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CAS No. : | 7554-65-6 | MDL No. : | MFCD00005245 |
Formula : | C4H6N2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RIKMMFOAQPJVMX-UHFFFAOYSA-N |
M.W : | 82.10 | Pubchem ID : | 3406 |
Synonyms : |
4-Methylpyrazole;Antizol;Fomepizolum;Antizol-Vet
|
Num. heavy atoms : | 6 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.25 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 23.55 |
TPSA : | 28.68 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) : | -6.39 cm/s |
Log Po/w (iLOGP) : | 0.78 |
Log Po/w (XLOGP3) : | 0.58 |
Log Po/w (WLOGP) : | 0.72 |
Log Po/w (MLOGP) : | -0.06 |
Log Po/w (SILICOS-IT) : | 1.56 |
Consensus Log Po/w : | 0.71 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.33 |
Solubility : | 3.83 mg/ml ; 0.0467 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.76 |
Solubility : | 14.4 mg/ml ; 0.176 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.51 |
Solubility : | 2.55 mg/ml ; 0.0311 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-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 |
---|---|---|
84% | Stage #1: With hydrazinium sulfate In water at 80℃; for 3 h; Stage #2: With sodium hydroxide In water at 3 - 30℃; Stage #3: With sodium hydrogencarbonate In water at 27 - 30℃; |
Into a 5 liter flask equipped with a mechanical stirrer were added 1750 ml of sterile USP water to which 266.7 g (2.05 moles) of hydrazine hydrosulfate were added gradually over one hour with stirring. To the above mixture was added dropwise 481 g (2.053 moles) of 3 and the reaction mixture was warmed to 80°C. Heating and stirring were maintained for 3 hours, the flask was cooled to 40°C, and the volatile components were distilled off under a reduced pressure of about 125 mm. The resulting mixture was EPO <DP n="10"/>cooled to 100C first with water and then with glycol; 20 ml of water were added to the flask, and cooling was continued to a temperature of 3°C. Thereafter 50percent sodium hydroxide solution was added with cooling so as to maintain the temperature below 30°C. The pH of the reaction mixture should be between 4 and 6. A solution of sodium bicarbonate containing 4.9 g of sodium bicarbonate to 55 ml of water was added to the flask. Additional sodium bicarbonate solution was added until the pH reached 7.0. The flask temperature was allowed to rise to 27°C with continued stirring. The contents of the flask were extracted with ethyl acetate and the aqueous layer was separated. The organic layer was dried over magnesium sulfate, filtered, and the extract was distilled under vacuum. The light fraction was removed at a pot temperature of 55-60°C at 125 mm pressure. The vacuum was improved to 5 mm for the remainder of the distillation; pot temperatures were permitted to rise to 100-110°C to produce 134.8 g (84percent based on 3) of 4-methylpyrazole, bp 77-80°C at 5 mm, as a clear, colorless to yellow liquid. Gas chromatographic analysis showed less than 0.1percent pyrazole and less than 10 ppm hydrazine. |
84% | Stage #1: With hydrazinium sulfate In water at 80℃; for 3 h; Stage #2: With sodium hydroxide In water at 3 - 30℃; Stage #3: With sodium hydrogencarbonate In water at 27℃; |
Into a 5 liter flask equipped with a mechanical stirrer were added 1750 ml of sterile USP water to which 266.7 g (2.05 moles) of hydrazine hydrosulfate were added gradually over one hour with stirring. To the above mixture was added dropwise 481 g (2.053 moles) of 3 and the reaction mixture was warmed to 80 C. Heating and stirring were maintained for 3 hours, the flask was cooled to 40 C., and the volatile components were distilled off under a reduced pressure of about 125 mm. The resulting mixture was cooled to 10 C. first with water and then with glycol; 20 ml of water were added to the flask, and cooling was continued to a temperature of 3 C. Thereafter 50percent sodium hydroxide solution was added with cooling so as to maintain the temperature below 30 C. The pH of the reaction mixture should be between 4 and 6. A solution of sodium bicarbonate containing 4.9 g of sodium bicarbonate to 55 ml of water was added to the flask. Additional sodium bicarbonate solution was added until the pH reached 7.0. The flask temperature was allowed to rise to 27 C. with continued stirring. The contents of the flask were extracted with ethyl acetate and the aqueous layer was separated. The organic layer was dried over magnesium sulfate, filtered, and the extract was distilled under vacuum. The light fraction was removed at a pot temperature of 55-60 C. at 125 mm pressure. The vacuum was improved to 5 mm for the remainder of the distillation; pot temperatures were permitted to rise to 100-110 C. to produce 134.8 g (84percent based on 3) of 4-methylpyrazole, bp 77-80 C. at 5 mm, as a clear, colorless to yellow liquid. Gas chromatographic analysis showed less than 0.1percent pyrazole and less than 10 ppm hydrazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82 g | With tetrabutyl-ammonium chloride In water at 20 - 80℃; for 4 h; | a, taking 3-amino-2-methyl acrolein 100g, toluene 500ml,Tetrabutylammonium chloride 16.3g was added to the reactor, take formamide 52.9g,Added to 79.4g of water made of 40percent aqueous solution of formamide, added to the reactor, the reaction at room temperature for 1h,Heating to 80 reaction 3h. After the reaction was completed, the temperature of the reaction solution was cooled to room temperature,The organic phase was taken, the organic phase was washed three times with 500ml of water, the organic phase was dried over anhydrous magnesium sulfate for 2h,Filtration, the filtrate was evaporated to give crude 4-methylpyrazole 91g;b, 4-methylpyrazole crude distillationThe crude 4-methylpyrazole obtained in step a was added into a vacuum distillation reactor with a rectification column,For the 0.09 ~ 0.097Mpa conditions collected 110 ~ 116 ° C distillate, to give a clear colorless liquid, which is 4 - methyl pyrazole refined products82g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | at 30 - 105℃; for 2 h; | To a stirred solution of 4-methyl-lH- pyrazole (1 g, 12.19 mmol), H2S04 (15 mL), oleum (4.4 mL) at 30-40 °C and fuming nitric acid (0.64 g, 15.23 mmol) was added and stirred at 105 °C for 2 h. Progress of the reaction was monitored by TLC. Upon completion the reaction mixture was diluted with water and purged with air for 30 min, and extracted with ethyl acetate, and washed with water and brine. Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.85 g, 55percent) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 10 Synthesis of 1,4-dimethylpyrazole (DP) In accordance with the procedure of Example 9, a normal pressure flow system reaction tube made of quartz was packed with 1.0 g of HY-zeolite catalyst, a kind of acidic faujasite and heated at 300 C., and 4-methylpyrazole (MP) and methanol were vaporized and continuously fed with respective partial pressures of 8.2 kPa and 42.5 kPa together with nitrogen under a total pressure of 1 atmosphere and at an S/V of 7.5*102 h-1. The gas obtained from the reactor was cooled and condensed to form a crude reaction solution, which was analyzed with a gas chromatography apparatus. As a result of the analysis, conversion ratio of the starting material MP was found to be 100% and 1,4-dimethylpyrazole (DP) was obtained with a yield of 100% based on the supplied MP. | |
92.1% | EXAMPLE 5 The reaction and operation were conducted in the same manner as in Example 1 except that 3,5-dimethylpyrazole was changed to 0.25 g (3.0 mmol) of 4-methylpyrazole. The conversion of 4-methylpyrazole was 92.1%, and the yield of 1,4-dimethylpyrazole was 85.2%. | |
68% | phosphoric acid; | Synthesis of 1,4-dimethylpyrazole (DP) In accordance with the procedure of Example 9, a normal pressure flow system reaction tube made of quartz was packed with 1.0 g of a phosphoric acid/silica (phosphoric acid 22%) catalyst and heated at 270 C., and 4-methylpyrazole (MP) and methanol were vaporized and continuously fed with respective partial pressures of 25.3 kPa and 25.3 kPa together with nitrogen under a total pressure of 1 atmosphere and at an S/V of 5.8*102 h-1. The gas obtained from the reactor was cooled and condensed to form a crude reaction solution, which was analyzed with a gas chromatography apparatus. As a result of the analysis, conversion ratio of the starting material MP was found to be 79%, and 1,4-dimethylpyrazole (DP) was obtained with a yield of 68% based on the supplied MP. |
With sulfuric acid; In methanol; | Example 5 10 g (0.122 mol) of 4-methylpyrazole, 1.25 g (0.0122 mol) of sulfuric acid and 20 g of glass Raschig rings with a diameter of 3 mm were heated to 145 C. as in Example 2 and reacted at 145 C. over the course of 5 hours with 118.65 g (3.7 mol) of methanol vaporized at 170 C. After concentration under atmospheric pressure, 11.2 g (94.4%) of 1,4-dimethylpyrazole were obtained, boiling point 151 C., with a content of 98.6% (GC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With N-iodo-succinimide; In chloroform; at 70℃; for 2h; | To a solution of 175 (0.5g, 6immrnol) in CHCI3(20m1) was added NIS(1.64g, 7.3 immol).The mixture was stirred at 70C for 2 hours, cooled to room temperature. The remaining aqueous layer was extracted with EtOAc(75rnL) and the combined organic layers were dried (MgSO4),filtered and concentrated in vacuum to yield the title product 176 (0.6g. yield: 47%). LCMS: m/z, 2089(M±H). |
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 23℃; for 18h; | A solution of <strong>[7554-65-6]4-methylpyrazole</strong> (10.0 g, 122 mmol) in lambda/,lambda/-dimethylformamide (100 mL) at 23 0C was treated with JV-iodosuccinimide (27.4 g, 122 mmol) for 18 h. The reaction mixture was diluted with water (100 mL) and then filtered. The filtrate was extracted with <n="45"/>ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (100 rnL) and dried over magnesium sulfate. The residue after evaporation was subjected to silica gel chromatography (80 g silica) using a gradient of ethyl acetate/hexanes (0:100 to 80:20) and appropriate fractions were combined and evaporated to give 5.39 g of the title compound as a solid.1H NMR (CDCl3) delta 7.35 (s, IH), 2.04 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | The reaction was performed under argon. Substituted azole (excess) and potassium tert-butoxide were dissolved at RT in dry and degassed DMSO. An exothermic reaction occurred. The mixture was stirred for 10 min to allow the reaction to finish and cool. Then, a substituted halopyridine was added. The reaction mixture was stirred for 24 h at 140C to give a suspension. It was cooled to RT. Water (50mL) was added: the product precipitated on stirring/sonication. The solid was filtered, washed with water, and extracted with dichloromethane and water. The organic layer was washed with water to extract DMSO. Purification by chromatography on silica (20g) removed the starting materials and by-products on elution with 0-0.4% CH3OH in CH2Cl2, and provided the pure product on elution with 0.4-1.0% CH3OH in CH2Cl2. Anal. Calc. for C14H12N4 (MW 236.27): C, 71.17; H, 5.12; N, 23.71. Found: C, 71.44; H, 5.10; N, 24.05%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium hydride In diethylene glycol dimethyl ether at 130℃; for 120h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With (S,S)-1,2-diaminocyclohexane; potassium carbonate;copper(l) iodide; In 1,4-dioxane; at 120℃; | In a glass tube was added successively 0.29 mmol 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester (CAS: 847547-09-5), 0.35 mmol <strong>[7554-65-6]4-methylpyrazole</strong>, 0.59 mmol potassium carbonate, 0.06 mmol CuI and a solution of 0.12 mmol trans-1,2-diaminocyclohexane in 0.4 ml dioxane (degased). The tube was filled with argon and sealed with a cap. The reaction mixture was heated at 120 C. overnight. The reaction mixture was cooled down to room temperature, dichloromethane and water were added. The aqueous phase was extracted 2 times with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated. The crude compound was purified on a 10 g Flashpack cartridge. Eluent: Heptane/ethylacetate to provide the title compound (57%) as a light yellow oil. MS (m/e): 295.0([M+H]+, 100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With caesium carbonate; In dimethyl sulfoxide; acetonitrile; | EXAMPLE 9 Synthesis of tetrahydro-4-[3-[4-(4-methyl-1H-pyrazol-1-yl)phenyl]thio]phenyl-2H-pyran-4-carboxamide tetrahydro-4-[3-(4-fluorophenyl)thio]phenyl-2H-pyran-4-carboxamide (2.0 g, 6.02 mmole, 1 eq), dimethylsulfoxide (20 ml, 10 vol), <strong>[7554-65-6]4-methylpyrazole</strong> (0.991 g, 12.07 mmole, 2.0 eq) and cesium carbonate (3.93 g, 12.07 mmole, 2.0 eq) were added to a reaction flask set for boiling at reflux under a nitrogen atmosphere, and the reaction mixture was heated with stirring at 139-142 C. for 5 hours under nitrogen.. After completion, the reaction was cooled (<30 C.) and quenched with water (20 ml, 10 vol).. This resulted in formation of a precipitate.. An exotherm of 10-15 C. was observed during the water addition.. The reaction slurry so formed, was cooled to room temperature (15-25 C.) and then granulated for 1 h.. The product was isolated by vacuum filtration and washed with water (20 ml, 10 vol) to obtain the crude product, which was dried overnight in a vacuum oven at 40 C. The crude product was dissolved in acetonitrile (70 ml) and propan-2-ol (115 ml) to form a solution which was filtered and then concentrated until the solution became cloudy, crystallization was established after a period of granulation in the temperature range 3-7 C., product was isolated by filtration, washed with cold propan-2-ol (20 ml) and dried to obtain a white solid (2.034 g, 86%): mp 202-204 C.; m/z 394 (m+1); (Found C, 66.99; H, 6.05; N, 10.47; S, 8.21. C22H23N3O2S requires C, 67.15; H, 6.05; N, 10.47; S, 8.21.) 1H NMR (300 MHz, DMSO) delta8.31 (s, 1H), 7.82 (d, 2H), 7.60 (s, 1H), 7.39 (m, 6H), 7.16 (dt, 1H), 7.10 (s, 1H), 3.73 (d, 2H), 3.46 (t, 2), 2.47 (d, 2H), 2.11 (s, 3H), 1.78 (m, 2H); IR (drifts) vmax 3370, 3181, 1682, 1506. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; In acetonitrile; for 1h; | . To a solution OF 4-METHYL-LH-PYRAZOLE (1 g, 12 mmol) and DMAP (0.15 g, 1.2 mmol) in CH3CN (20 ML) was added di-tert-butyl dicarbonate (2. 8 g, 13 mmol), and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue dissolved in EtOAc. The organic solution was washed with 1 N HC1, water and then brine, dried (MGS04), filtered, and concentrated under reduced pressure to provide 4-methyl-pyrazole-1-carboxylic acid tert-butyl ester as a light yellow oil (2.2 g, 100%) :H NMR (300 MHz, CDC13) 6 7.83 (s, 1H), 7.53 (s, 1H), 2.09 (s, 3H), 1.64 (s, 9H). |
84% | With dmap; In acetonitrile; at 20℃; | To a solution of 4-methyl-H-pyrazole (1 g, 12 mmol ) and 4-d i methyl am i nopy rid i no (0.15 g, 1.2 mmol) in acetonitrile (20 mL) di-ie/t-butyl dicarbonate (2.8 g, 13 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel; hexane/ethyl acetate 4: 1) to provide 4-methyl-pyrazole-l-carboxylic acid tert-butyl ester as a light yellow oil (1.8 g); yield 84%. |
81% | With triethylamine; In dichloromethane; at 20℃; for 6h; | j0280j To a solution of 4-methyl- 1H-pyrazole (3.1 g, 37.8 mol) and N,N-diethylethanamirie (10.5 mL, 75.3 mmol) in dichloromethane (100 mL) was added di-tert-butyl diearbonate (9.1 g, 41.7 mmol) and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with ethyl acetate (300 mL), washed with water (100 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica, 0-30% ethyl acetate in heptane) gave the title compound 5.56 g (81% yield) as a yellow oil. oea NMR (500 MHz, chloroform) 7.82 (s, 1H), 7.52 (s, 1H), 2 08 (s, 3H), 1.63 (s, 9H). |
70% | With triethylamine; In dichloromethane; at 20℃; for 4h; | Example 26; tert-Bxtiyl 4-(bromomethyl)- 1 H-pyrazole- 1 -carboxylate; Step 1 : Et3N (3 mL, 20 mmol, 2 eq) and then BoC2O (2.4 g, 11 mmol, 1.1 eq) were added to a solution of 4-methyl-l H-pyrazole (820 mg, 10 mmol, 1 eq) dissolved in DCM (10 mL) at rt. The mixture was stirred at rt for 4 h. After that, the reaction mixture was washed with water (10 mL), the aqueous layer was extracted with DCM (3 x 20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (1.53 g) in 70% yield as a white solid. LCMS, ESI-MS: m/z 127.1 [M+H-56]. |
With dmap; triethylamine; In tetrahydrofuran; at 20℃; for 0.5h; | 1.00 g of <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> and 2.5 ML of triethylamine were dissolved in 10 ML of tetrahydrofuran, to which 3.1 ML of di-tert-butyl dicarbonate and 73 mg of 4-(dimethylamino)pyridine were successively added, and this solution was stirred for 30 minutes at room temperature.. The reaction mixture was added to a mixture of water and ethyl acetate, and adjusted to PH 7 with 6M hydrochloric acid, and then the organic phase was separated therefrom.. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure to yield 2.23 g of tert-butyl <strong>[7554-65-6]4-methyl-1H-pyrazole</strong>-1-carboxylate as light yellow oil. NMR(400MHz,CDCl3) delta value: 1.64(9H,s), 2.09(3H,s), 7.54(1H,s), 7.84(1H,s) | |
To <strong>[7554-65-6]4-methylpyrazole</strong> (0.6OmL, 7.5mmol) and triethylamine (2.6mL, 18.8mmol) in CH2Cl2 (75mL) was added di-tert-butyl dicarbonate (1.8g, 8.3mmol), and the reaction was stirred for 1 hour at room temperature. 4-Dimethylaminopyridine (0.03g, 0.25mmol) was added, and the reaction was stirred for another 2 hours, until no starting material was seen by analytical tic. After aqueous work-up, the crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tetrakis(triphenylphosphine) palladium(0); triphenylphosphine; In tetrahydrofuran; at 20℃; for 18h; | Carbonic acid (lS,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ester ethyl ester (Intermediate AA) (2.00 g, 3.97 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (20 mL) is added followed by 4-methyl- pyrazole (0.36 g, 4.37 mmol) and triphenylphosphine (0.16 g, 0.60 mmol). Tetrakis(triphenyl- phosphine)palladium(O) (0.23 g, 0.20 mmol) is then added and the reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane / ethyl acetate 1:2).1H nmr (CDCl3, 400 MHz); 8.10(br s, IH), 7.35-7.15(m, 12H), 6.25(m, IH), 6.10(m, IH), 5.80(m, IH), 5.70(m, IH), 5.35(m, IH), 4.35(t, IH), 4.25(m, 2H), 3.25(m, IH), 2.20(m, IH), 2.05(s, 3H), MS (ES+) mle 496 (MH+). | |
With triphenylphosphine;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 20℃; for 18h; | Carbonic acid (lS,4R)-4-[2-chloro -6-(2r2-diphenyl-ethylamino)-purin -9-yl]-cyclopent-2-enyl ester ethyl ester (Intermediate AA) (2.00 g, 3.97 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (20 mL) is added followed by 4-methyl- pyrazole (0.36 g, 4.37 mmol) and triphenylphosphine (0.16 g, 0.60 mmol).Tetrakis(triphenyl- phosphine)palladium(O) (0.23 g, 0.20 mmol) is then added and the reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane / ethyl acetate 1:2).1H nmr (CDCb, 400 MHz); 8.10(br s, IH), 7.35-7.15(m, 12H), 6.25(m, IH), 6.10K IH), 5.80(m, IH), 5.70(m, IH), 5.35(m, IH), 4.35(t, IH), 4.25(m, 2H), 3.25(m, IH), 2.20(m, IH), 2.05(s, 3H), MS (ES+) tn/e 496 (MH*). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
ruthenium trichloride; In methanol; | EXAMPLE 37 Into a stainless steel autoclave having an internal capacity of 40 ml, 0.41 g (5.0 mmol) of 4-methylpyrazole, 0.64 g (20 mmol) of methanol, 26.0 mg (2 mol %) of ruthenium trichloride, 125 mg (10 mol %) of tributyl phosphite, 35.5 mg (0.25 mmol) of methyl iodide and 10 ml of 1,4-dioxane were charged and reacted at 150 C. for 20 hours under an argon pressure of 20 kg/cm2, whereby the yield of 1,4-dimethylpyrazole was 99.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In tetrahydrofuran; water at 20℃; | |
With triethylamine at 130℃; for 5h; | 14-1 4-methyl-1H-pyrazole-1-ylmethanol Reference Production Example 14-1 4-methyl-1H-pyrazole-1-ylmethanol The mixture of 1.93 g of 4-methyl-1H-pyrazole, 0.97 g of paraformaldehyde and 0.4 ml of triethylamine was stirred at 130 °C for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 1.72 g of 4-methyl-1H-pyrazole-1-ylmethanol. 1H-NMR(CDCl3, TMS, δ(ppm)):2.08(3H,s), 5.43(2H,s), 7.36(2H,s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydroxide; In dimethyl sulfoxide; at 90℃; | Example 245-Cyano-furan-2-carboxylic acid [4-(4-methyl-pyrazol-l-yl)-2-piperidin-l-yl- phenyl] -amide; EPO <DP n="71"/> a) l-[5-(4-Methyl-pyrazol-l-yl)-2-nitrtheta'phenyl]-piperidineA solution of l-(5-fluoro-2-nitro-phenyl)-piperidine (98 mg, 0.43 mmol, as prepared in Example 22, step (a), 3-methylpyrazole (49.2 mg, 0.6 mmol), and NaOH (22.4 mg, 0.56 mmol) were heated in 3 mL of DMSO at 90 0C overnight. The reaction was diluted with EtOAc (50 mL), washed with water (2 x 50 mL), dried (Na2SO4) and concentrated in vacuo to afford 117 mg (95%) the title compound as a yellow solid. Mass spectrum (ESI, m/z): Calcd.for C15H18N4O2 287.1 (M+H), found 287.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Into a 5 liter flask equipped with a mechanical stirrer were added 1750 ml of sterile USP water to which 266.7 g (2.05 moles) of hydrazine hydrosulfate were added gradually over one hour with stirring. To the above mixture was added dropwise 481 g (2.053 moles) of 3 and the reaction mixture was warmed to 80C. Heating and stirring were maintained for 3 hours, the flask was cooled to 40C, and the volatile components were distilled off under a reduced pressure of about 125 mm. The resulting mixture was EPO <DP n="10"/>cooled to 100C first with water and then with glycol; 20 ml of water were added to the flask, and cooling was continued to a temperature of 3C. Thereafter 50% sodium hydroxide solution was added with cooling so as to maintain the temperature below 30C. The pH of the reaction mixture should be between 4 and 6. A solution of sodium bicarbonate containing 4.9 g of sodium bicarbonate to 55 ml of water was added to the flask. Additional sodium bicarbonate solution was added until the pH reached 7.0. The flask temperature was allowed to rise to 27C with continued stirring. The contents of the flask were extracted with ethyl acetate and the aqueous layer was separated. The organic layer was dried over magnesium sulfate, filtered, and the extract was distilled under vacuum. The light fraction was removed at a pot temperature of 55-60C at 125 mm pressure. The vacuum was improved to 5 mm for the remainder of the distillation; pot temperatures were permitted to rise to 100-110C to produce 134.8 g (84% based on 3) of 4-methylpyrazole, bp 77-80C at 5 mm, as a clear, colorless to yellow liquid. Gas chromatographic analysis showed less than 0.1% pyrazole and less than 10 ppm hydrazine. | |
84% | Into a 5 liter flask equipped with a mechanical stirrer were added 1750 ml of sterile USP water to which 266.7 g (2.05 moles) of hydrazine hydrosulfate were added gradually over one hour with stirring. To the above mixture was added dropwise 481 g (2.053 moles) of 3 and the reaction mixture was warmed to 80 C. Heating and stirring were maintained for 3 hours, the flask was cooled to 40 C., and the volatile components were distilled off under a reduced pressure of about 125 mm. The resulting mixture was cooled to 10 C. first with water and then with glycol; 20 ml of water were added to the flask, and cooling was continued to a temperature of 3 C. Thereafter 50% sodium hydroxide solution was added with cooling so as to maintain the temperature below 30 C. The pH of the reaction mixture should be between 4 and 6. A solution of sodium bicarbonate containing 4.9 g of sodium bicarbonate to 55 ml of water was added to the flask. Additional sodium bicarbonate solution was added until the pH reached 7.0. The flask temperature was allowed to rise to 27 C. with continued stirring. The contents of the flask were extracted with ethyl acetate and the aqueous layer was separated. The organic layer was dried over magnesium sulfate, filtered, and the extract was distilled under vacuum. The light fraction was removed at a pot temperature of 55-60 C. at 125 mm pressure. The vacuum was improved to 5 mm for the remainder of the distillation; pot temperatures were permitted to rise to 100-110 C. to produce 134.8 g (84% based on 3) of 4-methylpyrazole, bp 77-80 C. at 5 mm, as a clear, colorless to yellow liquid. Gas chromatographic analysis showed less than 0.1% pyrazole and less than 10 ppm hydrazine. |
Yield | Reaction Conditions | Operation in experiment |
