Structure of 4522-35-4
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CAS No. : | 4522-35-4 |
Formula : | C3H3IN2 |
M.W : | 193.97 |
SMILES Code : | IC1=NNC=C1 |
MDL No. : | MFCD12022324 |
InChI Key : | RUKDVLFJSMVBLV-UHFFFAOYSA-N |
Pubchem ID : | 1239830 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 31.3 |
TPSA ? Topological Polar Surface Area: Calculated from |
28.68 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.92 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.9 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.01 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.61 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.24 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.14 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.23 |
Solubility | 1.15 mg/ml ; 0.00594 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.09 |
Solubility | 15.9 mg/ml ; 0.0818 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.19 |
Solubility | 1.26 mg/ml ; 0.00649 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.84 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.1 |
* 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 |
---|---|---|
Example 4N-(4-[l-(l-methyl-lH-pyrazol-3-yl)-lH-indol-5-yl]oxy}rhoyrintauidin-2-yl)benzene-l,3-diamine (Compound 75)Scheme 4Step 1: 3-iodo-lH-pyrazole.To a stirred suspension of lH-pyrazol-3-amine (1.0 g, 12 mMol) in concentrated HCl (16 mL) was added a solution of sodium nitrite (1.7 g, 24 mMol) in water (3.0 mL) over 5 minutes at 00C. To the resulting orange reaction mixture was added a solution of KI (5.0 g, 30 mMol) in water (7.0 mL) over 10 minutes, resulting in nitrogen evolution. The reaction mixture was stirred for 5 minutes, upon which nitrogen evolution ceased. TetaF (25 mL) was added, followed by water (25 mL). The aqueous mixture was extracted with Et2O (3 x 30 mL) and the combined organic extracts were washed with Na2S2O3 (2 x 30 mL), dried over magnesium sulfate, filtered and concentrated to afford the title compound. LRMS (ESI) calculated for C3H3IN2 [M+HJ+, 194.9; found 194.9. | ||
With hydrogenchloride; potassium iodide; sodium nitrite; In water; at 0 - 28℃; for 2.75h; | To a stirred suspension of 118 (2.00g, 24.O7mmol) in concentrated HC1 (32mL) was added a solution ofNaNO2 (3.32g. 48.i4mmoi) in water (5mL) over 5 minutes at 0C. To the resulting orange reaction mixture was added a solution of KI (9.99g, 60 iSmmol) in water (l0mL) over 10 minutes. The reaction mixture was stirred at 0C for 30 minutes and then kept at 28C for another 2 hours, TLC showed the reaction was complete, then, solvent THF (3OmL) was added,followed by water (3OmL). The aqueous mixture was extracted with EtOAc (3 x8OmL) and the combined organic extracts were washed with Na2S2O3 (2 x4OmL), dried over Na2SO4, filtered and concentrated in vacuum to afford product 180 (200 g, crude), the crude product was used directly for the next step without purification.LCMS: m/z, i94.9M+H)??. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 2h; | A mixture of <strong>[4522-35-4]3-iodopyrazole</strong> (prepared as described in WO2007/035309) (1.0 g, 5.1 mmol), 4-fluorobenzotrifluoride (0.72 mL, 5.7 mmol) and potassium carbonate (0.93g, 6.7 mmol) was stirred in lambda/,lambda/-dimethylformamide (10 mL) at 100 0C for 2 h. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (2 x 30 mL). The organic layers were combined, dried over magnesium sulfate and concentrated. The residue after evaporation was subjected to silica gel chromatography (40 g silica) using a gradient of ethyl acetate/chlorobutane (0:100 to 50:50), and appropriate fractions were combined and evaporated to give the title compound (1.27 g). 1H NMR (CDCl3) delta 7.79 (m, 3H), 7.71 (m, 2H), 6.67 (d, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 90℃; for 18h;Inert atmosphere; | Compound 51.1. Methyl 4-methyl-3-(lH-pyrazoI-5-yl)benzoate. To methyl 4- methyl-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 mL) was added 5-iodo-lH-pyrazole (674 mg, 3.5 mmol), and Pd(dppf)Cl2 FontWeight="Bold" FontSize="10" DCM (237 mg, 0.29 mmol). The mixture was degassed with argon and stirred for 10 minutes then an aqueous potassium carbonate solution (2 M, 8 mL) was added. The mixture was heated at 90 C for 18 h, then cooled and diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, dried (MgS04), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (Si02; 0-30 % EtOAc in hexanes) to yield 258 mg (41 %) of the title compound as a solid. m/z |
41% | Compound 51.1. Methyl 4-methyl-3-(lH-pyrazol-5-yl)benzoate. To methyl 4- methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (compound 5.4, 800 mg, 2.9 mmol) in dioxane (30 mL) was added 5-iodo-lH-pyrazole (674 mg, 3.5 mmol), and Pd(dppf)Cl2 DCM (237 mg, 0.29 mmol). The mixture was degassed with argon and stirred for 10 minutes then an aqueous potassium carbonate solution (2 M, 8 mL) was added. The mixture was heated at 90 C for 18 h, then cooled and diluted with EtOAc and filtered through Celite. The filtrate was washed with brine, dried (MgSC^), filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (S1O2; (M0-30 % EtOAc in hexanes) to yield 258 mg (41 %) of the title compound as a solid, m/z (ES+) 217 (M-H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3-Iodo-1H-pyrazole (19.44 g, 100 mmol) was charged to a flask followed byTHF (237 mL) and the solution was cooled to -10 C. NaH (4.41 g, 110 mmol)was added in portions keeping the internal temperature below -10 C. Thereaction was stirred for 30 min, then chloromethyl pivalate (17.45 mL, 120mmol) was added and the reaction was stirred for 1 h at -1 0 C and then allowedto warm to room temperature. The reaction was cooled in an ice bath andquenched with sat. NH4Cl then diluted with EtOAc and water. The organiclayer was washed with brine, dried over MgS04 and the solvent was removed.The product was purified by flash chromatography eluting with 0-50%EtOAc/hexane to give (3-iodo-1H-pyrazol-1-yl)methyl pivalate, as a white solid.LCMS calc.= 309.01; found= 308.87 (M+H+). | ||
