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CAS No. : | 112758-40-4 | MDL No. : | MFCD01313822 |
Formula : | C5H6N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NWDMGTFNIOCVDU-UHFFFAOYSA-N |
M.W : | 110.11 | Pubchem ID : | 2760056 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 28.94 |
TPSA : | 45.75 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.91 cm/s |
Log Po/w (iLOGP) : | 0.46 |
Log Po/w (XLOGP3) : | 0.08 |
Log Po/w (WLOGP) : | 0.53 |
Log Po/w (MLOGP) : | -0.63 |
Log Po/w (SILICOS-IT) : | 1.54 |
Consensus Log Po/w : | 0.4 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.97 |
Solubility : | 11.8 mg/ml ; 0.107 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.59 |
Solubility : | 28.0 mg/ml ; 0.254 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.51 |
Solubility : | 3.42 mg/ml ; 0.031 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.19 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: at 0℃; for 1.5 h; Stage #2: at 0 - 70℃; Stage #3: With sodium hydroxide In waterCooling with ice |
To cool DMF (65 ml_) at 0 3C, POCI3 (39 ml_) was added drop wise for 30 minutes, and maintained at 0 3C for 1 hour. To the mixture was added acetone semicarbazole (1 3 g, 1 14 mmol) portionwise at 0 3C and maintained at 70 9C for 4 hours. The mixture was poured over crushed ice (500 g), neutralized using 10percent NaOH solution and extracted using ethyl acetate (3x15OmL). The combined organic layers were washed with water (2x100 mL), saturated aqueous NaCI (100 mL), dried over anhydrous Na2SO4 and concentrated to obtain a crude product, which was purified by column chromatography (60-120 mesh silica gel) using 2-4percent methanol in chloroform as eluents to afford 3-methyl-1 H-pyrazole-4- carbaldehyde (4 g, 32percent) as solid. 1H NMR (CDCI3) δ 9.96 (s, 1 H), 8.0 (s, 1 H), 2.6 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h; | To a solution of ethyl 3-methyl-iH-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N- dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (x2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 2 as a white solid (5.47 g, 42 percent); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCls) δ 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, / = 5.4 Hz), 7.87 (1H, d, / = 5.4 Hz), 2.59 (s, 3H). |
42% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 14 h; | Preparation of 1-(2-chloropyrimidin-4-yl)-3-methyl-1H-pyrazole-4-carbaldehyde; Intermediate 1 To a solution of ethyl 3-methyl-1H-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N-dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (*2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 1 as a white solid (5.47 g, 42percent); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, J=5.4 Hz), 7.87 (1H, d, J=5.4 Hz), 2.59 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.106 g (44%) | With sodium hydroxide; In methanol; 1,1-dichloroethane; dichloromethane; | N2-[4-(4-amino-1-{1-[(3-methyl-1H-4-pyrazolyl)methyl]tetrahydro-1H-3-pyrrolyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.200 g, 0.415 mmol) in dichloroethane (5 mL) was treated with <strong>[112758-40-4]3-methyl-1H-pyrazol-4-carboxaldehyde</strong> (0.091 g, 0.83 mmol) and sodium triacetoxy borohydride (0.176 g, 0.83 mmol). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL) and ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (10 min), 20% methanol in dichloromethane (10 min) and 50% methanol in dichloromethane (8 min) as the eluent. The column afforded 0.106 g (44%) of pure N2-[4-(4-amino-1-{1-[(3-methyl-1H-4-pyrazolyl)methyl]tetrahydro-1H-3-pyrrolyl}-1H-pyrazolo [3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) delta 9.446 (s, 1H), 8.247 (s, 1H), 8.1275-8.1071 (d, 1H, J=8.16 Hz), 7.72-7.7003 (d, 1H, J=7.96 Hz), 7.6004-7.5793 (d, 1H, J=8.44 Hz), 7.398-7.286 (m, 5H), 7.172-7.134 (m, 1H), 5.379 (m, 1H), 4.0443 (s, 3H), 3.962 (s, 3H), 3.492 (m, 2H), 3.1 (m, 1H), 2.75 (m, 3H), 2.352-2.335 (m, 2H), 1.909 (s, 3H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 31m particle size, 33*4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.17 min (100%), MH+ 577.3. |
