tert-Butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate

To a solution of tert-butyl 4-(4-iodo-lH-pyrazol-l-yl)piperidine-l -carboxylate (1.00 g, 2.650 mmol) in DMSO (11 mL) were added 4, 4, 4The compoundTert-Butyl 4- (4-iodo-1H-pyrazol-1- yl) nicardine- 1 -carboxylate (1.00 g, 2.650 mmol)Dissolved in DMSO (llmL)Then, bis (pinacolato) diboron (942.5 mg, 3.710 mmol)And CH3C00K (1.04 g, 10.60 mmol), After pumping gas (N2) three times, Pd (PPh3) 2Cl2 (93.0 mg, 0.130 mmol) was added.After the reaction was stirred at 80 ° C for 2 hours, The mixture was cooled to room temperature and filtered off with suction. The filtrate was washed with brine (100 mL × 3), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (v / v) = 5/1) The title compound was obtained as a white solid (878.6 mg, 87.9percent).Bis(pinacolato)diboron (14.2 g, 55.9 mmol, 1.4 eq) and potassium acetate (15.8 g, 161 mmol, 4.0 eq) were added to a solution of tert-butyl 4-(4-iodo-lH-pyrazol-l-yl)piperidine-l- carboxylate (15.0 g, 39.8 mmol, 1.0 eq) in dimethylsulfoxide (DMSO) (173 ml) sequentially under nitrogen. Pd(PPhStep 2) tert-butyl 4-(4-(4, 4, 5, 5-tetramethyl-L3, 2-dioxaborolan-2-yl)-lH-pyrazol-l-yl) piperidine- 1 -carboxylate To a solution of 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2, 2'-bi(l, 3, 2-dioxaborolane) (281.6 mg, 1.11 mmol) in DMSO (6 mL) was added tert-butyl 4-(4-iodo-lH-pyrazol-l-yl) piperidine- 1 -carboxylate (298.8 mg, 0.792 mmol), CHThe compound boranoic acid pinacol ester (281.6 mg, 1.11 mmol) was dissolved in DMSO (6 mL).Then, under the protection of nitrogen, the reaction liquid is sequentially added.4-(4-Iodo-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (298.8 mg, 0.792 mmol), Potassium acetate (310.5 mg, 3.17 mol) and Pd(PPh3)2Cl2 (33.36 mg, 0.0475 mmol).The reaction solution was stirred at 80 ° C for 3 hours, then cooled to room temperature and then quenched with water (20 mL).The mixture was extracted with ethyl acetate (35 mL×2).The combined organic phases were washed with brine (30 mL x 2).Drying over anhydrous Na2SO4.(PE/EtOAc(v/v)=2/1)Purification to give the title compound as a white solid(250 mg, 83percent).tert-butyl-4-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (4) Bis(pinacolato)diboron (1.4 eq., 134 g, 0.52 mol) and potassium acetate (4 eq., 145 g, 1.48 mol) were added sequentially to a solution of compound 3 (140 g, 0.37 mol) in 1.5 L of DMSO. The mixture was purged with nitrogen several times and dichlorobis(triphenylphosphino) palladium (II) (0.05 eq., 12.9 g, 0.018 mol) was then added. The resulting mixture was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of celite and washed with EtOAc. The filtrate was washed with saturated NaCl (500 mL.x.2), dried over NaBis(pinacolato)diboron (1.4 eq., 134 g, 0.52 mol) and potassium acetate (4 eq., 145 g, 1.48 mol) were added sequentially to a solution of compound 23-1a (140 g, 0.37 mol) in 1.5 L of DMSO. The mixture was purged with nitrogen several times and dichlorobis(triphenylphosphino) palladium (II) (0.05 eq., 12.9 g, 0.018 mol) was then added. The resulting mixture was heated at 80 C. for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of celite and washed with EtOAc. The filtrate was washed with saturated NaCl (500 mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 5percent EtOAc in hexanes) to give compound 23-1 b as a white solid (55 g, 40percent).Bis(pinacolato)diboron (1.4 eq., 134 g, 0.52 mol) and potassium acetate (4 eq., 145 g, 1.48 mol) were added sequentially to a solution of compound 23-1 a (140 g, 0.37 mol) in 1. 5 L of DMSO. The mixture was purged with nitrogen several times and dichlorobis(triphenylphosphino) palladium (II) (0.05 eq., 12.9 g, 0.018 mol) was then added. The resulting mixture was heated at 80°C for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of celite and washed with EtOAc. The filtrate was washed with saturated NaCI (500 mL x 2), dried over Natert-butyl-4-[4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-d ioxaborolan-2-yl)-1 H-yrazol- 1- yl1ieridine-1 -carboxylate (4)Bis(pinacolato)diboron (1 .4 eq., 134 g, 0.52 mol) and potassium acetate (4 eq., 145 g, 1.48 mol) were added sequentially to a solution of compound 3 (140 g, 0.37 mol) in 1. 