3-Iodo-lH-pyrazole (19.44 g, 100 mmol) was charged to a flask followed by THF (237 mL) and the solution was cooled to -10 C. NaH (4.41 g, 110 mmol) was added in portions keeping the internal temperature below -10 C. The reaction was stirred for 30 min, then chloromethyl pivalate (17.45 mL, 120 mmol) was added and the reaction was stirred for 1 h at -10 C and then allowed to warm to room temperature. The reaction was cooled in an ice bath and quenched with sat. NH4C1 then diluted with EtOAc and water. The organic layer was washed with brine, dried over MgS04 and the solvent was removed. The product was purified by flash chromatography eluting with 0-50% EtOAc/hexane to give (3-iodo-lH-pyrazol-l-yl)methyl pivalate, as a white solid. LCMS calc. = 309.01 ; found = 308.87 (M+H+). | ||
Step A: (3-Iodo-lH-pyrazol-l -yl)methyl pivalate To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (1.40 g) in THF (25 mL) was added NaH (0.32 g, 60%wt) at 0 C. After stirring for 10 min at 0 C, chloromethyl pivalate (1.14 g) was added to the reaction at the same temperature. The reaction mixture was stirred for 1 h at room temperature. It was diluted with sat. NaHC03 aq. and extracted with EtOAc (2 times). The combined organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give (3-iodo-lH-pyrazol-l -yl)methyl pivalate, as a brown oil, which was used in the next step without further purification. LCMS 331 (M+Na)+. NMR (300 MHz, CDC13): 5 7.48 (1 H, d, J= 2 Hz), 6.45 (1 H, d, J= 2 Hz), 5.97 (2 H, s), 1.17 (9 H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of<strong>[4522-35-4]3-iodo-1H-pyrazole</strong> (0.75 g) in DMSO (19 mL), was added60% NaH (0.39 g) under ice cooling and stirred for 10 min. 4-bromopyridazinehydrobromide (1.4 g) was added and stirred at room temperature for 3 days.Then 60% NaH (0.16 g) was added at 0 OC and warmed to room temperatureand stirred for 1 day. The reaction mixture was diluted with water and EtOAc. The mixture was filtered with Celite, and extracted with EtOAc. The combinedorganic layer was washed with brine and dried with anhyd. Na2S04. It wasfiltered to remove insoluble matters and it was concentrated in vacuo. Theresidue was triturated (Hexane:EtOAc= 1:1) to obtain compound 2-1 as a brownsolid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To <strong>[4522-35-4]3-iodo-1H-pyrazole</strong> (763 mg, 3.93 mmol) in DMSO (15 mL) at 0 oc, wasadded sodium hydride (60% in mineral oil, 189 mg, 4.72 mmol). The reactionwas warmed to 25 C and stirred for 60 min before 4-fluoro-2-methoxypyridine (500 mg, 3.93 mmol) was added. The reaction mixture was stirred at 90 C for4.5 h before quenching by the addition of water. The reaction mixture wasextracted with EtOAc. The combined organic extracts were dried over MgS04and concentrated in vacuo. The crude mixture was purified by flashchromatography (ISCO Combiflash, 0-30% EtOAc in hexanes) to afford 4-(3-iodo-1H-pyrazol-1-yl)-2-methoxypyridine, as a white solid. LCMS calc.=301.97; found= 302.02 (M+Ht | ||
To 3-iodo-lH-pyrazole (763 mg, 3.93 mmol) in DMSO (15 mL) at 0 C, was added sodium hydride (60% in mineral oil, 189 mg, 4.72 mmol). The reaction was warmed to 25 C and stirred for 60 min before 4-fluoro-2-methoxypyridine (500 mg, 3.93 mmol) was added. The reaction mixture was stirred at 90 C for 4.5 h before quenching by the addition of water. The reaction mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 0-30% EtOAc in hexanes) to afford 4-(3- iodo-lH-pyrazol-l-yl)-2-methoxypyridine, as a white solid. LCMS calc. = 301.97; found = 302.02 (M+H)+. | ||
INTERMEDIATE 24 4-(3-Iodo-l H-pyrazol- 1 -yl)-2-methoxypyridine To 3-iodo-lH-pyrazole (763 mg, 3.93 mmol) in DMSO (15 mL) at 0 C, was added sodium hydride (60% in mineral oil, 189 mg, 4.72 mmol). The reaction was warmed to 25 C and stirred for 60 min before 4-fluoro-2-methoxypyridine (500 mg, 3.93 mmol) was added. The reaction mixture was stirred at 90 C for 4.5 h before quenching by the addition of water. The reaction mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 0-30% EtOAc in hexanes) to afford 4-(3-iodo-17J-pyrazol-l-yl)-2-methoxypyridine, as a white solid. LCMS calc. = 301.97; found = 302.02 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.70 g, 3.61 mmol), in DMSO (18.0 mL) wasadded sodium hydride (60% disp. in oil, 0.173 g, 4.33 mmol), and the resultingmixture was stirred for 0.5 h before adding 4-fluoro-2-trifluoromethyl pyridine(0.596 g, 3.61 mmol). The reaction mixture was stirred at 90 oc for 3 h. Thereaction was quenched by the addition of water and extracted with EtOAc. Thecombined organic extracts were washed with water and brine, dried overMgS04 and concentrated in vacuo. The crude mixture was purified by flashchromatography (ISCO, 40 g, 0-50 % EtOAc in hexanes) to afford 4-(3-iodo-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyridine, as a white solid. LCMS calc. =339.95; found= 339.93 (M+H)+. 1H NMR (500 MHz, CDCh): o 8.77 (d, J=5.3 Hz, 1 H); 8.03 (d, J = 3.8 Hz, 1 H); 7.91 (d, J = 2.6 Hz, 1 H); 7.77 (d, J =5.4 Hz, 1 H); 6.74 (d, J= 2.5 Hz, 1 H). | ||
To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.70 g, 3.61 mmol), in DMSO (18.0 mL) was added sodium hydride (60% disp. in oil, 0.173 g, 4.33 mmol), and the resulting mixture was stirred for 0.5 h before adding 4-fluoro-2-trifluoromethyl pyridine (0.596 g, 3.61 mmol). The reaction mixture was stirred at 90 C for 3 h. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS0 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO, 40 g, 0-50 % EtOAc in hexanes) to afford 4-(3-iodo- lH-pyrazol-l-yl)-2-(trifluoromethyl)pyridine, as a white solid. LCMS calc. = 339.95; found = 339.93 (M+H)+. 1H NMR (500 MHz, CDC13): delta 8.77 (d, J= 5.3 Hz, 1 H); 8.03 (d, J- 3.8 Hz, 1 H); 7.91 (d, J= 2.6 Hz, 1 H); 7.77 (d, J= 5.4 Hz, 1 H); 6.74 (d, J = 2.5 Hz, 1 H). | ||
INTERMEDIATE 20 4-(3-Iodo- lH-pyrazol-1 -yl)-2-(trifluoromethyl)pyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.70 g, 3.61 mmol), in DMSO (18.0 mL) was added sodium hydride (60% disp. in oil, 0.173 g, 4.33 mmol), and the resulting mixture was stirred for 0.5 h before adding 4-fluoro-2-trifluoromethyl pyridine (0.596 g, 3.61 mmol). The reaction mixture was stirred at 90 C for 3 h. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO, 40 g, 0-50 % EtOAc in hexanes) to afford 4-(3-iodo-lH-pyrazol-l-yl)-2-(trifluoromethyl)pyridine, as a white solid. LCMS calc. = 339.95; found = 339.93 (Mu+Eta)+. NMR (500 MHz, CDC13): delta 8.77 (d, J= 5.3 Hz, 1 H); 8.03 (d, J= 3.8 Hz, 1 H); 7.91 (d, J= 2.6 Hz, 1 H); 7.77 (d, J= 5.4 Hz, 1 H); 6.74 (d, J= 2.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In dimethyl sulfoxide; at 0 - 50℃; | To the stirred solution of 4-iodopyridazine (1 000 mg, 4.85 mmol) and 3-iodolH-pyrazole (951 mg, 4.90 mmol) in DMSO was added NaH ( 60% in oil, 233mg, 5.83 mmol) in portion at 0 C. The mixture was stirred at room temparature for 30 min or until bubbling ceased, then warmed up to 50 C and stirred at50 C overnight. The reaction mixture was cooled to room temperature,partitioned between EtOAc and water. The aqueous was extracted with EtOAcfor three times. The organic phases were combined, dried over Na2S04 andconcentrated in vacuo to give the crude product. This was purified by flashchromatography (Isco CombiFlash, 80 g Silica gel column, 0-100% EtOAc inhexanes) to afford 4-(3-iodo-1H-pyrazol-1-yl)pyridazine. LCMS calc.= 272.96;found= 272.96 (M+Ht. 1H NMR (500 MHz, CDCl)): o 9.64 (d, J = 3.0 Hz, 1H); 9.27 (d, J = 6.0 Hz, 1 H); 7.95 (d, J = 2.5 Hz, 1 H); 7.81 (dd, J = 2.5 Hz, J= 5.5 Hz, 1 H); 6.79 (d, J = 2.5 Hz, 1 H). | |
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 0 - 50℃; | To the stirred solution of 4-iodopyridazine (1000 mg, 4.85 mmol) and 3-iodo- lH-pyrazole (951 mg, 4.90 mmol) in DMSO was added NaH ( 60% in oil, 233 mg, 5.83 mmol) in portion at 0 C. The mixture was stirred at room temparature for 30 min or until bubbling ceased, then warmed up to 50 C and stirred at 50 C overnight. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water. The aqueous was extracted with EtOAc for three times. The organic phases were combined, dried over Na S04 and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Isco CombiFlash, 80 g Silica gel column, 0-100% EtOAc in hexanes) to afford 4-(3-iodo-lH-pyrazol-l -yl)pyridazine. LCMS calc. = 272.96; found = 272.96 (M+H)+. 1H NMR (500 MHz, CDC13): delta 9.64 (d, J = 3.0 Hz, 1 H); 9.27 (d, J = 6.0 Hz, 1 H); 7.95 (d, J = 2.5 Hz, 1 H); 7.81 (dd, J = 2.5 Hz, J = 5.5 Hz, 1 H); 6.79 (d, J = 2.5 Hz, 1 H). | |
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 0 - 50℃; | INTERMEDIATE 39 4-(3 -Iodo- 1 H-p yrazol- 1 -yl)pyridazine To the stirred solution of 4-iodopyridazine (1000 mg, 4.85 mmol) and 3-iodo-lH- pyrazole (951 mg, 4.90 mmol) in DMSO was added NaH ( 60% in oil, 233 mg, 5.83 mmol) in portion at 0 C. The mixture was stirred at room temparature for 30 min or until bubbling ceased, then wanned up to 50 C and stirred at 50 C overnight. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water. The aqueous was extracted with EtOAc for three times. The organic phases were combined, dried over Na2S04 and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Isco CombiFlash, 80 g Silica gel column, 0-100% EtOAc in hexanes) to afford 4-(3-iodo-lH-pyrazol-l- yl)pyridazine. LCMS calc. = 272.96; found = 272.96 (M+H)+. NMR (500 MHz, CDC13): delta 9.64 (d, J = 3.0 Hz, 1 H); 9.27 (d, J = 6.0 Hz, 1 H); 7.95 (d, J = 2.5 Hz, 1 H); 7.81 (dd, J = 2.5 Hz, J = 5.5 Hz, 1 H); 6.79 (d, J = 2.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 1h; | To a soluton of<strong>[4522-35-4]3-iodopyrazole</strong> (500 mg, 2.58mmol) and 3,5-dichloropyridazine(384 mg, 2.58 mmol) in anhydrous DMF (5 mL) at room temperature was addedpotassium tert-butoxide (289 mg, 2.58 mmol) in one portion. It was heated at100 C for 1 h. It was cooled to room temperature, diluted with EtOAc (50 mL),washed with satd aq. NaHC03 (10 mL) and water (100 mL). The aqueous layerwas separated and extracted with EtOAc (3 x 50 mL). The combined organiclayers were washed with water (1 00 mL), brine (1 00 mL), dried over Na2S04,filtered and concentrated. The residue was purified by flash chromatography(ISCO Combiflash, Gold 40 g, 0-60% EtOAc in hexanes) to give 3-chloro-5-(3-iodo-1H-pyrazol-1-yl)pyridazine, as a white solid. LCMS calc.= 306.92, found= 306.96 (M+Ht. 1H NMR (500 MHz, CHCh-d): o 9.54 (d, J= 2.3 Hz, 1 H);7.94 (d, J= 2.7 Hz, 1 H); 7.90 (d, J= 2.3 Hz, 1 H); 6.81 (d, J= 2.7 Hz, 1 H). | |
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 1h; | 3-Chloro-5-(3-iodo-lH-pyrazol-l -vDpyridazine To a soluton of <strong>[4522-35-4]3-iodopyrazole</strong> (500 mg, 2.58 mmol) and 3,5-dichloropyridazine (384 mg, 2.58 mmol) in anhydrous DMF (5 mL) at room temperature was added potassium teri-butoxide (289 mg, 2.58 mmol) in one portion. It was heated at 100 C for 1 h. It was cooled to room temperature, diluted with EtOAc (50 mL), washed with satd aq. NaHC03 (10 mL) and water (100 mL). The aqueous layer was separated and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, Gold 40 g, 0-60% EtOAc in hexanes) to give 3-chloro-5-(3- iodo-lH-pyrazol-l-yl)pyridazine, as a white solid. LCMS calc. = 306.92, found = 306.96 (M+H)+. NMR (500 MHz, CHCl3-d): delta 9.54 (d, J= 2.3 Hz, 1 H); 7.94 (d, J= 2.7 Hz, 1 H); 7.90 (d, J= 2.3 Hz, 1 H); 6.81 (d, J= 2.7 Hz, 1 H). | |