0.106 g (44%) | With sodium hydroxide; In methanol; 1,1-dichloroethane; dichloromethane; | N2-[4-(4-amino-1-{1-[(3-methyl-1H-4-pyrazolyl)methyl]tetrahydro-1H-3-pyrrolyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.200 g, 0.415 mmol) in dichloroethane (5 mL) was treated with <strong>[112758-40-4]3-methyl-1H-pyrazol-4-carboxaldehyde</strong> (0.091 g, 0.83 mmol) and sodium triacetoxy borohydride (0.176 g, 0.83 mmol). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (100 mL) and ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (15 min), 15% methanol in dichloromethane (10 min), 20% methanol in dichloromethane (10 min) and 50% methanol in dichloromethane (8 min) as the eluent. The column afforded 0.106 g (44%) of pure N2-[4-(4-amino-1-{1-[(3-methyl-1H-4-pyrazolyl)methyl]tetrahydro-1H-3-pyrrolyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) delta 9.446 (s, 1H), 8.247 (s, 1H), 8.1275-8.1071 (d, 1H, J=8.16 Hz), 7.72-7.7003 (d, 1H, J=7.96 Hz), 7.6004-7.5793 (d, 1H, J=8.44 Hz), 7.398-7.286 (m, 5H), 7.172-7.134 (m, 1H), 5.379 (m, 1H), 4.0443 (s, 3H), 3.962 (s, 3H), 3.492 (m, 2H), 3.1 (m, 1H), 2.75 (m, 3H), 2.352-2.335 (m, 2H), 1.909 (s, 3H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 mum particle size, 33*4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.17 min (100%), MH+ 577.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a solution of 3-methyl-1 H-pyrazole-4-carbaldehyde (9 g, 82 mmol) and diethyl succinate (57 g, 327 mmol) in t-butanol (50 mL), a solution of t-BuOK (37.3 g, 245 mmol) in t-butanol(40 mL) was added and the mixture was heated to 80 3C for 4 hours. The mixture was concentrated; the obtained residue was dissolved in water (50 mL), acidified (pH~2) using 6 N HCI and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with aqueous NaHCO3 (2x50 mL). The combined aqueous layers were acidified (pH~2) and extracted with ethyl acetate (2x100 mL). The combined ethyl acetate layers were washed with saturated aqueous NaCI (25 mL), dried over anhydrous Na2SO4 and concentrated to afford 3-(ethoxycarbonyl)-4-(3-methyl-1 H-pyrazol-4-yl)but-3-enoic acid (20 g, 100%) as gum. 1H NMR (CDCI3) delta 7.85 (s, 1 H), 7.65 (s, 1 H), 4.3 (t, 2H), 3.65 (s, 2H), 4.4 (s, 3H), 1.3 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 18h;Sealed tube; | 3. 3-Methyl-1-(3-(tetrahydrofuran-2-yl)pyridin-2-yl)-1H-pyrazole-4-carbaldehyde; To a screw-cap test tube containing 2-fluoro-3-(tetrahydrofuran-2-yl)pyridine (148 mg, 0.88 mmol) in dimethylformamide (2.2 mL) are added <strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong> (81 mg, 0.74 mmol) and potassium carbonate (152 mg, 1.1 mmol). The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and stirred in a preheated oil bath at 110 C. for 18 h with the aid of a magnetic stirrer. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate, filtered and the solvent evaporated in vacuo. The resulting residue is purified by silica gel using normal phase Isco chromatography eluting with hexane: acetone (gradient from 5 to 20% in acetone) to give 116 mg of the title compound. MS (m/z): 258 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 191-(3-Fluoro-2-pyridyl)-3-methyl-pyrazole-4-carbaldehyde; Potassium t-Butyl alcohol (29.25 g, 260.68 mmol) is added to a solution of <strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong> (26.00 g, 236.12 mmol) in dimethylformamide (250 mL) cooled with an aqueous bath. The mixture is stirred at room temperature for 10 min. Then, 2,3-difluoropyridine (25 g, 217.24 mmol) is added and the mixture is stirred at room temperature for 20 hr. The mixture is poured over an ice/water mixture and extracted in ethyl acetate (3×20 mL). Organics are dried over magnesium sulfate and solvent evaporated in vacuo. The residue is purified by silica gel chromatography using as eluent hexane/isopropyl alcohol to afford a crude material with residual dimethylformamide. The material is then dissolved in ethyl acetate (100 mL) and washed with water (3×20 mL). Aqueous phase is extracted with ethyl acetate (2×20 mL). Combined organics are dried over sodium sulfate and concentrated to give 19 g of the title compound. MS (m/z): 206 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PREPARATION 72-Chloro-4,4-difluoro-1'-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]; To a solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine (105 g, 375 mmol) in tetrahydrofuran (1.58 L) is added <strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong> (43.40 g, 394.12 mmol) and the mixture is stirred at room temperature for 1 hr. Then, powdered sodium triacetoxyborohydride (95.46 g, 450.42 mmol) is added in 3 portions. The mixture is stirred at room temperature for 15 h. Then, the reaction mixture is poured over an ice-sodium bicarbonate saturated aqueous solution (400 mL). Phases are separated. Aqueous phase is extracted with ethyl acetate (100 mL). Combined organic layers are washed with 50% brine and a solid precipitates in the organic phase. Organic phase is concentrated to give 170 g of the title compound. MS (m/z): 374 (M+1). | ||
To a solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'- piperidine] (105 g, 375 mmol) in tetrahydrofuran (1.58 L) is added 3 -methyl- 1H- pyrazole-4-carbaldehyde (43.40 g , 394.12 mmol) and the mixture is stirred at room temperature for 1 hr. Then, powdered sodium triacetoxyborohydride (95.46 g, 450.42 mmol) is added in 3 portions. The mixture is stirred at room temperature for 15 hr. Then, the reaction mixture is poured over an ice-sodium bicarbonate saturated aqueous solution (400 mL). Phases are separated. Aqueous phase is extracted with ethyl acetate (100 mL). Combined organic layers are washed with 50% brine and a solid precipitates in the organic phase. Organic phase is concentrated to give 170 g of the title compound. MS (m/z): 374 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | PREPARATION 461-(3-Chloro-2-pyridyl)-3-methyl-pyrazole-4-carbaldehyde; To a solution of 3-methyl-pyrazole-4-carbaldehyde (0.5 g, 4.5 mmol) in dry dimethylformamide (15 mL) is added potassium carbonate (2.5 g, 18 mmol,) at room temperature. The reaction mixture is stirred at 40 C. for 30 min and then 1-fluoro-2-chloropyridine (0.77 g, 6 mmol,) is added. The reaction mixture is heated at 70 C. for 16 h. After completion, the reaction mixture is cooled to room temperature, diluted with water and then extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduce pressure. The crude mixture is purified by chromatography on silica gel eluting with hexane/ethyl acetate (75:25, 65:35) to yield 0.525 g (52%) of the title compound. MS (m/z): 222 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). A solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (2.1 g, 7.5 mmol) and l-(2-fluoro-6-nitro-phenyl)-3-methyl-pyrazole-4-carbaldehyde (3 g) (as major compound in a mixture of regioisomers in the pyrazole) in dichloromethane (47 mL) is stirred at room temperature for 30 minutes. Then, sodium triacetoxy borohydride (3.94g) is added and the mixture is stirred overnight at that temperature. The reaction mixture is quenched carefully with sodium bicarbonate (saturated solution) and extracted with dichloromethane. Organic layer is washed with brine, decanted and dried over sodium sulfate. Solvent is evaporated and the residue is purified by normal phase Isco chromatography using as eluant dichloromethane and isopropanol to give 2.28 g of 2-chloro-4,4-difluoro- -[[l-(2-fluoro-6-nitro-phenyl)-3-methyl-pyrazol-4- yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (the compound is contaminated with the other pyrazole regioisomer in a ratio 80:20). MS (m/z): 513 (M+l). To a solution of 2-chloro-4,4-difluoro-l'-[[l-(2-fluoro-6-nitro-phenyl)-3-methyl- pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (2.28g, 4.46 mmol) and