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CAS No. : | 3920-50-1 | MDL No. : | MFCD00129925 |
Formula : | C4H4N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ICFGFAUMBISMLR-UHFFFAOYSA-N |
M.W : | 96.09 | Pubchem ID : | 12218383 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 5 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 23.98 |
TPSA : | 45.75 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.88 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 0.01 |
Log Po/w (WLOGP) : | 0.22 |
Log Po/w (MLOGP) : | -1.04 |
Log Po/w (SILICOS-IT) : | 1.2 |
Consensus Log Po/w : | 0.08 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.9 |
Solubility : | 12.0 mg/ml ; 0.125 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.52 |
Solubility : | 28.9 mg/ml ; 0.3 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.1 |
Solubility : | 7.69 mg/ml ; 0.08 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P362+P364-P332+P313 | UN#: | N/A |
Hazard Statements: | H315-H319 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
643 g | With formic acid In water at 0 - 25℃; for 12 h; Large scale | 2.3 kg of formic acid at 0-15 degrees Celsius was slowly added dropwise to 13.8 kg of Compound 3 in 15 L of water.Subsequently, the reaction mixture was magnetically stirred at 25 ° C for 12 hours,After the reaction was light yellow solid precipitation,Filter the 10 L water and wash the filter cake to obtain 643 g yellow solid compound 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With copper(l) iodide; 8-Hydroxyquinoline-N-oxide; caesium carbonate In dimethyl sulfoxide at 90℃; for 48 h; Inert atmosphere | A flask was charged with CuI (79 mg, 0.42 mmol), 8-hydroxyquinoline-N-oxide (134 mg, 0.83 mmol), Cs2CO3 (2.713 g, 8.33 mmol), 1H-pyrazole-3-carbaldehyde 42 (400 mg, 4.16 mmol). The flask was evacuated and backfilled with argon. Iodobenzene (0.70 mL, 6.24 mmol) and DMSO (5 mL) were added to the flask under argon atmosphere. After stirring at 90 °C for 48 h, the mixture was diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 68b as a pale yellow solid (329 mg, 46 percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.4% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | Add 1H-pyrazole-3-carbaldehyde (4.02 g, 41.8 mmol) to a 100 mL two-necked flask.Potassium carbonate (11.5 g, 83.2 mmol) and N,N-dimethylformamide (35 mL),Methyl iodide (3.89 mL, 62.5 mmol) was then added and stirred at room temperature overnight.Add water, extract with ethyl acetate (40 mL×6),The organic phase was washed with water (80 mL) and brine (EtOAc)Filter by suction, spin dry, and the residue was purified by silica gel column chromatography(petroleum ether/ethyl acetate (v/v) = 10/1),A pale yellow oil (2.37 g, 51.4percent) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
643 g | With formic acid; In water; at 0 - 25℃; for 12h;Large scale; | 2.3 kg of formic acid at 0-15 degrees Celsius was slowly added dropwise to 13.8 kg of Compound 3 in 15 L of water.Subsequently, the reaction mixture was magnetically stirred at 25 ° C for 12 hours,After the reaction was light yellow solid precipitation,Filter the 10 L water and wash the filter cake to obtain 643 g yellow solid compound 4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | A mixture of 2-(4-[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethanol (step 2 of Example 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg, 7.56 mmol) in ethanol (45 ml) was heated at reflux temperature for 2 h. After cooling, the mixture was concentrated. A mixture of the residue, lead tetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml) was stirred at room temperature for 16 h. The mixture was quenched with saturated NaHCO3 aqueous solution (150 ml). The whole was extracted with ethyl acetate (150 ml.x.4). The organic layer was washed with water (100 ml.x.5), brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 408 mg (16percent) of the title compound as an amber solid. | |
408 mg (16%) | With lead(IV) tetraacetate; sodium hydrogencarbonate; In ethanol; benzene; | Step 1. 2-{4-[5-(methyloxy)-2-(1H-pyrazol-3-yl)-1H-benzimidazol-1-yl]phenyl}ethanol A mixture of 2-(4-[2-amino-4-(methyloxy)phenyl]amino}phenyl)ethanol (step 2 of Example 71, 1.95 g, 7.56 mmol), pyrazol-3-carbaldehyde (726 mg, 7.56 mmol) in ethanol (45 ml) was heated at reflux temperature for 2 h. After cooling, the mixture was concentrated. A mixture of the residue, lead tetraacetate (4.61 g, 8.32 mmol) in benzene (50 ml) was stirred at room temperature for 16 h. The mixture was quenched with saturated NaHCO3 aqueous solution (150 ml). The whole was extracted with ethyl acetate (150 ml*4). The organic layer was washed with water (100 ml*5), brine (50 ml), dried (MgSO4), and concentrated. Purification by flash column chromatography eluding with dichloromethane/methanol (gradient elution from 20:1 to 10:1) to afford 408 mg (16percent) of the title compound as an amber solid. MS (EI) m/z: 334 (M+). 1H-NMR (DMSO-d6) delta: 7.6 (1H, br.s), 7.43 (2H, d, J=7.7 Hz), 7.29-7.23 (3H,m), 7.04 (1H, d, J=8.8 Hz), 6.90 (1H, d, J=8.8 Hz), 6.34 (1H, br.s), 3.85-3.81 (5H, m), 2.92 (2H, t, J=6.6 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | A mixture of 2-(4-[2-amino-5-chloro-4-(trifluoromethyl)phenyl]amino}phenyl)ethanol (step 2 of Example 104, 2.28 g, 5.85 mmol) and 1H-pyrazole-3-carbaldehyde (562 mg, 2.85 mmol) in ethanol (35 ml) was stirred under reflux temperature for 1 h. The mixture was concentrated and dissolved in benzene (40 ml). To this solution was added lead tetraacetate (2.85 g, 6.44 mmol) at rt. After stirring at room temperature for 18 h, to the mixture were added saturated aqueous sodium hydrogencarbonate (50 ml) and ethyl acetate. The organic layer was separated and washed with brine, dried (Na2SO4) and concentrated. Purification by flash column chromatography eluting with dichloromethane/methanol (20:1 to 10:1), then dichloromethane/2-propanol (5:1) afforded 979 mg (41percent) of the title compound as a slight brown solid. [2276] 1H-NMR (CDCl3/CD3OD=4/1) delta: 8.12 (1H, br.s), 7.74 (1H, s), 7.59 (1H, br.s), 7.47 (2H, d, J=7.9 Hz), 7.34-7.30 (3H, m), 6.36 (1H, br.s), 3.87 (2H, br.t, J=6.8 Hz), 2.95 (2H, t, J=6.8 Hz). MS (ESI) m/z: 407 (MH+), 405 ([M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With dmap; triethylamine; In N,N-dimethyl-formamide; at 0℃; for 1h; | Step 1: tert-Butyl 3-formyI-lH-pyrazole-l-carboxylate lnt-72 Pyrazol-3-carbaldehyde (6.2 g, 65 mmol) and DMAP (0.79 g, 6.5 mmol) were dissolved in DMF (50.0 mL), di-tert-butyldicarbonate (21 g, 97 mmol) was added to this solution. It was cooled down to 0 °C and TEA (4.5 mL, 32 mmol) was added. It was allowed to stir for lh at 0 °C. DGM (80 mL) was added to dilute the reaction, and it was washed with water (2x). The organic layer was concentrated and purified on silica gel to give teri-butyl 3-formyl-lH-pyrazole-l-carboxylate (9.1 g, 71percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The compound (72.0 mg) obtained in Example 43-1 was dissolved in methanol (3.5 ml) and then added with pyrazole-3-carboxaldehyde (24.5 mg) and sodium cyanoborohydride (35.9 mg). The reaction solution was adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 14 hours. The reaction solution was added with a 1 mol/l sodium hydroxide aqueous solution and then extracted with chloroform. Then, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After the solvent had been distilled off, the residue obtained was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining hydrochloride (52.3 mg) of the subject compound as a yellow solid. MS(FAB,Pos.):m/z=486[M+H]+1H-NMR(500MHz,DMSO-d6):delta=0.85(6H,t,J=7.5Hz),1.65(4H,m),2.88(4H,m),3.70(2H,brs),3 .78(2H,brs),4.00(2H,brs),4.10(2H,brs),4.28(2H,brs),6.34(1H,d ,J=2.1Hz),6.65(2H,d,J=8.5Hz),7.21(2H,d,J=8.5Hz),7.32(2H,d,J= 8.3Hz),7.38(2H,d,J=8.3Hz),7.51(2H,s),7.69(1H,d,J=2.1Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The compound (53.8 mg) obtained in Example 1-4 was dissolved in methanol (0.8 ml). Then, the solution was added with trimethyl orthoformate (50 mul), acetic acid (50 mul), and pyrazol-3-carboxaldehyde (manufactured by Merck, Inc.) (24.9 mg) and stirred at room temperature for 10 minutes. Subsequently, sodium cyanoborohydride (24.4 mg) was added, followed by stirring overnight at room temperature. The solvent was distilled off under reduced pressure and then the residue was dissolved in chloroform, followed by washing with 1 mol/l sodium hydroxide and saturated saline solution and drying with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Then, the residue was then purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (26.1 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=466[M+H]+1H-NMR(500MHz,DMSO-d6) :delta=0.88(6H,t,J=7.3Hz),1.53-1.69(8H,m),2.95(4H,brs),3.05(2H,brs),3.25-3.40(2H,m),3.55(2H,s),3.58(2H,s),3.62(2H,s),6.27(1H,s),7.04( 2H,s),7.50(2H,d,J=8.2Hz),7.81(2H,d,J=8.2Hz),8.51(1H,t,J=5.5H z). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In methanol;Heating / reflux; | Example 14 Synthesis of the compound represented by the following formula; [Show Image] A methanolic solution (2.7 ml) containing the compound A (55 mg) and 3-pyrazole carboxyaldehyde (15 mg) was heated to reflux through the night in the presence of acetic acid (20 mul). The resulting precipitate was collected, washed with methanol, dissolved in methanol (1 ml), THF (1 ml) and DMF (1 ml) with heating; 10percent palladium-carbon (30 mg) was added; and the mixture was stirred in a hydrogen stream through the night at room temperature. The reaction mixture was passed through a pad of Celite to remove the palladium-carbon and the filtrate was concentrated. The residue was dissolved in methanol and purified (MeOH) using Sephadex LH-20 (30 ml) to collect the yellow fraction, thereby giving the compound (36.4 mg) represented by the above formula (36.4 mg). ESI (m/z): 615.2 (M + H)+ 1H-NMR (300 MHz, DMSO-d6, delta ppm): 11.29 (1H, s), 9.82 (2H, br), 9.38 (1H, s), 8.89 (1H, d, J = 8.0 Hz), 8.81 (1H, d, J = 8.0 Hz), 7.91 (1H, br), 7.21 (1H, s), 7.02 (1H, s), 6.85 (1H, d, J = 8.0 Hz), 6.80 (1H, d, 8.0 Hz), 5.82-6.08 (2H, m), 5.38 (1H, s), 5.16 (1H, s), 4.99 (1H, br), 4.92 (1H, m), 4.24 (1H, m), 3.76-4.10 (4H, m), 3.43-3.52 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium methylate; In methanol; at 20℃; for 19h; | A solution of sodium methoxide (30 mg, 0.55 mmol) in anhydrous methanol (3 ml) was added to a stirred mixture of 2-diethylphosphonyl-2H-1,4-benzothiazin-3(4H)-one (150 mg, 0.5 mmol) and 1H-pyrazole-3-carboxaldehyde (50 mg, 0.5 mmol) in anhydrous methanol (20 ml). Stirring was continued for 19 hours at room temperature, then the precipitated solid was filtered off and washed with methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h; | Reference Example 11-1 1 1-Allyl-1H-pyrazole-5-carbaldehyde <strong>[3920-50-1]Pyrazole-3-carbaldehyde</strong> (3.00 g, 31.2 mmol) was dissolved in DMF (20 ml), and thereto were added potassium carbonate (6.47 g, 46.8 mmol) and allyl bromide (3.50 g, 32.8 mmol) with stirring. The mixture was stirred at room temperature for 6 hours, and thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (429 mg, 10 percent). 1H NMR (CDCl3, 400 MHz) delta 9.86 (s, 1H), 7.59 (d, 1H, J = 2.0 Hz), 6.93 (d, 1H, J = 2.0 Hz), 6.04 - 5.94 (ddt, 1H, J = 10.3, 17.1, 5.7 Hz), 5.19 (dd, 1H, J = 1.2, 10.3 Hz), 5.16 (d, 2H, J = 5.7 Hz), 5.09 (dd, 1H, J = 1.2, 17.1Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With caesium carbonate; In N,N-dimethyl-formamide; at 25℃; for 1h; | To a solution of 1H-pyrazole-3-carbaldehyde (5.00 g, 52.0 mmol, CAS: 3920-50-1) and BnBr (9.34 g, 54.6 mmol) in DMF (50 mL) was added Cs2CO3 (42.4 g, 130 mmol). The reaction mixture was stirred at 25 C. for 1 hour. On completion, the reaction mixture was diluted with water, extracted with ethyl acetate (3×100 mL). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (Petroleum ether: Ethyl acetate=20:1) to give the title compound (8.00 g, 83% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) delta 10.02 (s, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.43-7.33 (m, 3H), 7.29-7.24 (m, 2H), 6.85 (d, J=2.4 Hz, 1H), 5.42 (s, 2H). |
77% | With caesium carbonate; In N,N-dimethyl-formamide; for 1h; | Example 36: l-Benzyl-lH-pyrazole-3-carbaldehyde Int-61 Step 1: l-Benzyl-lH-pyrazole-3-carbaldehyde lnt-61 A 100 mL round bottomed flask was charged with pyrazol-3-carbaldehyde (250 mg, 2.60 mmol), CS2CO3 (2.12 g, 6.50 mmol), and DMF (10 mL). To the suspension was added benzyl bromide (325 uL, 2.7 mmol), and the reaction was stirred for 1 h. The reaction mixture was poured into water (50 mL) and the mixture was extracted with EtOAc (50 mLx3). The combined organic layers were washed with brine, dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified on silica gel to provide 1 -benzyl- lH-pyrazole-3-carbaldehyde (372 mg, 77%). NMR (CDC13) delta 10.01 - 9.98 (m, 1H), 7.42 (d, J= 2.3 Hz, 1H), 7.41 - 7.32 (m, 3H), 7.28 - 7.23 (m, 2H), 6.82 (d, J= 2.4 Hz, 1H), 5.40 (s, 2H). |
32% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97%). |
With potassium carbonate; In N,N-dimethyl-formamide; | (a) 1-Benzyl-1H-pyrazole-3-carbaldehyde To a solution of benzyl bromide (0.29 g) in N,N-dimethylformamide (9 ml) was added 1H-pyrazole-3-carboxaldehyde (0.15 g) and potassium carbonate (0.24 g). The mixture was stirred at room temperature for 24 hours, silica gel was added, the solvent removed by evaporation and the crude material purified by chromatography (isohexane:ether, 2:1) to give the product as an oil (0.18 g). 1H NMR delta (CDCl3) 10.0 (s, 1H), 7.5-7.2 (mn, 5H), 6.8 (d, 1H), 5.4 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With formic acid; sodium tris(acetoxy)borohydride; In pyridine; n-heptane; dichloromethane; water; ethyl acetate; acetonitrile; | EXAMPLE 21 3-(1H-Indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-2-[(2H-pyrazol-3-ylmethyl)-amino]-propionamide, [R-(R*,S*)] To a stirred solution of pyrazole-3-carboxaldehyde (96 mg, 1 mmol, supplied as dimer) in pyridine (10 mL) was added 2-amino-3-(1H-indol-3-yl)-2-methyl-N-(1-phenyl-ethyl)-propionamide (161 mg, 0.5 mmol) followed by sodium triacetoxyborohydride (848 mg, 4 mmol). After stirring over night at room temperature another portion of sodium triacetoxyborohydride (424 mg, 2 mmol) was added. After stirring over night at room temperature the pyridine was removed under reduced pressure. The residue was taken up in CH2Cl2 (100 mL) and saturated NaHCO3. The aqueous phase was extracted with CH2Cl2 (100 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and the solvent was removed under reduced pressure. The residue was initially purified by chromatography on normal phase silica using 95percent EtOAc in heptane as eluent. The solvent was removed under reduced pressure and the residue was dissolved in aqueous acetonitrile and acidified using formic acid. Purification by chromatography on reverse phase silica using 25percent CH3CN in H2O (0.1percent formic acid in mobile phases) as eluent gave pure product. The solvent was removed under reduced pressure and the residue was suspended between EtOAc and saturated NaHCO3. The EtOAc was dried (MgSO4) and the solvent was removed under reduced pressure to give pure product as a glass (20 mg, 10percent); IR (film): 3260, 3059, 2979, 2927, 1651, 1515, 1456, 1374, 1266, 1105, 1048, 1011, 932, 741 cm-1; NMR (DMSO-d6): delta1.22 (3H, s); 1.35 (3H, d, J=6.8 Hz); 2.26 (1H, s); 2.96-3.05 (2H, m); 3.50-3.75 (2H, m); 4.93 (1H, s); 6.10 (1H, s); 6.89-6.93 (2H, m); 7.00-7,04 (1H, m); 7.18-7.32 (6H, m); 7.35 (0.5H, s); 7.52 (1H, d, J=7.8 Hz); 7.60 (0.5H, s); 8.05-8.20 (1H, m); 10.82 (1H, s); 12.52 (0.5H, s); 12.73 (0.5H, s); MS m/e (ES+): 424.1 (27percent); 402.1 (100percent, M++H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 90℃; for 0.5h; | 3.9 mg of 1H-pyrazole-3-carboxaldehyde was added to a dimethylformamide (0.5 ml) solution of 15 mg of 4-(2-fluoro-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 200, and the reaction liquid was stirred at 90°C for 30 minutes. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel.(TM). 60F254, Art 5744 (by Merck), chloroform/methanol = 9/1) to obtain the entitled compound as a white solid. 1HNMR(CDCl3)delta: 3.20(3H,s), 6.94-6.99(1H,m), 7.01-7.15(4H,m), 7.25-7.65(2H,m), 7.31(1H,dd,J=8.9,2.7Hz), 7.66(1H,d,J=2.3Hz), 7.98(1H,d,J=8.9Hz), 8.40(1H,d,J=2.7Hz) ESI-MS(m/e):466[M+H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | EXAMPLE 3 Synthesis of 3-pyrazolecarbaldehyde-(5-nitro-2-pyridyl)hydrazone (compound 3) A desired product was obtained in the same manner as in Example 1 by using 3.20 g (20.8 mmol) of 5-nitro-2-pyridylhydrazine and 1.90 g (19.8 mmol) of 3-pyrazolecarbaldehyde. Yield: 3.92 g (16.9 mmol) [yield rate: 85percent] Melting point: 286° to 287° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; at 100℃; for 5h; | Reference Production Example 6-1 1-(hydroxymethyl)-3-formyl-1H-pyrazole The mixture of 0.96 g of 3-formyl-1H-pyrazole, 0. 60 g of paraformaldehyde and 0.3 ml of triethylamine was stirred at 100 °C for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. The filterate was concentrated under reduced pressure to obtain 1.21 g of 1-(hydroxymethyl)-3-formyl-1H-pyrazole. The crude product was used for next process without purification. 1H-NMR(CDCl3,TMS,delta(ppm)):5.63(2H,s),6.84(1H,d),7.67(1H,d),9.96(1H,s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.8% | With hydroxylamine hydrochloride; sodium acetate; In ethanol; at 50℃; for 2h; | To a 100 ml three-necked flask, 1.25 g (18 mmol) of hydroxylamine hydrochloride, 1.47 g (18 mmol) of sodium acetate and 40 ml of ethanol were added, and 0.96 g (10 mmol) of 3-formalpyrazole was added thereto with stirring, and the mixture was heated to 50 C for 2 h. After completion of the reaction, a milky white turbid liquid was obtained, which was cooled to room temperature, filtered, and the filtrate was evaporated to give an oily viscous solid, which was dissolved in 50 ml of water.Extract 50 times with 50 ml of ethyl acetate.The organic phase was dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated to dryness to a pale yellow viscous solid, 0.96 g.The yield was 86.8%. |
85.3% | With hydroxylamine hydrochloride; sodium acetate; In ethanol; at 50℃; for 2h; | 1.18 g (20 mmol) of hydroxylamine hydrochloride, 1.63 g (20 mmol) of sodium acetate and 40 ml of ethanol were added to a 100 ml three-necked flask, and 0.96 g (10 mmol) of 3-formaldehyde pyrazole was added thereto with stirring. The temperature was raised to 50 C and the reaction was carried out for 2 h. After the reaction, a milky white turbid liquid was obtained, which was cooled to room temperature, filtered, and the filtrate was evaporated to give an oily viscous solid. Dissolved in 50 ml of water, The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated to dryness to give a pale yellow viscous solid, 0.94 g. The yield was 85.3%. |
84% | With hydroxylamine hydrochloride; sodium acetate; In ethanol; at 60℃; for 3h; | 1.04 g (15 mmol) of hydroxylamine hydrochloride, 1.23 g (15 mmol) of sodium acetate and 40 ml of ethanol were added to a 100 ml three-necked flask, and 0.96 g (10 mmol) of 3-formalpyrazole was added thereto with stirring.The temperature was raised to 60 C and the reaction was carried out for 3 h. After the reaction, the milky white turbid liquid was obtained and cooled to room temperature.filter,The filtrate was evaporated to give an oily viscous solid, which was dissolved in 50 ml of water.Extract 50 times with 50 ml of ethyl acetate.The organic phase was dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated to dryness to give a pale yellow viscous solid 0.99 g.The yield was 89.5%. |
With pyridine; hydroxylamine hydrochloride; at 20℃; for 5h; | Reference Production Example 7-1 3-cyano-1H-pyrazole 2.18 g of 3-formyl-1H-pyrazole was dissolved to 12 ml of pyridine. 1.58 g of hydroxylamine hydrochloride was added to the solution, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. 30 ml of acetic anhydride was added to the residue followed by stirring at 100 C for 5 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. 30 ml of ethanol was added to the residue, and then the mixture was stirred at 100 C for 3 hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.86 g of 3-cyano-1H-pyrazole. 1H-NMR(CDCl3,TMS,delta(ppm)):6.79(1H,d),7.75(1H,d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -40 - 20℃; for 18h; | 2-(Trimethylsilyl)ethoxymethyl chloride (14 ml, 78 mmol) was added portionwise over 10 minutes, at -40° C., to a solution of pyrazole-3-carboxaldehyde (5 g, 52 mmol) and diisopropylethylamine (13.6 ml, 78 mmol), in dichloromethane (100 ml). The reaction mixture was then warmed to room temperature and stirred for a further 18 hours, after which time it was quenched with brine and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulphate and concentrated under reduced pressure to provide the crude product (14.6 g). A portion of this (3 g) was purified by flash chromatography on silica gel eluting with ethyl acetate:pentane (5:95 to 10:90 to 20:80, by volume) to provide the title compound (14.6 g, 100percent) as a 1.1:1 mixture of regioisomers. 1H-NMR (400 MHz, CDCl3): 5-0.05 (s, 9H, regioisomer B), -0.02 (s, 9H, regioisomer A), 0.87-0.94 (m, 2HA+2HB), 3.58 (t, 2HA+2HB), 5.51 (s, 2H, A), 5.81 (s, 2H, B), 6.87 (s, 1H, A), 6.97 (s, 1H, B), 7.62 (m, 1 HA+1 HB), 9.95 (s, 1H, B), 10.01 (s, 1H, A); LC-MS: ESI+: m/z 227 [MH+]. | |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at -40 - 20℃; for 16h;Inert atmosphere; | To a suspension of 0.60 g (6.24 mmol, 1.0 eq.) of 1H-pyrazole-3-carbaldehyde in 12 mL ofmethylene chloride at -40 °C under a nitrogen atmosphere was added 1.63 mL (9.37 mmol,1.5 eq.) of 1VN-diisopropylethyl amine, followed by 1.66 mL (9.37 mmol, 1.5 eq.) of[2- (chloromethoxy)ethyl]trimethylsilane. The mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was then diluted with 20 mL brine, and extracted with 3 x 30 mL of methylene chloride. The combined organic extracts were dried(Na2SO4), filtered, and the solvent was removed in vacuo. The residue was absorbed on CELITE® and purified by flash chromatography (Si02, eluting with a gradient of 0-30percent ethyl acetate/hexanes) to provide 1 g (66percent) of a mixture of 1-((2-(trimethylsilyl)ethoxy)methyl)- 1H-pyrazole-5 -carbaldehyde and 1 -((2-(trimethyl silyl)ethoxy)methyl)- 1H-pyrazole-3 - carbaldehyde in an approximately 1:1 ratio. |
Yield | Reaction Conditions | Operation in experiment |
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tert-Buty\\ 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (prepared as described in Method 1 below; 200 mg, 0.51 mmol) and lH-pyrazole-3-carbaldehyde (50.7 mg, 0.53 mmol) were stirred at ambient temperature in dichloromethane (5 ml) for 1 hour. Sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added and the mixture stirred at ambient temperature for 48 hours. The resulting solution was absorbed onto an SCX-2 column, which was washed with methanol (2 column volumes) and then the product eluted with a 2M solution of ammonia in methanol (2 column volumes) to give a foam. This was dissolved in 1,4-dioxane (2 ml), a 4M solution of hydrogen chloride in 1,4-dioxane (2 ml) was added and the solution stirred at ambient temperature for 48 hours. The product was filtered and washed with diethyl ether and air-dried. The resulting solid was dissolved in water, basified with 2N sodium hydroxide and the resulting solid filtered, washed with water and dried under vacuum to give the title compound (61 mg, 44 percent). NMR Spectrum:1H NMR (DMSO d6) delta 1.71 (m, 4H), 2.07 (m, 2H), 2.56 (m, IH), 2.95 (m, 2H), 3.53 (s, 2H), 4.86 (s, 2H), 6.16 (s, IH), 6.60 (m, IH), 6.78 (d, IH), 6.97 (t, IH), 7.18 (d, IH), 7.37 (d, 2H), 7.64 (m, IH), 7.91 (d, 2H), 9.55 (s, IH), 12.59 (m, IH); Mass Spectrum: M+H+ 376. EPO <DP n="40"/> |
Yield | Reaction Conditions | Operation in experiment |
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With NaH; In tetrahydrofuran; mineral oil; | Preparation of 3-(2H-pyrazol-3-yl)-acrylonitrile: To a suspension of the phosphonium salt (900 mg, 2.35 mmol) in THF (10 mL) under nitrogen was added NaH (60percent in mineral oil, 99 mg, 2.5 mmol) in one portion. The suspension stirred at room temperature for 10 minutes, then pyrazole-3-carboxaldehyde (211 mg, 2.20 mmol) was added as a solid in one portion. The reaction was heated to reflux for 30 minutes, then cooled to room temperature and saturated aqueous NH4C{,(10 mL) was added. The mixture was extracted with CH2Cl2 (25 mL*3) and the combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (EtOAc/hexane, 1:1) gave the alkene (white solid) as an approximately 1.5:1 mixture of the E:Z isomers (232 mg, 1.95 mmol, 89percent). Data for E-isomer: 1H NMR (CDCl3) delta 5.92 (d, 1H, J=16.5 Hz), 6.54 (d, 1H, J=2.4 Hz), 7.43 (d, 1H, J=16.8 Hz), 7.60 (d, 1H, J=2.4 Hz). Data for Z-isomer: 1H NMR (CDCl3) delta 5.46 (d, 1H, J=12.0 Hz), 6.98 (d, 1H, J=2.4 Hz), 7.24 (d, 1H, J=12.3 Hz), 7.66 (d, 1H, J=2.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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110.0 mg of the compound obtained in Synthesis Example 29-2 was dissolved in 2 ml of methanol, and then 2 ml of a 4 mol/l hydrochloric acid/dioxane was added to the solution, followed by stirring for 3 hours at room temperature. On completion of the reaction, the solvent was distilled off. Subsequently, it was dissolved in 4 ml of anhydrous methanol and then 92.2 mul of triethylamine and 21. 2 mg of pyrazole-3-carboxyaldehyde were added to the solution and the whole was stirred for 16 hours at room temperature. After the solvent was distilled off, 4 ml of anhydrous methanol was added thereto and the whole was cooled to 0°C. Then, 13.9 mg of sodium borohydride was added to the solution and the whole was stirred for 25 minutes while being gradually returned to room temperature. On completion of the reaction, the solvent was distilled off and the residue was purified by means of silica gel column chromatography (10 g, chloroform/methanol=5/1). After the compound was dissolved in 2 ml of a 1 mol/l hydrochloric acid, water was distilled off. Consequently, 55.6 mg of hydrochloride of the above-mentioned compound was obtained as a light-orange solid product. MS(FAB,Pos.):m/z=578[M+1]+1H-NMR(500MHz,DMSO-d6): delta=1.72-1.91(4H,m),2.91(2H,br),3.64(3H,s ), 4.07-4.22 (6H,m), 4.53-4.57 (1H,m), 4.76-4.77 (2H,m), 5.98-5.99 (1 H,m), 6.22-6.23 (1H,m), 6.45-6.51 (1H,m), 6.78-6.79 (1H,m), 7.45-7.4 9 (2H,m), 7.52-7.57 (2H,m), 7.63-7.65 (2H,m), 7.79-7.80 (1H,m), 7.83-7.86 (1H,m), 7.93-8.00 (3H,m), 8.06-8.08 (1H,m), 8.70-8.83 (2H,m), 9. 00 (2H,br), 9.76 (2H,br). |
Yield | Reaction Conditions | Operation in experiment |
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The crude trifluoroacetate salt was dissolved in tetrahydrofuran (6.50 mL) then lH-pyrazole- 3-carbaldehyde (85 mg, 0.885 mmol, 1.5 eq) followed by sodium triacetoxyborohydride (184 mg, 0.870 mmol, 1.5 eq) were added. The reaction mixture was stirred at room temperature for 3 h and then partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-10percent methanol/dichloromethane afforded the target compound (112 mg, 48 percent) as the free base.[00152] 1H-NMR (d6-DMSO) delta: 2.28 - 2.45 (m, 1 H), 2.89 (br d, 1 H, J = 12.2 Hz), 3.18 - 3.26 (m,l H), 3.52 - 3.71 (m, 3 H), 3.78 (br d, 1 H, J = 10.9 Hz), 3.87 (br d, 1 H, J = 14.6 Hz), 3.98 (dd, 1 H, J = 3.0, 10.9 Hz), 6.19 - 6.33 (br m, 1 H), 7.86 (br s, 1 H), 8.16 (d, 1 H, J = 4.9 Hz), 8.23 (br s, 1 H), 8.38 (d, I H1 J = 4.9 Hz), 9.05 - 9.11 (br m, 1 H), 10.06 (br s, 1 H), 12.84 (br s, 1 H). MS m/z: 411 (M+H). [00153] |
Yield | Reaction Conditions | Operation in experiment |
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29% | To a stirred suspension of NaH (274 mg, 11.4 mmol) in DMF (20 mL) was added solution of lH-pyrazole-3-carbaldehyde (1.0 g, 10.4 mmol) in DMF (10 mL) dropwise at 0 °C and the mixture was stirred at room temperature for 10 min. The reaction mixture was cooled to 0 °C and SEM-C1 (1.90 g, 11.4 mmol) was added dropwise. The mixture was warmed to room temperature and stirred at the same temperature for 16 h: The reaction mixture was quenched with water and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed water (20 mL), dried over anhydrous Na2S04 and Concentrated under reduced pressure. The residue was purified by column (0725) chromatography (silica gel, 10percent EtOAc/hexane as eluent) to provide compound A75-1 (350 mg, 29percent) as colorless gum. | |
Step 1 Preparahon of 1-{I2-(tnmethylsilyl)ethoxy]methyl}-1W-pyrazole-3- carbaldehyde (C80)Sodium hydnde (60percent dispersion in mineral oil, 0 668 g 16 7 mmol) was added to dimethylformamidpsi (45 mL) at 25°C, and the mixture was stirred for 10 minutes A solution of1W-pyrazole-3-carbaldehyde (1 46 g, 15 2 mmol) in dimethylformamide (10 mL) was added to the reaction mixture over 15 minutes, and the reaction was allowed to stir for an additional 15 minutes The mixture was cooled to O°C and treated with 2-(triotamethylsiotalyl)ethoxymethyl chloride (2 96 mL, 15 2 mmol) drop-wise over 10 minutes, after which the solution was warmed to 25°C and stirred for 2 hours. The reaction mixture was poured into aqueous sodium bicarbonate solution (5percent solution, 50 mL) that had been pre-cooted to O°C, and the resulting mixture was extracted with diethyl ether (3X) The combined organic layers were dned over magnesium sulfate and concentrated, the crude product was purified by silica gel chromatography (gradient hexanes to 30percent ethyl acetate in hexanes) to provide C80 as a clear liquid Yield 3 5 g quantitative as a mixture of regioisomers MS (APCI) rn/z 227 26(M*1) | ||
Sodium hydride (60percent dispersion in mineral oil, 0.668 g, 16.7 mmol) was added to dimethylformamide (45 mL) at 25°C, and the mixture was stirred for 10 minutes. A solution of 1H-pyrazole-3-carbaldehyde (1.46 g, 15.2 mmol) in dimethylformamide (10 mL) was added to the reaction mixture over 15 minutes, and the reaction was allowed to stir for an additional 15 minutes. The mixture was cooled to 0oC and treated with 2-(trimethylsilyl)ethoxymethyl chloride (2.96 mL, 15.2 mmol) drop-wise over 10 minutes, after which the solution was warmed to 25°C and stirred for 2 hours. The reaction mixture was poured into aqueous sodium bicarbonate solution (5percent solution, 50 mL) that had been pre-cooled to 0oC, and the resulting mixture was extracted with diethyl ether (3X). The combined organic layers were dried over magnesium sulfate and concentrated; the crude product was purified by silica gel chromatography (gradient: hexanes to 30percent ethyl acetate in hexanes) to provide 21n-1 as a clear liquid. Yield: 3.5 g, quantitative as a mixture of regioisomers. MS (APCI) m/z 227.26 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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To a solution of lH-pyrazole-3-carbaldehyde (3.00 g, 31.22 mmol) in TEtaF was added 60percent NaH (1.64 g, 41.00 mmol) in mineral oil. After 20 minutes, p-toluenesulfonyl chloride (7.82 g, 41.00 mmol) was added. After 2 hours, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 10-50percent EtOAc in heptane. The major fractions were combined and the solvent was concentrated in vacuo to afford (l-(toluene- 4-sulfonyl)-lH-pyrazole-3-carbaldehyde) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With sodium tris(acetoxy)borohydride; acetic acid; In 1,4-dioxane; 1,2-dichloro-ethane; for 1.66667h; | (2S)-2-((lH-Pyrazol-3-yl)methylamino)-3-(4-fluorophenyl)-N-(l-methyl-3-(2-(methylamino)pyridin4-yl)-lH-pyrazol-5-yl)propanamide (23.2). To (2S)-2-amino-3- (4-fluorophenyl)-N-( 1 -methyl-3 -(2-(methylamino)pyridin-4-yl)- 1 H-pyrazol-5 - yl)propanamide (79 mg, 214 mumol) was added lH-pyrazole-3-carbaldehyde (29 mg, 300 mumol), then DCE and dioxane were added as solvents, followed by acetic acid (13 mul, 225 mumol) and NaBH(O Ac)3 (136 mg, 643 mumol). Heating was continued for 1 hr. 40min. The reaction was concentrated and purified by reverse phase HPLC purification to afford 23.2 (27 mg, 28percent) as a white solid. IH NMR (400 MHz, MeOH) delta ppm 7.77 - 8.01 (m, 1 H) 7.55 (br. s., 1 H) 7.25 (dd, J=8.61, 5.48 Hz, 2 H) 7.03 (t, J=8.80 Hz, 2 H) 6.91 (dd, J=5.67, 1.37 Hz, 1 H) 6.51 - 6.65 (m, 1 H) 6.23 (d, J=I.96 Hz, 1 H) 3.74 - 3.91 (m, 2 H) 3.60 - 3.63 (m, 1 H) 3.59 (s, 3 H) 2.97 - 3.11 (m, 2 H) 2.89 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
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36% | With 4-methyl-morpholine; In ethanol; for 4h;Reflux; | Example 6A2-Amino-4-(1H-pyrazol-3-yl)-6-sulfanylpyridine-3,5-dicarbonitrile1.72 ml (15.61 mmol) of N-methylmorpholine were added to 0.75 g (7.81 mmol) of 1H-pyrazole-3-carbaldehyde and 1.56 g (15.61 mmol) of 2-cyanothioacetamide in 26 ml ethanol, and the mixture was heated under reflux for 4 h.The precipitate formed was filtered off and washed with a little ethanol.Yield: 673 mg (36percent of theory)LC-MS (Method 3): Rt=0.44 min; MS (ESIpos): m/z=243 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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30% | With methanol; sodium tris(acetoxy)borohydride; | A suspension of Example 10 (25.0 mg, 0.059 mmol), lH-pyrazole-3-carbaldehyde (17.0 mg, 0.18 mmol) and NaBH(OAc)3 (37.0 mg, 0.18 mmol) in MeOH (1.5 mL) was stirred overnight and purified by preparative HPLC to yield the title compound (6.80 mg, 30percent). HRMS (ESI+) calcd for C22H22C1N5 391.1564, found 391.1568. HPLC (method A): Rf 1.24 min, 100percent purity. |
30% | With methanol; sodium tris(acetoxy)borohydride; at 20℃; | A suspension of Example 10 (25.0 mg, 0.059 mmol), 1H-pyrazole-3-carbaldehyde (17.0 mg, 0.18 mmol) and NaBH(OAc)3 (37.0 mg, 0.18 mmol) in MeOH (1.5 mL) was stirred overnight and purified by preparative HPLC to yield the title compound (6.80 mg, 30percent). HRMS (ESI+) calcd for C22H22ClN5 391.1564, found 391.1568. HPLC (method A): Rf 1.24 min, 100percent purity. |
Yield | Reaction Conditions | Operation in experiment |
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28% | Example 70 (48.0 mg, 0.12 mmol) was dissolved in DCM (3 mL) and lH-pyrazole-3- carbaldehyde (14.3 mg, 0.15 mmol) and NaBH(OAc)3 (31.6 mg, 0.15 mmol) were added.The reaction mixture was stirred for 2 days. DIPEA (43.2 mu, 0.25 mmol), lH-pyrazole- 3-carbaldehyde (14.3 mg, 0.15 mmol) and NaBH(OAc)3 (31.6 mg, 0.15 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (10 mL) and quenched with water (5 mL). The organic fraction was washed with sat aq Na2C03 (10 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound as a yellow solid (13.9 mg, 28percent). HRMS (ESI+) calcd for C2oH2oClN7 394.1541, found 394.1543. HPLC (method B): Rf 3.99 min, 97percent purity. | |
With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Example 70 (48.0 mg, 0.12 mmol) was dissolved in DCM (3 mL) and 1H-pyrazole-3-carbaldehyde (14.3 mg, 0.15 mmol) and NaBH(OAc)3 (31.6 mg, 0.15 mmol) were added. The reaction mixture was stirred for 2 days. DIPEA (43.2 muL, 0.25 mmol), 1H-pyrazole-3-carbaldehyde (14.3 mg, 0.15 mmol) and NaBH(OAc)3 (31.6 mg, 0.15 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (10 mL) and quenched with water (5 mL). The organic fraction was washed with sat aq Na2CO3 (10 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC to give the title compound as a yellow solid (13.9 mg, 28percent). HRMS (ESI+) calcd for C20H20ClN7 394.1541, found 394.1543. HPLC (method B): Rf 3.99 min, 97percent purity. |
Yield | Reaction Conditions | Operation in experiment |
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8.6% | With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; for 18h; | Example 84 (75.0 mg, 0.24 mmol) was dissolved in DCM (10 mL) and lH-pyrazole-3- carbaldehyde (55.3 mg, 0.58 mmol), AcOH (14.4 mu,, 0.25 mmol) and NaBH(OAc)3 (152 mg, 0.72 mmol) were added. The reaction mixture stirred for 18 h, diluted with DCM (20 mL) and quenched with water (10 mL). The organic fraction was washed with sat aq Na2CC>3 (10 mL), dried (MgS04) and concentrated in vacuo. The residue was purified by reverse phase chromatography to give the title compound as a white solid (8.14 mg, 8.6percent). HRMS (ESI+) calcd for C2iH21ClN6 393.1589, found 393.1589. HPLC (method B): Rf 3.90 min, 99percent purity. |
8.6% | With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 18h; | Example 84 (75.0 mg, 0.24 mmol) was dissolved in DCM (10 mL) and 1H-pyrazole-3-carbaldehyde (55.3 mg, 0.58 mmol), AcOH (14.4 muL, 0.25 mmol) and NaBH(OAc)3 (152 mg, 0.72 mmol) were added. The reaction mixture stirred for 18 h, diluted with DCM (20 mL) and quenched with water (10 mL). The organic fraction was washed with sat aq Na2CO3 (10 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase chromatography to give the title compound as a white solid (8.14 mg, 8.6percent). HRMS (ESI+) calcd for C21H21ClN6 393.1589, found 393.1589. HPLC (method B): Rf 3.90 min, 99percent purity. |
Yield | Reaction Conditions | Operation in experiment |
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Synthesis of Compounds of Formula II. To a solution of amine XLV (0.25 mmol) and appropriate aldehyde (0.27 mmol) in DCM, acetic acid (0.2 mL) was added at room temperature and the resulting mixture was allowed to stir for 30 minutes. Then sodium triacetoxyborohydride (STAB) (0.26 gm, 1.26 mmol) was added to reaction mixture and the resulting mixture was allowed to stir at 50° C. for 1 h. After completion of reaction, the crude mixture was diluted with DCM washed with water, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 60-120 mesh; MeOH-DCM, 2:8) to afford product in 32-45percent yield. |
Yield | Reaction Conditions | Operation in experiment |
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84% | With triethylamine; In acetonitrile; at 50℃; | Dimethylsulfamoyl chloride (3.09 mL; 28.62 mmol) was added to a solution of -Eta- pyrazole-3-carbaldehyde (2.5 g; 26.02 mmol) and triethylamine (5.96 mL; 41.63 mmol) in ACN (25 mL) and the reaction mixture was stirred at 50°C overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine and dried over MgS04, filtered and evaporated to dryness. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-45mueta?, 80g; mobile phase: 99percent DCM, 1 percent MeOH). The product fractions were collected and evaporated to dryness yielding 4.42 g of intermediate 43 (84percent) |
84% | With triethylamine; In acetonitrile; at 50℃; | Dimethylsulfamoyl chloride (3.09 mL; 28.62 mmol) was added to a solution of 3- carboxaldehyde pyrazole (2.5 g; 26.02 mmol) and Et3N (5.96 mL; 41.63 mmol) in ACN (25 mL) and the reaction mixture was stirred at 50°C overnight. The reaction mixture was poured into ice water and extracted with EtOAc. The organic layer was washed with brine and dried over MgS04, filtered and evaporated to dryness. The crude product was purified by chromatography over silica gel (irregular SiOH, 15-45muetaiota, 80g; mobile phase: 99percent DCM, 1 percent MeOH). The pure fractions were collected and evaporated to dryness yielding 4.42 g (84percent) of intermediate 34. |
Yield | Reaction Conditions | Operation in experiment |
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8.3 g | With 18-crown-6 ether; potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20 - 120℃; | Example A: Ethyl 2-(3-formyl-lH-pyrazol-l-yl)nicotinate To ethyl 2-chloronicotinate (8 g, 43.1 mmol) und lH-pyrazole-3-carbaldehyde (4.6 g, 47.9 mmol) in N,N-dimethylformamide (80 mL) K2C03 (12 g, 87 mmol), 18-CROWN- 6 (0.5 g, 1.892 mmol) und KI (0.4 g, 2.410 mmol) were added, the mixture heated to 120°C for lhr and then stirred overnight at room temperature. The mixture then was concentrated, 250 mL of dichloromethane added, washed subsequently with water and brine, dried (MgS04), filtered and concentrated to give 11.2 g of a yellow oil. Purification by chromatography over silica gel (eluent CH2C12 +0-6percent methanol) and evaporation of the combined product fractions gave 8.3 g of the title compound as amorphous solid. ESI-MS [M+H]+: 246.1. 1H-NMR (400 MHz, DMSO), delta [ppm]: 9.96 (s), 8.77 (m, 1H), 8.67 (m, 1H), 8.26 (m, 1H), 7.67 (m, 1H), 7.06 (d, 1H), 4.25 (q, 2H), 1.12 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;Sealed tube; | Intermediate 15: 1 -(6-(trifluoromethyl)pyridin-3-yl)- 1 H-pyrazole-3-carbaldehyde A mixture of 1H-pyrazole-3-carbaldehyde (0.700 g, 7.29 mmol), 5-bromo-2-(trifluoromethyl)pyridine (2.31 g, 10.2 mmol, 1.4 equiv), cesium carbonate (4.75 g, 14.6 mmol,2.0 equiv), copper(l) iodide (0.069 g, 0.36 mmol, 0.05 equiv), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.23 mL, 1.46 mmol, 0.2 equiv) in DMF (9.5 mL) was heated in a sealed reaction vessel at 110 00 for 16 hours. The reaction was then cooled to room temperature and saturated aqueous ammonium chloride (100 mL) was added. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (Na2SO4), filtered, andconcentrated in vacuo. Silica gel column chromatography (EtOAc/heptane) provided 1-(6-(trifluoromethyl) pyridin-3-yl)- 1 H-pyrazole-3-carbaldehyde (0.470 g, brown solid) in 27percent yield.1H NMR (400 MHz, ODd3) oe 10.13 (5, 1H), 9.18 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 8.7, 2.0 Hz,1H), 8.12 (m, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H). MS m/z 241.9 (M + H)Rt-0.78 mm. |
27% | With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;Sealed tube; | A mixture of 1H-pyrazole-3-carbaldehyde (0.700 g, 7.29 mmol), 5-bromo-2-(trifluoromethyl)pyridine (2.31 g, 10.2 mmol, 1.4 equiv), cesium carbonate (4.75 g, 14.6 mmol,2.0 equiv), copper(l) iodide (0.069 g, 0.36 mmol, 0.05 equiv), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.23 mL, 1.46 mmol, 0.2 equiv) in DMF (9.5 mL) washeated in a sealed reaction vessel at 110 00 for 16 hours. The reaction was then cooled toroom temperature and saturated aqueous ammonium chloride (100 mL) was added. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried (Na2504), filtered, and concentrated in vacuo. Silica gel column chromatography (EtOAc/heptane) provided 1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-3-carbaldehyde (0.470 g, brown solid) in 27percent yield.1H NMR (400 MHz, ODd3) oe 10.13 (5, 1H), 9.18 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 8.7, 2.0 Hz, 1H), 8.12 (m, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H). MS m/z 241.9 (M + H) Rt-0.78 mm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; In toluene; at 110℃; for 18h;Sealed tube; | To a mixture of 1H-pyrazole-3-carbaldehyde (1.52 g, 15.82 mmol), 1-chloro-4-iodobenzene (5.66 g, 23.73 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.450 g, 3.16 mmol), copper(l) iodide (0.151 g, 0.791 mmol) and K2003 (4.37 g, 31.6 mmol) was added toluene (20mL). The reaction was sealed and heated to 110 00 for 18 hours. The reaction mixture was then cooled to room temperature and diluted with water (50 mL), and extracted with EtOAc (3 x 30 mL). The combined organic was then dried (Na2SO4) and concentrated to give crude l-(4- chlorophenyl)-1H-pyrazole-3-carbaldehyde (1.86 g, 9.0 mmol), to which was added (R)-2- methylpropane-2-sulfinamide (1.20 g, 9.90 mmol), CuSO4 (2.155 g, 13.50 mmol) and DOE (30ml). The reaction was sealed, heated at 60 00 for 18 hours. A dark green suspension resulted. The reaction mixture was then cooled to 20 00, filtered through a pad of celite, rinsed with DCM. The solution was then concentrated to give final crude product as a light green oil. The residue was purified via silica gel chromatography (EtOAc/Heptane). m/z 310.3 (M + H) | |
With copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; potassium carbonate; In toluene; at 110℃; for 18h;Sealed tube; | To a mixture of 1H-pyrazole-3-carbaldehyde (1.52 g, 15.82 mmol), 1-chloro-4-iodobenzene(5.66 g, 23.73 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.450 g, 3.16 mmol),copper(l) iodide (0.151 g, 0.791 mmol) and K2C03 (4.37 g, 31.6 mmol) was added toluene (20mL). The reaction was sealed and heated to 110 °C for 18 hours. The reaction mixture wasthen cooled to room temperature and diluted with water (5OmL), and extracted with EtOAc(3x3OmL). The combined organic was then dried (Na2SO4) and concentrated to give crude 1-(4-chlorophenyl)-1H-pyrazole-3-carbaldehyde (1.86 g, 9.0 mmol), to which was added (R)-2-methylpropane-2-sulfinamide (1.20 g, 9.90 mmol), CuSO4 (2.155 g, 13.50 mmol) and DCE (30ml). The reaction was sealed, heated at 60 00 for 18 hours. A dark green suspension resulted. The reaction mixture was then cooled to 2OoC, filtered through a pad of celite, rinsed with DCM. The solution was then concentrated to give final crude product as a light green oil. The residue was purified via silica gel chromatography (EtOAc/Heptane). LCMS (B) m/z 310.3 (M +H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h; | Step 1 : l-(3-Bromobenzyl)- lH-pyrazole-3-carbaldehyde To a solution of pyrazol-3-carbaldehyde (10.0 g, 104 mmol) in DMF (333 mL) was added K2CO3 (43 g, 312 mmol) followed by 3-bromobenzyl bromide (27.3 g, 109 mmol) at rt, and the mixture was stirred for 14 h. The reaction was filtered through a celite pad and the residual solid was rinsed with EtOAc. The filtrate was concentrated in vacuo. To the residue was added water (200 mL) and the mixture was extracted with Hexane:EtOAc (1:1, 200 mLx3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified on silica to provide l-(3- bromobenzyl)-lH-pyrazole-3-carbaldehyde (21.1 g, 76percent) as a colorless solid. LCMS (FA): m/z = 261 A (M+H). |
45% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; In acetonitrile; at 20℃; | General procedure: A mixture of 1H-imidazole-2-carbaldehyde 40 (200 mg, 2.08 mmol), potassium carbonate (0.8630 g, 6.24 mmol) and 3-(bromomethyl)-1,1'-biphenyl 38 (0.7716 g, 3.12 mmol) in acetonitrile (10 mL) was stirred overnight at room temperature, then the solvent was removed, diluted with water, and extracted with ethyl acetate (3 x 30 mL). The combined organic phases were washed with brine, dried with Na2SO4, filtered, concentrated and purified by silica gel chromatography to afford 44 as a pale yellow solid (527 mg, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate (2 g, 7.54 mmol, 1.00 eq.), 1H-pyrazole-3- carbaldehyde (725 mg, 7.55 mmol, 1.00 eq.) and Cs2CO3 (4.9 g, 15.04 mmol, 2.00 eq.) in DMF(40 mL). The resulting solution was stirred for 16 hours at 80C. The reaction was then quenched by the addition of water. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1:4). This resulted in 1.9 g (95%) of tert-butyl N-[3-(3-formyl-1H-pyrazol-1-yl)cyclobutyl]carbamate as a white solid. LC-MS: (M+H7 = 266. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; | To a 50-mL round-bottom flask was placed a solution of [(lr,3r)- 3-(3-phenyl-l ,2-oxazole-5-amido)cyclobutyl]methyl 4-methylbenzene-l -sulfonate (1.28 g, 3.00 mmol, 1 .00 equiv) in DMF (20 mL), then Cs2C03 (1.95 g, 5.98 mmol, 2.00 equiv) and 1 H- pyrazole-3-carbaldehyde (432 mg, 4.50 mmol, 1.50 equiv) were added. The resulting solution was stirred for 3 h at 100°C, then the solids were removed by filtration. The filtrate was purified by Flash-Prep-HPLC (CombiFlash-1 : Column, CI 8; mobile phase, X: H20 (0.5percent NH4HCO3), Y: CAN, X/Y=90/'l 0 increasing to X/Y=5/95 within 40 min; Detector, UV 254 nm) affording 450 mg (43percent) of 3-phenyl-N-[(lr,3r)-3-[(3-formyl-lH-pyrazol-l - yl)methyl]cyclobutyl]-l ,2-oxazole-5-carboxamide as a yellow solid. LCMS (ES, m/z): [M+H]+ = 351.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3h; | To a 50-mL round-bottom flask was placed a solution of [(l s,3s)-3-(3-phenyl-l ,2-oxazole-5-amido)cyclobutyl]methyl 4-methylbenzene-l -sulfonate (1.3 g, 3.05 mmol, 1.00 equiv) in DMF (15 mL), then Cs2C03 (1.96 g, 6.02 mmol, 2.00 equiv) and l H-pyrazole-3-carbaldehyde (432 mg, 4.50 mmol, 1.50 equiv) were added. The resulting solution was stirred for 3 h at 100°C, then the solids were removed by filtration. The filtrate was purified by Flash-Prep-HPLC (CombiFlash-1 : Column, C18; mobile phase, X: H20 (0.5percent NH4HCO3), Y: ACN, X/Y=90/10 increasing to X/ACN=5/95 within 40 min; Detector, UV 254 nm) affording 430 mg (40percent) of 3-phenyl-N-[(l s,3s)-3-[(3-formyl-lH-pyrazol-l - yl)methyl]cyclobutyl]- l ,2-oxazole-5-carboxamide as a yellow solid. LCMS (ES, m/z): [M+H]+ = 351.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40%; 32% | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate (2 g, 7.54 mmol, 1.00 eq.), lH-pyrazole-3- carbaldehyde (725 mg, 7.55 mmol, 1.00 eq.) and Cs2C03 (4.9 g, 15.04 mmol, 2.00 eq.) in DMF (40 mL). The resulting solution was stirred for 16 hours at 80C. The reaction was then quenched by the addition of water. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1 :4). This resulted in 1.9 g (95%) of tert-butyl Nu- [3-(3-formyl-lH-pyrazol-l -yl)cyclobutyl]carbamate as a white solid. LC-MS : (M+H)+ = 266. Mixture was purified by Prep-SFC with the following conditions (prep SFC 350-2): column, Chiralpak AS-H, 5*25cm, 5um; mobile phase, C02 (75%), methanol (25%); Detector, UV 220 nm. This resulted in 600 mg (32%) of tert-butyl N-[czs-3-(3-formyl-lH-pyrazol-l - yl)cyclobutyl] carbamate as yellow oil, and 760 mg (40%) of tert-butyl N-[trans-3-(3-formy- lH-pyrazol-l-yl)cyclobutyl]carbamate as a white solid. |
760 mg; 600 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 16h; | into a 100-mL round-bottom flask, was placed a solution of tert-butyl N-[3- (methanesulfonyloxy)cyclobutyl]carbamate (2 g, 7.54 mmol, 1.00 eq.), lH-pyrazole-3- carbaldehyde (725 mg, 7.55 mmol, 1.00 eq.) and Cs2C03 (4.9 g, 15.04 mmol, 2.00 eq.) in DMF (40 mL). The resulting solution was stirred for 16 hours at 80C. The reaction was then quenched by the addition of water. The resulting solution was extracted with of ethyl acetate and the organic layers combined. The resulting mixture was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/hexane (1 :4). This resulted in 1.9 g (95%) of tert-butyl N- [3-(3-formyl-lH-pyrazol-l-yl)cyclobutyl]carbamate as a white solid. LC-MS: (M+H)+ = 266. Mixture was purified by Prep-SFC with the following conditions (prep SFC 350-2): column, Chiralpak AS-H, 5*25cm, 5um; mobile phase, C02 (75%), methanol (25%); Detector, UV 220 nm. This resulted in 600 mg (32%) of tert-butyl N-[cz's-3-(3-formyl-lH-pyrazol-l- yl)cyclobutyl] carbamate as yellow oil, and 760 mg (40%) of tert-butyl N-[^as-3-(3-forrnyl- lH-pyrazol-l-yl)cyclobutyl]carbamate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
500 mg | With sodium hydride; In tetrahydrofuran; at 20℃; for 2h; | A mixture of ethyl 2-[bis(2,2,2-trifluoroethoxy)phosphoryl]acetate (3.04 g, 9.15 mmol), sodium hydride (400 mg, 16.66 mmol), 1H-pyrazole-5-carbaldehyde (800 mg, 8.32 mmol) in tetrahydrofuran (100 mL) was stirred for 2 h at room temperature. The reaction was quenched with water. The resulting mixture was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was purified by flash chromatography on a silica gel column eluted with ethyl acetate/petroleum ether (1/3) to afford ethyl (2Z)-3-(1H-pyrazol-5-yl)prop-2-enoate (500 mg, 2.99 mmol) as a white solid. LCMS (ESI) [M+H]+=167. |
Tags: 3920-50-1 synthesis path| 3920-50-1 SDS| 3920-50-1 COA| 3920-50-1 purity| 3920-50-1 application| 3920-50-1 NMR| 3920-50-1 COA| 3920-50-1 structure
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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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