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 1h; | INTERMEDIATE 40 3-Chloro-5-(3-iodo-lH-pyrazol-l-yl pyridazine To a soluton of <strong>[4522-35-4]3-iodopyrazole</strong> (500 mg, 2.58 mmol) and 3,5-dichloropyridazine (384 mg, 2.58 mmol) in anhydrous DMF (5 mL) at room temperature was added potassium tert-butoxide (289 mg, 2.58 mmol) in one portion. It was heated at 100 C for 1 h. It was cooled to room temperature, diluted with EtOAc (50 mL), washed with satd aq. NaHC03 (10 mL) and water (100 mL). The aqueous layer was seperated and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, Gold 40 g, 0-60% EtOAc in hexanes) to give 3-chloro-5-(3-iodo-lH-pyrazol-l-yl)pyridazine, as a white solid. LCMS calc. = 306.92, found = 306.96 (M+H)+. NMR (500 MHz, CHC13- d): 5 9.54 (d, J= 2.3 Hz, 1 H); 7.94 (d, J= 2.7 Hz, 1 H); 7.90 (d, J= 2.3 Hz, 1 H); 6.81 (d, J= 2.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To <strong>[4522-35-4]3-iodopyrazole</strong> (124 mg, 0.641 mmol) in DMF (2 mL)was added potassiumtert-butoxide (53 mg, 0.472 mmol) at 0 C. The mixture was stirred at roomtemperature for 15 min. It was transfered into a solution of 5- chloro-3-(trifluoromethyl)pyridazine (78 mg, 0.427 mmol) in DMF (2 mL) at 0 C. Itwas warmed to room temperature, stirring for 30 min. It was diluted withEt0Ac(20 mL), washed with water (3 x 20 niL), the combined aqueous layerswere extracted with EtOAc (30 mL), the combined organic layers were washedwith brine (30 mL), dried over Na2S04, filtered and concentrated. The residuewas purified by flash chromatography (ISCO Combiflash, 12 g, 0-1 00% EtOAcin hexanes) to give a mixture of<strong>[4522-35-4]3-iodopyrazole</strong> and the desired product (1 :2,180 mg). It was disolved in anhydrous CH2Cb (2 mL) and added a little bit ofDMAP and of di-tert-butyl dicarbonate (~ 100 mg). It was stirred at roomtemperature for 10 min and purified by flash chromatography (IS COCombiflash, 0-40% EtOAc in hexanes) to give 5-(3-iodo-1H-pyrazol-1-yl)-3-(trifluoromethyl)pyridazine, as white solid. LCMS calc. = 340.95, found =340.84 (M+H/. 1H NMR (500 MHz, CHCb-d): 6 9.78 (d, J= 2.5 Hz, 1 H);8.17(d,J=2.5Hz, 1 H); 8.04(d,J=2.7Hz, 1 H); 6.84(d,J=2.7Hz, 1 H). | ||
To <strong>[4522-35-4]3-iodopyrazole</strong> (124 mg, 0.641 mmol) in DMF (2 mL)was added potassium teri-butoxide (53 mg, 0.472 mmol) at 0 C. The mixture was stirred at room temperature for 15 min. It was transferee into a solution of 5- chloro-3- (trifluoromethyl)pyridazine (78 mg, 0.427 mmol) in DMF (2 mL) at 0 C. It was warmed to room temperature, stirring for 30 min. It was diluted with EtOAc(20 mL), washed with water (3 x 20 mL), the combined aqueous layers were extracted with EtOAc (30 mL), the combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, 12 g, 0-100% EtOAc in hexanes) to give a mixture of <strong>[4522-35-4]3-iodopyrazole</strong> and the desired product (1 :2, 180 mg). It was disolved in anhydrous CH2C12 (2 mL) and added a little bit of DMAP and of di-teri-butyl dicarbonate (~ 100 mg). It was stirred at room temperature for 10 min and purified by flash chromatography (ISCO Combiflash, 0-40%> EtOAc in hexanes) to give 5-(3-iodo-lH-pyrazol-l-yl)-3- (trifluoromethyl)pyridazine, as a white solid. LCMS calc. = 340.95, found = 340.84 (M+H)+. NMR (500 MHz, CHCl3-d): delta 9.78 (d, J= 2.5 Hz, 1 H); 8.17 (d, J= 2.5 Hz, 1 H); 8.04 (d, J= 2.7 Hz, 1 H); 6.84 (d, J= 2.7 Hz, 1 H). | ||
Step C: 5-(3-Iodo-lH-pyrazol-l -yl)-3-(trifluoiOmethyl)pyridazine To <strong>[4522-35-4]3-iodopyrazole</strong> (124 mg, 0.641 mmol) in DMF (2 mL)was added potassium tert- butoxide (53 mg, 0.472 mmol) at 0 C. The mixture was stirred at room temperature for 15 min. It was transfered into a solution of 5- chloro-3- (trifluoromethyl)pyridazine (78 mg, 0.427 mmol) in DMF (2 mL) at 0 C. It was wanned to room temperature, stirring for 30 min. It was diluted with EtOAc(20 mL), washed with water (3 x 20 mL), the combined aqueous layers were extracted with EtOAc (30 mL), the combined organic layers were washed with brine (30 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, 12 g, 0-100% EtOAc in hexanes) to give a mixture of <strong>[4522-35-4]3-iodopyrazole</strong> and the desired product (1 :2, 180 mg). It was disolved in anhydrous CH2C12 (2 mL) and added a little bit of DMAP and of di-fert-butyl dicarbonate (~ 100 mg). It was stirred at room temperature for 10 min and purified by flash chromatography (ISCO Combiflash, 0-40% EtOAc in hexanes) to give 5 -(3- iodo-lH-pyrazol-l-yl)-3-(trifluoromethyl)pyridazine, as white solid. LCMS calc. = 340.95, found = 340.84 (M+H)+. NMR (500 MHz, CHCl3-d): delta 9.78 (d, J= 2.5 Hz, 1 H); 8.17 (d, J= 2.5 Hz, 1 H); 8.04 (d, J= 2.7 Hz, 1 H); 6.84 (d, J = 2.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (7.26 g) in DMSO (200 mL) was added NaH (1.80 g, 60%wt) at 0 C, and it was stirred for 15 min. To the reaction mixture was added mixture of 4-fluoropyridine (5.00 g) and NaH (1.80 g) in DMSO (175 mL) at room temperature. It was stirred for 2 h at 90 C. The reaction mixture was cooled to room temperature, and it was diluted with EtOAc and H20. The mixture was extracted with EtOAc (2 times), and the combined organic layer were washed with H20 and brine and dried over Na2S04. It was filtered to remove insoluble matters and it was concentrated in vacuo. The residue was triturated with EtOAc to give compound 1-5 as a pale brown solid. |
Yield | Reaction Conditions | Operation in experiment |
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INTERMEDIATE 27 3 ,5 -Difluoro-4-(3 -iodo- 1 H-pyrazol- 1 -vDpyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.70 g, 3.61 mmol), in DMSO (15.1 mL) was added sodium hydride (60% in oil, 0.159 g, 3.97 mmol) and stirred for 0.5 h before 3,4,5- trifluoropyridine (0.48 g, 3.61 mmol) was added. The reaction mixture was stirred at 90 C for 3 h. This was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 40 g, 0-30 % EtOAc in hexanes) to give 3,5-difluoro-4-(3-iodo- lH-pyrazol-l-yl)pyridine, as a white solid. LCMS calc. = 307.94; found = 307.92 (M+H)+. 1H NMR (500 MHz, CDC13): delta 8.53 (s, 2 H); 7.65 (dd, J= 3.9, 2.3 Hz, 1 H); 6.72 (d, J= 2.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 28 5-Fluoro-4-(3-iodo-lH-pyrazol-l-yl)-2-methoxypyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.20 g, 1.031 mmol), in DMSO (5.20 mL) was added sodium hydride (60% in oil, 0.045 g, 1.134 mmol) and stirred for 0.5 h before 4- bromo-5-fluoro-2-methoxypyridine (0.212 g, 1.031 mmol) was added. The reaction mixture was stirred at 80 C for 4 h. This was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 12 g, 0-20 % EtOAc in hexanes) to give 5- fluoro-4-(3-iodo-lH-pyrazol-l-yl)-2-methoxypyridine, as a white solid. LCMS calc. = 319.96; found = 320.05 (M+H)+. NMR (500 MHz, CDC13): delta 8.13 (d, J= 2.8 Hz, 1 H); 7.97 (d, J = 1.7 Hz, 1 H); 7.37 (m, 1 H); 6.67 (d, J= 2.6 Hz, 1 H); 3.94 (t, J = 1.2 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 30 4- (3-Iodo-lH-pyrazol-l-yl)-2-methoxy-5-(trifluoromethyl)pyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.30 g, 1.547 mmol), in DMSO (7.73 mL) was added sodium hydride (60% in oil, 0.068 g, 1.701 mmol) and stirred for 0.5 h before 4-iodo- 5- trifluoromethyl-2-methoxypyridine (0.469 g, 1.547 mmol) was added. The reaction mixture was stirred at 80 C for 4 h. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 24 g, 0-20 % EtOAc in hexanes) to give 4-(3-iodo-lH-pyrazol-l-yl)-2-methoxy-5-(trifluoromethyl)pyridine, as a white solid. LCMS calc. = 369.96; found = 369.83 (M+H)+. NMR (500 MHz, CDC13): delta 8.58 (s, 1 H); 7.63 (s, 1 H); 7.01 (d, J ^ 2.8 Hz, 1 H); 6.65 (d, J= 2.6 Hz, 1 H); 4.03(d, J= 3.3 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step B: 5-(3-Iodo-lH-pyrazol-l-yl)-3-isopropoxypyridazine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (270 mg, 1.390 mmol) in anhydrous DMF (2 mL) at 0 C was added potassium iert-butoxide (143 mg, 1.275 mmol). It was stirred at room temperature for 10 min, and then 5-chloro-3-isopropoxypyridazine (200 mg, 1.159 mmol) was added neat. The mixture was stirred at room temperature for 15 min. It was heated at 100 C for 1 h. It was cooled to room temperature, diluted with EtOAc (20 mL), washed with water (3x20 mL). The combined aqueous layers were extracted with EtOAc (30 mL), washed with brine (20 mL), dried over Na2S04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, 12 g, 0-50% EtOAc in hexanes) to give the titled product, as a white solid. LCMS calc. = 331.01 ; found = 330.88 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In N,N-dimethyl-formamide; at 100℃; for 1h; | Step B: 3-(ter?-Butoxy)-5-(3-iodo-lH-pyrazol-l-yl)pyridazine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.208 g, 1.072 mmol) in DMF (5.36 mL) was added potassium teri-butoxide (0.132 g, 1.179 mmol) and then stirred at room temperature for 10 min. 3-(t<?r/-Butoxy)-5-chloropyridazine (0.2 g, 1.072 mmol) was added, then stirred at 100 C for 1 h, and cooled to room temperature. EtOAc and water were added and the organic was washed with water and brine, dried over MgS04, filtered and concentrated. The residue was purified by flash chromatography (ISCO Combiflash, 24 g, 0-30% EtOAc in hexanes) to give 3-(tert-Butoxy)-5-(3-iodo-lH- pyrazol-l-yl)pyridazine, as a white solid. LCMS calc. = 288.95; found = 288.87 (M+H-tert-Bu)+. NMR (500 MHz, CDC13): delta 9.22 (d, J= 2.2 Hz? 1 H); 7.83 (d, J= 2.5 Hz, 1 H); 7.09 (d, J= 2.3 Hz, 1 H); 6.70 (d, J= 2.5 Hz, 1 H); 1.69 (s, 9 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step B: 5-(3-Iodo-lH-pyrazol-l-yl)-2-methylpyridazin-3(2 /)-one To a clean dry flask was added sodium hydride (200 mg, 5.00 mmol) and anhydrous NMP (10 mL). The mixture was cooled to 0 C. 3-Iodopyrazole (959 mg, 4.95 mmol) was added to the mixture in one portion. The mixture was stirred for 10 min at room temperature, then 5-chloro-2-methylpyridazin-3(2H)-one (650 mg, 4.50 mmol) was added in one portion. The mixture was stirred at 100 C for 2 h. The reaction mixture was cooled to room temperature, water (100 mL) was added, and the resulting mixture was extracted with EtOAc (100 mL). The organic layer was washed with water (3 x 50 mL) and the combined aqueous layers were extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (ISCO Combiflash, 40 g, 0-100% EtOAc in hexanes) to give 5-(3-iodo-lH-pyrazol-l-yl)-2-methylpyridazin-3(2H)-one, as a white solid. LCMS calc. = 302.97; found = 302.95 (Mu+Eta)+. NMR (500 MHz, CDC13): delta 8.47 (d, J = 2.6 Hz, 1 H); 7.79-7.74 (d, J = 2.6 Hz, 1 H); 6.93 (d, J = 2.6 Hz, 1 H); 6.74 (d, J = 2.6 Hz, 1 H); 3.84 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 58 4-(3-Iodo-lH-pyrazol-l-yl)pyrimidine-2-carbonitrile To a solution of 3-iodo-lH-pyrazole (298 mg, 1.536 mmol) in anhydrous DMSO (4 mL) added NaH (86 mg, 2.151 mmol) at 0 C. The mixture was stirred for 30 min at 0C, followed by the addition of 4-chloropyrimidine-2-carbonitrile (214 mg, 1.536 mmol) in DMSO(l mL). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with water (10 mL) and extracted with EtOAc(40 mL x 3). The organic layer was collected and dried over Na2S04. The solvent was removed in vacuo to give the crude product. This was purified by flash chromatography (IS CO Combiflash, lOg, Biotage Si column, -30 mL/min, 100% hexanes 5min, gradient to 100% EtOAc in hexanes 15min) to afford 4-(3-iodo-lH- pyrazol-l-yl)pyrimidine-2-carbonitrile. LCMS calc. = 297.95; found = 297.92 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; copper diacetate; caesium carbonate; In 1,4-dioxane; at 80℃; | INTERMEDIATE 56 5-(3-Iodo-lH-pyrazol-l-yl)-2-methoxypyrimidine A solution of 3-iodo-lH-pyrazole (0.7 g, 3.61 mmol), 2-methoxypyrimidine -4- boronic acid (0.722 g, 4.69 mmol), DMAP (1.763 g, 14.43 mmol), copper(II) acetate (0.655 g, 3.61 mmol), and cesium carbonate (2.94 g, 9.02 mmol) in 1,4-dioxane (18.0 mL) was heated at 80 °C overnight. The reaction was allowed to room temperature and filtered. The filtrate was diluted with EtOAc and water, and the seperated aq. layer was extracted with EtOAc. The combined organics were dried over MgS04, filtered and concentrated. The residue was purified with flash chromatography (ISCO Combiflash, 40 g, 0-70percent EtOAc in hexanes) to give 5-(3-iodo-lH-pyrazol-l-yl)-2- methoxypyrimidine, as a white solid. LCMS calc. = 302.97; found = 302.86 (M+H)+. lR NMR (500 MHz, CDC13): delta 8.82 (s, 2 H); 7.66 (d, J= 2.6 Hz, 1 H); 6.68 (d, J= 2.5 Hz, 1 H); 4.07 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; copper diacetate; caesium carbonate; In 1,4-dioxane; at 80℃; | INTERMEDIATE 57 5-(3-Iodo-lH-pyrazol-l-yl)-2-(trifluorometyl)pyrimidine A solution of 3-iodo-lH-pyrazole (0.7 g, 3.61 mmol), 2-trifluoromethylpyrimidine -4- boronic acid (0.722 g, 4.69 mmol), DMAP (1.763 g, 14.43 mmol), copper(II) acetate (0.655 g, 3.61 mmol), and cesium carbonate (2.94 g, 9.02 mmol) in 1 ,4-dioxane (18.0 mL) was heated at 80 °C overnight. The reaction was allowed to room temperature and filtered. The filtrate was diluted with EtOAc and water, and the seperated aq. layer was extracted with EtOAc. The combined organics were dried over MgS04, filtered and concentrated. The residue was purified with flash chromatography (ISCO Combiflash, 40 g, 0-5 percent EtOAc in hexanes) to give 5-(3-iodo-lH-pyrazol-l-yl)-2- (trifluorometyl)pyrimidine, as a white solid. LCMS calc. = 340.94; found = 340.88 (M+H)+. NMR (500 MHz, CDC13): 8 9.25 (s, 2 H); 7.86 (d, J= 2.5 Hz, 1 H); 6.78 (d, J= 2.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 59 4-(3-Iodo-lH-pyrazol-l -yl)-2-methylpyrimidine To a solution of 3-iodo-lH-pyrazole (500 mg, 2.58 mmol) in anhydrous DMSO (6 mL) was added NaH (155 mg, 3.87 mmol) at 0 C. The mixture was stirred for 30 min at 0 C, followed by the addition of 4-chloro-2-methylpyrimidine (331 mg, 2.58 mmol) in DMSO (2 mL). The resulting mixture was stirred at 90 C overnight. The mixture was cooled to room temperature, quenched with water (10 mL) and extracted EtOAc (40 mL x 3). The organic layer was collected and dried over Na2S04. The solvent was removed in vacuo to give the crude product. This was purified by flash chromatography (ISCO Combiflash, 24 g, Biotage Si column, -60 mL/min, 100% hexanes 5 min, gradient to 100% EtOAc in hexanes 15 min) to afford 4-(3-iodo-17J- pyrazol-l-yl)-2-methylpyrimidine. LCMS calc. = 286.98; found = 286.95 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 0 - 90℃; for 4.5h; | INTERMEDIATE 60 4-(3-Iodo-lH-pyrazol-l-yl)-2-methoxypyrimidine To the stirred solution of 4-bromo-2-methoxypyrimidine (500mg, 2.65 mmol) and 3- iodo-lH-pyrazole (518 mg, 2.67 mmol) in DMSO was added NaH ( 60%> in oil, 132mg, 3.31 mmol) in portion at 0 C. The mixture was stirred at room temparature for 30 min or until bubbling ceased, then warmed up to 90 C and stirred at 90 C for 4 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water. The aqueous was extracted with EtOAc for three times. The organic phases were combined, dried over Na2S04 and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Isco CombiFlash, 80 g Silica gel column, 0-50% EtOAc in hexanes) to afford 4-(3-iodo-lH-pyrazol-l-yl)- 2-methoxypyrimidine. LCMS calc. = 302.97; found = 302.99 (M+H)+. 1H NMR (500 MHz, CDC13): delta 8.58 (d, J = 1.5 Hz, 1 H); 8.42 (d, J = 2.0 Hz, 1 H); 7.57 (d, J = 1.5 Hz, 1 H); 6.67 (d, J = 2.0 Hz, 1 H); 4.08 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 61 4-(3-Iodo-lH-pyrazol-l-yl)-N,N-dimethylpyrimidin-2-amine NaH (119 mg, 60% in oil, 2.97 mmol) was added to a solution of 3-iodo-lH-pyrazole (480 mg, 2.48 mmol) in anhydrous DMF (10 mL) at 25 C under N2. The mixture was stirred for 10 min and 4-bromo-N,N-dimethylpyrimidin-2-amine (500 mg, 2.48 mmol) was added. The resulting mixture was stirred for another 2 h at 25 C under N2. The reaction mixture was then quenched with saturated aq. NH4C1 solution and extracted with with EtOAc. The organic layer was washed with brine, dried (Na2S04) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Isco Combiflash Rf, RediSep Silica 40 g, 30% EtOAc in hexanes, then 30-100% EtOAc in hexanes) to afford 4-(3-iodo-lH-pyrazol-l-yl)-N,N- dimethylpyrimidin-2-amine. LCMS calc. = 314.99; found = 315.99 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 6 3-Iodo-l-(4-(methylsulfonyl)phenyl)-lH-pyrazole To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.7 g, 3.61 mmol) in DMSO (18.0 mL) was added sodium hydride (60% disp. in oil, 0.173 g, 4.33 mmol) and the resulting mixture was stirred for 0.5 h before adding 4-methylsulfoylfluorobenzene (0.629 g, 3.61 mmol). The reaction mixture was stirred at 90 C for 3 h. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flas chromatography (ISCO, 40 g, 0-60 % EtOAc in hexanes) to afford 3-iodo-l-(4-(methylsulfonyl)phenyl)-lH-pyrazole, as a white solid. LCMS calc. = 348.94; found = 348.92 (M+H)+. 1H NMR (500 MHz, CDC13): delta 8.03 (dd, J= 8.7, 1.7 Hz, 2 H); 7.89 (dd, J= 8.7, 1.7 Hz, 2 H); 7.84 (d, J= 2.6 Hz, 1 H); 6.69 (d, J= 2.6 Hz, 1 H); 3.09 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 7 Methyl 4-(3 -iodo- 1 H-p yrazol- 1 -yPbenzoate To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.7 g, 3.61 mmol) in DMSO (18.0 mL) was added sodium hydride (60% disp. in oil (0.173 g, 4.33 mmol), and the resulting mixture was stirred for 0.5 h before adding methyl 4- fluoro benzoate (0.556 g, 3.61 mmol). The reaction mixture was stirred at 90 C overnight. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO, 40 g, 0-20 % EtOAc in hexanes) to afford methyl 4-(3-iodo-lH-pyrazol-l-yl)benzoate, as a white solid. LCMS calc. - 328.97; found = 328.96 (M+H)+. NMR (500 MHz, CDC13): delta 8.12 (m, 2 H); 7.81 (d, J= 2.4 Hz, 1 H); 7.76 (m, 2 H); 6.65 (m, 1 H); 3.94 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 8 4-(3 -Iodo- lH-p yrazol- 1 - vPbenzonitrile To 3-iodo-lH-pyrazole (801 mg, 4.13 mmol) in DMSO (10 mL) at 0 C, was added sodium hydride (60% in mineral oil, 198 mg, 4.95 mmol). The reaction was warmed to 25 C and stirred for 60 min before methyl 4-fluorobenzonitrile (500 mg, 4.13 mmol) was added. The reaction mixture was stirred at 90 C for 4.5 h before quenching by the addition of water. The reaction mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combifiash, 0-30% EtOAc in hexanes) to afford 4-(3-iodo-lH-pyrazol-l-yl)benzonitrile, as a pale yellow crystaline solid. LCMS calc. = 295.96; found = 295.90 (M+H)+. NMR (500 MHz, CDC13): delta 7.83 (m, 3 H); 7.78 (d, J= 8.5 Hz, 2 H), 6.71 (d, J= 2.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylene-diamine)copper(II)] chloride; oxygen; In dichloromethane; at 25℃;Sealed tube; | INTERMEDIATE 10 1 -(4-Fluorophenyl)-3 -iodo- 1 H-pyrazole A mixture of 3-iodo-lH-pyrazole (1 g, 5.16 mmol), (4-fluorophenyl)boronic acid (0.866 g, 6.19 mmol) and [Cu(Cl) (OH)(Me2NCH2CH2NMe2)]2 (0.479 g, 1.031 mmol) in CH2C12 (20.6 mL) was sealed and stirred at 25 C under an atmosphere of oxygen (balloon) overnight. The reaction was filtered over Celite to remove insoluble solids and the filter was washed well with CH2C12. The filtrate was concentrated in vacuo and purified by flash chromatography (ISCO Combiflash, 40 g silica gel column, 0- 10% EtOAc in hexanes) to afford l-(4-fluorophenyl)-3 -iodo- 1 H-pyrazole, as white solid. LCMS calc. = 288.96; found = 288.86 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 11 l-(4-Chlorophenyl)-3-iodo-lH-pyrazole To 3 -iodo- 1 H-pyrazole (743 mg, 3.83 mmol) in DMSO (10 mL) at 0 C, was added sodium hydride (60% in mineral oil, 184 mg, 4.60 mmol). The reaction was warmed to 25 C and stirred for 60 min before l-chloro-4-fluorobenzene (500 mg, 4.13 mmol) was added. The reaction mixture was stirred at 90 C for 2 days before quenching by the addition of water. The reaction mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 0-20% EtOAc in hexanes) to give product, as a white solid. LCMS calc. = 304.93; found = 304.92 (Mu+Eta)+. NMR (500 MHz, CDC13): delta 7.73 (d, J= 2.5 Hz, 1 H); 7.64-7.61 (m, 2 H); 7.46-7.43 (m, 2 H); 6.66 (d, J= 2.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 12 2-Chloro-4-("3-iodo-lH-pyrazol-l-yl)benzonitrile To a solution of 3-iodo-lH-pyrazole (702 mg, 3.62 mmol) in anhydrous DMSO (10 mL) was added NaH (183 mg, 4.58 mmol) at 0 C. The mixture was stirred for 30 min at 0 C, followed by the addition of 2-chloro-4-fluorobenzonitrile (534 mg, 3.43 mmol) in DMSO (1 mL). The resulting mixture was stirred at 90 C overnight. The mixture was cooled to room temperature, quenched with water (20 mL) and extracted with EtOAc (3 x 60 mL). The organic layer was collected and dried over Na2S04. The solvent was removed in vacuo to give the crude product. This was purified by flash chromatography (Combiflash ISCO, 24 g, Biotage Si column, ~60 mL/min, 100% hexanes for 5 min, gradient to 100%) EtOAc in hexanes over 15 min ) to afford 2-chloro-4-(3-iodo-lH-pyrazol-l-yl)benzonitrile. LCMS calc. = 329.93; found = 330.06 (M+H)+. ]H NMR (500 MHz, CD3OD): 8 8.30 (d, J= 2.7 Hz, 1 H); 8.13 (s, 1 H); 7.92 (s, 2 H); 6.77 (, d, J= 2.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 14 3-(3-Iodo-lH-pyrazol-l-yl)pyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (1.00 g, 5.16 mmol) in DMSO (15.1 mL) was added sodium hydride (60% in oil, 0.247 g, 6.19 mmol), and stirred for 0.5 h before 3- fluoropyridine (0.443 mL, 5.16 mmol) was added. The reaction mixture was stirred at 90 C overnight. This was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 40 g, 0-50 % EtOAc in hexanes) to give 3-(3- iodo-lH-pyrazol-l-yl)pyridine, as a white solid. LCMS calc. = 271.96; found = 271.85 (M+H)+. 1H NMR (500 MHz, CDC13): delta 8.93 (d, J= 2.5 Hz, 1 H); 8.57 (dd, J= 4.7, 1.1 Hz, 1 H); 8.04 (d, J= 8.4 Hz, 1 H); 7.79 (d, J= 2.5 Hz, 1 H); 7.41 (dd, J = 8.3, 4.8 Hz, 1 H); 6.68 (d, J= 2.4 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 15 5-(3-Iodo-lH-pyrazol-l -yl)-2-(trifluorometyl)pyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.588 g, 3.03 mmol) in DMSO (15.0 mL) was added sodium hydride (60% in oil, 0.145 g, 3.64 mmol) and stirred for 0.5 h before 5-fluoro- 2-(trifluoromethyl)pyridines added. The reaction mixture was stirred at 90 C overnight. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by passing through the silica gel funnel with CH2C12 to give 5-(3-iodo-lH-pyrazol-l -yl)-2- (trifiuorometyl)pyridine, as a yellow solid. LCMS calc. = 339.95; found = 339.89 (M+H)+. 1H NMR (500 MHz, CDC13): delta 9.03 (d, J= 2.3 Hz, 1 H); 8.24 (dd, J= 8.4, 2.1 Hz, 1 H); 7.86 (d, J= 2.5 Hz, 1 H); 7.80 (d, J= 8.5 Hz, 1 H); 6.73 (d, J = 2.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 16 3-(3-Iodo-lH-pyrazol-l-yl)-5-(trifluorometyl pyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.70 g, 3.61 mmol), in DMSO (15.0 mL) was added sodium hydride (60% in oil, 0.159 g, 3.97 mmol), and stirred for 0.5 h before 3- fluoro-5-trifluoromethylpyridine (0.596 g, 3.61 mmol) was added. The reaction mixture was stirred at 90 C overnight. This was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 40 g, 0-20 % EtOAc in hexanes) to give 3-(3-iodo-lH-pyrazol-l-yl)-5-(trifluorometyl)pyridine, as a white solid. LCMS calc. = 339.95; found = 339.86 (M+H)+. 1H NMR (500 MHz, CDC13): delta 9.12 (br s, 1 H); 8.83 (br s, 1 H); 8.32 (br s, 1 H); 7.85 (br s, 1 H); 6.73 (d, J= 1.7 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 17 5-(3-Iodo-lH-pyrazol-l-yl)nicotinonitrile To 3-iodo-l/J-pyrazole (500 mg, 2.58 mmol) in DMSO (2.6 mL) at 0 C, was added sodium hydride (60% in mineral oil, 113 mg, 2.84 mmol). The reaction was warmed to 25 C and stirred for 60 min before 5-fluoronicotinonitrile (315 mg, 2.58 mmol) was added. The reaction mixture was stirred at 85 C for 5 h before quenched by the addition of water. The reaction mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 0-50% EtOAc in hexanes) to afford 5-(3-iodo-lH-pyrazol-l-yl)nicotinonitrile, as a white solid. LCMS calc. = 296.96; found = 296.88 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 18 3 -Fluoro-4-(3 -iodo- 1 H-pyrazol- 1 - vDpyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.70 g, 3.61 mmol) in DMSO (15.1 mL) was added sodium hydride (60% in oil, 0.159 g, 3.97 mmol) and stirred for 0.5 h before 3,4- difluoro pyridine (0.415 g, 3.61 mmol) was added. The reaction mixture was stirred at 90 C for 2.5 h. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 40 g, 0-20 % EtOAc in hexanes) to give 3- fluoro-4-(3-iodo-lH-pyrazol-l-yl)pyridine, as a white solid. LCMS calc. = 289.95; found = 289.92 (M+H)+. NMR (500 MHz, CDC13): delta 8.61 (d, J= 3.8 Hz, 1 H); 8.48 (d, J= 5.4 Hz, 1 H); 8.02 (d, J= 2.4 Hz, 1 H); 8.00 (d, J= 5.4 Hz, 1 H); 6.70 (d, J= 2.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In dimethyl sulfoxide; mineral oil; at 0 - 90℃; for 4.5h; | INTERMEDIATE 19 4-(3 -Iodo- 1 H-p yrazol- 1 - ylV 2-methylpyridine To a stirred solution of 4-fluoro-2-methylpyridine (1 g, 9.0 mmol) and 3-iodo-lH- pyrazole (1.76 g, 9.1 mmol) in DMSO was added NaH ( 60% in oil, 0.45 g, 11.25 mmol) in portion at 0 C. The mixture was stirred at room temparature for 30 min or until bubbling ceased, then warmed to 90 C and stirred at 90 C for 4 h. The reaction mixture was cooled to room temperature, partitioned between EtOAc and water. The aqueous was extracted with EtOAc three times. The organic phases were combined, dried over Na2S04 and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Isco CombiFlash, 120 g Silica gel column, 0-100% EtOAc in hexanes) to afford 4-(3-iodo-lH-pyrazol-l-yl)-2-methylpyridine. LCMS calc. = 285.98; found = 285.92 (M+H)+. NMR (500 MHz, CDC13): delta 8.57 (br s, 1 H); 7.87 (br s, 1 H); 7.56 (br s, 1 H); 7.35 (br s, 1 H); 6.71 (br s, 1 H); 2.66 (s, 3 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 21 4-(3 -Iodo- 1 H-pyrazol- 1 -ylV2-isopropoxypyridine To a solution of <strong>[4522-35-4]3-iodopyrazole</strong> (0.30 g, 1.547 mmol) in DMSO (7.73 mL) was added sodium hydride (60% in oil, 0.068 g, 1.701 mmol). The resulting mixture was stirred for 0.5 h before 4-bromo-2-isopropoxypyridine (0.334 g, 1.547 mmol) was added. The reaction mixture was stirred at 80 C overnight. The reaction was quenched by the addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 24 g, 0-10 % EtOAc in hexanes) to give 4-(3 -iodo- 1 H-pyrazol- l-yl)-2-isopropoxypyridine, as a white solid. LCMS calc. = 330.00; found = 329.91. (Mu+Eta)+. NMR (500 MHz, CDC13): 5 8.17 (d, J= 5.7 Hz? 1 H); 7.78 (d, J= 2.6 Hz, 1 H); 7.20 (dd, J= 5.7, 1.9 Hz, 1 H); 6.93 (d, J= 1.9 Hz, 1 H); 6.64 (d, J= 2.5 Hz, 1 H); 5.34 (m, 1 H); 1.36 (d, J = 6.2 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [2,2]bipyridinyl; copper diacetate; sodium carbonate; In 1,2-dichloro-ethane; at 70℃;Inert atmosphere; | INTERMEDIATE 22 4-(3-Iodo-lH-pyrazol-l-yl -N7V-dimethylpyridin-2-amine To a suspension of 3-iodo-lH-pyrazole (100 mg, 0.516 mmol) and N,N-dimethyl-4- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-amine (1 2 mg, 0.773 mmol), Na2C03 (109 mg, 1.031 mmol) in anhydrous dichloroethane (4 mL) added a suspension of Cu(OAc)2 (94 mg, 0.516 mmol) and 2,2'-bipyridine (81 mg, 0.516 mmol) in dichloroethane (4 mL). The reaction was stirred at 70 C under N2 overnight. The mixture was filtered through the Celite and washed with EtOAc (5 mL x 3), the filtrate was collected and removed in vacuo to give the crude product. This was purified by flash chromatography (ISCO Combiflash, lOg, Biotage Si column, -30 mL/min, 100% hexanes 5 min, gradient to 100% EtOAc in hexanes 15 min) to afford 4-(3-iodo-lH-pyrazol-l-yl)-N,N-dimethylpyridin-2-amine. LCMS calc. = 315.01 ; found = 315.10 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
INTERMEDIATE 23 Methyl 4-(3-iodo- lH-pyrazol- 1 -yl)picolinate To 3-iodo-lH-pyrazole (625 mg, 3.22 mmol) in DMSO (15 mL) at 0 C,was added sodium hydride (60% in mineral oil, 155 mg, 3.87 mmol). The reaction was stirred for 30 min before methyl 4-fluoropicolinate (500 mg, 3.22 mmol) was added and the reaction was stirred at 90 C for 4.5 h. The reaction mixture was quenched by the addition of water and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgS04 and concentrated in vacuo. The crude mixture was purified by flash chromatography (ISCO Combiflash, 0-100%) EtOAc in hexanes) to afford methyl 4-(3-iodo-lH-pyrazol-l-yl)picolinate, as a colorless solid. LCMS calc. = 329.97; found = 329.88 (M+H)+. |
Tags: 4522-35-4 synthesis path| 4522-35-4 SDS| 4522-35-4 COA| 4522-35-4 purity| 4522-35-4 application| 4522-35-4 NMR| 4522-35-4 COA| 4522-35-4 structure
A327312 [1395443-04-5]
3-Iodo-1,4-dimethyl-1H-pyrazole
Similarity: 0.71
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