iron (2.5g) in ethanol (1 lmL) and water (1 lmL), a few drops of acetic acid is added. The reaction mixture is stirred at 90C for 70 min. The mixture is then filtered over celite and concentrated under vacuum. Remained solution is basified with sodium bicarbonate(saturated solution) and extracted with dichloromethane. Organic layer is decanted, dried over sodium sulfate and solvent evaporated to obtain 1.8 g of 2-[4-[(2-chloro-4,4- difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]- -yl)methyl]-3-methyl-pyrazol-l- yl]-3-fluoro-aniline that is used in next step without further purification (the compound is contaminated with the other pyrazole regioisomer in a ratio 80:20). MS (m/z): 483 (M+l). A mixture of 0.5 mL of acetic acid, formaldehyde (37.81 muKappa), and ethanedial (59.61 muKappa), is heated at 70C. A solution of 0.5 mL of acetic acid, ammonium acetate(29.74 mg) and 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]- l'-yl)methyl]-3-methyl-pyrazol-l-yl]-3-fluoro-aniline (250 mg, 0.52 mmol) is added drop wise to the flask over 15 min. The solution is continuously stirred at 70C overnight. The reaction mixture is cooled to room temperature and poured slowly and carefully over 15 mL of a solution of sodium bicarbonate (90 mg/mL). The desired compound is then extracted with ethyl acetate. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated. Crude is purified by normal phase Isco chromatography using as eluent dichloromethane/methanol mixtures from 98/2 to 90/10. Further purification by RP HPLC is needed to yield 89.7 mg of the title compound as free base. MS (m/z): 534 (M+l). The tartrate salt is essentially prepared as described in Example 1. MS (m/z): 534(M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). A mixture of l-(2-fluoro-6-nitro-phenyl)-3 -methyl- lH-pyrazole-4-carbaldehyde (620 mg; 2.49 mmol) (as major compound in a mixture of regioisomers in the pyrazole) and Iron (1.40 g) in ethanol (5.1 mL) and water (5.1 mL) with few drops of acetic acid is heated at 90C for 2h. After that time, it is filtered over celite, and eluted with more ethanol. Mixture is concentrated under vacuum, basified with sodium bicarbonate (saturated aqueous solution) and extracted with dichloromethane. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure to give 500 mg of the title compound, as major product in a mixture of regioisomers in the pyrazole, that is used without further purification. MS (m/z): 220 (M+l). To a solution of l-(2-amino-6-fluoro-phenyl)-3-methyl-lH-pyrazole-4- carbaldehyde (500 mg, 2.28 mmol) (as major compound in a mixture of regioisomers in the pyrazole) in dichloromethane (15.21 mL), pyridine (553.31 muKappa) is added. Then, methyl chloroformate (194.17 mu) is added dropwise at 0C and the mixture is stirred at room temperature for 30 min. Water is added and the mixture is extracted with dichloromethane. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to give 418 mg of the title compound. MS (m/z): 278 (M+l). To a solution of methyl N-[3-fluoro-2-(4-formyl-3-methyl-pyrazol-l- yl)phenyl]carbamate (335 mg, 1.2 mmol) (as major compound in a mixture of regioisomers in the pyrazole) in tetrahydrofuran (6 mL) under nitrogen atmosphere and cooled to 0C, sodium hydride (60% in mineral oil) (58.3 mg) is added. Then, methyl iodide (0.4 mL) is added and the reaction mixture is stirred at 0C for 1 hour. After that time, water is added and the mixture is extracted with ethyl acetate. Organic layer is decanted, dried over sodium sulfate and solvent evaporated. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to give 287 mg of the title compound, as major product in a mixture of regioisomers in the pyrazole, that is used without further purification. MS (m/z): 292 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). A mixture of l-(2-fluoro-6-nitro-phenyl)-3 -methyl- lH-pyrazole-4-carbaldehyde (620 mg; 2.49 mmol) (as major compound in a mixture of regioisomers in the pyrazole) and Iron (1.40 g) in ethanol (5.1 mL) and water (5.1 mL) with few drops of acetic acid is heated at 90C for 2h. After that time, it is filtered over celite, and eluted with more ethanol. Mixture is concentrated under vacuum, basified with sodium bicarbonate (saturated aqueous solution) and extracted with dichloromethane. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure to give 500 mg of the title compound, as major product in a mixture of regioisomers in the pyrazole, that is used without further purification. MS (m/z): 220 (M+l). To a solution of l-(2-amino-6-fluoro-phenyl)-3-methyl-lH-pyrazole-4- carbaldehyde (500 mg, 2.28 mmol) (as major compound in a mixture of regioisomers in the pyrazole) in dichloromethane (15.21 mL), pyridine (553.31 muKappa) is added. Then, methyl chloroformate (194.17 mu) is added dropwise at 0C and the mixture is stirred at room temperature for 30 min. Water is added and the mixture is extracted with dichloromethane. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to give 418 mg of the title compound. MS (m/z): 278 (M+l). To a solution of methyl N-[3-fluoro-2-(4-formyl-3-methyl-pyrazol-l- yl)phenyl]carbamate (335 mg, 1.2 mmol) (as major compound in a mixture of regioisomers in the pyrazole) in tetrahydrofuran (6 mL) under nitrogen atmosphere and cooled to 0C, sodium hydride (60% in mineral oil) (58.3 mg) is added. Then, methyl iodide (0.4 mL) is added and the reaction mixture is stirred at 0C for 1 hour. After that time, water is added and the mixture is extracted with ethyl acetate. Organic layer is decanted, dried over sodium sulfate and solvent evaporated. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to give 287 mg of the title compound, as major product in a mixture of regioisomers in the pyrazole, that is used without further purification. MS (m/z): 292 (M+l). To a solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'- piperidine] (210 mg, 0.75 mmol) in dichloromethane (3.00 mL), methyl N-[3-fluoro-2-(4- formyl-3-methyl-pyrazol-l-yl)phenyl]-N-methyl-carbamate (284.27 mg) (as major compound in a mixture of regioisomers in the pyrazole) is added. The mixture is stirred 10 min at room temperature. Then, sodium triacetoxyborohydride (331.5 mg) is added, and the reaction is stirred at room temperature overnight. The mixture is diluted with dichloromethane and quenched slowly with sodium bicarbonate (saturated solution). The organic phase is then extracted with more dichloromethane, decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent dichloromethane and methanol to give 160 mg of methyl N-[2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2, 3-c]pyran-7,4'- piperidine]- -yl)methyl]-3-methyl-pyrazol-l-yl]-3-fluoro-phenyl]-N-methyl-carbamate. MS (m/z): 555 (M+l).The tartrate salt is essentially prepared as described in Example 1. MS (m z): 555 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). A mixture of l-(2-fluoro-6-nitro-phenyl)-3 -methyl- lH-pyrazole-4-carbaldehyde (620 mg; 2.49 mmol) (as major compound in a mixture of regioisomers in the pyrazole) and Iron (1.40 g) in ethanol (5.1 mL) and water (5.1 mL) with few drops of acetic acid is heated at 90C for 2h. After that time, it is filtered over celite, and eluted with more ethanol. Mixture is concentrated under vacuum, basified with sodium bicarbonate (saturated aqueous solution) and extracted with dichloromethane. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure to give 500 mg of the title compound, as major product in a mixture of regioisomers in the pyrazole, that is used without further purification. MS (m/z): 220 (M+l). To a solution of l-(2-amino-6-fluoro-phenyl)-3-methyl-lH-pyrazole-4- carbaldehyde (500 mg, 2.28 mmol) (as major compound in a mixture of regioisomers in the pyrazole) in dichloromethane (15.21 mL), pyridine (553.31 muKappa) is added. Then, methyl chloroformate (194.17 mu) is added dropwise at 0C and the mixture is stirred at room temperature for 30 min. Water is added and the mixture is extracted with dichloromethane. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate and hexane to give 418 mg of the title compound. MS (m/z): 278 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). A mixture of l-(2-fluoro-6-nitro-phenyl)-3 -methyl- lH-pyrazole-4-carbaldehyde (620 mg; 2.49 mmol) (as major compound in a mixture of regioisomers in the pyrazole) and Iron (1.40 g) in ethanol (5.1 mL) and water (5.1 mL) with few drops of acetic acid is heated at 90C for 2h. After that time, it is filtered over celite, and eluted with more ethanol. Mixture is concentrated under vacuum, basified with sodium bicarbonate (saturated aqueous solution) and extracted with dichloromethane. Organic layer is decanted, dried over magnesium sulfate and solvent evaporated under reduced pressure to give 500 mg of the title compound, as major product in a mixture of regioisomers in the pyrazole, that is used without further purification. MS (m/z): 220 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; at 20℃; | To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). A solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (2.1 g, 7.5 mmol) and l-(2-fluoro-6-nitro-phenyl)-3-methyl-pyrazole-4-carbaldehyde (3 g) (as major compound in a mixture of regioisomers in the pyrazole) in dichloromethane (47 mL) is stirred at room temperature for 30 minutes. Then, sodium triacetoxy borohydride (3.94g) is added and the mixture is stirred overnight at that temperature. The reaction mixture is quenched carefully with sodium bicarbonate (saturated solution) and extracted with dichloromethane. Organic layer is washed with brine, decanted and dried over sodium sulfate. Solvent is evaporated and the residue is purified by normal phase Isco chromatography using as eluant dichloromethane and isopropanol to give 2.28 g of 2-chloro-4,4-difluoro- -[[l-(2-fluoro-6-nitro-phenyl)-3-methyl-pyrazol-4- yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (the compound is contaminated with the other pyrazole regioisomer in a ratio 80:20). MS (m/z): 513 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 3 -methyl- lH-pyrazole-4-carbaldehyde (1 g, 9.08 mmol) in acetonitrile (10 mL) is added potassium carbonate (1.76 g, 12.71 mmol) and 2,3- difluornitrobenzene (1.73 g, 10.90 mmol) and the mixture is stirred at room temperature overnight. Water is added and the organic phase is extracted with ethyl acetate. Organic layer is dried over sodium sulfate and the solvent evaporated under reduced pressure. The residue is purified by normal phase Isco chromatography using as eluent ethyl acetate/hexane (20-80%) to give a 62% yield of a mixture of regioisomers containing the title compound as major product that is used with no further purification. NMR is consistent with desired structure, although mixture of regiosomers is detected: NMR (MeOD): 9.98 (s, 1H), 8.65 (d, 1H, J= 1.6 Hz), 7.99-7.26 (m, 3H), 2.49 (s, 3H). A solution of 2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (2.1 g, 7.5 mmol) and l-(2-fluoro-6-nitro-phenyl)-3-methyl-pyrazole-4-carbaldehyde (3 g) (as major compound in a mixture of regioisomers in the pyrazole) in dichloromethane (47 mL) is stirred at room temperature for 30 minutes. Then, sodium triacetoxy borohydride (3.94g) is added and the mixture is stirred overnight at that temperature. The reaction mixture is quenched carefully with sodium bicarbonate (saturated solution) and extracted with dichloromethane. Organic layer is washed with brine, decanted and dried over sodium sulfate. Solvent is evaporated and the residue is purified by normal phase Isco chromatography using as eluant dichloromethane and isopropanol to give 2.28 g of 2-chloro-4,4-difluoro- -[[l-(2-fluoro-6-nitro-phenyl)-3-methyl-pyrazol-4- yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (the compound is contaminated with the other pyrazole regioisomer in a ratio 80:20). MS (m/z): 513 (M+l). To a solution of 2-chloro-4,4-difluoro-l'-[[l-(2-fluoro-6-nitro-phenyl)-3-methyl- pyrazol-4-yl]methyl]spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine] (2.28g, 4.46 mmol) and iron (2.5g) in ethanol (1 lmL) and water (1 lmL), a few drops of acetic acid is added. The reaction mixture is stirred at 90C for 70 min. The mixture is then filtered over celite and concentrated under vacuum. Remained solution is basified with sodium bicarbonate(saturated solution) and extracted with dichloromethane. Organic layer is decanted, dried over sodium sulfate and solvent evaporated to obtain 1.8 g of 2-[4-[(2-chloro-4,4- difluoro-spiro[5H-thieno[2,3-c]pyran-7,4'-piperidine]- -yl)methyl]-3-methyl-pyrazol-l- yl]-3-fluoro-aniline that is used in next step without further purification (the compound is contaminated with the other pyrazole regioisomer in a ratio 80:20). MS (m/z): 483 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; copper diacetate; In dichloromethane; at 20℃; for 48h;Molecular sieve; | A screw-cap test tube containing molecular sieves (4A) and a solution of 3- methyl-lH-pyrazole-4-carbaldehyde (100 mg, 0.91 mmol), 2,6-dimethylphenylboronic acid (150 mg, 1 mmol), copper(II) acetate (247 mg, 1.36 mmol) and pyridine (147 mu, 1.8 mmol) in dry dichloromethane (4.5 mL) is shaked at room temperature for 48 hr. The mixture is filtered over celite, washed with methanol and the solvent evaporated in vacuo. Resulting product is purified by silica gel using normal phase Isco chromatography eluting with hexane: acetone (gradient from 5 to 30% in acetone) to give 67 mg of the title compound. MS (m/z): 215 (M+l) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 50℃; for 20h;Cooling with ice; | A mixture of 3 -methyl- lH-pyrazole-4-carbaldehyde (15.25 g, 138.49 mmoles) and 2,3-difluorobenzamide (26.11 g, 166.19 mmoles) in dimethylformamide (228.75 mL) is cooled with ice/water bath and then potassium tert-butoxide (17.09 g, 152.34 mmoles) is added. The resulting mixture is stirred at 50C for 20 hr. Reaction mixture is cooled down to room temperature. Then, ice/water (300 mL) is added and the mixture is extracted with ethyl acetate (3 x 200 mL). Organics are combined, dried over sodium sulfate and concentrated to afford a light brown oil containing 20% of the other pyrazole regioisomer. The residue is purified by silica gel chromatography using as eluent ethyl acetate/hexane to afford 17.4 g of the title compound. MS (m/z): 248 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.25 g | With titanium(IV) tetraethanolate; In tetrahydrofuran; at 80℃; for 18h; | Intermediate 66: (R,E)-2-methyl-N-((3-methyl-1 H-pyrazol-4-yl)methylene)propane-2- sulfinamide3-methyl-1 H-pyrazole-4-carbaldehyde (2.03g, 18.44mmol) was dissolved in THF (30ml) and (R)-2-methylpropane-2-sulfinamide (2.35, 19.39mmol) was added followed by Ti(OEt)4 (8.41 mmol, 36.90mmol). The resulting reaction mixture was stirred at 80C for 18h. LCMS shows mostly product. The reaction mixture was diluted with EtOAc (300 ml_), washed with 4% aqueous NaCI (2 x 150, 2X50 ml_). The combined aq. layers were back extracted with EtOAc (100ml). The combined organic layers were washed with brine (100ml), dried over Na2S04, filtered and concentrated. Purified by column chromatography (REDI 80g, EtOAc/heptane 20-100% over 33 min 100% for 7min.) to give title compound (2.25g, 10.55mmol).1 H NMR (400 MHz, MeOD) delta 8.55 (s, 1 H), 2.53 (s, 3H), 1.25 (s, 9H). MS 214.2 m/z (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃;Cooling with ice; | To a solution of 3-methyl-iH-pyrazole-4-carbaldehyde, intermediate 12 (0.33 g, 3.0 mmol) in 10 mL of THF was added 0.12 g of 60 % sodium hydride with ice bath cooling and then it was stirred for 20 minute at the same temperature. To this, was added of 10 mL solution of l-methyl-N-(4-(methansulfonyl)pyrimidin-2-yl)-iH- indazol-5-amine (0.6g, 2.0 mmol) in THF. The reaction was allowed to warm up to room temperature and then stirred for 2 hours at rt. The reaction was quenched with water, extracted with dichloromethane (x2) and washed with brine. The collected organic layers were dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was solidified with heptane and then collected by filtration to afford the desired intermediate 13 as a white solid (0.45 g, 66 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h; | To a solution of ethyl 3-methyl-iH-pyrazole-4-carbaldehyde (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N- dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (x2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 2 as a white solid (5.47 g, 42 %); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCls) delta 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, / = 5.4 Hz), 7.87 (1H, d, / = 5.4 Hz), 2.59 (s, 3H). |
42% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h; | Preparation of 1-(2-chloropyrimidin-4-yl)-<strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong>; Intermediate 1 To a solution of ethyl <strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong> (6.4 g, 58.0 mmol) in 60 mL of anhydrous N,N-dimethylformamide were added potassium carbonate (10.8 g, 77.8 mmol) and 2,4-dichloropyrimidine (8.64 g, 58.0 mmol) at room temperature. The resulting suspension was stirred for 14 hours at room temperature with monitoring a reaction with LC-MS or thin layer chromatography (TLC). The reaction mixture was diluted with ethyl acetate and washed with brine (*2). The collected organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a mixture of heptanes and ethyl acetate to afford the desired intermediate 1 as a white solid (5.47 g, 42%); MS (ESI) m/z 223 [M+H]+, 1H NMR (300 MHz, CDCl3) delta 10.06 (s, 1H), 9.04 (s, 1H), 8.70 (d, 1H, J=5.4 Hz), 7.87 (1H, d, J=5.4 Hz), 2.59 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Preparation of 1-(2-(3-isobutyryl-1-methyl-1H-indol-5-ylamino)pyrimidin-4-yl)-<strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong>; intermediate 6 To a solution of <strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong> (273 mg, 2.48 mmol) in anhydrous DMF (5 mL) was added 60% NaH (130 mg, 3.25 mmol) at 0 C. After being stirred for 30 min at room temperature, it was cooled to 0 C. To this, was added intermediate 5 (542 mg, 1.65 mmol) and then stirred for 6 hours at 60 C. Quenching the reaction by addition of ice and 20 mL of water resulted precipitation of brown solids. The resulted solids were collected by filtration, rinsed with water and the dried in vacuo to provide the desired intermediate 6 as a brown solid (424 mg, 80%); MS (ESI) m/z 403 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a solution of <strong>[112758-40-4]3-methyl-1H-pyrazole-4-carbaldehyde</strong> (59.0 mg, 0.53 mmol) in 2 mL of DMF was added 28.6 mg of NaH (60%, 0.72 mmol) at 0 C. The resulting slurry was stirred at rt for 30 min and then was cooled to 0 C. To the resulting mixture was added a solution of the above intermediate (0.10 g, 0.36 mmol) in DMF (1 mL). The mixture was heated at 60 C. for 30 min and was quenched with MeOH. Solvent was removed in vacuo. Cold water was added and solid precipitate was filtered to give the desired Intermediate 1 as a yellow solid (0.11 g, 87%); MS (ESI) m/z 355.2 [M+H]+. |
Tags: 112758-40-4 synthesis path| 112758-40-4 SDS| 112758-40-4 COA| 112758-40-4 purity| 112758-40-4 application| 112758-40-4 NMR| 112758-40-4 COA| 112758-40-4 structure
[ 25016-12-0 ]
1,3-Dimethyl-1H-pyrazole-4-carbaldehyde
Similarity: 0.88
[ 1001020-17-2 ]
3-(tert-Butyl)-1H-pyrazole-4-carbaldehyde
Similarity: 0.88
[ 1197230-88-8 ]
1H-Pyrazole-4-carbaldehyde hydrochloride
Similarity: 0.82
[ 26033-20-5 ]
3-Phenyl-1H-pyrazole-4-carbaldehyde
Similarity: 0.81
[ 25016-12-0 ]
1,3-Dimethyl-1H-pyrazole-4-carbaldehyde
Similarity: 0.88
[ 1001020-17-2 ]
3-(tert-Butyl)-1H-pyrazole-4-carbaldehyde
Similarity: 0.88
[ 1197230-88-8 ]
1H-Pyrazole-4-carbaldehyde hydrochloride
Similarity: 0.82
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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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