5 L of DMSO. The mixture was purged with nitrogen several times and dichlorobis(triphenylphosphino) palladium (II) (0.05 eq., 12.9 g, 0.018 mol) was then added. The resulting mixture was heated at 80°C for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of Celite® and washed with EtOAc. The filtrate was washed with saturated NaCI (500 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 5percent EtOAc in hexanes) to give compound 4 as a white solid (55 g, 40percent).Bis(pinacolato)-diboron (1.4 eq., 134 g, 0.52 mol) and potassium acetate (4 eq., 145 g, 1.48 mol) were added sequentially to a solution of compound 3 (140 g, 0.37 mol) in 1. 5 L of DMSO. The mixture was purged with nitrogen several times and dichlorobis(triphenylphosphino) palladium (II) (0.05 eq., 12.9 g, 0.018 mol) was then added. The resulting mixture was heated at 80°C for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of Celite® and washed with EtOAc. The filtrate was washed with saturated NaCl (500 ml. x 2), dried over Natert-butyl-4-[4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]biperidine-1-carboxylate (4) 1.3 kg of compound (CZT-8) was dissolved in 6.5 liters of dry tetrahydrofuran, Nitrogen protection, Down to -10 degrees, A solution of 3.2 liters of 2N isopropylmagnesium chloride in tetrahydrofuran was slowly added, After the completion of heating to 20 degrees, Add 1.0 publicjinEven boronic acid6.5 liters of tetrahydrofuran solution, Control the temperature between 20 degrees to 30 degrees, After the completion of the reaction at room temperature for 9 hours.Add 9 liters of ethyl acetate and 10 liters of water, Stir for 2 hours, Dispensing, Dried and concentrated.Recrystallization gave 1.2 kg of a white solid(CZT-9). Yield 81percentC. A mixture of tert-butyl 4-(4-bromo- lH-pyrazol- 1 -yl)piperidine- 1-carboxylate (20.0 g, 0.61 mmol), 4, 4, 5, 5-tetramethyl-2-(4, 4, 5, 5-tetramethyl-l, 3, 2- dioxaborolan-2-yl)-l, 3, 2-dioxaborolane (30.8 g, 0.12 mmol) and potassium acetate (17.8 g, 0.18 mol) in 50 mL of dimethyl sulfoxide was purged with nitrogen gas for 10 min. After the addition of [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.55 g, 4.85 mmol), the mixture was purged with nitrogen gas for another 10 minutes, heated at 80 °C overnight under nitrogen atmosphere and filtered through celite and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (2 x 200 mL). The organic layer was dried over anhydrous sodium sulfate. After filtration and removal of the solvent, the residue was purified by column chromatograph eluted with hexane to afford an oil which was recrystallized from hexane to afford tert-butyl 4-(4-(4, 4, 5, 5- tetramethyl- 1 , 3 , 2-dioxaborolan-2-yl)- lH-pyrazol- 1 -yl)piperidine- 1 -carboxylate as a white solid in 44percent yield (10 g). 1H NMR (400 MHz, CDC1d) tert-Butyl 4-(4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine- 1 -carboxylateTo a (NTo a (NStep A: Step 2: Compound 96-2 (134 mg, 0.5 mmol) and cesium carbonate (245 mg, 0.75 mmol) was added to a solution of 4-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-pyrazole (97 mg, 0.5 mmol) in DMF, the reaction mixture was stirred at 90° C. for 12-16 h, and the reaction solution was cooled to room temperature, diluted with water, extracted with EA, and the combined organic phase was washed with brine, dried over anhydrous NaStep B: ferf-butyl 4-[4-(4Tert-butyl-1-carboxylate 4-methanesulfonyloxy piperidine (2.00 g, 7.16 mmol)Was added to a solution of 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1.50 g, 7.70 mmol) andCesium carbonate (3.50 g, 11.00 mmol)In N, N-dimethylformamide (15 mL)The reaction solution was reacted at 100 ° C for 24 h, Cooled to room temperature, Extracted with water (100 mL) and ethyl acetate (100 mL)The aqueous phase was extracted with ethyl acetate (100 mL x 3), the organic phases were combined and washed with saturated brine (100 mL x 3)Dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated solution was passed through a column (petroleum ether / ethyl acetate (v / v) = 2/1)To give 