Pyrazole-4-boronic acid pinacol ester

Off-white to tan powder

1 -( 1 -Ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl- 1 , 3, 2-dioxaborolan-2-yl)-l H-pyrazole (60.00 g, 224 mmol) is combined with CPME (120 mL) and 2, 3-dimethylbutane-2, 3-dtol (26.49 g, 224 mmol). The reaction is cooled to 5-10 °C then a solution of anhydrous HQ in CPME (3.1 M, 86.8 mL, 269 mmol) is added over 15 minutes, followed by additional CPME (15 mL). The reaction is stirred at 20-25 °C and monitored for completion. After 7 hours, additional HCI solution (3 mL, 9.3 mmol) is added to the reaction and stirring is continued for an additional 15 hours to give 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)-l H-pyrazole hydrochloride salt, which is not isolated.mL) is added over 10 minutes. The reaction mixture temperature increases to 20 °C following the addition. Additional CPME (10 mL) is added and the reaction mixture is stirred for 15 minutes then cooled in an ice bath. After 3 hours the reaction mixture is filtered and the solid (triethylamine hydrochloride) is washed with cold CPME (3 x 60 mL). The filtrate and washes are combined to give 426 g of solution containing 102, 3 mg of 4- (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazo]e/g solution (total 8.15 g, 94percent )yield of 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyTazole) which is used directly in the next step.4-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (1) [0166] To a mixture of 2, 3-dimethylbutane-2, 3-diol (25.0 kg, 211.6 mol) and 1-(1-ethoxyethyl)-4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (24, 55.0 kg, 206.7 mol) in 1, 2-dichloroethane (750 kg) was slowly added a solution of HCl in MTBE (25.0 kg, 20-30percent of HCl) at 0-5° C. The resulting reaction mixture was then stirred at 10-20° C. for 3-5 hours. After the selective deprotection reaction was complete as monitored by HPLC (1: below 1percent), the reaction mixture was degassed and refilled with nitrogen before being cooled to −15° C. The cooled reaction mixture was then added triethylamine (TEA, 30.0 kg, 296.5 mol) to adjust pH to 7-8. The mixture was then gradually warmed to ambient temperature before being treated with water (150 kg). The two phases were separated and the organic layer was washed with brine (60 kg) and dried over sodium sulfate (NaIn the reaction kettle, adding tetrahydrofuran 4.5 kg and 1 - BOC - 4 - brompyrazole (2.01 kg, 9.2 µM), stirring 0.5 hours, cooling to -20 °C, maintain -10 °C -0 °C dropwise 3.2molBu3MgLi [preparation method: 1.0eq butyl magnesium chloride in -10 °C -0 °C lower drop by adding 2.0 equivalent butyl lithium in], TLC detection reaction, maintain the exchange completion -10 °C -0 °C dropwise dimethylamine fundamental frequency that mellow boron ester (1.61 kg, 9.4 µM) dissolved in 1 kg of the mixed solution in tetrahydrofuran, the completion of the dropping, thermal insulation 2 hours, natural heating stirring overnight. The control temperature of not more than 30 °C after adding glacial acetic acid, after detecting the protecting group removal, stop stirring filtration, the mother liquor recovered, solid add triethylamine (1.01 kg, 10 µM) and ethyl acetate 8 kg after, heating to reflux reaction, the proportion of internal standard detecting product is not increased when, after lowering the filtering, the filtrate obtained after the distillation is a kind of white solid, by adding heptane cooling to 0 °C beating, filtering, 50 - 60 °C vacuum drying to obtain white solid pyrazole -4 - boric acid frequency that alcohol ester 1.36 kg, GC: 99.1percent, HNMR consistent with the literature value, yield 76percent.In the reaction kettle, add 2 - methyl tetrahydrofuran 4.5 kg and 1 - BOC - 4 - iodine pyrazole (2.65 kg, 9.0 µM), stirring 0.5 hours, cooling to -20 °C, maintain -10 °C -0 °C dropwise 2.95 µM Bu3MgLi [preparation method: 1.0eq isopropyl magnesium chloride in -10 °C -0 °C lower drop by adding 2.0 equivalent butyl lithium in], TLC detection reaction, maintain the exchange completion -10 °C -0 °C dropwise dimethylamine fundamental frequency that mellow boron ester (1.57 kg, 9.2 µM) dissolved in 1 kg of the mixed solution in tetrahydrofuran, the completion of the dropping, thermal insulation 2 hours, natural heating stirring overnight. The control temperature of not more than 20 °C hydrogen chloride gas, after detecting the protecting group removal, stop stirring filtration, the mother liquor recovered, solid add triethylamine (1.01 kg, 10 µM) and ethyl acetate 10 kg after, heating to reflux reaction, the proportion of internal standard detecting product is not increased when, after lowering the filtering, the filtrate obtained after the distillation yellow solid, adding hexane cooling to 0 °C beating, filtering, 50 - 60 °C vacuum drying to obtain white solid pyrazole -4 - boric acid frequency that alcohol ester 1.38 kg, GC: 99.5percent, HNMR consistent with the literature value, yield 79percent.4-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (17).; A flask equipped with a mechanical stirrer, nitrogen inlet, addition funnel and thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (15, 225.1 g, 0.85 mol) and THF (2200 mL). This mixture was cooled to -6° C. in an ice/salt/brine bath and isopropyl magnesium chloride (2 M in THF, 510 ml, 1.02 mol, 1.2 equiv) was added at a rate such that the temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was added 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (isopropylpinacolborate, 16, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about 1/2 of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to room temperature over 1 hr and stirred at room temperature for an additional 1 hr. The reaction was cooled to 6° C. and saturated aqueous ammonium chloride solution (2.2 L) was added with a temperature increase to 25° C. The mixture was stirred for 5 minutes before being diluted with toluene (10 L). The layers were separated (a large amount of solid is present in the aqueous layer) and the organic layer was sequentially washed with water (6.x.2.2 L), brine (2.x.2.2 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Residual toluene was co-evaporated with heptane to afford 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (17, 90.3 g, 164.9 g theoretical, 54.8percent) as a white solid. For 17: 4-(4, 4, 5, 5-Tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (1) [0161] A flask equipped with a mechanical stirrer, a nitrogen inlet, an addition funnel and a thermowell was charged with 1-trimethylsilyl-4-iodopyrazole (225.1 g, 0.85 mol) and THF (2200 mL) at ambient temperature. This mixture was cooled to approximately −6° C. in an ice/salt/brine bath before a solution of isopropyl magnesium chloride in THF (2 M solution in THF, 510 mL, 1.02 mol, 1.2 equiv) was added at a rate such that the internal temperature did not exceed 0° C. The extent of metal/halogen exchange was monitored by GC and was found complete after about 10 min. To the orange brown solution was then added 2-isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (isopropylpinacolborate, 347 mL, 1.7 mol, 2.0 equiv) slowly at first keeping the temperature below 0° C. and then fairly rapidly after about half of the compound was added allowing the temperature to reach 5° C. (the reaction becomes quite thick and then thins out slowly). The reaction is then stirred at 0° C. for 10 min before being warmed to ambient temperature over 1 h and stirred at ambient temperature for an additional 1 h. The reaction mixture was cooled to approximately 6° C. and the saturated aqueous ammonium chloride solution (NHUnder a nitrogen atmosphere, 7.35 g of 1-H-4-bromopyrazole, 14.0 g of diboronic acid pinacol ester, 6.0 g of potassium acetate, 2.15 g of tetrabutylammonium bromide, 0.1 g were placed in a 500 ml four-necked flask. Pd(PPh3)2Cl2, and 100 ml of 1, 4-dioxane was added thereto, and the mixture was stirred under reflux with heating for 12 hours, and was subjected to HPLC. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was filtered under reduced pressure.Swirled white product 8.8g, Yield 94.0percent, HPLC 98.4percent.

4-Pyrazoleboronic Acid Pinacol Ester is used in the preparation of Rho kinase (ROCK) inhibitors as wella s other biologically active compounds.

Molecular Weight:194.04
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:194.1226579
Monoisotopic Mass:194.1226579
Topological Polar Surface Area:47.1
Heavy Atom Count:14
Complexity:217
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes