Structure of 1H-Pyrazole-4-carboxaldehyde
CAS No.: 35344-95-7
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CAS No. : | 35344-95-7 |
Formula : | C4H4N2O |
M.W : | 96.09 |
SMILES Code : | O=CC1=CNN=C1 |
MDL No. : | MFCD02179514 |
InChI Key : | LRGBDJBDJXZTTD-UHFFFAOYSA-N |
Pubchem ID : | 5130673 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
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 ? Topological Polar Surface Area: Calculated from |
45.75 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.23 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.95 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.22 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-1.04 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.2 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.07 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.3 |
Solubility | 48.2 mg/ml ; 0.501 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.47 |
Solubility | 286.0 mg/ml ; 2.98 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.1 |
Solubility | 7.69 mg/ml ; 0.08 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 |
No |
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 |
-7.56 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) |
1.0 |
* 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 |
---|---|---|
36% | With dmap; In 1,1-dichloroethane; at 0 - 20℃; for 3h; | Step I. 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>; 2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.8 g, 1.9 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.6 g, 6.2 mmol) and DMAP (1.5 g, 12 mmol) in DCE (70 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The solvent was concentrated and the product was purified by flash chromatography on silica gel using DCM/EtOAc (1:1) as eluent to provide the title compound as white solid. Yield: 0.34 g (36percent); MS (ESI) (M+H)+=465.0. |
36% | With dmap; In 1,1-dichloroethane; at 0 - 20℃; for 3h; | Step I. 1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (0.8 g, 1.9 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.6 g, 6.2 mmol) and DMAP (1.5 g, 12 mmol) in DCE (70 mL) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 3 h. The solvent was concentrated and the product was purified by flash chromatography on silica gel using DCM/EtOAc (1:1) as eluent to provide the title compound as white solid. Yield: 0.34 g (36percent); MS (ESI) (M+H)+=465.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | With N-ethyl-N,N-diisopropylamine;dmap; In dichloromethane; at 20℃; for 3h; | Step B: 1-({2-tert-Butyl-1-[(trans-4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>; 2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (400 mg, 1.03 mmol), <strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (300 mg, 3.09 mmol) (see Example 126, step H for preparation) and DMAP (catalytic) were stirred in 10 mL of DCM containing DIPEA (0.90 mL, 5.15 mmol) at rt for 3 h. The solution washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using hexanes/EtOAc (1:1) as eluent. Yield: 131 mg (28percent). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.16-1.26 (m, 2H), 1.35-1.48 (m, 2H), 1.54-1.56 (m, 9H), 1.72 (dd, J=8.69, 3.03 Hz, 2H), 1.95-2.04 (m, 1H), 2.11-2.19 (m, 2H), 4.17-4.21 (m, 2H), 4.37-4.46 (m, 1H), 4.50-4.59 (m, 1H), 7.44 (d, J=8.59 Hz, 1H), 7.96 (dd, J=8.69, 1.86 Hz, 1H), 8.08 (s, 1H), 8.44 (d, J=1.37 Hz, 1H), 8.64 (s, 1H), 9.91 (s, 1H). |
28% | With N-ethyl-N,N-diisopropylamine;dmap; In dichloromethane; at 20℃; for 3h; | Step B: 1-({2-tert-Butyl-1-[(trans-4-fluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong>2-tert-Butyl-1-[(4-fluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (400 mg, 1.03 mmol), <strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (300 mg, 3.09 mmol) (see Example 126, step H for preparation) and DMAP (catalytic) were stirred in 10 mL of DCM containing DIPEA (0.90 mL, 5.15 mmol) at rt for 3 h. The solution was washed with saturated aqueous NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using hexanes/EtOAc (1:1) as eluent. Yield: 131 mg (28percent). 1H NMR (400 MHz, CHLOROFORM-D) delta 1.16-1.26 (m, 2H), 1.35-1.48 (m, 2H), 1.54-1.56 (m, 9H), 1.72 (dd, J=8.69, 3.03 Hz, 2H), 1.95-2.04 (m, 1H), 2.11-2.19 (m, 2H), 4.17-4.21 (m, 2H), 4.37-4.46 (m, 1H), 4.50-4.59 (m, 1H), 7.44 (d, J=8.59 Hz, 1H), 7.96 (dd, J=8.69, 1.86 Hz, 1H), 8.08 (s, 1H), 8.44 (d, J=1.37 Hz, 1H), 8.64 (s, 1H), 9.91 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | dmap; In acetonitrile; at 20℃; for 0.5h; | 4-FORMYL-PYRAZOLE-1-CARBOXYLIC acid tert-butyl ester (56). To a solution of 55 (0.31 g, 3.26 mmol) in acetonitrile (30 ml) was added BOC anhydride (0.71 g, 3.26 mmol) followed by DMAP (0.02 g). After 30 minutes of stirring at room temperature, the solvent was evaporated, water and EtOAc were added. Organic layer was separated, washed with 0.5 N HCl (10 ml) and brine (15 ml), dried (NA2S04) and concentrated to give 0.41 g (76percent yield) of the desired product which was used in the next step to prepare di-Boc-protected 2 without purification. |
71% | With dmap; In acetonitrile; at 20℃; | 1003831 Step A: Boc2O (2183 mg, 10.0 mmol) was added to a stirred solution of iH<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (961 mg, 10.0 mmol) in acetonitrile (30 mL) at room temperature, followed by 4-dimethylaminopyridine (?DMAP?) (61.1 mg, 0.500 mmol). After stirring overnight, the reaction was concentrated to dryness and partitioned between ethyl acetate (30 mL) and water (30 mL). The organics were isolated and washed with 0.5N HCL (30 mL) and with brine (30 mL). The organics were isolated, dried (Mg504), filtered and concentratedan oil, which was loaded onto a Biotage 40M column with 4/1 hexanes/ethyl acetate and eluted with the same solvent. Product containing fractions were pooled and concentratedan oil, which eventually solidified to a solid, tert-butyl 4-formyl-1H-pyrazole-1-carboxylate(1.4 g, 71percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; for 2h;Heating / reflux; | 1H-PYRAZOLE-4-CARBALDEHYDE (55). To a solution of 1- (4-METHOXY-BENZYL)-1H- pyrazole (0.21 mol) (Synth. Commun. 1990, 20/18 ; 2849) in dry DMF (235 ml) was added POCL3 (1.5 eq. ) dropwise at room temperature. The mixture was then heated at 95°C for 16 hrs. After cooling to room temperature, the reaction mixture was neutralized by adding ice and saturated sodium carbonate solution. EtOAc (800 ml) was added and the organic layer was separated and washed several times with water. After drying (Na2SO4), the solvent was removed and the crude product was purified over silica gel to give 16.4 g (35percent yield) desired aldehyde 1-(4-METHOXY-BENZYL)-LH- pyrazole-4-carbaldehyde. It was heated with 150 ml TFA for 2 hrs. TFA was evaporated and the basified crude product was purified on silica gel to give 5.3 g of 55. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
226.3 mg(51%) | With acetic acid; In ethanol; | Example 12 Production of alpha-(4-pyrazolyl)-N-t-butylnitrone To a suspension of 1,1-dimethylnitroethane (546.0 mg, 5.29 mmol) and zinc (515.5 mg, 7.89 mmol) in ethanol (3.0 ml) was added acetic acid (950.0 mg, 15.8 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 45 minutes. After cooling the mixture to 5° C. again, <strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (255.4 mg, 2.66 mmol) was added dropwise to the mixture while stirring and stirred at room temperature overnight. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (chloroform/methanol=10/1). Yield: 226.3 mg(51percent) 1H-NMR(CDCl3) 1.60(s, 9H), 6.56(d, 1H, J=2.0 Hz), 7.64(d, 1H, J=2.0 Hz), 7.71(s, 1H), 8.43(brs, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22%; 48% | To a solution of 20mg (0.04 mmol) (6R3 75, 7a5)-2-amino-6-{(lR)-l-[3,5- bis(trifluoromethyl)phenyl]ethoxy}-7-(4-fluorophenyl)hexahydro-3H-pyrrolizin-3-one in 1 mL anhydrous dichloromethane and 7 muL (0.04 mmol) DIEA under nitrogen atmosphere was added crushed 4A molecular sieves followed by 40 mg (0.04 mmol) aromatic heterocyclic aldehyde . After 5 minutes of stirring, the solution was then treated with 40 mg (0.2 mmol) Na(OAc)3BH and the resulting suspension stirred vigorously at room temperature, overnight. The mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (2 x 5 mL). The organics were combined and treated as stated in Example 3, step E. The residue was purified by preparative TLC plate eluding with methanol/dichloromethane (1/9) to afford two products. The less polar product was found to be the mono substituted compound 5.3 mg (22percent),MS: 571 (MH)+,and the slightly more polar product 11.2 mg (48percent) was di-substituted,MS: 651 (MH)+. Conversion to the HCl salts of each were accomplished according to the procedure for Example GJM-5, step C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | Preparation 53: 1 -Cyclopropylmethyl- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> <n="62"/>--61-Add lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.200 g, 2.08 mmol) to a suspension of sodium hydride (0.092 g, 2.29 mmol) in DMF (3 mL) at 0 0C. Stir for 20 min. at 0 0C. Add a solution of l-(bromomethyl)cyclopropane (0.295 g, 2.18 mmol) in DMF (4 mL) dropwise to the reaction mixture. Stir reaction to ambient temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, dry combined organics (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0: 100 to 60:40 ethyl acetate:hexanes) to give the title preparation (175 mg, 56percent). GC-MS: m/z = 150 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In acetonitrile; at 150℃; for 0.333333h;Microwave irradiation; | Preparation 12: 1 -(2-Hydroxy-ethyl)- lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Combine lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.110 g, 1.14 mmol), 2-bromoethanol(0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150 0C for 20 min. Cool to room temperature and filter, wash with acetonitrile. Concentrate filtrate to give l-(2-hydroxy-ethyl)-lH-pyrazole-4- carbaldehyde (0.155 g, 97percent). GC-MS (m/z): 140 (M+). |
97% | With potassium carbonate; In acetonitrile; at 150℃; for 0.333333h;Microwave irradiation; | Preparation 52: l-(2-Hydroxy-ethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> Combine lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.110 g, 1.14 mmol), 2-bromoethanol(0.172 g, 1.37 mmol), and potassium carbonate (0.236 g, 1.71 mmol) in acetonitrile (2 mL). Heat in microwave at 150 0C for 20 min.. Cool to room temperature and filter, washing with acetonitrile. Concentrate filtrate to give the title preparation (0.155 g, 97percent). GC-MS: m/z = 140 [M+]. |
89% | With potassium carbonate; In acetonitrile; at 150℃; for 0.666667h;Sealed tube; Microwave irradiation; | 1-(2-Hydroxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> In a 30-mL sealed tube, <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (500 mg, 5.20 mmol, 1.00 equiv), potassium carbonate (1.08 mg, 7.80 mmol, 1.50 equiv) and 2-bromoethan-1-ol (775.3 mg, 6.20 mmol, 1.19 equiv) were mixed in CH3CN (10 mL) at room temperature. The reaction mixture was then irradiated with microwave for 40 min at 150° C. After the reaction was done, the reaction mixture was cooled to room temperature, filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with dichloromethane/methanol (1percent to 5percent gradient) to afford 1-(2-hydroxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (650 mg, 89percent) as yellow solid. MS: m/z=140.8 [M+H]+ |
69% | With potassium carbonate; In acetonitrile; at 150℃; for 0.5h;Microwave irradiation; | 1H-Pyrazole-4-carboxaldehyde (0.50 g, 5.21 mmol), 2-bromoethanol (1.30 g, 10.41 mmol) and potassium carbonate (0.79 g, 5.73 mmol) combined with acetonitrile (5 mL) in a microwave vial. The microwave vial was heated at 150 °C in a microwave for 30 minutes. The reaction mixture was filtered and the solvent evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with 0- 100percent ethyl acetate in iso-hexane to afford the title compound (0.50 g, 69percent). 1HNMR (400 MHz, CDCl3): delta 9.86 (s, 1 H); 8.02 (s, 1 H); 7.99 (s, 1 H); 4.33-4.25 (m, 2 H); 4.05 (t, J = 4.8 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | Preparation 55: 1 -(2,2,2-Trifluoro-ethyl)- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> Add 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.40Og, 4.16 mmol) as a solution in DMF (2 mL) dropwise to a suspension of sodium hydride (0.333 g, 8.32 mmol) in DMF (5 mL) at 0 0C. Stir for 15 min. at 0 0C. Add 2,2,2-trifluoroethyl-p-toluenesulfonate (1.27 g, 5.00 mmol) and DMF (3 mL) to the reaction mixture. Heat to 60 0C for 18 hr. Quench with aqueous saturated sodium bicarbonate solution and add ethyl acetate. Separate organic layer. Extract aqueous layer twice with ethyl acetate, wash combined organics with brine, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0: 100 to 100:0 ethyl acetate:hexanes) to give the title preparation (309 mg, 42%). GC-MS: m/z = 178 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.82% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;Sealed tube; | To the stirred solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> 19-4 (200 mg, 2.08 mmol) in DMF (2 ml) in a sealed tube were added potassium carbonate (719.19 mg, 5.20 mmol, 314.06 uL) and bromocyclopropane 19-5 (251.80 mg, 2.08 mmol, 166.76 uL). The reaction mixture was heated at H0C for 16 hours and then cooled to room temperature, diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography to afford l-cyclopropylpyrazole-4-carbafdehyde 19-6 (25 mg, 183.62 umol, 8.82% yield) as gum. NMR (400 MHz, DMSO-d6) d 9.75 (s, 1H), 8.53 (s, 1H), 7.95 (s, 1 1 1 ), 3.86-3.82 (m, 1 1 1 ), 1. 10-1.08 (m, 2) 1 ).. 1.03-0.98 (m, 21 1). |
With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 18h; | Preparation 54: 1 -Cyclopropyl- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Dissolve lH-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> in N,N-dimethylformamide (1.9 mL). Add potassium carbonate (0.539 g, 3.90 mmol) and cyclopropylbromide (0.346 g, 2.86 mmol). Heat in a pressure tube to 130 0C for 18 hr. Cool to ambient temperature and add DCM and water. Separate layers and extract water layer 3 times with DCM. Wash combined DCM layers with brine, dry (magnesium sulfate), filter, and concentrated to give the free base of the title preparation. GC-MS: m/z = 136 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In dichloromethane; at 20℃; for 18h; | Preparation 61 : l-(l,2-Dimethyl-lH-imidazole-4-sulfonyl)-l H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Dissolve lH-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (0.150 g, 1.56 mmol) in DCM (5 mL). Add triethylamine (240 muL, 1.72 mmol) and l,2-dimethyl-lH-imidazole-4-sulfonyl chloride (0.334g, 1.72 mmol). Stir at ambient temperature for 18 hr. Concentrate, and purify via silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate: hexanes to give the title preparation (317mg, 80percent). GC-MS: m/z = 254 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Preparation 50: l-(3,5-Dimethylisoxazol-4-ylmethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> Add N,N-dimethylformamide (3 mL) to sodium hydride (0.092 g, 2.29 mmol) and stir at 0 0C. Add l-H-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (0.200 g, 2.08 mmol) and stir at 0 0C for 20 min.. Dissolve 4-chloromethyl-3,5-dimethylisoxazole (0.318 g, 2.18 mmol) in N,N-dimethylformamide (4 mL) and add to reaction mixture. Stir reaction at room temperature for 18 hr. Quench with aqueous saturated sodium bicarbonate solution. Add ethyl acetate and separate organic layer. Extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 25:75 to 75:25 ethyl acetate:hexanes), to give the title preparation (387 mg, 91percent). GC-MS: m/z = 205 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With dimethylaminoacetic acid; potassium carbonate;copper(l) iodide; In dimethyl sulfoxide; at 110℃; for 66h; | Preparation 62: 1 -(I -Methyl- lH-imidazol-4-y I)- 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>In an oven-dried flask, combine 4-bromo-l -methyl- lH-imidazole (0.200 g, 1.24mmol), copper (I) iodide (0.022g, 0.113 mmol), N,N-dimethylglycine (0.023 g, 0.226 mmol), and potassium carbonate (0.312 g, 2.26 mmol). Purge with nitrogen 3 times.Add l-H-<strong>[35344-95-7]pyrazole-4-carboxaldehyde</strong> (0.109 g, 1.13 mmol), and DMSO (1.7 mL). Heat to 110 0C for 48 hr. Cool to ambient temperature and partition between ethyl acetate and water. Separate organic layer and extract aqueous layer twice with ethyl acetate. Dry <n="64"/>--63-combined organic layers (magnesium sulfate), filter and concentrate. Add copper (I) iodide (0.022 g, 0.113 mmol), N,N-dimethylglycine (0.023 g, 0.226 mmol), potassium carbonate (0.312 g, 2.26 mmol), and DMSO (1.7 mL). Purge with nitrogen 3 times. Heat to 110 0C for 18 hr. Cool to ambient temperature and partition between ethyl acetate and water. Separate organic layer and extract aqueous layer twice with ethyl acetate. Dry combined organic layers (magnesium sulfate), filter, concentrate, and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate: hexanes) to give the title preparation (39 mg, 20percent). GC-MS: m/z = 176 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In acetonitrile; at 150℃; for 0.333333h;Microwave irradiation; | Preparation 56: Racemic l-(2-Hydroxy-propyl)-l H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Combine 1 H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.150g, 1.56 mmol), racemic l-bromo-2- propanol (0.26Og, 1.87 mmol), and potassium carbonate (0.323g, 2.34 mmol) in <n="63"/>--62-acetonitrile (2 mL). Heat in microwave at 150 0C for 20 min.. Filter, wash with acetonitrile and concentrate filtrate. Purify via silica gel chromatography, eluting with 0: 100 to 100:0 ethyl acetate:hexanes) to give the title preparation (177 mg, 73percent). GC- MS: m/z = 154 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 60℃; for 6h;Inert atmosphere; | To a mixture of 4-fluorobenzonitrile (2.49 g, 20.6 mmol) and 4-formylpyrazole (1.98 g, 20.6 mmo) in 50 mL of DMF at 0 0C was added 95percent sodium hydride (0.54 g, 22.7 mmol) under nitrogen. The mixture was heated to 60 0C for 6 hours and cooled to room temperature, Water was added carefully and the mixture was then extracted with ethyl acetate. The combined extracts were washed with water and brine, and then dried over sodium sulfate, filtered, and concentrated in vacuo to provide crude 4~(4-formyMH-pyrazol-l-yl)benzonitrile. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Alternate synthesis: l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong>Sodium hydride (60percent>, 6.3 g, 1.0 eq) was added to a solution of lH-pyrazole-4- carbaldehyde (15 g, 156 mmol) in DMF (150 ml) at 0°C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by column chromatography using a hexane/EtOAc gradient (10: 1 to 0: 100). Pure fractions were combined and evaporated under reduced pressure to yield l-(2-phenoxyethyl)-lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (24 g, 71percent). | |
71% | Sodium hydride (60percent, 6.3 g, 1.0 eq) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (15 g, 156 mmol) in DMF (150 ml) at 0° C. The mixture was allowed to warm and was stirred at room temperature. (2-Bromoethoxy)benzene (30.2 g, 1 eq) was then added and the resulting mixture was stirred overnight at room temperature. It was quenched by addition of aqueous ammonium chloride, diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using a hexane/ EtOAc gradient (10:1 to 0:100). Pure fractions were combined and evaporated under reduced pressure to yield 1-(2-phenoxyethyl)-<strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (24 g, 71percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In tetrahydrofuran; at 70℃; for 14h; | Intermediate 390A: Ethyl (E)- -(lH-pyrazol-4-yl)acrylate To a stirred solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (2 g, 20.8 mmol) in THF (30 mL) was added (carbothoxymethylene)triphenylphosphorane (8 g, 22.9 mmol). The reaction mixture was then heated at 70 °C for 14 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (3percent methanol /chloroform) to isolate ethyl 3-(lH-pyrazol-4-yl)acrylate (2.5 g, 73percent yield). NMR (400 MHz, DMSO-de) delta 13.14 (br s, IH), 8.18 (s, IH), 7.93 (s, IH), 7.57 (d, J=15.6 Hz, IH), 6.32 (d, J=16.1 Hz, IH), 4.15 (q, J=7.0 Hz, 2H), 1.24 (t, J=7.3 Hz, 3H); LCMS m/z 165 (M-H). |
60% | In tetrahydrofuran; at 70℃; for 8h;Inert atmosphere; | (E)-ethyl 3- ( lH-pyrazol-4-yl)acrylate[(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836g, 2.4 mmol) was added to a solution of iH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in THF (6 mL) at room temperature. This solution was heated at 70°C under anitrogen atmosphere for 8h. HPLC/MS analysis indicated completion of the reaction and both E and Z isomers of product were observed. The reaction mixture was cooled down to room temperature and evaporated in vacuo to get the crude product. This crude was purified by silica gel column chromatography using 0-80percent EtOAc in hexanes as eluent to provide, after evaporation of pooled fractions, pure (E)-ethyl 3-( H-pyrazol-4-yl)acrylate (0.198g, 60percent) as a white solid. ES+ (M+H)+ 167 |
60% | In tetrahydrofuran; at 20 - 70℃; for 8h;Inert atmosphere; | [(Ethoxycarbonyl)methylene]triphenylphosphorane (0.836 g, 2.4 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.192 g, 2 mmol) in THF (6 mL) at room temperature. This solution was heated at 70° C. under a nitrogen atmosphere for 8 h. [0446] HPLC/MS analysis indicated completion of the reaction and both E and Z isomers of product were observed. The reaction mixture was cooled down to room temperature and evaporated in vacuo to get the crude product. This crude was purified by silica gel column chromatography using 0-80percent EtOAc in hexanes as eluent to provide, after evaporation of pooled fractions, pure (E)-ethyl 3-(1H-pyrazol-4-yl)acrylate (0.198 g, 60percent) as a white solid. ES+(M+H)+167 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃; | (E)-methyl 3-(l -methyl- lH-pyrazol-4-yl)acrylateCs2C03 (1.304g, 4 mmol) was added to a solution of lH-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100°C overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3 -(1 -methyl- lH-pyrazol-4- yl)acrylate (0.278 g). ES+ (M+H)+ 167 | |
0.278 g | With caesium carbonate; In 1,4-dioxane; dimethyl sulfoxide; at 20 - 100℃; | Cs2CO3 (1.304 g, 4 mmol) was added to a solution of <strong>[35344-95-7]1H-<strong>[35344-95-7]pyrazole-4-carbaldehyde</strong></strong> (0.192 g, 2 mmol) in dioxane (8 mL) at room temperature. Trimethylphosphonoacetate (0.364 g, 0.40 mmol) was added to this suspension, followed by DMSO (2 mL). The reaction mixture was heated to 100° C. overnight. It was then diluted with EtOAc (40 mL), and washed with water (40 mL) and brine (20 mL). The organic layer was concentrated under vacuum. The crude was purified by silica gel column chromatography using a 0-100percent gradient of EtOAc in hexanes to provide (E)-methyl 3-(1-methyl-1H-pyrazol-4-yl)acrylate (0.278 g). ES+(M+H)+167 |
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