2H-PYRAZOLE-3-CARBALDEHYDE

Colorless Solid

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.Example 4 General procedure for the preparation of substituted pyrazole-3-carboxaldehydes. A suspension of the appropriately substituted phenyhydrazine hydrochloride (100 mmol) and solid NaHCO3 (120 mmol) was stirred under N2 in 100 mol of methanol. After 1-4 h, a solution of the appropriately substituted 4, 4-diethoxy-1-phenylbutan-1, 3-dione (100 mmol) in 100 mL of MeOH was added and the mixture was stirred for 2-24 h at room temperature, then was refluxed for 2-4 h. The solvent was removed using a rotary evaporator and the residue was dissolved in a mixture of 50 mL of 1N aqueous HCl and 50-150 mL of THF. The acidic two-phase mixture was refluxed for 1-4 h and, after cooling to room temperature, was partitioned between 200 mL of ether and 200 mL of water. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2 SO4, and concentrated to give a brown solid which was purified by recrystallization or MPLC to give the desired pyrazole-3-carboxaldehyde. The physical data of some of the aldehydes is listed in Table BTo a solution of 1H-pyrazole-3-carbaldehyde (10.0 g, 104 mmol, CAS3920-20-1) and (4-methoxy carbonyl-phenyl) boronic acid (22.5 g, 125 mmol, CAS99768-12-4) in DCM (50 mL) was added Cu(OAc)2 (22.7 g, 125 mmol) and pyridine (32.9 g, 416 mmol). The reaction mixture was stirred at rt for 18 hours under oxygen gas (balloon). On completion, the mixture was concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (12.0 g, 50% yield) as a white solid. 1H NMR (400 MHz, CDCl3) delta 10.10 (s, 1H), 8.24-8.14 (m, 2H), 8.06 (d, J=2.4 Hz, 1H), 7.90-7.82 (m, 2H), 7.02 (d, J=2.4 Hz, 1H), 3.95 (s, 3H).To a solution of 6-(4-methoxyphenyl)-2-(methylsulfonyl)-5i7- spiro[pyrido[4, 3-i/]pyrimidine-8, 3'-pyrrolidin]-7(6//)-one (100 mg, 0.26 mmol, 1.0 equiv.) in DCM (5 mL) was added liT-pyrazole-3-carbaldehyde (50 mg, 0.52 mmol, 2.0 equiv.) and AcOH (60.0 pL, catalytic amount) at room temperature. The resulting mixture was stirred for lh, and then NaBLLCN (16.0 mg, 0.25 mmol, 1.0 equiv) was added. After 0.5 h, the reaction mixture was quenched with ice water (10 mL) and extracted with DCM (10 mL x 3). All the organic layers were combined and washed with brine (30 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by RP-prep- HPLC to afford T-((liT-pyrazol-3-yl)methyl)-6-(4-methoxyphenyl)-2- ( ethylsulfonyl)-5//-spiro[pyrido[4, 3-6/]pyrimidine-8, 3'-pyrrolidin]-7(6//)-one (60.0 mg, 49% yield) as a white solid. LC-MS: m/z 469 [M+H]+.To a solution of 6-(4-methoxyphenyl)-2-(methylsulfonyl)-5i7- spiro[pyrido[4, 3-i/]pyrimidine-8, 3'-pyrrolidin]-7(6 /)-one (56.0 mg, 0.15 mmol, 1.0 equiv.) in DCE (3 mL) was added 7i7-pyrazole-3-carbaldehyde (28.0 mg, 0.29 mmol, 2.0 equiv.) and AcOH (60.0 pL, catalytic amount) at room temperature. The resulting mixture was stirred for 1 h, after which NaBTbCN (10.0 mg, 0.158 mmol, 1.1 equiv.) was added. The reaction mixture was stirred for an additional 0.5 h before being quenched with ice water (2.0 mL) and extracted with DCM (5 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over Na2S04 and concentrated under reduce pressure. The resulting residue was purified by RP-prep-HPLC to afford pyrazol-3 -yl ( ethyl )-2-((cyclopropyl methyl )amino)-6-(4-methoxyphenyl)-5//- spiro[pyrido[4, 3-i/]pyrimidine-8, 3'-pyrrolidin]-7(6//)-one (Example 101). [00167] NMR (400 MHz, CDCb) d: 8.47 (br s, 1H), 8.13 (s, 1H), 7.54(s, 1H), 7.18 (d, J= 8.6 Hz, 2H), 6.99 (d, J= 8.6 Hz, 2H), 6.34 (s, 1H), 4.79 (d, J = 15.4 Hz, 1H), 4.52 (d, 7= 15.4 Hz, 1H), 4.38 (d, = 13.2 Hz, 1H), 4.31 (d, J =13.2 Hz, 1H), 4.11 (d, 7= 10.8 Hz, 1H), 3.83 (s, 3H), 3.67 (d, = 10.8 Hz, 1H), 3.65-3.47 (m, 1H), 3.35-3.28 (m, H), 3.26-3.16 (m, 1H), 2.61-2.51 (m, 1H), 2.48-2.37 (m, 1H), 1.15-1.04 (m, 1H), 0.60-0.50 (m, 2H), 0.32-0.23 (m, 2H) [one NH not observed underneath CDCb]. LCMS: m/z 460 [M+H]+.General procedure: A mixture of 3-isopropyl-lH-pyrazole (464A, 2 g, 18 mmol) and 3, 4-dihydro-2H- pyran (3.05 g, 36 mmol) was heated in a seal tube at 120 0 C for 12 hours. The reaction mixture was cooled down to room temperature, concentrated, and purified by preparative HPLC to give Compound 464B. LC-MS (ESI) m/z: 195 [M+l]+.

Molecular Weight:96.09
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:96.032362755
Monoisotopic Mass:96.032362755
Topological Polar Surface Area:45.8
Heavy Atom Count:7
Complexity:74.1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes