetron hydrochloride. ; Example (2) Preparation of Granisetron base; 75OmL of methyl isobutyl ketone, 4Og of triethylamine and 5Og of 1-methyl indazole-3-carboxylic acid were placed in a 2L RBF. The reaction mass was stirred and treated with 34g of ethyl chloro formate at 20C to 25C to get a mixed anhydride and then condensed with 48g of endo-9-methyl-9-azabicycolo [3.3.1] nonan-3-amine and stirred the reaction mass till the completion of reaction. To the reaction mixture 500 mL of water was added and the organic layer separated, washed with 5% sodium carbonate(50OmL) solution and distilled the organic layer to obtain Granisetron freebase with HPLC purity 99.91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of 1 -methyl- 1 H-indazole-3 -carboxylic acid (46.0 mg; 0.26 mmol), HOBt (44.4 mg; 0.33 mmol), EDC (84.0 mg; 0.44 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. 2-(2-chloro-5-nitro-phenyl)-2-methyl-propylamine (50.0 mg; 0.22 mmol), prepared as described in 131(A), was added and the stirring was maintained at the same temperature for additional 16 hours. The reaction was diluted with DCM and washed in sequence with 0.5M IQ2CO3 (twice), IN HCl and brine. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to furnish the title compound as a white solid. This compound was used as such in the next step.LCMS (RT): 4.5 min (Method A); MS (ES+) gave m/z: 387.09 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6.1% | To a solution of (iS)-?-butyl -4-(2-fluoro-4-(5-((methoxycarbonothioylamino) methyl)-2~oxooxazolidin-3-yl)phenyl)piperazine-l-carboxylate (0.5 g, 1.07 mmol)(prepared according to the procedure described in the step 2 of example 1) in DCM (5 ml), trifluoroacetic acid (0.4 ml, 4.28 mmol) was added drop wise and stirred well for12 hours. DCM was evaporated under reduced pressure and the residue was washed with diethyl ether (15ml) and the precipitate obtained was dried under high vacuum. This precipitate (0.52g, 1.07mmol) was then dissolved in dry THF (5ml) into which N- methyl indazole-3-carboxylic acid (0.19g, 1.07mmol), 1-hydroxybenztriazole hydrate(HOBt) (0.03g, 0.22mmol), benzotriazole-] -y.-oxy-tris-(dimethylarnino)- phosphoniumhexafluoro phosphate (BOP) (0.57g, 1.28mmol) and <n="55"/>Diisopropylethy'lamine (DIPEA) (0.9ml, 5.22 mmol) were added under stirring. The resulted reaction mass was stirred until completion of the reaction which was confirmed by TLC after 15 hours. The reaction mass was then poured into crushed ice. Semisolid residue obtained after decanting the aqueous supernatent liquid was then dissolved in DCM followed by brine wash. The organic layer was separated, dried over Na2SO4 and the solvent was removed under vacuum. The crude reaction material was purified by flash chromatography on silica gel using a Biotage SP-I system (12+M) cartridge using ethyl acetate and hexane as eluent to afford the title compound (0.03g, 6.1%). 1H-NMR (DMSOd6): (52.1(s, 3H), 3.06 (bs, 4H), 3.46 -3.47 (m, 2H), 3.88 (m, 3H), 4.10- 4.19 (m, 6H), 4.73 (m, IH), 7.10 -7.19 (m, 2H), 7.26 (m, IH), 7.46 - 7.53 (m, 2H), 7.72 - 7.75 (m, IH), 7.98 - 8.00 (m, I H), 8.55 (m, I H, D2O exchangeable). Mass (m/z): 527.1 (M+ +1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
D. Example 15 Synthesis of (R)-1-Methyl-1H-indazole-3-carboxylic acid[1-(2-cyclopropyl-5-m-tolyl-thiazole-4-carbonyl)-piperidin-3-yl]-amideD.1.1. (R)-1-Methyl-1H-indazole-3-carboxylic acid[1-(2-cyclopropyl-5-m-tolyl-thiazole-4-carbonyl)-piperidin-3-yl]-amide1-Methyl-1H-indazole-3-carboxylic acid (21.1 mg, 0.12 mmol) was dissolved in DMF (1 ml) followed by the addition of TBTU (42.4 mg, 0.132 mmol) and DIEA (77.6 mg, 0.60 mmol). Stirring at RT was continued for 15 min. (R)-(3-Amino-piperidin-1-yl)-(2-cyclopropyl-5-m-tolyl-thiazol-4-yl)-methanone (50 mg, 0.12 mmol) was added and stirring at RT was continued for 16 h followed by the addition of formic acid (0.25 ml) and direct purification of the reaction mixture via preparative HPLC to give 17.5 mg of (R)-1-Methyl-1H-indazole-3-carboxylic acid[1-(2-cyclopropyl-5-m-tolyl-thiazole-4-carbonyl)-piperidin-3-yl]-amide. LC-MS: tR=1.07 min; [M+H]+=499.99. | ||
D.I.I. (R)-l-Methyl-lH-indazole-3-carboxylic acid [l-(2-cyclopropyl-5-m-tolyl- thiazole-4-carbonyl)-piperidin-3-yl]-amide 1 -Methyl- lH-indazole-3-carboxylic acid (21.1 mg, 0.12 mmol) was dissolved in DMF (1 ml) followed by the addition of TBTU (42.4 mg, 0.132 mmol) and DIEA (77.6 mg, 0.60 mmol). Stirring at RT was continued for 15 min. (R)-(3-Amino-piperidin-l-yl)- (2-cyclopropyl-5-m-tolyl-thiazol-4-yl)-methanone (50 mg, 0.12 mmol) was added and stirring at RT was continued for 16h followed by the addition of formic acid (0.25 ml) and direct purification of the reaction mixture via preparative HPLC to give 17.5 mg <n="36"/>of (R)-I -Methyl- lH-indazole-3-carboxylic acid [l-(2-cyclopropyl-5-m-tolyl-thiazole- 4-carbonyl)-piperidin-3-yl]-amide. LC-MS: tR = 1.07 min; [M+H]+ = 499.99.(Precursors were prepared according to procedures described above) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.6% | Calcium oxide (7.0 g, 0.124 mole, 2.0 molar equiv.) was added to technical methanol (150 ml) and the mixture was heated under reflux for 2 hours in a nitrogen atmosphere. Indazole-3-carboxylic acid (10 g, 0.062 mole) was then added and the reflux was continued for 2 hours. Dimethyl sulfate (15.6 g, 11.8 ml, 0.124 mole, 2.0 molar equiv.) was added dropwise under reflux for 2 hours and the reflux was continued for a further 2 hours (the composition of the reaction mixture by HPLC was: 96.49% 1-MICA, 0.75% 2-MICA, and 2.76% ICA). Water (100 ml) and 46% aqueous sodium hydroxide solution were added to produce pH of about 14. Then, conc. hydrochloric acid was added to the reaction mixture to produce pH of about 4. Calcium sulfate was collected by filtration and washed on filter with hot methanol (3 x 30 ml). The methanol was removed under reduced pressure from the filtrate. The residuary mixture was stirred vigorously for 6 hours with a control pH of about 4. The solid product was collected by filtration, washed with water (3 x 30 ml), and dried in oven at 50C overnight to give crude 1-MICA (10.4 g, 95.8% yield, purity by HPLC: 99.0%). The crude 1-MICA (10.4 g) was treated by slurry in methanol-water (3:7) mixture at heating under reflux for 4 hours. The suspension was cooled to room temperature and the solid product was collected by filtration, washed with methanol-water (3:7) mixture (3×10 ml), and dried in oven at 50C overnight to give pure 1-MICA (9.3 g, 85.6% yield, purity by HPLC: 99.70%). | |
83.8% | Magnesium (3 g, 0.123 mole, 2 molar equiv.) was added to technical 1-propanol (100 ml) and the mixture was heated to reflux under nitrogen atmosphere. Then, sublimed iodine (0.2 g) as catalyst was added and the reflux was continued for 4 hours to obtain magnesium propoxide. Indazole-3-carboxylic acid (10 g, 0.0617 mole) was then added and the reflux was continued for 2 hours. Dimethyl sulfate (13.3 g, 10 ml, 0.105 mole, 1.7 molar equiv.) was added dropwise under reflux for 2 hours and the reflux was continued for a further 3 hours (the composition of the reaction mixture by HPLC was: 97.09% 1-MICA, 0.37% 2-MICA, and 2.54% ICA). The mixture was kept at room temperature overnight (the composition of the reaction mixture by HPLC was: 97.61% 1-MICA, 0.19% 2-MICA, and 2.21% ICA). Water (100 ml) and 46% aqueous sodium hydroxide solution were added to the reaction mixture to produce pH of about 14. Then, conc. hydrochloric acid was added to the suspension to produce pH of about 4 and obtain a solution. The 1-propanol was removed under reduced pressure from the solution. The residuary mixture was stirred for 6 hours with a control of pH of about 4. The solid product was collected by filtration, washed with water (3 x 30 ml), and dried in oven at 50C overnight to give crude 1-MICA (10.2 g, 93.9% yield, purity by HPLC: 98.73%). The crude compound (10.2 g) was treated by slurry at heating under reflux in methanol-water (3:7) mixture (31 ml) for 4 hours. The precipitate was collected by filtration after cooling the mixture to room temperature, washed with methanol-water (3:7) mixture (3 × 10 ml), and dried in oven at 50C overnight to prepare pure 1-MICA (9.1 g, 83.8% yield, purity by HPLC: 99.71%). | |
79.2% | Magnesium ethoxide (14.10 g, 0.124 mole, 2 molar equiv.) was added to technical 1-propanol (100 ml) under nitrogen atmosphere and the mixture was heated under reflux for 2 hours. Indazole-3-carboxylic acid (10 g, 0.0617 mole) was then added and the reflux was continued for a further 2 hours. Dimethyl sulfate (13.3 g, 10 ml, 0.105 mole, 1.7 molar equiv.) was added dropwise under reflux for 2 hours to the suspension and the reflux was continued for a further 2 hours (the composition of the reaction mixture by HPLC was: 96.03% 1-MICA, 1.50% 2-MICA, and 2.50% ICA). The mixture was kept at room temperature overnight (the composition of the reaction mixture by HPLC was: 97.52% 1-MICA, 1.44 % 2-MICA, and 1.04% ICA). Water (100 ml) and 46% aqueous sodium hydroxide solution were added to the mixture to produce pH of about 14. Then, conc. hydrochloric acid was added to the suspension to produce pH of about 4 and obtain a solution. The 1-propanol removed under reduced pressure from the solution. The residuary mixture was stirred vigorously for 6 hours with a control of the pH of about 4. The solid product was collected by filtration, washed with water (3 x 15 ml), and dried in oven overnight at 50÷C to yield crude 1-MICA (10.8 g, 99.4% yield, purity by HPLC: 99.3%). The crude 1-MICA (10.8 g) was treated by slurry in methanol-water (3:7) mixture (33 ml) at heating under reflux for 4 hours. The solid product was collected by filtration after cooling the mixture to room temperature, washed with methanol-water (3:7) mixture (3 x 10 ml), and dried in oven overnight at 50C to give pure 1-MICA (8.6 g, 79.2% yield, purity by HPLC: 99.87%). |
65.4% | Barium oxide (19 g, 0.124 mole, 2 molar equiv.) was added to technical 1-propanol (150 ml) under nitrogen atmosphere and the mixture was heated under reflux for 2 hours. Indazole-3-carboxylic acid (10 g, 0.062 mole) was then added and the mixture was heated under reflux for 2 hours. Dimethyl sulfate (15.6 g, 11.8 ml, 0.124 mole, 2 molar equiv.) was added dropwise under reflux for 2 hours (the composition of the reaction mixture by HPLC was: 99.14% 1-MICA, 0.16% 2-MICA, and 0.71% ICA). The mixture was kept at room temperature overnight (the composition of the reaction mixture by HPLC was: 99.28% 1-MICA, 0.15% 2-MICA, and 0.56% ICA). Water (100 ml) and 46% aqueous sodium hydroxide solution were added to the mixture to produce pH of about 14. Then, 20% aqueous sulfuric acid was added to produce pH of about 4, barium sulfate was collected by filtration and washed on filter with hot 1-propanol (3 x 30 ml). The 1-propanol was removed under reduced pressure from the filtrate and the residuary mixture was stirred vigorously for 6 hours with a control of the pH of about 4. The solid product was collected by filtration, washed with water (3 x 30 ml) and dried in oven at 50% C overnight to yield crude 1-MICA (8.7 g, 80.1% yield, purity by HPLC: 99.50%). The crude 1-MICA was treated by slurry in methanol- water (3:7) mixture (30 ml) at heating under reflux for 4 hours. The precipitate was collected by filtration after cooling the mixture to room temperature, washed with methanol-water (3:7) mixture (3 x 10 ml) and dried in oven at 50C overnight to give pure 1-MICA (7.1 g, 65.4% yield, purity by HPLC: 99.88%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.3% | Magnesium ethoxide (14.10 g, 0.124 mole, 2 molar equiv.) was added to technical 1-propanol (100 ml) under nitrogen atmosphere and the mixture was heated under reflux for 2 hour. Indazole-3-carboxylic acid (10 g, 0.0617 mole) was then added and the reflux was continued for 2 hours. Trimethyl phosphate (14:7 g, 12.3 ml, 0.105 mole, 1.7 molar equiv.) was added dropwise under reflux for 2 hours and the reflux was continued for a further 5 hours (the composition of the reaction mixture by HPLC was: 95.61% 1-MICA, 1.89% 2-MICA, and 2.50% ICA). The mixture was kept at room temperature overnight (the composition of the reaction mixture by HPLC was: 97.24% 1-MICA, 2.17% 2-MICA, and 0.58% ICA). Water (100 ml) and 46% aqueous sodium hydroxide solution were added to the reaction mixture to produce pH of about 14. Then, conc. hydrochloric acid was added to the suspension to produce pH of about 4 and obtain a solution. The propanol was removed under reduced pressure from the solution. The residuary mixture was stirred vigorously for 6 hours with a control of the pH of about 4. The solid product was collected by filtration, washed with water (3 x 30 ml), and dried in oven at 50C overnight to give crude 1-MICA (10.1 g, 93.0% yield, purity by HPLC: 99.24%). The crude 1-MICA (10.1 g) was treated by slurry in methanol-water (3:7) mixture (31 ml) at heating under reflux for 4 hours. The solid product was collected by filtration, washed with methanol-water (3:7) mixture (3 × 10 ml), and dried in oven at 50C to obtain pure 1-MICA (8.5 g, 78.3% yield, purity by HPLC: 99.78%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Example 27 To a 50 mL flask containing 20 mL of DMF was added 1 ml_ of oxalyi chloride slowly and stirred for 10 min at RT. 100 mg of i-Methyl-I H-indazole-3-carboxyiic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH4OH. The solvent was evaporated under vacuum and the residue dissolved in CH3CN and water and purified with prep HPLC (0% to 95% water/ Acetonitrile) to afford 27 (32 mg, 43%).1H-NMR (DMSO, 300 MHz): delta 10.37 (s, 1 H), 8.50 (s, 1 H), 8.10 (d, J = 6.9 Hz, 1 H), 7.72-7.64 (m, 4H), 7.40 (s, 1 H), 7.26-7.23 (m, 2H), 7.04-6.80 (m, 4H), 4.85 (me, 1 H), 4.12 (S, 3H), 3.22-3.10 (m, 3H), 2.78-2.70 (m, 1 H)1 0.66 (m, 2H)1 0.52 (m, 2H). LCMS m/z [M+H]+ C32H27N5O3S requires: 561.65. Found 562.04 HPLC Tr (min), purity %: 3.46, 98% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In methanol; at 20℃; for 14h; | Preparation Example 17 <strong>[50890-83-0]1-methyl-1H-indazole-3-carboxylic acid</strong> (2.64 g) was mixed with methanol (20 ml) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (4.57 g) and methylamine (40% methanol solution, 2.0 ml) were added thereto at room temperature. After stirring at room temperature for 14 hours, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with water-saturated brine (1:1) and further saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain N,1-dimethyl-1H-indazole-3-carboxamide (1.84 g) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 18h; | Example 1.6: (S)-N.1 -dimethyl-N-(4-(1 -methvl-1 H-pyrrole-2-carboxamidoH - phenylbutan-2-vQ-1H-indazole-3-carboxamideTo a solution of 1 -methyl- 1H-pyrrole-2-carboxylic acid ((S)-3-methylamino-4-phenyl-butyl)- amide hydrochloride (160 mg, 0.497 mmol), 1 -methyl- 1 H-indazole-3-carboxylic acid(107 mg, 0.597 mmol), HOBt (91 mg, 0.597 mmol) and triethylamine (0.345 ml, 2.49 mmol) in DCM (5 ml) was added EDC x HCI (1 14 mg, 0.746 mmol). The reaction was stirred at rt for 18 h. The mixture was diluted with DCM and washed with sat. Na2C03 and brine, dried (MgS04), filtered and concentrated. Purification by flash chromatography (DCM:MeOH, 97:3) gave the title compound (97 mg, 45%). [1H-NMR (DMSO, 600 MHz, rotamers) 7.97 - 7.88 (d, 1 H), 7.68-7.52 (m, 3H), 7.29-7.13 (m, 5H), 7.16-7.11 (m, 1 H), 6.88-6.83 (d, 1 H), 6.74-6.60 (d, 1 H), 6.01-5.95 (dd, 1H), 5.10 (m, 1 H), 3.98/4.07 (s, 3H), 3.81/3.69 (s, 3H), 3.86-2.86 (m, 4H), 3.09/2.98 (s, 3H), 1.96-1.66 (m, 2H); LCMS RtF = 1.24 min; [M+H]+ = 444.4]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With dmap; dicyclohexyl-carbodiimide; In tetrahydrofuran; at 20℃; for 24h; | General procedure: To a solution of 5-(1,4-diazepan-1-yl)-5-(4-phenoxyphenyl)pyrimidine-2,4,6(1H,3H,5H)-trione (394 mg, 1 mmol) in 10 ml THF was added DCC (206 mg, 1 mmol), DMAP (132 mg, 1 mmol) and the substituted carboxylic acids (1 mmol). The mixture was stirred at room temperature for 24 h before filtering. The solvents of the filtrate were removed in vacuo and the resulting crude products purified by flash column chromatography to yield pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sulfuric acid; for 4h;Reflux; | To the stirred suspension of N-methyl indazolic acid (10 g, 0.056 mol) in 100 ml methanol added 10 ml sulphuric acid dropwise. The reaction mixture heated to reflux for 4 h. After completion of reaction, reaction mass concentrated and neutralized with saturated sodium bicarbonate solution and extracted with 100 ml ethyl acetate, ethyl acetate layer wash with 50 ml water, dried over anhydrous sodium sulphate and concentrate on Rotavapor solid obtained was filtered, washed with chilled ethyl acetate (10 ml), Yield. 85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With hydrazine hydrate; acetic acid;Reflux; | To the suspension of 1-methyl-1H-indazole-3-carboxylate (10 g, 0.52 mol) in ethanol 20 ml were added hydrazine hydrate (5.2 g, 0.10 mol) and 1 ml of glycial acetic acid. The reaction mass was heated at reflux temp for 4-6 h. After completion of reaction, reaction mixture was cooled to room temperature separated solid was filtered and washed with chilled 5 ml ethanol and dried at 50-60 C. Yield. 89% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With 1,1'-carbonyldiimidazole; In tetrahydrofuran; at 20℃; for 1.5h; | To a solution of <strong>[50890-83-0]1-methylindazole-3-carboxylic acid</strong> (ig, 5.67 mmol) in dry THE (15 mL), CDI (1 g, 6.24 mmol) is added. The mixture is stirred at rt for 1 .5 h, then ammonium hydroxide (13 mL of a 30% solution in water) is added and the mixture stirred for additional 15 mm. Solvents are evaporated, the crude dissolved in EtOAc, washed with 0.1 N hydrochloric acid, sat. NaHCO3 and brine. The organic layer is separated, dried and evaporated under vacuum to obtain the title compound (840 mg, 83%) used in the next step without any further purification.1H NMR (300 MHz, DMSO-d6): 64.12 (5, 3H), 7.26 (ddd, J= 1.0, 6.7, 7.6 Hz, 1H),7.33 (br, s, 1 H), 7.46 (ddd, J = 1 .0, 6.8, 8.0 Hz, 1 H), 7.65 (br, 5, 1 H), 7.71 (dd, J =8.2 Hz, 1H), 8.16 (dd, J=8.2 Hz, 1H) |
83% | Example 6a 10456] Toa solutionofl-methylindazole-3-carboxylic acid (1 g, 5.67 mmol) in dry THF (15 mE), CDI (1 g, 6.24 mmol) is added. The mixture is stirred at it for 1.5 h, then ammonium hydroxide (13 mE of a 30% solution in water) is added and the mixture stirred for additional 15 mm. Solvents are evaporated, the crude dissolved in EtOAc, washed with 0.1 N hydrochloric acid, sat. NaHCO3 and brine. The organic layer is separated, dried and evaporated under vacuum to obtain the title compound (840 mg, 83%) used in the next step without any thither purification.10457] ?H NMR (300 MHz, DMSO-d5): oe 4.12 (s, 3H),7.26 (ddd, J=1.0, 6.7,7.6Hz, 1H), 7.33 (br, s, 1H), 7.46 (ddd, J=1.0, 6.8, 8.0 Hz, 1H), 7.65 (br, s, 1H), 7.71 (dd, J=8.2 Hz, 1H), 8.16 (dd, J=8.2 Hz, 1H) | |
83% | To a solution of 1 -methylindazole-3-carboxylic acid (1 g, 5.67 mmol) in dry THF (15 ml_), CDI (1 g, 6.24 mmol) is added. The mixture is stirred at rt for 1 .5 h, then ammonium hydroxide (13 ml_ of a 30% solution in water) is added and the mixture stirred for additional 15 min. Solvents are evaporated, the crude dissolved in EtOAc, washed with 0.1 N hydrochloric acid, sat. NaHCO3 and brine. The organic layer is separated, dried and evaporated under vacuum to obtain the title compound (840 mg, 83%) used in the next step without any further purification. 1H NMR (300 MHz, DMSO-c/6): delta 4.12 (s, 3H), 7.26 (ddd, J = 1 .0, 6.7, 7.6 Hz, 1 H), 7.33 (br, s, 1 H), 7.46 (ddd, J = 1 .0, 6.8, 8.0 Hz, 1 H), 7.65 (br, s, 1 H), 7.71 (dd, J = 8.2 Hz, 1 H), 8.16 (dd, J = 8.2 Hz, 1 H) |
83% | To a solution of 1 -methyl indazole-3-carboxylic acid (1 g, 5.67 mmol) in dry THF (15 ml_), CDI (1 g, 6.24 mmol) is added. The mixture is stirred at rt for 1 .5 h, then ammonium hydroxide (13 ml_ of a 30% solution in water) is added and the mixture stirred for additional 15 min. Solvents are evaporated, the crude dissolved in EtOAc, washed with 0.1 N hydrochloric acid, sat. NaHCO3 and brine. The organic layer is separated, dried and evaporated under vacuum to obtain the title compound (840 mg, 83%) used in the next step without any further purification. 1H NMR (300 MHz, DMSO-d6): delta 4.12 (s, 3H), 7.26 (ddd, J = 1 .0, 6.7, 7.6 Hz, 1 H), 7.33 (br, s, 1 H), 7.46 (ddd, J = 1 .0, 6.8, 8.0 Hz, 1 H), 7.65 (br, s, 1 H), 7.71 (dd, J = 8.2 Hz, 1 H), 8.16 (dd, J = 8.2 Hz, 1 H) |
Tags: 50890-83-0 synthesis path| 50890-83-0 SDS| 50890-83-0 COA| 50890-83-0 purity| 50890-83-0 application| 50890-83-0 NMR| 50890-83-0 COA| 50890-83-0 structure
[ 1201-24-7 ]
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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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