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37% | With potassium carbonate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In toluene; at 20℃; | A mixture of 197 (300 mg, 0.86 mmol, scheme 42), 4-methyl-lF-pyrazole (69mg, 0.86 mmol), Cul (16.4 mg, 0.086 mmol), trans-N1,N2-dimethylcyclohexane-l,2-diamine (24.4 mg, 0.172 mmol) [J.C. Antilla, A. Klapars, et. al. JACS, 2002,124,11684-1688] and K2CC>3 (238 mg, 1.72 mmol) in toluene (1.7 mL) was stirred at room temperaturein an atmosphere of nitrogen nitrogen overnight, diluted with EtOAc (100 mL), filteredthrough a Celite pad, and concentrated under reduced pressure. The residue was purifiedby flash chromatography with gradient elution with EtOAc/hexane (1:1) to EtOAc/hexane(2:1) to afford title compound 256 (88.8 mg, 37% yield) as a white solid. MS (m/z): 352.06(M+l). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate;copper(l) iodide; cis-N,N'-dimethyl-1,2-diaminocyclohexane; In N,N-dimethyl-formamide; at 180℃; for 1h;Microwave irradiation; | A suspension of 4-methyl-lH-pyrazole (0.72 g, 0.0088 mol), 5-bromopyrimidin-2-amine (1.3 g, 7.3 mmol), copper(I) iodide (58.2 mg, 0.306 mmol), N,N'-dimethylcyclohexane-l,2-diamine (0.193 mL, 1.22 mmol), potassium carbonate (1.77 g, 12.8 mmol) in N,N-dimethylformamide (5.0 mL) was irradiated under microwave at 180 0C for 1 h. After cooling, the mixture was purified by chromatography on silica gel with methanol in methylene chloride (0-10%) to afford the desired product. LCMS: (M+H) = 176.0. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate;copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; In toluene; at 130℃; for 12h; | 6.16. Synthesis of (S)-2-Amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-propionic acid 1-(2-Bromo-5-methoxy-phenyl)-2,2,2-trifluoro-ethanol (0.570 g, 2.0 mmol), 4-methyl pyrazole (0.164 g, 2.0 mmol), CuI (0.057 g, 0.3 mmol), K2CO3 (0.580 g, 4.2 mmol), (1R,2R)-N,N'-dimethyl-cyclohexane-1,2-diamine (0.071 g, 0.5 mmol) and toluene (10 ml) were combined in a 20 ml pressure tube, and the mixture was heated at 130 C. (oil bath temperature) for 12 h. The mixture was diluted with ethyl acetate and washed with H2O (2*20 ml), brine, and dried over sodium sulfate. Removal of solvent gave a crude product, which was purified by ISCO column chromatography using 5-10% ethyl acetate in hexane as solvent to afford 2,2,2-trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (90 mg). 2,2,2-Trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethanol (0.090 g, 0.31 mmol), (S)-3-[4-(2-amino-6-chloro-pyrimidine-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.122 g, 0.31 mmol), 1,4-dioxane (2 ml), Cs2CO3 (0.503 g, 1.55 mmol) were combined in a microwave vial and heated to 180 C. for 45 min. The mixture was filtered and concentrated. To the residue, 5% methanol in DCM (50 ml) was added. The mixture was filtered. The filtrate was concentrated to give crude product which was taken in 20% TFA in DCM (30 ml) and stirred for 30 minutes at room temperature. LCMS indicated the completion of the reaction with desired product. The reaction mixture was concentrated to give crude product, which was dissolved in MeOH and H2O (1:1), and purified by preparative HPLC using MeOH/H2O/TFA as solvent system to give (S)-2-amino-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[5-methoxy-2-(4-methyl-pyrazol-1-yl)-phenyl]-ethoxy]-pyrimidin-4-yl)-phenyl]-propionic acid. LCMS: M+1=543. 1H-NMR (400 MHz, CD3OD): delta (ppm) 2.20 (s, 3H), 3.22 (m, 1H), 3.40 (m, 1H), 3.84 (s, 3H), 4.35 (t, 1H), 6.84 (s, 1H), 6.98 (m, 1H), 7.18 (m, 1H), 7.26 (m, 1H), 7.40 (d, 1H), 7.48 (d, 2H), 7.66 (d, 2H), 7.96 (d, 2H). | |
90 mg | With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; In toluene; at 130℃; for 12h; | A solution of 1- (2-bromo-5-methoxy-phenyl) -2,2,2-trifluoro-ethanol (0.570 g, 2.0 mmol), <strong>[7554-65-6]4-methylpyrazole</strong>(0.184 g, 2.0 mmol), CuI (0.057 g, 0.3 mmol), K2CO3 (0.580 g, 4.2 mmol), (1R, 2R) -N, N'-dimethyl(0.071 g, 0.5 mmol) and toluene (10 ml) were combined in a 20 ml pressure tube, and the mixture 130Lt; 0 & gt; C (oil bath temperature) for 12 hours. The mixture was diluted with ethyl acetate, washed with H2O (2 x 20 ml), brine and treated with sulfurSodium sulfate is dry. The solvent was removed to give the crude product which was purified by ISCO column chromatography using 5-10% ethyl acetate in hexane as solvent to give 2,2,2-trifluoro-l- [5-methoxy-2- ( 4-methyl-pyrazol-l-yl) -phenyl] -ethanol (90 mg). |
Yield | Reaction Conditions | Operation in experiment |
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16% | With caesium carbonate; In 1,4-dioxane; at 95℃; for 24h; | Preparation of Compound 114a, 1-(2-chloroethyl)-4-methyl-1H-pyrazoIe <n="111"/>4-Methyl pyrazole (0.177 g, 2.16 mmol), 1-chloro-2-iodoethane (1.20 g, 6.30 mmol) and cesium carbonate (1.10 g, 3.38 mmol) in 1 ,4-dioxane (5.0 ml_) were heated at 95 0C for 24h. After cooling to ambient temperature, dichloromethane (10 mL) was added. Following filtration to remove solids, the filtrate was reduced and subjected to silica gel chromatography (gradient of 0-70% EtOAc in hexane) which gave compound 114a (0.049 g, 0.34 mmol) as clear oil in 16% yield. 1 H NMR (300 MHz, CHLOROFORM-d) d ppm 2.12 (s, 3 H) 3.92 (t, J=5.84 Hz, 2 H) 4.49 (t, J=5.93 Hz, 2 H) 7.33 (s, 1 H) 7.46 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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To a suspension of NaH (60% in mineral oil, 3.5 g, 146 mmol, washed with 200 mL of hexane) in THF (200 mL) was added 4-methyl-1 H-pyrazole (10 g, 122 mmol) at 0 0C dropwise. After stirring at RT for 1 h, to above suspension was added MeI (7.3 mL, 117 mmol) dropwise at 0 0C. The reaction mixture was stirred overnight. The NaI by-product was removed by filtration and the filtrate solution was used directly in the next step.At 00C, to above THF solution of 1 ,4-dimethyl pyrazole was added n-BuLi (2.5M in hexane, 58.5 mL, 146 mmole). The reaction solution was stirred for 2 hour at RT and then cooled to -78C [J. Heterocyclic Chem. 41 , 931 (2004)]. To the reaction solution was added 2-isopropoxy-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (27.2 g, 146 mmole). After 15 min at -78C, the reaction was allowed to warm to 00C and stir for 3h. The reaction was diluted with saturated NH4CI solution and extracted with DCM. The organics were dried over Na2SO4 and concentrated under vacuum to afford the title compound as a brown solid (21 g, 78%) which was used directly without further purification: LC-MS: 141 (M-C6H12)"1", 223 (M+H)+. 1H NMR (CDCI3): delta 7.28 (s, 1 H), 4.03 (s, 3H), 2.22 (s, 3H), and 1.32 (s, 12H). | ||
PREPARATION 129 (2-Bromo-5-fluorophenyl)(1 ,4-dimethyl-1 H-pyrazol-5-yl)methanol Sodium hydride (60% dispersion in mineral oil, 0.35 g, 8.65 mmol) was suspended in 12 ml tetrahydrofuran. A solution of 4-methyl-1 H-pyrazole (0.60 g, 7.3 mmol) in 2 ml tetrahydrofuran was added dropwise and the mixture was stirred for 1 h at room temperature. Methyl iodide (0.45 ml, 7.23 mmol) was added drop-wise and the mixture was stirred overnight forming a precipitate. The mixture was filtered and the solid was washed with a little tetrahydrofuran. The filtrates combined to give a crude solution of 1 ,4-dimethyl-1 H-pyrazole. The crude solution was cooled in an ice-bath and n-butyl lithium (1 .6 M in hexanes, 5.40 ml, 8.64 mmol) was added dropwise with stirring over 15 min under a nitrogen atmosphere. The cooling bath was removed and the mixture was stirred at ambient temperature for 2 h. The mixture was cooled to -78 C and a solution of 2-bromo-5- fluorobenzaldehyde (1 .76 g, 8.67 mmol) in 3 ml tetrahydrofuran was added over 1 min. The mixture was stirred overnight, warming to room temperature. The mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue was purified using the Isolera purification system (ethyl acetate-hexane gradient, 0: 100 rising to 100:0) to give 720 mg (2.41 mmol, 33%) of the title compound as a white solid. Purity 100%. 1 H N MR (300 MHz, CHLOROFORM-d) delta ppm 7.45-7.54 (m, 2H), 7.19 (s, 1 H), 6.91 -6.98 (m, 1 H), 6.04 (s, 1 H), 3.84 (s, 3H), 2.70 (br s, 1 H), 1 .75 (s, 3H). UPLC/MS (3 min) retention time 1 .53 min. LRMS: m/z 299, 301 (M+1 ). | ||
Sodium hydride (60% dispersion in mineral oil, 0.35 g, 8.65 mmol) was suspended in 12 ml tetrahydrofuran. A solution of 4-methyl-1 H-pyrazole (0.60 g, 7.3 mmol) in 2 ml tetrahydrofuran was added dropwise and the mixture was stirred for 1 h at room temperature. Methyl iodide (0.45 ml, 7.23 mmol) was added drop-wise and the mixture was stirred overnight forming a precipitate. The mixture was filtered and the solid was washed with a little tetrahydrofuran and the filtrates combined to give a crude solution of 1 ,4-dimethyl-1 H-pyrazole. The crude solution was cooled in an ice-bath under nitrogen and n-butyl lithium (1 .6 M in hexanes, 3.70 ml, 5.92 mmol) was added drop-wise with stirring over 15 min. After addition, the mixture was stirred at room temperature for 2 h. The mixture was then cooled to -78 C and a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (1 .49 g, 5.89 mmol) in 2 ml tetrahydrofuran was added over 1 min. The mixture was stirred overnight, warming to room temperature. The solution was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic extract was washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue was purified using the Isolera purification system (ethyl acetate-hexanes gradient, 0:100 rising to 100:0) to give 710 mg (2.03 mmol, 41 %) of the title compound as a white solid. Purity 96%. 1H NMR (300 MHz, DMSO-d6) delta ppm 8.13 (d, 1 H, J = 2.3 Hz), 7.86 (d, 1 H, J = 8.2 Hz), 7.66 (dd, 1 H, J = 8.2, 2.3 Hz), 7.08 (s, 1 H), 6.51 (d, 1 H, J = 5.3 Hz), 5.93 (d, 1 H, J = 4.7 Hz), 3.83 (s, 3H), 1.42 (s, 3H). UPLC/MS (3 min) retention time 1 .72 min. LRMS: m/z 349, 351 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; L-proline;copper(l) iodide; In dimethyl sulfoxide; at 160℃; for 0.75h;Microwave irradiation; | Example 10: Preparation of S-re-ethyl-S-^-methylpyrazol-i-vD-phenylibicyclofS^.noctane^^- dione <n="65"/>3-(5-Bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (100mg, 0.31 mmol), <strong>[7554-65-6]4-methylpyrazole</strong> (38mg, 0.46mmol), potassium phosphate (264mg, 1.24mmol), L-proline (36mg, 0.31 mmol) and copper (I) iodide (60mg, 0.31 mmol) are combined in a microwave vial, suspended in DMSO and heated under microwave irradiation at 1600C for 45 minutes. The mixture is filtered and purified by preparative reverse-phase HPLC to give 3-[2-ethyl-5-(4-methylpyrazol-1-yl)phenyl]bicyclo- [3.2.1]octane-2,4-dione. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With ferrocene; sulfuric acid; dihydrogen peroxide; dimethyl sulfoxide; In water; at 40 - 50℃; for 0.333333h; | 0.047 g (0.25 mmol) of ferrocene was weighed and placed in a two-neck flask and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 0.07 ml (0.88 mmol) of <strong>[7554-65-6]4-methylpyrazole</strong>, 1.7 ml of dimethyl sulfoxide, 1.7 ml of a 1 N dimethyl sulfoxide solution of sulfuric acid, 0.7 ml of a 3.0 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.15 ml of a 30% hydrogen peroxide aqueous solution, and the mixture was stirred for 20 minutes. During the stirring, the temperature of the reaction system rose up in the range of from 40C to 50C. Thereafter the resulting solution was cooled to room temperature. Formation of 4-methyl-3-trifluoromethylpyrazole (19F-NMR yield: 45%) was confirmed by 19F-NMR with 2,2,2-trifluoroethanol as an internal standard. The subsequent procedure was conducted in the same manner as in Example 1 and 4-methyl-3-trifluoromethylpyrazole was obtained as a colorless oil (0.054g, yield: 36%). 1H-NMR(deuterated dimethyl sulfoxide):delta2. 12(s, 3H), 7. 73 (s, 1H), 13. 29(brs, 1H). 13C-NMR(deuterated dimethyl sulfoxide):delta7. 62, 113. 5, 122. 5(q, JCF=268. 7Hz), 129. 8, 138. 7 (q, JCF= 34. 2Hz). 19F-NMR(deuterated dimethyl sulfoxide):delta-59. 8. MS (m/z):150 [M]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With pyridinium p-toluenesulfonate; In dichloromethane; at 55℃; for 12h; | To a solution of Compound 1 (2 g, 24.36 mmol, 1.96 mL, 1 eq) in DCM (30 mL) was added PPTS (612.16 mg, 2.44 mmol, 0.1 eq) and 3,4-dihydro-2H-pyran (6.15 g, 73.08 mmol, 6.68 mL, 3 eq). The mixture was stirred at 55 C. for 12 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with 80 mL and extracted with ethyl acetate (80 mL*2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Silica gel, Petroleum ether/Ethyl acetate=50/1 to 5:1). Compound 2 (2.5 g, 15.04 mmol, 61% yield) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3) delta=7.37 (d, J=6.0 Hz, 2H), 5.32 (dd, J=2.4, 9.7 Hz, 1H), 4.09-3.99 (m, 1H), 3.69 (dt, J=2.8, 11.3 Hz, 1H), 2.08 (s, 3H), 2.07-1.99 (m, 2H), 1.78-1.51 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 2-bromo-3-(bromomethyl)thiophene With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: 4-methyl-1H-pyrazole In tetrahydrofuran; mineral oil at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: 2-bromo-1-(bromomethyl)-3-methylbenzene With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: 4-methyl-1H-pyrazole In tetrahydrofuran; mineral oil at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: 2-bromo-5-fluorobenzyl bromide With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 0.5h; Stage #2: 4-methyl-1H-pyrazole In tetrahydrofuran; mineral oil at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Production Example 62 A mixture of 0,28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of <strong>[7554-65-6]4-methylpyrazole</strong>, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60C for 1.5 hours. To the mixture, 0.05 g of <strong>[7554-65-6]4-methylpyrazole</strong> was added and further stirred while heating at 60C for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(<strong>[7554-65-6]4-methylpyrazole</strong>-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 61"). [Show Image] 1H-NMR (CDCl3) delta: 8.89 (d, J=0.5 Hz, 1H), 8.81 (d, J=5.1 Hz, 1H), 8.08-8.07 (m, 1H), 8.04 (dd, J=5.1,0.6 Hz, 1H), 7.67-7.65 (m, 1H), 7.57-7.54 (m, 2H), 7.51 (s, 1H), 2.19 (s, 3H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Production Example 62A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of <strong>[7554-65-6]4-methylpyrazole</strong>, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60 C. for 1.5 hours. To the mixture, 0.05 g of <strong>[7554-65-6]4-methylpyrazole</strong> was added and further stirred while heating at 60 C. for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(<strong>[7554-65-6]4-methylpyrazole</strong>-1-yl)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as ?active compound 61?).Active Compound 611H-NMR (CDCl3) delta: 8.89 (d, J=0.5 Hz, 1H), 8.81 (d, J=5.1 Hz, 1H), 8.08-8.07 (m, 1H), 8.04 (dd, J=5.1, 0.6 Hz, 1H), 7.67-7.65 (m, 1H), 7.57-7.54 (m, 2H), 7.51 (s, 1H), 2.19 (s, 3H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Production Example 62A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of <strong>[7554-65-6]4-methylpyrazole</strong>, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60C for 1.5 hours. To the mixture, 0.05 g of <strong>[7554-65-6]4-methylpyrazole</strong> was added and further stirred while heating at 60C for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(<strong>[7554-65-6]4-methylpyrazole</strong>-l-yl)pyridin-4-yl]-5- (trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 61").Active compound 611 H-NMR (CDC13) delta: 8.89 (d, J=0.5 Hz, IH), 8.81 (d, J=5.1 Hz, IH), 8.08-8.07 (m, IH), 8.04 (dd, J=5.1, 0.6 Hz, IH), 7.67-7.65 (m, IH), 7.57-7.54 (m, 2H), 7.51 (s, IH), 2.19 (s, 3H) |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of <strong>[7554-65-6]4-methylpyrazole</strong>, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60C for 1.5 hours. To the mixture, 0.05 g of <strong>[7554-65-6]4-methylpyrazole</strong> was added and further stirred while heating at 60C for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(<strong>[7554-65-6]4-methylpyrazole</strong>-l-yl)pyridin-4-yl]-5- (trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 61").Active compound 611H-NMR (CDCI3) delta: 8.89 (d, J=0.5 Hz, 1H), 8.81 (d, J=5.1 Hz, 1H), 8.08-8.07 (m, 1H), 8.04 (dd, J=5.1, 0.6 Hz, 1H), 7.67-7.65 (m, 1H), 7.57-7.54 (m, 2H), 7.51 (s, 1H), 2.19 (s, 3H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | A mixture of 0.28 g of 2-(3-fiuoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of <strong>[7554-65-6]4-methylpyrazole</strong>, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60C for 1.5 hours. To the mixture, 0.05 g of <strong>[7554-65-6]4-methylpyrazole</strong> was added and further stirred while heating at 60C for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(<strong>[7554-65-6]4-methylpyrazole</strong>-l-yl)pyridin-4-yl]-5- (trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 61"). Active compound 611 H-NMR (CDC13) delta: 8.89 (d, J=0.5 Hz, IH), 8.81 (d, J=5.1 Hz, IH), 8.08-8.07 (m, IH), 8.04 (dd, J=5.1, 0.6 Hz, IH), 7.67-7.65 (m, IH), 7.57-7.54 (m, 2H), 7.51 (s, IH), 2.19 (s, 3H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Production Example 62A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.11 g of <strong>[7554-65-6]4-methylpyrazole</strong>, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60C for 1.5 hours. To the mixture, 0.05 g of <strong>[7554-65-6]4-methylpyrazole</strong> was added and further stirred while heating at 60C for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(<strong>[7554-65-6]4-methylpyrazole</strong>-l-yl)pyridin-4-yl]-5- (trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 61").Active compound 611 H-NMR (CDCI3) delta: 8.89 (d, J=0.5 Hz, IH), 8.81 (d, J=5.1 Hz, IH), 8.08-8.07 (m, IH), 8.04 (dd, J=5.1, 0.6 Hz, IH), 7.67-7.65 (m, IH), 7.57-7.54 (m, 2H), 7.51 (s, IH), 2.19 (s, 3H) | |
With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 3h; | Production Example 62A mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole,0.11 g of <strong>[7554-65-6]4-methylpyrazole</strong>, 0.55 g of potassium carbonate and 3 ml of DMF was stirred while heating at 60C for 1.5 hours. To the mixture, 0.05 g of <strong>[7554-65-6]4-methylpyrazole</strong> was added and further stirred while heating at 60C for 1.5 hours. Then, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.25 g of 2-[3-(<strong>[7554-65-6]4-methylpyrazole</strong>-l-yl)pyridin-4-yl]-5- (trifluoromethyl)benzoxazole (hereinafter, referred to as "active compound 61 "). Active compound 611 H-NMR (CDC13) delta: 8.89 (d, J=0.5 Hz, IH), 8.81 (d, J=5.1 Hz, IH), 8.08-8.07 (m, IH), 8.04 (dd, J=5.1, 0.6 Hz, IH), 7.67-7.65 (m, IH), 7.57-7.54 (m, 2H), 7.51 (s, IH), 2.19 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With salicylaldehyde-oxime; caesium carbonate; copper(II) oxide; In acetonitrile; at 80℃; for 24h;Inert atmosphere; | A dried flask under nitrogen was charged with 4-bromo-1-methyl-2-nitro-benzene (40 mmol), <strong>[7554-65-6]4-methylpyrazole</strong> (20 mmol), Cs2CO3 (13 g), Cu2O (290 mg, 2 mmol), salicylaldoxime (1.1 g, 8 mmol) and 12 mL of acetonitrile. The mixture was heated at 80 C. for 24 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through celite. The filtrate was washed with water, dried and concentrated under reduced pressure. Column chromatography on silica gel (DCM/Hexane 30-100%) gave 4-methyl-1-(4-Methyl-3-nitro-phenyl)-1H-pyrazole as a yellow solid (60% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With ferrocene; dihydrogen peroxide; dimethyl sulfoxide; In water; at 20℃; for 12.0417h;Inert atmosphere; | General procedure: A substrate (0.5 mmol), Cp2Fe (9.3 mg, 0.05 mmol), BrCF2CO2Et (194 muL, 1.5 mmol), and DMSO (2.5 mL) were charged in a two-neck flask in Ar atmosphere. Then, a 30% aqueous solution of H2O2 (0.10 mL, H2O2 1.0 mmol) was added continuously over 2.5 min. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was poured into H2O and the product was extracted to ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous solution of NaCl, dried with Na2SO4, and then concentrated under vacuo. The product was isolated using silica gel chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sulfuric acid; nitric acid; at 30 - 105℃; for 2.0h; | To a stirred solution of 4-methyl-lH- pyrazole (1 g, 12.19 mmol), H2S04 (15 mL), oleum (4.4 mL) at 30-40 C and fuming nitric acid (0.64 g, 15.23 mmol) was added and stirred at 105 C for 2 h. Progress of the reaction was monitored by TLC. Upon completion the reaction mixture was diluted with water and purged with air for 30 min, and extracted with ethyl acetate, and washed with water and brine. Combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.85 g, 55%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With 5-(di-tert-butylphosphino)-1?, 3?, 5?-triphenyl-1?H-[1,4?]bipyrazole; caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃;Inert atmosphere; | Preparation of 2-[(R)-5-(4-Methyl-pyrazol-1-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]honane-7-carboxylic acid tert-butyl ester (8-1a) In a sealable reaction tube was combined 2-(R)-5-bromo-indan-1-yl)-2,7-diaza-spiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3-1a, 300 mg, 0.71 mmol), <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (88 mg, 1.07 mmol), tris(dibenzylideneacetone)dipalladium (65 mg, 0.071 mmol), 5-(di-tert-butyl-phosphanyl)-1',3',5'-triphenyl-1'H-[1,4']bipyrazolyl (72 mg, 0.14 mmol), cesium carbonate (377 mg, 1.07 mmol) and a stir bar. Anhydrous 1,4-dioxane (3 mL) was added and the mixture was purged with nitrogen for 10 minutes. The reaction was sealed and heated at 100 C. overnight. The reaction was cooled to room temperature, opened, and diluted with 150 mL ethyl acetate. The organic solution was washed with 100 mL water, dried (MgSO4), filtered through a plug of Celite and concentrated in vacuo to give a yellow oil. Purification on an ISCO (Teledyne Isco Inc., Lincoln Nebr.) silica column eluting with a 0-100% ethyl acetate in heptanes gradient provided 239 mg (79%) of the title compound (8-1a) as a yellow solid. MS (ES+) 423.0 (M+H)+. 1H NMR (CDCl3) delta 1.42 (s, 9H), 1.62-1.70 (m, 4H), 1.85-1.96 (m, 1H), 2.09-2.16 (m, 4H), 2.81 (dd, 1H), 3.02 (dd, 1H), 3.06-3.15 (m, 4H), 3.22-3.35 (m, 4H), 3.87-3.91 (m, 1H), 7.27 (d, 1H), 7.39 (dd, 1H), 7.45-7.51 (m, 2H), 7.63 (s, 1H). |
With 5-(di-tert-butylphosphino)-1?, 3?, 5?-triphenyl-1?H-[1,4?]bipyrazole; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere; Sealed tube; | General procedure: In a sealable reaction tube was combined tert-butyl 2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (300 mg,0.71 mmol), <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> 7b (88 mg, 1.07 mmol), tris(dibenzylideneacetone)dipalladium (65 mg, 0.071 mmol), 5-(di-tert-butyl-phosphanyl)-1',3',5'-triphenyl-1'H-[1,4']bipyrazolyl (72 mg, 0.14 mmol), and cesium carbonate (377 mg, 1.07 mmol). Anhydrous 1,4-dioxane (3 mL) was added and the mixture was purged with nitrogen for 10 min. The reaction was sealed and heated at 100 C overnight. The reaction was cooled to room temperature, and diluted with 150 mL of ethyl acetate. The organic solution was washed with water (100 mL), dried (MgSO4), filtered through a plug of Celite and concentrated under reduced pressure to give a yellow oil. The crude product was purified by silica gel chromatography eluting with 0100% ethyl acetate in heptanes to give 8b (239 mg, 79%) as a yellow solid. 1H NMR (500 MHz, CdCl3) 7.63 (s, 1 H) 7.517.45 (m, 2 H), 7.39 (dd, 1 H), 7.27 (d, 1 H), 3.913.87 (m, 1 H), 3.353.22 (m, 4 H), 3.153.06 (m, 4 H), 3.02 (dd, 1 H), 2.81 (dd, 1 H), 2.162.09 (m, 4 H), 1.961.85 (m, 1 H), 1.701.62 (m, 4 H), 1.42 (s, 9 H). MS (ESI): m/z 423.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.7% | With caesium carbonate; In N,N-dimethyl-formamide; at 85℃; for 24h; | 0.2 ml (2.47 mmol) of 4-methyl-lH-pyrazole and 0.4 g (1.24 mmol) of cesium carbonate were added to a solution of 0.15 g (0.62 mmol) of 5-bromo-2,6-dichloropyrimidin-4-amine (Intermediate 3) in 3 ml of DMF. The mixture was heated at 85 C for 24 h. The DMF was concentrated in vacuum. The residue was washed with water and dried to give 0.16 g (78.7 %) of a white solid. 1H-RMN (300 MHz, DMSO-d6): delta = 2.07 (s, 3H), 2.10 (s, 3H), 7.69 (s, 1H), 7.72 (s, 1H), 8.31 (s, 1H), 8.39 (s, 1H), 8.16 (d, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; In N,N-dimethyl-formamide; at 110℃; for 3h; | Example 4-28 4- { 8-[5-Ethoxy-4-methyl-2-(4-methyl-lH-pyrazol- 1 -yl)benzyl]-2-oxo-l -oxa-3,8- diazaspiro[4.5]dec-3-yl}benzoic acid, TFA saltStep 1. Synthesis of 5-ethoxy-4-meth -2-(4-methyl-lH-pyrazol-l-yl)benzaldehyde A solution of 2-bromo-5-ethoxy-4-methylbenzaldehyde (100 mg, 0.41 mmol), 4-methyl- lH-pyrazole (40.5 mg, 0.49 mmol), K2C03 (114 mg, 0.82 mmol), Cul (78 mg, 0.41 mmol) in DMF (2 mL) was stirred at 110 C for 3 hours. The reaction mixture then was filtered concentrated and the residue was purified on a silica gel column eluting with 30% EtOAc in hexanes and then with 5% MeOH in DCM to provide the title intermediate (20 mg).1H-N (CDC13): delta 9.89 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.39 (s, 1H), 7.25 (s, 1H), 4.15 (q, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 1.46 (t, J- 7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In 1,4-dioxane; at 100℃; for 3h;Inert atmosphere; | Example 271 4-((3 S,4S)- 1 -( 1 -cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3 -ylamino)-6-(4- methyl- 1 H-pyrazol- 1 -yl)pyrrolo [ 1 ,2-b]pyridazine-3 -carboxamide [00399] The title compound was prepared from 20 mg (0.046 mmol) of 6-bromo-4- ((3S,4S)-l-(l-cyanocyclopropanecarbonyl)-4-methylpyrrolidin-3-ylamino)pyrrolo[l,2- b]pyridazine-3-carboxamide (prepared from the product of Step 1 of Example 158 using the methods previously described in Step 1 of Example 191 by replacing cyanoacetic acid with cyclopropylcyanoacetic acid), potassium carbonate (32.0 mg, 0.232 mmol), 4- methyl-lH-pyrazole (15.2 mg, 0.18 mmol), (l S,2S)-Nl,N2-dimethylcyclohexane-l,2- diamine (13.2 mg, 0.09 mmol) and dioxane (0.30 mL). The resulting mixture was sparged with argon for ~ 5 min. then copper iodide (17.7 mg, 0.09 mmol) was added and the mixture was heated at 100 C for 3h. After cooling to rt, the mixture was purified by preparative LC/MS using the following conditions: (column: Waters XBridge CI 8, 19 x 250 mm, 5-muiotaeta particles; guard column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; mobile phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;mobile phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; gradient: 10-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.). Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 6.8 mg of the title compound. Analytical LCMS (method H) retention time = 1.98 min. (MH+ 433.2). XH NMR (500MHz, METHANOL^, appeared as rotomers) delta 8.39 -8.32 (m, 1H), 8.14 (s, 1H), 8.07 (dd, J=12.4, 1.5 Hz, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.34 - 7.24 (m, 1H), 5.20 - 5.00 (m, 2H), 4.55 - 4.41 (m, 3H), 4.13 - 3.90 (m, 3H), 3.04 - 2.80 (m, 1H), 2.34 (s, 3H), 1.99 - 1.65 (m, 4H), 1.49 - 1.38 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethylamine; In diethyl ether; toluene; at 0℃; for 1h; | General procedure: 10 mmol of phosgene (5 ml of a solution 2 M in toluene) was added dropwise to a stirred solution of pyrazol-1H (20 mmol, 1.361 g) and NEt3 (22 mmol, 3.5 ml) in diethyl ether (200 ml) at 0 C. After 1 h of reaction, Et3N·HCl was observed as a white precipitate. The solution was filtered and the solvent evaporated until a white solid started to appear. The suspension was held at -40 C for 2 h. The liquid phase was filtered off, then the solid was dried under vacuum and identified as 1 (yield 1.562 g, 9.7 mmol, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | To a suspension of FeCl3 (104 mg; 0.641 mmol) in CH2Cl2 (65 mL) was added 4-Me-pzH (0.158 mL; 1.92 mmol) under an Ar atmosphere with stirring. To the resulting solution, Et3N (0.629 mL, 4.52 mmol) was added dropwise with stirring under Ar. Then the reaction mixture was exposed to air, sealed, and kept under stirring at room temperature for 30 h. The resulting dark red solution was filtered and yellow single crystals of 1 formed by slow evaporation of the filtrate. Yield: 54 mg; 18%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.31% | With potassium phosphate;copper(l) iodide; N,N`-dimethylethylenediamine; In N,N-dimethyl-formamide; at 150℃; for 17h;microwave irradiation; | A mixture of 4-bromo-2-fluorophenol (3 g, 15.71 mmol), 4-methyl-lH-pyrazole (1.934 g, 23.56 mmol), copper(I) iodide (0.150 g, 0.785 mmol), potassium phosphate (6.67 g, 31.4 mmol), and Nl,N2-dimethylethane-l,2-diamine (0.277 g, 3.14 mmol) in DMF (45 mL) was heated under microwave irradiation at 150 C for 17 h. The mixture was poured into water, neutralized with 6 M HCl, and extracted with EtOAc. The organic phases were combined, dried over MgS04, filtered, and concentrated. The residue was purified by column chromatography (hexane/EtOAc gradient) to give the title compound (100 mg, 3.31 % yield). Exact mass calculated for CioH9FN20: 192.1, found LCMS mlz = 193.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | The reaction was performed under argon. Substituted azole (excess) and potassium tert-butoxide were dissolved at RT in dry and degassed DMSO. An exothermic reaction occurred. The mixture was stirred for 10 min to allow the reaction to finish and cool. Then, a substituted halopyridine was added. The reaction mixture was stirred for 24 h at 140C to give a suspension. It was cooled to RT. Water (50mL) was added: the product precipitated on stirring/sonication. The solid was filtered, washed with water, and extracted with dichloromethane and water. The organic layer was washed with water to extract DMSO. Purification by chromatography on silica (20g) removed the starting materials and by-products on elution with 0-0.4% CH3OH in CH2Cl2, and provided the pure product on elution with 0.4-1.0% CH3OH in CH2Cl2. Anal. Calc. for C16H16N4 (MW 264.33): C, 72.70; H, 6.10; N, 21.20. Found: C, 73.08; H, 6.25; N, 21.59%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | The reaction was performed under argon. Substituted azole (excess) and potassium tert-butoxide (excess) were dissolved at RT in dry and degassed DMSO. An exothermic reaction occurred. The mixture was stirred for 10 min to allow the reaction to finish and cool. Then, a substituted halopyridine was added. The reaction mixture was stirred for 24 h at 110C to give a suspension. It was cooled to RT. Water (50mL) was added: the product precipitated on stirring/sonication. The solid was filtered, washed with water, and extracted with ether and water. The organic layer was washed with water to extract DMSO. Purification by chromatography on silica (20g) removed the starting materials and by-products on elution with 0-0.4% CH3OH in CH2Cl2, and provided the pure product on elution with 0.4-1.0% CH3OH in CH2Cl2. Anal. Calc. for C10H11N3 (MW 173.21): C, 69.34; H, 6.40; N, 24.26. Found: C, 69.99; H, 6.24; N, 24.89%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | The reaction was performed under argon. Substituted azole (excess) and potassium tert-butoxide were dissolved at RT in dry and degassed DMSO. An exothermic reaction occurred. The mixture was stirred for 10 min to allow the reaction to finish and cool. Then, a substituted halopyridine was added. The reaction mixture was stirred for 24 h at 140C to give a suspension. It was cooled to RT. Water (50mL) was added: the product precipitated on stirring/sonication. The solid was filtered, washed with water, and extracted with dichloromethane and water. The organic layer was washed with water to extract DMSO. Purification by chromatography on silica (20g) removed the starting materials and by-products on elution with 0-0.4% CH3OH in CH2Cl2, and provided the pure product on elution with 0.4-1.0% CH3OH in CH2Cl2. Anal. Calc. for C13H13N5 (MW 239.28): C, 65.25; H, 5.48; N, 29.27. Found: C, 65.04; H, 5.51; N, 29.87%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Step 1 : ferf-Butyl 1-(4-methyl-1 H-pyrazol-1-yl)cyclopropanecarboxylate Into a 25 mL round bottom flask were added sodium hydride (60% dispersion in mineral oil, 164.3 mg, 4.1 mmol) and anhydrous tetrahydrofuran (8 mL). The mixture was cooled with an ice-water bath before a solution of <strong>[7554-65-6]4-methylpyrazole</strong> (204.2 mg, 2.487 mmol) in anhydrous tetrahydrofuran (2 mL) was added. The mixture was stirred in the ice-water bath for 30 minutes before ferf-butyl 2,4-dibromobutanoate (0.48 mL, 2.2 mmol) was added dropwise at 0C. The reaction mixture was stirred at 0C for 30 minutes and then at room temperature for 18 h. The solvent was removed under reduced pressure and water and ethyl acetate were added to the residue. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (0-50% ethyl acetate in heptanes) to afford ferf-butyl 1-(4-methyl-1 H-pyrazol-1- yl)cyclopropanecarboxylate (218 mg, 44%). 1H NMR (400 MHz, CDCI3) delta 1.33 (s, 9H), 1.45-1.51 (m, 2H), 1.61-1.67 (m, 2H)H), 1.98-2.01 (m, 3H)H), 7.21 (s, 1 H), 7.23-7.26 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With N-iodo-succinimide; In acetonitrile; at 60℃; for 0.5h; | Compound 250.1. 5-Iodo-4-methyl-lH-pyrazole. NIS (5.62g, 24.98mmol) was added portion-wise to a solution of 4-methyl- lH-pyrazole (Aldrich, 2.05g, 24.97mmol) in acetonitrile (50 mL). The mixture was heated at 60 C for 30 minutes, then cooled to room temperature. The mixture was partitioned between EtOAc (300 mL) and water (80 mL). The organic layer was washed with saturated sodium thiosulfate (50 mL), brine (50 mL), dried (MgS04) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc, 5: 1) to yield the title compound as a white solid (2.3 g, 45%). m/z (ES+) 209 (M+H)+. |
41% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 20℃; for 16h; | Compound 56.1.5-Iodo-4-methyl-lH-pyrazole. To a solution of 4-methyl-lH- pyrazole (2.15 g, 26.1 mmol) dissolved in DMF (20 mL) was added N-iodosuccinimide (6.19 g, 26.1 mmol). The mixture was stirred at RT for 16 hours and then diluted with water and filtered. The filtrate was extracted with EtOAc (2 x 50 mL), then the combined organic extracts were washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Si02; 0-50 % EtOAc in hexanes compound as a white solid, m/z (ES+) 209 (M+H) |
31.58% | With N-iodo-succinimide; In N,N-dimethyl-formamide; at 25℃; for 1h;Inert atmosphere; | Into a 250-mL 3-necked round-bottom flask under N2 atmosphere, were placed 4- methyl-lH-pyrazole (5.00 g, 60.897 mmol, 1.00 equiv), DMF (100.00 mL), and NIS (14.39 g, 63.942 mmol, 1.05 equiv). The resulting solution was stirred for 1 h at 25 C and then quenched with water. The resulting solution was extracted with ethyl acetate and the organic layer was separated and concentrated in vacuum. The residue was by Flash chromatography to give the title compound (4 g, 31.58%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21 mg | In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | General Procedure D. General procedure: The appropriate carboxylic acid (1.0 equiv) was treated with oxalyl chloridie (1.1 equiv) in CH2Cl2 (0.5 M) at 0° C. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under N2 and the acid chloride was redissolved in anhydrous CH2Cl2 (0.5 M). The appropriate pyrazole (1.0 equiv) was dissolved in CH2Cl2 and cooled to 0° C. The acid chloride was added dropwise and the reaction mixture was stirred at room temperature for 3 h. The mixture was diluted withEtOAc, washed with saturated aqueous NaCl, and dried over Na2SO4. Evaporation under reduced pressure yielded the crude product that was purified by flash chromatography(SiO2). |
In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | 4.1.2. General procedure for pyrazole amide synthesis General procedure: The appropriate carboxylic acid (1.0 equiv) was treated with oxalylchloride (1.1 equiv) in CH2Cl2 (0.5 M) at 0 °C. The reaction mixture wasstirred at room temperature for 1 h. The solvent was removed under N2and the acid chloride (1 equiv) was dissolved in anhydrous CH2Cl2(0.5 M). The appropriate pyrazole (1.0 equiv) was dissolved in CH2Cl2(0.5 M) and cooled to 0 °C. The acid chloride (1 equiv) in CH2Cl2 (0.5 M) was added dropwise and the reaction mixture was stirred atroom temperature for 3 h. The mixture was diluted with EtOAc, washedwith saturated aqueous NaCl, and dried over Na2SO4. Evaporationunder reduced pressure yielded the crude product that was purified byflash chromatography (SiO2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.5% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere; | A solution of SA (350 mg, 0.88 mmol) and K2C03 (243.5 mg, 1.76 mmol) in 10 mL dry DMF was added 4-methyl-lH-pyrazole (144.6 mg, 1.76 mmol) under N2 at room temperature. The reaction mixture was stirred for 18h at this temperature. The reaction mixture was poured to water, extracted with EtOAc (2*50 mL), the organic layers were washed with brine, dried over anhydrous Na2S04, filtered and concentrated, purified by flash chromatography silica column (petroleum ether/ ethyl acetate 10: 1 to 2: 1) to afford SA-6 (230 mg, yield: 65.5%) as a white powder.1H NMR (400 MHz, CDC13), delta (ppm), 7.35 (s, 1H), 7.18 (s, 1H), 4.92-4.79 (m, 2H), 2.59-2.55 (m, 1H), 2.23-2.15 (m, 1H), 2.10 (s, 3H), 2.07-2.03 (m, 1H), 1.88-1.80 (m, 3H), 1.76-1.61 (m, 6H), 1.49- 1.22 (m, 16H), 1.13-1.05 (m, 3H), 0.68 (s, 3H). LCMS: rt = 1.29 mm, m/z = 399.2 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.2% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 15h;Inert atmosphere; | To a solution of l-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K2C03 (496 mg, 3.59 mmol) in DMF (3 inL) was added 4-methyl- lH-pyrazole (196 mg, 2.391 mmol) in one portion. Then the mixture stirred under N2 was heated to 110 C and reacted for 15 h. LCMS analysis showed the starting material disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 inL) and washed with H20 (20 mL) and brine (20 mL). The organic layer was dried over Na2S04, filtered and concentrated to give crude material which was purified by silica column chromatography (PE/EA = 10/1 to 5/1) to afford pure product 4-methyl- 1 -(3 -nitro-5 -(trifluoromethyl)phenyl)-lH-pyrazole (500 mg, 1.678 mmol, 70.2% yield): NMR (400 MHz, CD3OD): delta 8.83 (s, IH), 8.46 (s, IH), 8.35 (s, IH), 8.30 (s, IH), 7.64 (s, IH), 2.18 (s, 3H). ES-LCMS: m/z 272.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In acetone; at 20 - 60℃; for 48h;Inert atmosphere; | 4-(Chloromethyl)benzylalcohol (5.47g, 34.9mmol) was dissolved in acetone (50mL) <strong>[7554-65-6]4-methylpyrazole</strong> (2.86g, 34.9mmol) and potassium carbonate (5.07g, 36.7mmol) were added and the reaction mixture was stirred at rt for 18 hrs and at 60C for 30 hrs after which time the solvent was removed in vacuo and the residue taken up in EtOAc (lOOmL), this solution was washed with water (lx30mL), brine (lx30mL), dried (MgS04) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as [4-(4-methyl-pyrazol-l-ylmethyl)-phenyl]-methanol (3.94g, 18.90mmol, 54% yield). [M+H]+ = 203 |
54% | With potassium carbonate; In acetone; at 20 - 60℃; for 48h;Inert atmosphere; | 4-(chloromethyl)benzylalcohol (5.47 g, 34.9 mmo) was disso?ved in acetone (50 mL). 4Methypyrazoe (2.86 g, 34.9 mmo) and potassium carbonate (5.07 g, 36.7 mmo) were added and the reaction mixture was stirred at rt for 18 hrs and at 60 C for 30 hrs after which time the sovent was removed in vacuo and the residue taken up in EtOAc (100 mL). This soution was washed with water (30 mL), brine (30 mL), dried (MgSO4) and evaporated in vocuo. The residue was purified by flash chromatography (sHica), &uent gradient of 10 to 80% EtOAc in isoHexane, fractions combined and evaporated in vacuo to give a white soHd identified as [4-(4methy pyrazo 1-ymethy)-pheny]-methano (3.94 g, 18.90 mmo, 54% yie?d).[MH]= 203 |
54% | With potassium carbonate; In acetone; at 20 - 60℃; for 48h; | V. [4-(4-Methyl-pyrazol-1-ylmethyl)-phenyl]-methanol 4-(Chloromethyl)benzylalcohol (5.47 g, 34.9 mmol) was dissolved in acetone (50 mL). 4-Methylpyrazole (2.86 g, 34.9 mmol) and potassium carbonate (5.07 g, 36.7 mmol) were added and the reaction mixture was stirred at rt for 18 hrs and at 60 C for 30 hrs after which time the solvent was removed in vacuo and the residue taken up in EtOAc (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (MgSCu) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as (4-(4-methyl-pyrazol-1-ylmethyl)-phenyl]-methanol (3.94 g, 18.90 mmol, 54% yield). [MuEta]+ = 203 |
54% | With potassium carbonate; In acetone; at 20 - 60℃; for 48h; | 4-(chloromethyl)benzylalcohol (5.47 g, 34.9 mmol) was dissolved in acetone (50 mL). <strong>[7554-65-6]4-methylpyrazole</strong> (2.86 g, 34.9 mmol) and potassium carbonate (5.07 g, 36.7 mmol) were added and the reaction mixture was stirred at rt for 18 hrs and at 60 C for 30 hrs after which time the solvent was removed in vacuo and the residue taken up in EtOAc (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (MgS04) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as [4-(4-methylpyrazol-1-ylmethyl)-phenyl]-methanol (3.94 g, 18.90 mmol, 54% yield). [MH]+ = 203 |
23.07% | With potassium carbonate; In acetonitrile; at 60℃; for 18h;Inert atmosphere; | Example 10F. (4-((4-Methyl-lH-pyrazol-l-yl)methyl)phenyl)methanolTo a round bottom flask under N2 was added: (4-(chloromethyl)phenyl)methanol (10.04 g, 60.9 mmol), 4-methyl-lH-pyrazole (5.05 ml, 60.9 mmol) and dry MeCN (100 mL). Next, potassium carbonate (9.26 g, 67.0 mmol) was added and the white suspension was heated to 60 C for 18 h. The volatiles were removed in vacuo. The residue was partitioned between EtOAc (100 mL) and water (150 mL). Aqueous layer was neutralised to pH 7 with 1 N HCI and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (100 mL), brine (50 mL) then dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by chromatography (10-80% EtOAc in iso-hexanes) to afford (4-((4-methyl-lH-pyrazol-l-yl)methyl)phenyl)methanol (2.9 g, 14.05 mmol, 23.07 % yield) as a free- flowing oil that solidified on standing. [M+H]+ = 203.2 |
With potassium carbonate; In acetone; at 20 - 60℃; for 48h;Inert atmosphere; | 4-(Chloromethyl)benzylalcohol (5.47 g, 34.9 mmol) was dissolved in acetone (50 mL).4-Methylpyrazole (2.86 g, 34.9 mmol) and potassium carbonate (5.07 g, 36.7 mmol) were added and the reaction mixture was stirred at rt for 18 hrs and at 60 C for 30 hrs after which time the solvent was removed in vacuo and the residue taken up in EtOAc (100 mL). This solution was washed with water (30 mL), brine (30 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica), eluent gradient of 10 to 80% EtOAc in iso-Hexane, fractions combined and evaporated in vacuo to give a white solid identified as [4-(4-methyl-pyrazol-1-ylmethyl)-phenyl]-methanol (3.94 g, 18.90 mmol, 54% yield). [MH]+ = 203 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; | tert-Butyl 4-(2-((methylsulfonyl)oxy)ethyl) piperidine- 1 -carboxylate (step 1) (500 mg, 1.70 mmol) and 4-methyl-i H-pyrazole (168 mg, 2.04 mmol) were placed in a flask with dry DMFmL). Potassium carbonate (471 mg, 3.41 mmol) was added and the reaction mixture was stirred at 10000 overnight. The resulting mixture was partitioned between EtOAc and water.The organic phase was washed with water and brine, dried over MgSO4, filtered and the solvent was removed in vacuo. The product was purified by chromatography on silica eluting with- iso-hexane/ (EtOAc:MeOH - 10:1) to afford the title compound;1H NMR (400 MHz, DMSO-d6) O 7.49 (iH, 5), 7.20 (iH, 5), 4.05 (2H, t), 3.90 (2H, m), 2.65 (2H, m), 2.00 (3H, 5), 1.69 (2H, t), 1.62 (2H, m), 1.40 (9H, 5), 1.31 (iH, m), 1.00 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With potassium carbonate; In acetone; at 50℃; for 12h; | To a solution of Al (200 mg, 0.453 mmol) in acetone (5 mL) was added K2C03 (93.8 mg, 0.679 mmol) and 4-methyl-lH-pyrazole (44.5 mg, 0.543 mmol) at 50C. The mixture was stirred at 50C for 12 hrs, then poured into water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (10 mL), dried over Na2S04, filtered and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give compound 60 (107 mg, 53%) as an off-white solid. [437] 60: 1H NMR (400 MHz, CDC13) delta 7.38 (s, 1H), 7.20 (s, 1H), 4.97-4.82 (m, 2H), 3.51- 3.35 (m, 2H), 3.30 (s, 3H), 2.63-2.55 (m, 1H), 2.28-2.16 (m, 1H), 2.12 (s, 3H), 2.08-2.00 (m, 2H), 1.79-1.66 (m, 5H), 1.63-1.56 (m, 3H), 1.53-1.47 (m, 3H), 1.42-1.30 (m, 2H), 1.27-1.19 (m, 6H), 1.18-1.07 (m, 2H), 1.05-0.92 (m, 1H), 0.91-0.80 (m, 1H), 0.71 (s, 3H). LCMS Rt = 1.028 min in 2 min chromatography, MS ESI calcd. for C27H43N20 [M+H]+ 443, found 443. |
11% | With caesium carbonate; In acetonitrile; at 20℃; for 16h;Inert atmosphere; | Prepared according General Procedure B from compound All (130 mg, 0.29 mmol) and 4- methyl-lH-pyrazole (247 mg, 3.01 mmol) with the substitution of cesium carbonate (480 mg, 1.5 mmol) in anhydrous acetonitrile (8 mL), with semi-purification by column chromatography on silica gel followed by reverse phase preparative HPLC to provide 20 as an off-white solid (15 mg, 1 1%): mp 67-71 C; 1H NMR (500 MHz, CDC13) delta 7.33 (s, 1H), 7.16 (s, IH), 4.87 (d, JAB = 18.0 Hz, IH), 4.79 (d, JAB = 17.5 Hz, 1H), 3.46 (d, J = 10.0 Hz, 1H), 3.37 (d, J = 10.0 Hz, 1H), 3.28 (s, 3H), 3.13 (s, 3H), 2.56 (t, J = 8.5 Hz, IH), 2.23-2.15 (m, IH), 2.09 (s, 3H), 2.07-2.00 (m, 2H), 1.75-1.65 (m, 4H), 1.62-1.45 (m, 6H), 1.40-1.08 (m, I IH), 1.02-0.94 (m, IH), 0.89- 0.82 (m, IH), 0.69 (s, 3H) ppm; ESI MS m/z 443 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With caesium carbonate; In acetonitrile; at 65℃; for 16h;Inert atmosphere; | Prepared according General Procedure E, Step 2 from compound Cll (80 mg, 0.18 mmol) and 4-methyl-lH-pyrazole (45 mg, 0.54 mmol) with the substitution of cesium carbonate (177 mg, 0.54 mmol) in anhydrous acetonitrile (6 mL) at 65 C, with purification by column chromatography on silica gel to provide compound 28 as a white solid (58 mg, 73%): mp 158- 160 C; 1H MR (500 MHz, CDC13) delta 7.34 (s, 1H), 7.16 (s, 1H), 4.86 (d, JAB = 17.5 Hz, 1H), 4.78 (d, JAB = 18.0 Hz, 1H), 3.54 (d, J = 9.0 Hz, 1H), 3.32 (s, 3H), 3.19 (d, J= 9.0 Hz, 1H), 2.54 (t, J = 9.5 Hz, 1H), 2.23-2.13 (m, 1H), 2.09 (s, 3H), 2.07-2.02 (m, 1H), 1.97-1.87 (m, 2H), 1.80-1.35 (m, 12H), 1.33-1.10 (m, 10H), 0.66 (s, 3H) ppm; ESI MS m/z 443 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With copper(l) iodide; potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 195℃; for 5h;Microwave irradiation; | Step 1: 6-Bromo-2-methylisoquinolin-1-one (300.0 mg, 1.27 mmol), <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (210.0 mg, 2.54 mmol), CuI (30.0 mg, 0.127 mmol) and K2CO3 (360.0 mg, 2.54 mmol) in NMP (3.0 mL) were microwaved at 195 C. for 5 h. Extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA=5:1) gave the title compound of step 1 (160.0 mg, 52%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) delta 8.49 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.74 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 3.62 (s, 3H), 2.19 (s, 3H). LCMS: 240.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With caesium carbonate; In dimethyl sulfoxide; at 40℃; | General procedure: Similar to as described in General Procedure A, ethyl 6-chloro-2- (3- [2- [(3R)-3-hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl] ethynyl]phenyl)pyrimidine-4-carboxylate was reacted <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> to give the title compound (157.5 mg, 97%) as alight yellow solid. LC-MS (ES, mlz): 432, 434 [M+H]. To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N,N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). The reaction washeated to 100 C and stirred at this temperature for 2 hours. The reaction was then cooled to room temperature and acidified to pH = 1 with 10 % aqueous HCl solution if product contains a carboxylic acid, or diluted with water if neutral. The solution was extracted with twice with dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was either used directly in subsequent reactions or purified byflash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With C31H28NO6PPdS; caesium carbonate; In water; at 90℃; for 24h;Schlenk technique; Inert atmosphere; | To a 10 ml Schlek reaction tube under the protection of an inert gas such as high purity nitrogen, 0.05 mmol of a water-soluble palladium on water-bound monophosphine salt compound (16), 1.0 mmol of 4-nitrobromobenzene, 1.1mmol of <strong>[7554-65-6]4-methylpyrazole</strong>, 3 mmol of cesium carbonate and 5 ml of water were added and the reaction tube was purged with nitrogen three times and then heated to 90 C with an oil bath under magnetic stirring. The reaction was refluxed for 24 hours. The oil bath was removed and the reaction was concentrated with a rotary evaporator. The residue was chromatographed on silica gel using ethyl acetate as the developing solvent to give pure product 4-nitrophenyl-<strong>[7554-65-6]4-methylpyrazole</strong> in 92% |
80% | With potassium tert-butylate; In dimethylsulfoxide-d6; at 60℃; for 5h; | General procedure: A mixture of the appropriate N-nucleophile (2 mmol), 4-bromonitrobenzene(2 mmol), t-ButOK or KOH (in the case of 1g, 1h)(2.2 mmol) in dimethyl sulfoxide (2.5 mL) was stirred at 60 C for 5 h(8 h in the case of 1b). After cooling and addition of water (60 mL),either a solid precipitated which was filtered, washed with water andrecrystallised from an appropriate solvent to give the product, or asuspension was generated which was extracted with ethyl acetate(3 × 30 mL), dried over Na2SO4, concentrated under reduced pressureand recrystallised from an appropriate solvent to give the desiredproduct |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere; | Compound 305.1. 7V,7V,4-Trimethyl-lH-pyrazole-l-sulfonamide. Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-lH-pyrazole (10.4 g, 127.2 mmol) in CH2C12 (200 mL). N,N- dimethylsulfamoyl chloride (17.14 mL, 167.1 mmol) and triethylamine (35 mL, 251.1 mmol) were added to the reaction. The reaction mixture was stirred for 30 min at 0 C in a water/ice bath and then stirred overnight at room temperature. The reaction was quenched with NaHCC>3 (sat.) (40 mL) and the aqueous phase was extracted with 3 x 200 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexanes (1 :6) as the eluent to afford the title compound (22.2 g, 92%) as a light yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With gold(I) chloride; In 1,2-dichloro-ethane; for 16h;Inert atmosphere; Reflux; | General procedure: To a 100 mL round-bottomed flask was addedpyrazole (438 mg, 6.43 mmol, 1.5 equiv), gold(I) chloride (9.97 mg,0.043 mmol, 1 mol %), and ethyl 2-butynoate (0.5 ml, 4.29 mmol, 1.0 equiv)in ClCH2CH2Cl (12 ml) to give a very light yellow solution (with a little solid).The mixture was heated at 90 C under nitrogen for 15 h (LCMS indicated 82%conversion with 5% other isomers: entry 16). Most of the solvent wasevaporated under reduced pressure and the crude residue was directlysubject to flash silica gel column chromatography purification up to 50%EtOAc in hexane to afford 545 mg (70%) of 3a as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With p-toluenesulfonic acid monohydrate In isopropanol at 130℃; for 2h; Microwave irradiation; | 5.1.10. 3-Fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (5a) A mixture of p-toluenesulfonic acid monohydrate (0.827 g, 4.35mmol), 4 (2.86 g, 21.7 mmol), 4-methyl-1H-pyrazole (1.93 mL, 23.9mmol), and IPA (14 mL) was irradiated with microwave at 130 C for 2h. The mixture was diluted with sat. NaHCO3, and extracted with EtOAc.The organic layer was separated, washed with water and brine, driedover Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, EtOAc/hexane) to give 5a (3.33 g,18.8 mmol, 86%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 2.12(3H, s), 7.76 (1H, s), 7.93 (1H, dd, J = 7.0, 5.5 Hz), 8.18 (1H, dd, J = 1.9,0.8 Hz), 8.49 (1H, d, J = 5.3 Hz), 8.74 (1H, d, J = 4.2 Hz). |
86% | With p-toluenesulfonic acid monohydrate In isopropanol at 130℃; for 2h; Microwave irradiation; | 5.1.10. 3-Fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine (5a) A mixture of p-toluenesulfonic acid monohydrate (0.827 g, 4.35mmol), 4 (2.86 g, 21.7 mmol), 4-methyl-1H-pyrazole (1.93 mL, 23.9mmol), and IPA (14 mL) was irradiated with microwave at 130 C for 2h. The mixture was diluted with sat. NaHCO3, and extracted with EtOAc.The organic layer was separated, washed with water and brine, driedover Na2SO4, and concentrated in vacuo. The residue was purified bycolumn chromatography (silica gel, EtOAc/hexane) to give 5a (3.33 g,18.8 mmol, 86%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 2.12(3H, s), 7.76 (1H, s), 7.93 (1H, dd, J = 7.0, 5.5 Hz), 8.18 (1H, dd, J = 1.9,0.8 Hz), 8.49 (1H, d, J = 5.3 Hz), 8.74 (1H, d, J = 4.2 Hz). |
3.3 g | With toluene-4-sulfonic acid In isopropanol at 130℃; for 2h; Microwave irradiation; | 13.C C) 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine C) 3-fluoro-4-(4-methyl-1H-pyrazol-1-yl)pyridine A mixture of p-toluenesulfonic acid monohydrate (0.83 g), 4-chloro-3-fluoropyridine (2.9 g), 4-methyl-1H-pyrazole (1.9 mL) and 2-propanol (14 mL) was irradiated with microwave at 130°C for 2 hr. To the mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.3 g). 1H NMR (300 MHz, DMSO-d6) δ 2.12 (3H, s), 7.76 (1H, s), 7.93 (1H, dd, J = 7.0, 5.5 Hz), 8.18 (1H, dd, J = 1.9, 0.8 Hz), 8.49 (1H, d, J = 5.3 Hz), 8.74 (1H, d, J = 4.2 Hz). |
3.3 g | With toluene-4-sulfonic acid In isopropanol at 130℃; for 2h; Microwave irradiation; | 4.A A) 3-fluoro-4- (4-methyl-lH-pyrazol-l-yl) pyridine A mixture of p-toluenesulfonic acid monohydrate (0.83 g) , 4-chloro-3-fluoropyridine (2.9 g) , 4-methyl-lH-pyrazole (1.9 mL) and 2-propanol (14 mL) was irradiated with microwave at 130°C for 2 hr. To the mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.3 g) . NMR (300 MHz, DMS0-d6) δ 2.12 (3H, s) , 7.76 (1H, s), 7.93 (1H, dd, J = 7.0, 5.5 Hz), 8.18 (1H, dd, J = 1.9, 0.8 Hz), 8.49 (1H, d, J = 5.3 Hz), 8.74 (1H, d, J = 4.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.1% | methyl 4-((4-methyl-1H-pyrazol-1-yl)methyl)benzoateInto a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (820 mg, 9.99 mmol, 1.00 equiv) in N,N-dimethylformamide (30 mL) with stirring at 0 C. This was followed by the addition of 60% sodium hydride in mineral oil (600 mg, 25.00 mmol, 1.50 equiv) in portions at 0 C. in 10 min. To this was added methyl 4-(bromomethyl)benzoate (2.29 g, 10.00 mmol, 1.00 equiv) in portions at 0 C. Then it was stirred for 2 h at 25 C. The mixture was diluted with 50 mL of water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated. This resulted in 2.10 g (91.1%) of methyl 4-[(4-methyl-1H-pyrazol-1-yl)methyl]benzoate as a yellow solid. MS (ESI) m/z 231 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In acetonitrile; at 60℃; | [00599] Intermediate 62a: benzyl 2-(4-methylpyrazol-1-yI)acetate[00600] Benzyl bromoacetate (0.l7mL, 1.lmmol) was added to a flask containing fomepizole (0.O7mL, 0.91 mmol) and potassium carbonate (379mg, 2.74mmol) in MeCN (3mL). Thereaction mixture was heated to 60 C and left to stir overnight. The reaction was then cooled to room temperature and quenched by the addition of water (2OmL) and extracted with EtOAc (3 x2OmL). The combined organic layers were dried over Na2504, filtered and concentrated in vacuo.The residue was purified by column chromatography using an eluent of 0-10% EtOAc in heptane togive benzyl 2-(4-methylpyrazol-1-yl)acetate (205mg, 0.89mmol, 97% yield) as a white solid.1H NMR (CDCI3,400MHz) O/ppm: 7.40- 7.33 (6H, m), 7.24 (1H, 5), 5.20 (2H, 5), 4.89 (2H, 5), 2.09(3H, 5).MS Method 2: RT: 1.61 mm, mlz 231.2 [M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 12h; | The reference gathers the precedent 23 of the methane sulfonic acid [trans-4 - (4-oxo-7 - [ 2 - (trimethyl silicon alkyl) ethoxy] methyl} - 4,7-dihydro -1H-pyrrolo [2,3-h] [1,6] naphthyridin-1-yl) cyclohexyl] methyl ester (1.53g, 3 . 03mmol) the N, N- dimethyl formamide (30 ml) solution cooling to 0 C, and add 4-methyl -1H-pyrazole (500muL, 6 . 06mmol), then, slowly added sodium hydride (petrolatum in 55 weight % dispersion, 264 mg, 6 . 06mmol). Subsequently, the temperature is increased to room temperature and the stirring 12 hours. Furthermore, the ice in the water in the reaction mixture, extraction with ethyl acetate. The resulting organic layer washed with a saturated sodium chloride aqueous solution, after drying with anhydrous sodium sulfate, concentrated under reduced pressure. Residues to silica gel column chromatography (ethyl acetate ? ethyl acetate/methanol = 10/1(v/v)) purification, to obtain the colorless amorphous title compound (1.33g, yield 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 90h;Inert atmosphere; | In a vial under N2, a mixture of 4'-((3,5-dimethyl-lH-l,2,4-triazol-l-yl)methyl)-5-fluoro- [l,l'-biphenyl]-2-carbonitrile (0.038 g, 0.12 mmol), 4-methyl-lH-pyrazole (0.020 mL, 0.24 mmol) and potassium carbonate (0.040 g, 0.29 mmol) in DMF (2 mL) was heated at 100C for 18 h. Additional 4-methyl-lH-pyrazole (0.020 mL, 0.24 mmol) was added and the mixture was heated at 100C for another 3 days. The cooled mixture was acidified with formic acid (0.050 mL) and the solution was purified by reverse-phase preparative LC (Method D). The product obtained was lyophilized from ACN-H2O to afford the title compound (0.038 g, 0.10 mmol, 84% yield) as a white solid. LC (Method B): 1.828 min. MS (APCI): calcd for C22H21N6 [M + H]+ m/z 369.2, found 369.2. H NMR (400 MHz, CDCI3) delta ppm 7.77 - 7.84 (m, 3H), 7.73 (dd, J = 2.20, 8.40 Hz, 1H), 7.58 - 7.63 (m, 3H), 7.28 - 7.33 (m, 2H), 5.30 (s, 2H), 2.43 (s, 3H), 2.38 (s, 3H), 2.18 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 90h;Inert atmosphere; | In a vial under N2, a mixture of 5-fluoro-4'-((3-methyl-4H-l,2,4-triazol-4-yl)methyl)- [1,1 '-biphenyl] -2-carbonitrile (0.043 g, 0.15 mmol), 4-methyl-lH-pyrazole (0.020 mL, 0.24 mmol) and potassium carbonate (0.047 g, 0.34 mmol) in DMF (2 mL) was heated at 100C for 18 h. Additional 4-methyl-lH-pyrazole (0.020 niL, 0.24 mmol) was added and heating was continued at the same temperature for 3 days. The cooled reaction mixture was acidified with formic acid (0.050 mL) and this mixture was purified by reverse-phase preparative LC (Method D). The product obtained was lyophilized from ACN-H2O to afford the title compound (0.043 g, 0.12 mmol, 82% yield) as a white solid. LC (Method B): 1.698 min. MS (APCI): calcd for C2iH19N6 [M + H]+ m/z 355.2, found 355.1. H NMR (400 MHz, CDC13) delta ppm 8.16 (s, 1H), 7.79 - 7.87 (m, 3H), 7.74 (dd, J = 1.90, 8.60 Hz, 1H), 7.61 - 7.66 (m, 2H), 7.60 (s, 1H), 7.22 - 7.26 (m, 2H), 5.19 (s, 2H), 2.44 (s, 3H), 2.18 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 18h;Sealed tube; | To a solution of 4'-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5- fluoro-[l,l'-biphenyl]-2-carbonitrile (205a, 0.088 g, 0.229 mmol) and 4-methyl-lH- pyrazole (0.028 g, 0.343 mmol) in DMF (3 mL) was added potassium carbonate (0.095 g, 0.687 mmol) and the resulting mixture was stirred at 120C (block temperature) in a sealed vial for 18 h. The cooled mixture was filtered (0.45 muiotaeta syringe filter) to remove the potassium salts and the residue was washed with a little DMF. The combined filtrate was evaporated to give a gum which was purified by flash chromatography (ISCO/ 0- 100% EtOAc-DCM) to give 4'-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3- yl)methyl)-5-(4-methyl-lH-pyrazol-l-yl)-[l,l'-biphenyl]-2-carbonitrile (0.102 g, 100% yield) as a colourless gum which solidified on standing in vacuo to give a white solid. This material was used as such in the next step. LC-MS (Method J): 1.340 min, [M + H]+ = 447.2; H NMR (400 MHz, OMSO-d6) delta ppm 8.50 (s, IH), 8.01 (d, / = 7.8 Hz, IH), 7.96 (d, /= 7.8 Hz, IH), 7.95 (s, IH), 7.65 (s, IH), 7.59 (d, /= 8.2 Hz, 2H), 7.27 (d, /= 8.2 Hz, 2H), 6.95 (s, 1H), 5.55 (s, 2H), 2.81 (q, J= 7.4 Hz, 2H), 2.51 (s, 3H), 2.50 (s, 3H), 2.07 (s, 3H), 1.25 (t, J= 7.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.8 g | In acetonitrile; at 50℃; for 16h; | To a 50 ml round bottom flask were added (S)-tert-butyl 2-oxooxetan-3-ylcarbamate (1870 mg, 9.99 mmol, 1.0 eq.), 4-methyl-i H-pyrazole (984 mg, i2 mmol, i.2 eq.) and MeCN (30 ml). The resulting solution was heated to 50 C for 16 hours. The mixture was concentrated under reduced pressure to a light yellow residue. The residue was dissolved in hot MeOH (5 ml). After the reaction was cooled, a white solid precipitatedfrom the solution. To the resulting mother liquor was added water (1 ml x 3) to precipitate more solid. All solids were combined to provide 1.8 g of the title comround which was used in the next stej without jurification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69.73% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h; | To a mixture of 135.la (prepared from 3-bromo-6- nitroaniline and mesyl chloride, followed by methyl iodide) (1 .Og, 3 .23mmol, 1 .Oeq) and 4-methyl- 1H-pyrazole (0.4g, 4.8Smmol, 1.Seq) in dimethylformamide (6mL), Cs2CO3 (3.06g, 9.69mmol, 3.Oeq) was added. Reaction mixture was allowed to stir for 4h at 100 C. After completion of the reaction, the reaction mixture was transferred into water to obtain precipitate which was filtered and washed with water to obtain crude product. This was purified by column chromatography using 100% CH2C12 as eluantto obtain pure 135.1 (0.7g, 69.73%). MS(ES): m/z 311.25 [M+H]t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tert-butyl XPhos; In tert-butyl alcohol; at 80℃;Inert atmosphere; | General procedure: A mixture of bicyclic pyrimidine or pyridine (50-100mg, 1.0eq.), pyrazole (1.2 eq.),Pd2(dba)3 (0.05 eq.), tBuXPhos (0.1 eq.), and K3PO4 (1.5 eq.) in tBuOH (1.5-3 ml) was stirred at80 C for 15-16 h under a nitrogen atmosphere. After the mixture was cooled to ambienttemperature, water was added, and the mixture was extracted with chloroform twice. Theorganic layers were combined and concentrated under reduced pressure to give the crudeproduct. The residue was purified by silica gel column chromatography to afford desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With iron(III)-acetylacetonate; caesium carbonate; copper(II) oxide; In N,N-dimethyl-formamide; at 90℃; for 36h;Inert atmosphere; | General procedure: The compound was synthesized according to a known procedure with modifications.11 To an 8-dram vial equipped with a magnetic stir bar was added 5-iodo-1-methyl-1H-indole (1 equiv), 1Hpyrazoleor <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (1.5 equiv), Fe(acac)3 (30 mol%), CuO (10 mol%), Cs2CO3 (2equiv), and DMF (1 mL/mmol indole). The reaction mixture was purged with N2 (under strongstream over 5 min), placed into a preheated bath at 90 C, and stirred for 36 h. After cooling toroom temperature, the reaction mixture was diluted with H2O (10 mL) and EtOAc (20 mL),followed by filtration over a pad of Celite and Na2SO4, and washed with EtOAc (20 mL). Thefiltrate was added into a separatory funnel containing H2O (100 mL). Organic layer wasseparated, and the aqueous layer was further extracted with EtOAc (20 mL x 2). Combinedorganic layers were washed with H2O (50 mL) and brine (2 x 50 mL). After drying over Na2SO4and filtration, the crude mixture was concentrated to dryness. Purification by flash columnchromatography yielded the desired products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With copper(I) oxide; (E)-2-hydroxylbenzaldehyde oxime; caesium carbonate; In acetonitrile; at 80℃;Inert atmosphere; | A mixture of Cu20 (2.6 mg, 0.019 mmol), Cs2CO3 (241 mg, 0.740 mmol), salicylaldoxime (10 mg, 0.074 mmol), and <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (45.5 mg, 0.555 mmol) was added to a solution of Intermediate 9 (250 mg, 0.370 mmol) in CH3CN (10 mL). The resulting mixture was stirred at 80 C overnight under N2, allowed to cool to rt, filtered, and concentrated in vacuo. The crude product was purified byprep-TLC (PE/EA=1O/1) to give trans-4-((tert-butyldimethyl silyl)oxy)-N-((trans-4-(4-methoxy-3 - methylphenyl)cyclohexyl)methyl)-N-(3 -(4-methyl- 1H-pyrazol- 1- yl)phenyl)cyclohexanecarboxamide (100 mg, 43%) as a light yellow oil. LCMS: 630.5 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With copper(l) iodide; caesium carbonate; In N,N-dimethyl-formamide; at 20 - 120℃; for 16.5h;Inert atmosphere; | A mixture of <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (23 mg, 0.28 mmol), tert-butyl (35)-3-[[4-[2-[(5- iodo-2-methyl- 1 -naphthyl)oxy]-3 -pyridyl]pyrimidin-2-yl]amino]piperidine- 1 -carboxylate (120 mg, 0.188 mmol), cuprous iodide 911 mg, 0.057 mmol), cesium carbonate (123 mg, 0.38 mmol) in DMF (1.5 mL) was evacuated and filled with nitrogen twice. The reaction mixture was stirred at rt for 30 mm, and then at 120 C overnight. After 16 hours, the mixture was cooled to room temperature and the mixture diluted with DCM and water, followed by separation of the layers. The organic phase was washed with saturated NaC1(aq), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica column 5 to 80% (isopropylacetate/MeOH (3:1):heptanes) to provide 92 mg of the title compound (74% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 16h; | To a stirred solution of 6-chloro-5-(8-chloroquinolin-6-yl)pyrazin-2-amine (120 mg, 0.41 mmol, 1 eq.) in DMF (5 mL), was added <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (84 mg, 1.03 mmol, 2.5 eq.) and Cs2CO3 (335 mg, 1.03 mmol, 2.5 eq.). Resulting mixture was heated at 100 C. for 16 h. Progress of reaction was monitored by TLC and LCMS On completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL*2). Combined organic layers were washed with water (100 mL*2), dried over anhydrous Na2SO4 and concentrated under vacuum to obtain the solid residue which was purified by normal phase column chromatography to afford the desired product as pale yellow solid (60 mg, 43%). LCMS: 337.2 [M+1]+. 1H NMR: (400 MHz, DMSO-d6) delta 8.96 (d, J=3.51 Hz, 1H), 8.36 (d, J=7.45 Hz, 1H), 8.07 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.61 (dd, J=4.17, 8.11 Hz, 1H), 7.41 (d, J=9.65 Hz, 2H), 7.09 (s, 2H), 2.08 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In 1,4-dioxane; water; at 105℃; for 6h; | To a 2-necked, round-bottomed flask equipped with an overhead magnetic stirrer, reflux condenser, and nitrogen inlet were added 3-bromo-6-methylpyridine-2-carboxylic acid (0.50 g, 2.314 mmol), copper iodide (22 mg, 0.1 16 mmol), and Cs2C03 (1.5 g, 4.63 mmol). To these solids were added dioxane (3 ml_), then water (0.12 ml_), then 4- methylpyrazole (0.38 ml_, 4.63 mmol), and finally Trans-N, N'-dimethyl-cyclohexane-1 ,2- diamine (0.073 ml_, 0.463 mmol). The mixture was then warmed to 105 C for 6 hours. The mixture was cooled and then MTBE and water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 2 with 6N HCI. The resulting precipitate was removed by filtration. The mother-liquors were concentrated and purified by RP on C18 column (eluent: from H2O+0.1 % formic acid to H2O: MeCN + 0.1 % formic acid 75:25). The fractions containing desired product were evaporated to afford 6-methyl-3-(4-methyl-1 H-pyrazol-1-yl)pyridine-2-carboxylic acid (p94, 454 mg, y=88%) as white solid. MS (/T7/z): 218.2 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; for 2h;Sealed tube; Microwave irradiation; | In a microwave vial was placed ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (266 mg, 1) and 4-methyl-lH-pyrazole (164 mg, 2.0 mmol), and K2C03 (276 mg, 2.0 mmol). Then DMSO (2 ml) was added. The tube was sealed and heated at 100 C for 2 h. The mixture was poured into EtOAc/H20 (30 mL/30 mL). The organic layer was dried (Na2S04) and filtered. After removal of solvent, the product was purified by silica gel chromatography using 20-40% EtOAc/hexane as the eluent to give ethyl 6-methoxy-4-(4-methyl-lH-pyrazol-l-yl)quinoline-3-carboxylate (295 mg, 0.948 mmol, 95 % yield). LC-MS (Method 1): = 3.33 min, m/z (M+H)+= 312. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | To a solution of <strong>[7554-65-6]4-methyl-1H-pyrazole</strong> (0.10 g, 0.001218 mol) in anhydrous THF (5 mL), which was cooled in an ice water bath under an argon atmosphere, was added sodium hydride (60% dispersion in oil, 0.17 g, 0.004263 mol). After addition, the resulting mixture was stirred for three hours. (R)-3-Bromo-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (8) (0.428 g, 0.001218 mol) was added to above solution, and the resulting reaction mixture was allowed to stir overnight at room temperature under argon. The reaction was quenched by water and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under vacuum. The product was purified by a silica gel column using DCM and ethyl acetate (19:1) as eluent to afford 0.28 g (66%) of the titled compound as a white solid.1H NMR (400 MHz, DMSO-d6) d 10.38 (s, 1H, NH), 8.46 (d, J = 2.0 Hz, 1H, ArH), 8.23 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H, ArH), 8.10 (d, J = 8.8 Hz, 1H, ArH), 7.41 (s, 1H, Pyrazole-H), 7.17 (s, 1H, Pyrazole-H), 6.24 (s, 1H, OH), 4.40 (d, J = 14.0 Hz, 1H, CH), 4.22 (d, J = 14.0 Hz, 1H, CH), 1.97 (s, 3H, CH3), 1.36 (s, 3H, CH3).HRMS [C +16H16F3N4O2 ]: calcd 353.1225, found 353.1232[M+H]+.Purity: 99.75% (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45.7% | To a solution of 4-methyl- lH-pyrazole (5.70 mg, 0.069 mmol) in DMF (1.5 mL) was added isopropyl (S)-2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'- bipyridin]-5'-yl)-2-(tert-butoxy)acetate (20 mg, 0.035 mmol) and CS2CO3 (22.60 mg, 0.069 mmol). The mixture was stirred at 65 C for 2 hrs. LCMS showed the starting material was consumed completely. The mixture was poured into water (5.0 mL) and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL x 2), dried over Na2SC>4, filtered and concentrated. The residue was dissolved in MeOH (1.5 mL), water (1.5 mL) and NaOH (27.7 mg, 0.694 mmol) were added. The mixture was stirred at 70 C for 12 hrs. LCMS showed the starting material was consumed completely. The pH of mixture was adjusted with HC1 (1 N) to 5~6, and concentrated. The residue was dissolved in DMF (2 mL), and filtered. The filtrate was purified by prep-HPLC {Instrument: Gilson 281 (PHG-009; Column: Xtimate Prep C18 OBD, 21.2x 250 mm, 10 pm; Mobile Phase A: water (10 mmol NH4HCO3); B: MeCN; Gradient 95-95 %B in 8.0 min, stop at 13.0 min; Flow Rate (ml/min) 30.00} to give the desired product (S)-2-(tert-butoxy)-2-(4'-(4,4-dimethylpiperidin-l-yl)-6'- methyl-5-(2-(4-methyl-lH-pyrazol-l-yl)ethoxy)-[2,3'-bipyridin]-5'-yl)acetic acid (8.5 mg, 0.016 mmol, 45.7 % yield) as white solid. LCMS (M +H) = 536.2; Retention time (10 mM NH4HC03) = 1.45 min. NMR (400 MHz, MeOD): d 8.31 (d, J = 2.8 Hz, 1H), 8.08 (s, 1H), 7.52-7.51 (brs, 1H), 7.51 (dd, J = 2.8, 8.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.33-7.32 (brs, 1H), 5.76 (s, 1H), 4.53 (t, J = 4.8 Hz, 2H), 4.46 (t, J = 4.8 Hz, 2H), 3.06-2.70 (m, 4H), 2.62 (s, 3H), 27 (s, 3H), 1.47-1.20 (m, 4H), 1.17 (s, 9H), 0.87 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With chloro(1,3-bis(2,6-di-i-propylphenyl)imidazol-2-ylidene)gold(I); silver(I) triflimide; In 1,2-dichloro-ethane; at 80℃; for 48h;Inert atmosphere; | General procedure: To a solution of IPrAuCl (6.2 mg, 0.01 mmol) and AgNTf2 (4 mg, 0.01 mmol) in 1,2-dichloroethane (3 mL), was added o-alkynylarylazide 1a (43.8 mg, 0.2 mmol) and benzotriazole 2a (95 mg, 0.8 mmol) stepwisely at rt. The reaction mixture was stirred at 80 C with TLC monitoring until complete consumption of the starting material 1a (48 h). Concentration of the reaction mixture, followed by purification through flash chromatography (petroleum/EtOAc = 5/1 as the eluent) afforded 3a (38 mg) and 3a (8.5 mg) as two yellow solid products (75 % total yield, 3a/3a=4.5/1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.2% | With potassium carbonate; In acetonitrile; at 120℃; for 26h; | 4-Methyl-1 H-pyrazole (0.506 mL, 6.35 mmol) was added to ethyl 2-bromothiazole- (0902) 5-carboxylate (0.633 mL, 4.24 mmol) in acetonitrile (8 mL), followed by potassium carbonate (1 .464 g, 10.59 mmol) and the reaction mixture was stirred in a heating block at 120 C for eight hours. Then, an additional portion of 4-methyl-1 /-/-pyrazole (0.26 mL; 3.2 mmol) was added and heating resumed for eighteen hours. After the mixture was cooled, it was poured into water (50 ml_) and extracted with ethyl acetate (3X). The combined organics were washed with water and saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with ethyl acetate:hexanes (0:1 to 1 :4) to afford ethyl 2-(4-methyl-1 /-/-pyrazol-1 - yl)thiazole-5-carboxylate (0.665 g, 2.80 mmol, 66.2 % yield) as a colorless solid. 1H NMR (400 MHz, CD3SOCD3) d 1 .30 (t, J = 7 Hz, 3 H), 2.10 (s, 3 H), 4.30 (q, J = 7 Hz, 2 H), 7.79 (s, 1 H), 8.25 (s, 1 H), 8.34 (t, J = 1 Hz, 1 H); LC-MS (LC-ES) M+H = 238. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With caesium carbonate In N,N-dimethyl-formamide for 24h; Reflux; | 40.1 Step 1: Preparation of 4-(4-methyl-1H-pyrazol-1-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine After dissolving the intermediate compound (S2, 200mg, 1.17mmol) prepared in step 2 of Example 1-1 in N,N-dimethylformamide (DMF), 4-methyl-1H-pyrazole (0.38) ml, 4.71mmol) and cesium carbonate (Cs2CO3, 1.53g, 4.71mmol) were added, heated to reflux, and stirred for 1 day. The reaction mixture was diluted with ethyl acetate (EA), washed with brine, dried over magnesium sulfate, filtered and concentrated, and the concentrate was recrystallized from ethyl acetate (EA) to obtain an intermediate compound (S48, 90 mg, 35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
120 mg | With trans-N,N’-dimethylcyclohexane-1,2-diamine; copper (I) iodide; Cs2CO3 In N,N-dimethyl-formamide at 115℃; for 7h; Inert atmosphere; | 31.1 Step 1: Preparation of 1-(4-(1,3-dioxolan-2-yl)phenyl)-4-methyl-1H-pyrazole (Compound 88c Compound 88a (300 mg), Compound 88b (161.3 mg), trans-N,N’-dimethyl-1,2-cyclohexanediamine (74.5 mg),CuI (50.0 mg), and cesium carbonate (1.71 g) were added into DMF (5.0 mL). The mixture was heated to 115 °C, andkept for reaction under the protection of nitrogen at this temperature for 7 h. H2O (10 mL) was added into the reactionmixture to quench the reaction. The reaction mixture was extracted with EA (10 mL33). The organic phases werecombined, washed with water (10 mL 33), dried over anhydrous sodium sulfate, filtered, concentrated under reducedpressure, and separated and purified by silica gel column chromatography (PE:EA=3:1) to provide Compound 88c (120mg). MS m/z (ESI): 231.2 [M+H |
120 mg | With trans-N,N’-dimethylcyclohexane-1,2-diamine; copper (I) iodide; Cs2CO3 In N,N-dimethyl-formamide at 115℃; for 7h; Inert atmosphere; | 31.1 Step 1: Preparation of 1-(4-(1,3-dioxolan-2-yl)phenyl)-4-methyl-1H-pyrazole (Compound 88c Compound 88a (300 mg), Compound 88b (161.3 mg), trans-N,N’-dimethyl-1,2-cyclohexanediamine (74.5 mg),CuI (50.0 mg), and cesium carbonate (1.71 g) were added into DMF (5.0 mL). The mixture was heated to 115 °C, andkept for reaction under the protection of nitrogen at this temperature for 7 h. H2O (10 mL) was added into the reactionmixture to quench the reaction. The reaction mixture was extracted with EA (10 mL33). The organic phases werecombined, washed with water (10 mL 33), dried over anhydrous sodium sulfate, filtered, concentrated under reducedpressure, and separated and purified by silica gel column chromatography (PE:EA=3:1) to provide Compound 88c (120mg). MS m/z (ESI): 231.2 [M+H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With Cs2CO3 In N,N-dimethyl-formamide at 20℃; for 16h; | 504.1 Step 1. Synthesis of 1- (4-methoxybenzyl) -4-methyl-1H-pyrazole A mixture of 4-methyl-1H-pyrazole (5.00 g, 60.90 mmol), PMBCl (11.44 g, 73.08 mmol) and Cs 2CO 3 (39.68 g, 121.8 mmol) in DMF (50 mL) was stirred at rt for 16 h. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 3). Thecombined organic layers were dried over Na 2SO 4, filtered, and concentrated in vacuo to provide the title compound (12.0 g, yield: 97%) as colorless oil. |
97% | With Cs2CO3 In N,N-dimethyl-formamide at 20℃; for 16h; | 504.1 Step 1. Synthesis of 1- (4-methoxybenzyl) -4-methyl-1H-pyrazole A mixture of 4-methyl-1H-pyrazole (5.00 g, 60.90 mmol), PMBCl (11.44 g, 73.08 mmol) and Cs 2CO 3 (39.68 g, 121.8 mmol) in DMF (50 mL) was stirred at rt for 16 h. The resulting mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 3). Thecombined organic layers were dried over Na 2SO 4, filtered, and concentrated in vacuo to provide the title compound (12.0 g, yield: 97%) as colorless oil. |
A439984[ 56010-88-9 ]
4-Methyl-1H-pyrazole hydrochloride
Reason: Free-salt
Precautionary Statements-General | |
Code | Phrase |
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P103 | Read label before use |
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P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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