950 mg of a colorless solid in a yield of 35.2percent.Step 2: tert-butyl 4-[4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l- carboxvlate\ S; To a solution of 4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-pyrazole (4.12 g, 21.2 mmol, Aldrich, Cat. 525057) in N, N-dimethylformamide (20 mL) was added sodium hydride (1.78 g, 44.5 mmol) at 0 To tert-butyl 4-hydroxypiperidine-1-carboxylate (402 mg, 2.0 mmol) in methylene chloride (20 mL) and triethylamine (303 mg, 3.0 mmol) at 4° C. was added methanesulfonyl chloride (274 mg, 2.4 mmol) drop-wise. To a stirred solution of tert-butyl 4-(4-bromo-lH-pyrazol-1-yl)piperidine-1-carboxylate (25.0g, 0.076 mole) in THF ( 500 ml) at- 70°C was added BuLi 1.6 Min Hexane solution (10 56.75 ml, 0.091 mole) dropwise followed by addition of 2-Isopropoxy-4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (18.52 ml , 0.091 mole) at same temperature. Reaction mixture wasstirred at -70°C for lh then warmed to room temperature and continued stirring for 2h atroom temperature. Reaction mixture was quenched with ammonium chloride solution (25 ml)water (500 ml), and ethyl acetate (750 ml) was added to reaction mixture, followed by15 extraction with ethylacetate (100 ml x 2). The combined organic layer was washed withbrine, concentrated under vacuum to get crude product which was crystallized from nHeptaneto give pure title compound.Yield: 51 percent (14.7g)HPLC Purity: 96.7percent20 MS (m/z): 378 (M + 1) 1HNMR (400 MHz, CDCh) 8: 7.81 (s, lH), 7.75 (s, lH), 4.27 (m, 3H), 2.9 (m, 2H), 2.14 (m, 2H), 1.91 (m, 2H), 1.49 (s, 9H), 1.33 (s, 12 H).In a 250 ml reaction flask equipped with a magnetic stir and refluxing device, followed by the addition of N-Boc-4-piperidine hydrazine crude, 5.2 grams of 2-chloro-malondialdehyde, 0.4 g of boron trifluoride diethyl ether and 100 ml of toluene, heated to reflux dehydration condensation, detection reaction is no longer done. under nitrogen protection, after the reaction solution is cooled, the solvent is dried. Add 50 ml of absolute ethanol, 6.0 g tetrahydroxy diboron, 17.1 g of diisopropylethylamine, 0.24 g of NiCl2 (dppp) and 0.23 g of PPh3 were added and, after stirring, 80 °C for 4 hours, After cooling the generated inorganic salt, the filtrate is evaporated to dryness, after adding 80 ml of ethyl acetate, washed, the organic layer was added with 7.2 grams of pinacol, after the reaction is complete, washed, organic layer of diatomite filter steaming, N-hexane / ethyl acetate (1:10), after filtration, 10.1 g of a white crystalline solid product was obtained, Yield 61percent, GC: 98.5percent, HNMR (400 MHz, CDCl3): 7.79 (S, 1H), 7.73 (s, 1H), 4.28 (m, 3H), 2.88 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.47 (s, 9H) S, 12H).In a 250 ml reaction flask equipped with a magnetic stir and refluxing device, followed by the addition of N-Boc-4-piperidine hydrazine crude, 6.4 grams of 2-bromomalondialdehyde, 0.5 g of boron trifluoride diethyl ether with 120 ml of toluene, heated to reflux dehydration condensation, detection reaction is no longer done. under nitrogen protection, after the reaction solution is cooled, the solvent is dried. Add 50 ml of absolute ethanol, 5.8 g of tetrahydroxy diboron, 16.5 g of diisopropylethylamine, 0.23 g of NiCl2 (dppp) and 0.22 g of PPh3 were added and, after stirring, room temperature reaction for 12 hours, Filter out the resulting inorganic salt, The filtrate is evaporated to dryness, After adding 80 ml of ethyl acetate, washed, the organic layer was added with 6.0 grams of pinacol, after the reaction is complete, washed, organic layer of diatomite filter steaming, N-hexane / acetone (1: 9) and filtered to give 8.8 g of a white solid product in 55percent yield, GC: 98.2percent, HNMR (400 MHz, CDCl3): 7.80 (s, 1H), 7.72 (s, 4.28 (m, 3H), 2.87 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.46 (s, 9H), 1.32 (s, 12H).

Molecular Weight:377.3
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:4
Exact Mass:377.2485867
Monoisotopic Mass:377.2485867
Topological Polar Surface Area:65.8
Heavy Atom Count:27
Complexity:540
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes