Boronicacid,B-(1,3,5-trimethyl-1H-pyrazol-4-yl)-

Preparation of 8-(1-ethyl-propyl)-2, 6-dimethyl-3-(l, 3, 5-trimethyl-7H-pyrazol-4-yl)- imidazo[1, 2-b]pyridazine.; A. l, 3, 5-Trimethylpyrazole-4-boronic acid.; To a dry flask is added 300 mg (1.59 mmol) of 4-bromo-l, 3, 5-trimethyl pyrazole to 4.0 ml THF. The mixture is cooled to -78°C and leq of n-BuLi (1.6 M) is added via syringe. The mixture is stirred 1.5 hrs, and 0.19ml of trimethylborate (1.08 eq) is added. The reaction mixture is stirred 2 hrs, allowing bath to reach -10°C, then 1.5 ml of 5N HCl is added and stirred 30 minutes longer. The aqueous layer is extracted 3 times with ethyl acetate. The combined organics are dried over MgSO4, filtered, and evaporated to an oil. The oil is dissolved in methanol/methylene chloride and re-evaporated. The residue is triturated with acetone/ethyl acetate then filtered to obtain title compound as a white solid 92.1 mg (37.6percent). Example 98.; Preparation of 8-(1-ethyl-propyl)-2, 6-dimethyl-3-(l, 3, 5-trimethyl-7H-pyrazol-4-yl)- imidazo[1, 2-b]pyridazine.; A. l, 3, 5-Trimethylpyrazole-4-boronic acid.; To a dry flask is added 300 mg (1.59 mmol) of 4-bromo-l, 3, 5-trimethyl pyrazole to 4.0 ml THF. The mixture is cooled to -78°C and leq of n-BuLi (1.6 M) is added via syringe. The mixture is stirred 1.5 hrs, and 0.19ml of trimethylborate (1.08 eq) is added. The reaction mixture is stirred 2 hrs, allowing bath to reach -10°C, then 1.5 ml of 5N HCl is added and stirred 30 minutes longer. The aqueous layer is extracted 3 times with ethyl acetate. The combined organics are dried over MgSO4, filtered, and evaporated to an oil. The oil is dissolved in methanol/methylene chloride and re-evaporated. The residue is triturated with acetone/ethyl acetate then filtered to obtain title compound as a white solid 92.1 mg (37.6percent). 1H-NMR (DMSOd6): .pound.5.92 (s); 3.72 (s, 3H); 2.34 (s, 3H); 2.26 (s, 3H) ppm.(l, 3, 5-trimethyl-lH-pyrazol-4-yl)boronic acid (33 mg, 0.21 mmol), the product from Preparative Example 5A (50 mg, 0.18 mmol), K3PO4 (133 mg, 0.63 mmol), 1, 2- dimethoxyethane (2.4 mL), H20 (0.6 mL) and PdChtdppf) (6.5 mg, 8.9 muetaiotaomicron) were added into a 10 mL round bottom flask and the mixture was refluxed under N2 for 18 h. Additional PdCl2(dppf) (4 mg, 5.4 mupiiotaomicron) and K3P04 (118 mg, 0.56 mmol) were added and the mixture was refluxed for additional 12 h. Then, another portion of PdCbidppf) (4 mg, 5.4 mutauetaomicron) was added and the mixture was refluxed for additional 10 h. The solvent was evaporated and the residue was loaded on silica gel and purified by column chromatography (EtOAc/hexane; from 1 :1 to 2:1) and then by preparative TLC (CH2Cl2/MeOH; 15:1) to yield the product as a colorless wax (5 mg, 8 %). NMR (500 MHz, CDC13) delta 8.99 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J = 8.5, 1.7 Hz, 1H), 7.94 - 7.88 (m, 2H), 7.88 - 7.82 (m, 2H), 7.54 - 7.44 (m, 2H), 7.35 (d, J - 8.6 Hz, 1H), 3.85 (s, 3H), 2.59 (s, 3H), 2.51 (s, 3H). i3C NMR (126 MHz, CDCI3) S 150.7, 147.0, 145.9, 145.8, 145.3, 138.1, 133.9, 132.9, 128.4, 128.3, 128.2, 127.8, 126.4, 126.3, 126.0, 124.7, 121.6, 119.2, 118.9, 118.8, 36.1, 13.7, 11.2. HRMS (APCI): calcd. for C23H19N3O [M+H]+ = 354.1601 ; found M+H]+ = 354.1599.General procedure: A solution of potassium carbonate (41.5 mg, 0.30 mmol) in water (0.5 mL) was added to a mixture of 2-(4-bromophenyl)-4-hydroxy-1, 6-naphthyridine-3-carbonitrile (33 mg, 0.1 mmol) and the corresponding bromoaryl reagent (0.11 mmol) in a microwave vial, followed by addition of a solution of 1, 1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (6.5 mg, 8.9 mumol) in acetonitrile (0.5 mL). The mixture was heated by microwave for 30 min to 150°C. The mixture was concentrated i. vac. The residue was dissolved in 1 mL of DMSO, filtered, and purified by HPLC. The reaction was conducted in 0.1 mmol scale unless indicated differently.Example 28: Preparation of N-[3-amino-4~(l, 3, 5-trimethylpyrazol-4-yl)phenyl](4- chlorophenyl)carboxamide (77):; Preparation of 4-(l, 3, 5-trimethylpyrazol-4-yl)benzene-l, 3-diamine (76):; The boronic acid 73 (236 mg, 1 mmol) and 74 (296 mg, 1.2 mmol) was dissolved in 5mL dimethoxyethane and 5 mL EtOH. The 2 ml of 2 M Na2C03 was added and the mixture was bubbled with Ar for 1 min before add Pd(Ph3P)4 (116 mg, 0.1 mmol). The reaction was heated at 110 °C for 0.5 h under the microwave irradiation. The reaction mixture was worked-up with EtOAc extraction and product was purified by flash column and afforded 75 as yellow solid. The compound 75 was transferred to 76 (119 mg, 55percent) using hydrogenation.

(1,3,5-Trimethylpyrazol-4-yl)boronic Acid is an intermediate used in the synthesis of potent and selective phosphodiesterase 10A inhibitor.

Molecular Weight:153.98
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:154.0913578
Monoisotopic Mass:154.0913578
Topological Polar Surface Area:58.3
Heavy Atom Count:11
Complexity:145
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes