* 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.
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere
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 4,4,4,,4,,5,5,5*,5*-octamethyl-2,2,-bi(l,3,2- dioxaborolane) (942.5 mg, 3.710 mmol) and CH3COOK (1.04 g, 10.60 mmol) sequentially. The mixture was degassed and charged with N2 several times, then Pd(PPh3)2Cl2 (93.0 mg, 0.130 mmol) was added. The resulted mixture was stirred at 80 °C for 2 hours, then cooled to rt, and filtered through a pad of celite. The filtrate was washed with brine (100 mL x 3), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (878.6 mg, 87.9percent). MS (ESI, pos. ion) m/z: 378.0 (M+l).
87.9%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere
The 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).
83%
With potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere
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(PPh3)4 (3.98 g) was then added. The reaction was heated at 8O0C for 2 hours. The mixture was cooled to room temperature (r.t.), filtered through celite and washed with ethyl acetate. The filtrate was washed with brine twice, dried, and chromatographed (5percent-30percent of ethyl acetate in hexanes) to give a yellowish solid, 12.5 g, in 83percent yield.
83%
at 80℃; for 3 h; Inert atmosphere
Step 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), CH3COOK (310.5 mg, 3.17 mol) and Pd(PPh3)2Cl2 (33.36 mg, 0.0475 mmol) sequentially under nitrogen atmosphere. The mixture was stirred at 80 °C for 3 hours, then cooled to rt, quenched with H20 (20 mL) and extracted with EtOAc (35 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a white solid (250 mg, 83percent). MS (ESI, pos. ion) m/z: 378.0 (M+l).
83%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In dimethyl sulfoxide at 80℃; for 3 h; Inert atmosphere
The 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).
40%
With potassium acetate In dimethyl sulfoxide
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*2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluding with 5percent EtOAc in hexanes) to give compound 4 as a white solid (55 g, 40percent).
40%
With potassium acetate In dimethyl sulfoxide at 80℃; for 2 h;
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 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).
40%
With potassium acetate In dimethyl sulfoxide at 80℃; for 12 h;
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 23-1a (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).
40%
With potassium acetate In dimethyl sulfoxide at 80℃; for 2 h;
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 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).
40%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere
tert-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).
40%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere
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 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).
40%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In dimethyl sulfoxide at 80℃; for 2 h; Inert atmosphere
tert-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]biperidine-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*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).
With isopropylmagnesium chloride In tetrahydrofuran at -10 - 30℃; for 9 h; Inert atmosphere; Large scale
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 81percent
44%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 0.166667 h; Inert atmosphere
C. 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, CDC13) δ 7.79 (s, 1H), 7.72 (s, 1H), 4.32-4.13 (m, 3H), 2.95-2.80 (m, 2H), 2.15-2.05 (m, 2H), 1.93-1.82 (m, 2H), 1.47 (s, 9H), 1.31 (s, 12H).
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 12 h; Inert atmosphere; Sealed tube
d) tert-Butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine- 1 -carboxylateTo a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- (1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10 percent ethyl acetate in hexane) to give the product in 59 percent yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3[(M+H]+ (RT: 1.83 min).
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 110℃; for 12 h; Inert atmosphere
To a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10percent ethyl acetate in hexane) to give the product in 59percent yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3 [(M+H]' (RT: 1.83 min).
Reference：
[1] Patent: CN106317024, 2017, A, . Location in patent: Paragraph 0062; 0063; 0064; 0065'; 0066
[2] Patent: WO2015/81257, 2015, A2, . Location in patent: Page/Page column 81-82
[3] Patent: WO2010/48131, 2010, A1, . Location in patent: Page/Page column 54-55
[4] Patent: WO2013/53983, 2013, A1, . Location in patent: Page/Page column 31; 32
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[6] Patent: US2015/11548, 2015, A1, . Location in patent: Paragraph 0137
[7] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
3
[ 141699-59-4 ]
[ 877399-74-1 ]
Yield
Reaction Conditions
Operation in experiment
29%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1 h; Stage #2: at 100℃;
Step A: Preparation of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate: A 1 L, 1-neck flask was charged with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20.0 g, 103 mmol), and DMF (250 mL). The reaction mixture was cooled to 0° C. and NaH (2.73 g, 108 mmol) (95percent) was added. The reaction mixture was stirred at 0° C. for 1 hour. tert-Butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (30.2 g, 108 mmol; prepared as in WO 06/021881) was added and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with EtOAc, and the organic layer washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified on a Biotage 40S column eluding with EtOAc/Hexane 10percent to 25percent EtOAc. The product was isolated as a white solid (11.3 g, 29percent).
Reference：
[1] Patent: US2007/238726, 2007, A1, . Location in patent: Page/Page column 124
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4092 - 4108
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[4] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1018 - 1026
[5] Journal of Medicinal Chemistry, 2013, vol. 56, # 6, p. 2294 - 2310
[6] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[7] Patent: WO2013/17989, 2013, A1,
[8] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[9] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[10] Patent: WO2014/89280, 2014, A1,
[11] Patent: EP2764866, 2014, A1,
[12] Patent: WO2014/193647, 2014, A2,
[13] Patent: US2015/11548, 2015, A1,
[14] Patent: WO2015/81257, 2015, A2,
[15] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[16] Patent: CN106317024, 2017, A,
[17] Patent: CN104119331, 2018, B,
[18] Patent: CN106831720, 2017, A,
[19] Patent: US2016/206608, 2016, A1,
[20] Patent: WO2013/53983, 2013, A1,
4
[ 269410-08-4 ]
[ 141699-59-4 ]
[ 877399-74-1 ]
Yield
Reaction Conditions
Operation in experiment
44%
With caesium carbonate In N,N-dimethyl-formamide at 90℃; Inert atmosphere
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 Na2SO4 and concentrated to give the crude product which was purified by Combi-flash column chromatography [PE:EA=100:0-50:50] to give the title compound 96-3 (2 g, yield 44percent), MS m/z (ESI): 378.2[M+1]+.
39%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h;
Step B: ferf-butyl 4-[4-(4l4l5l5-tetramethyl-1 l3l2-dioxaborolan-2-yl)-1 -/-pyrazol-1-yllpiperidine- 1-carboxylate (Title Compound)A mixture of terf-butyl 4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (7.33 g, 26.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.09 g, 26.2 mmol), and Cs2C03 (12.8 g, 39.3 mmol) in DMF (50 mL) was heated at 100 °C for 24 h. The mixture was cooled to RT and diluted with water (100 mL) and extracted with EtOAc (3 x 60 mL). The combined organic phases were washed with water (3 x 50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. The residue was purified by flash chromatography (20 to 40percent ethyl acetate:hexanes) to afford 3.84 g (39percent) of the title compound as a white solid. 1H NMR (400 MHz, CDCI3): 57.81 (s, 1H), 7.74 (s, 1H), 4.17-4.35 (m, 3H), 2.89 (m, ^-.-12 Hz, 2H), 2.14 (d, =14.65 Hz, 2H), 1.90 (qd, J=12.25, 4.42 Hz, 3H), 1.48 (s, 9H), 1.33 (s, 12H); MS (ESI): 379.15 [M+H]+; HPLC tR = 3.17 min.
35.2%
With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 24 h;
Tert-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.
28.74%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: at 90℃;
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 0C. The resulting solution was stirred at r.t. for one hour, and then tert-butyl 4- [(methylsulfonyl)oxy]ρiρeridine-l-carboxylate (6.3 g, 22 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 9O0C overnight. Then the reaction mixture was cooled to r.t., quenched with water, 0 and extracted with AcOEt. The organic layer was washed with NaHCO3 aqueous solution and brine successively, dried with MgSO4, and concentrated. The residue was purified by flash column chromatography on a silica gel column using 30percent ethyl acetate in hexane as eluent to afford the desired compound (2.30 g, 28.74percent). LCMS (M+H)+: m/z = 378.4.
884 mg
With caesium carbonate In N,N-dimethyl-formamide at 100℃;
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. The reaction was brought to ambient temperature and was stirred for 1 hour. The reaction mixture was concentrated in vacuo and diluted in diethyl ether (20 mL). The solution was washed with 1N hydrochloric acid (3 mL), water (3 mL), and saturated sodium bicarbonate (3 mL). The organics were dried (sodium sulfate) and concentrated in vacuo to afford tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate in quantitative yield.quantitative yield. The product was used directly in the next step without thrther purification. A mixture of 4-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl-1H-pyrazole (427 mg, 2.2 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (2.0 mmol), and cesium carbonate (847 mg, 2.6 mmol) in DMF (5 mL) was stirred at 100° C. overnight. The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc (3x). The combined organic layers were dried over Na2S04, filtered and concentrated to provide crude pale yellow oil 884 mg. MS (mlz): 378 (M+H).
Reference：
[1] Patent: US2017/8889, 2017, A1, . Location in patent: Paragraph 0309; 0311
[2] Patent: WO2011/100502, 2011, A1, . Location in patent: Page/Page column 37
[3] Patent: CN106336413, 2017, A, . Location in patent: Paragraph 0509; 0510; 0511; 0512
[4] Patent: WO2010/75270, 2010, A1, . Location in patent: Page/Page column 68-69
[5] Patent: WO2011/143646, 2011, A1, . Location in patent: Page/Page column 41-42
[6] Patent: US2012/165305, 2012, A1, . Location in patent: Page/Page column 29
[7] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299
[8] Patent: US2014/121200, 2014, A1, . Location in patent: Paragraph 0333; 0334
[9] Patent: WO2010/59771, 2010, A1, . Location in patent: Page/Page column 30-31
5
[ 877399-50-3 ]
[ 61676-62-8 ]
[ 877399-74-1 ]
Yield
Reaction Conditions
Operation in experiment
51%
With n-butyllithium In tetrahydrofuran; hexane at -70 - 20℃; for 3 h;
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).
Reference：
[1] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1018 - 1026
[2] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[3] Patent: CN107417603, 2017, A, . Location in patent: Paragraph 0021
7
[ 76-09-5 ]
[ 877399-73-0 ]
[ 877399-74-1 ]
Reference：
[1] Patent: CN106831720, 2017, A, . Location in patent: Paragraph 0016; 0018; 0019
8
[ 76-09-5 ]
[ 13675-18-8 ]
[ 36437-19-1 ]
[ 1196486-69-7 ]
[ 877399-74-1 ]
Yield
Reaction Conditions
Operation in experiment
10.1 g
Stage #1: With boron trifluoride diethyl etherate In tolueneReflux; Inert atmosphere Stage #2: With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); N-ethyl-N,N-diisopropylamine; triphenylphosphine In ethanol at 80℃; for 4 h; Inert atmosphere Stage #3: Inert atmosphere
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).
Stage #1: With boron trifluoride diethyl etherate In tolueneReflux; Inert atmosphere Stage #2: With 1,3-bis[(diphenylphosphino)propane]dichloronickel(II); N-ethyl-N,N-diisopropylamine; triphenylphosphine In ethanol at 20℃; for 12 h; Inert atmosphere Stage #3: Inert atmosphere
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).
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
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 4,4,4,,4,,5,5,5*,5*-octamethyl-2,2,-bi(l,3,2- dioxaborolane) (942.5 mg, 3.710 mmol) and CH3COOK (1.04 g, 10.60 mmol) sequentially. The mixture was degassed and charged with N2 several times, then Pd(PPh3)2Cl2 (93.0 mg, 0.130 mmol) was added. The resulted mixture was stirred at 80 C for 2 hours, then cooled to rt, and filtered through a pad of celite. The filtrate was washed with brine (100 mL x 3), dried over anhydrous Na2S04, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (878.6 mg, 87.9%). MS (ESI, pos. ion) m/z: 378.0 (M+l).
87.9%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
The 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, 87.9%).
83%
With potassium acetate;tetrakis(triphenylphosphine) palladium(0); In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
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(PPh3)4 (3.98 g) was then added. The reaction was heated at 8O0C for 2 hours. The mixture was cooled to room temperature (r.t.), filtered through celite and washed with ethyl acetate. The filtrate was washed with brine twice, dried, and chromatographed (5%-30% of ethyl acetate in hexanes) to give a yellowish solid, 12.5 g, in 83% yield.
83%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; at 80℃; for 3h;Inert atmosphere;
Step 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), CH3COOK (310.5 mg, 3.17 mol) and Pd(PPh3)2Cl2 (33.36 mg, 0.0475 mmol) sequentially under nitrogen atmosphere. The mixture was stirred at 80 C for 3 hours, then cooled to rt, quenched with H20 (20 mL) and extracted with EtOAc (35 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a white solid (250 mg, 83%). MS (ESI, pos. ion) m/z: 378.0 (M+l).
83%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 3h;Inert atmosphere;
The 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 Na 2SO 4.(PE/EtOAc(v/v)=2/1)Purification to give the title compound as a white solid(250 mg, 83%).
40%
With potassium acetate; In dimethyl sulfoxide;
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*2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluding with 5% EtOAc in hexanes) to give compound 4 as a white solid (55 g, 40%).
40%
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In dimethyl sulfoxide; at 80℃; for 2h;
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×2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes) to give compound 4 as a white solid (55 g, 40%).
40%
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In dimethyl sulfoxide; at 80℃; for 12h;
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 23-1a (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 5% EtOAc in hexanes) to give compound 23-1 b as a white solid (55 g, 40%).
40%
With potassium acetate;bis-triphenylphosphine-palladium(II) chloride; In dimethyl sulfoxide; at 80℃; for 2h;
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 80C 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 5% EtOAc in hexanes) to give compound 23-1 b as a white solid (55 g, 40%).
40%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
tert-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 80C 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 5% EtOAc in hexanes) to give compound 4 as a white solid (55 g, 40%).
40%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
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 80C 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 Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes) to give compound 4 as a white solid (55 g, 40%).
40%
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
tert-butyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]biperidine-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*2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 5% EtOAc in hexanes) to give compound 4 as a white solid (55 g, 40%).
155mg
With bis-triphenylphosphine-palladium(II) chloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 0.666667h;Sealed tube; Inert atmosphere;
In a sealed tube, to a degassed and stirred solution of fc/7-butyl 4-(4-iodo- 1 /7-pyrazol- l-yl)piperidine-l -carboxylate (step 1 intermediate) (500 mg, 1.32 mmol) in DMSO (10 mL) were added bis(pinacolato)diboron (503 mg, 1.98 mmol), dichlorobis(triphenylphosphine)palladium(II) (46 mg, 0.07 mmol) and potassium acetate (519 mg, 5.29 mmol) at RT. The mixture was purged with nitrogen for 10 min and heated at 80 C for 30 min. The reaction mixture was cooled to RT and diluted with water. The aqueous mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 155 mg of the desired product. 1 H NMR (400 MHz, DMSO-i/r.) d 1.16 (s, 12H), 1.41 (s, 9H), 1.74-1.80 (m, 2H), 1.96-2.01 (m, 2H), 2.86-2.92 (m, 2H), 3.98- 4.05 (m, 2H), 4.35-4.39 (m, 1H), 7.59 (s, 1H), 7.95 (s, 1H); ESI-MS ( m/z ) 378 (M+H)+.
With cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; at 60℃; for 4h;
etaATU (2.16 g) was added to a mixture of triethylamine (1.13 ml), 4-fluoro-l,2- diaminobenzene (0.72 g) and 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH- pyrazol-4-yl)pyrazine-2-carboxylic acid (2.1 g) in DMF (25 ml) at ambient temperature and was stirred for 2 hours. The reaction mixture was diluted with dilute aqueous sodium hydrogen carbonate solution. The precipiate was isolated by filtration and dried in a vacuum oven. The material so obtained was added to acetic acid (20 ml), and the resulting mixture was stirred and heated to 1100C for 3 hours. The solvent was then evaporated in vacuo and the residue was added to trifiuoroacetic acid (20 ml) and stirred at ambient temperature for 1 hour. The solvent was evaporated in vacuo and the crude product was purified by SCX ion exchange chromatography. The desired product was eluted from the column using 7M NetaVmethanol and the eluent was evaporated. There was thus obtained the title compound (3.05 g); NMR Spectrum: (DMSOd6) 1.91 (m, 2eta), 2.09 (d, 2H), 2.70 (t, 2H), 3.13 (d, 2H), 4.25 (m, IH), 7.08 (t, IH), 7.43 (brs, IH), 7.54 (s, IH), 7.68 (brs, IH), 8.10 (s, IH), 8.33 (s, IH), 8.47 (s, IH); Mass Spectrum: M+H+ 379; RT 2.16 min.The 3 -amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4- yl)pyrazine-2-carboxylic acid used as a starting material was prepared as follows :- l,r-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.245 g) was added to a mixture of caesium fluoride (18.85 g), <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (14.4 g) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine-l-carboxylate (30.4 g) in methanol (450 ml) at ambient temperature. The resulting mixture was stirred at 600C for 1 hour at which time a further portion of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate (15.0 g) was added and the resultant mixture was stirred for a further 3 hours at 600C. The reaction mixture was evaporated in vacuo and the residue was redissolved in <n="131"/>ethyl acetate (500 ml). The organic solution was washed twice with water (2 x 250 ml), dried with magnesium sulphate, filtered and evaporated in vacuo. The material so obtained was purified by flash silica chromatography on Flash 75 equipment, elution gradient 0 to 4% methanol in dichloromethane. Pure fractions were evaporated to dryness. There was 5 thus obtained methyl 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)-lH-pyrazol-4- yl)pyrazine-2-carboxylate (24.98 g); NMR Spectrum: (DMSOd6) 1.50 (s, 9H), 1.66 (s, 2H), 1.98 (m, 2H), 2.18 (d, 2H), 2.93 (t, 2H), 3.98 (s, 3H), 4.30 (m, IH), 6.37 (brs, 2H), 7.92 (s, IH), 7.95 (s, IH), 8.44 (s, IH); Mass Spectrum: M-H+ 401; RT 2.09 min.2M sodium hydroxide solution (8.70 ml) was added to a solution of methyl 3- i o amino-6-( 1 -( 1 -(tert-butoxycarbonyl)piperidin-4-yl)- 1 H-pyrazol-4-yl)pyrazine-2- carboxylate (3.5 g) in methanol (40 ml) and stirred at ambient temperature for 2 hours. The resultant solution was concentrated in vacuo until half of the methanol had been removed. Water (20 ml) was then added and the solution was acidified to pH4 by addition of 2M hydrochloric acid causing the product to precipitate. This material was filtered and dried is invacuo. There was thus obtained 3-amino-6-(l-(l-(tert-butoxycarbonyl)piperidin-4-yl)- lH-pyrazol-4-yl)pyrazine-2-carboxylic acid (3.25 g); NMR Spectrum: (DMSOd6) (DMSOd6) 1.45 (s, 9H), 1.82 (m, 2H), 2.06 (d, 2H), 2.95 (t, 2H), 4.07 (d, 2H), 4.40 (m, IH), 7.32 (brs, 2H), 8.07 (s, IH), 8.43 (s, IH), 8.67 (s, IH); Mass Spectrum: M-H+ 387; RT 1.86 min.
tetrakis(triphenylphosphine)palladium (0); In 1,4-dioxane; water; 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate;
Tetrakis(triphenylphosphine)palladium(0) (0.915 g) was added to a solution of <strong>[50735-34-7]methyl 2-amino-5-bromo-pyridine-3-carboxylate</strong> (3.66 g), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (6.57 g) and caesium carbonate (4.31 ml) in dioxane (150 ml) and water (38 ml) under an atmosphere of nitrogen. The resulting mixture was stirred at 80 C. for 2 hours, then evaporated to dryness and redissolved in ethyl acetate (200 ml). This mixture was washed with water (200 ml) and then saturated with brine (200 ml). The organic layer was dried over magnesium sulfate, filtered and then evaporated under reduced pressure. The residue was purified by flash silica chromatography (elution gradient 0 to 5% 7M methanolic ammonia in DCM). There was thus obtained methyl 2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxylate (2.99 g); Mass Spectrum: M+H+ 402.24; RT 1.78 min.
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium[ No CAS ]
[ 6966-01-4 ]
[ 877399-74-1 ]
nickel(II) chloride, nickel(II) bromide, bis(triphenylphosphine)nickel(II) chloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium[ No CAS ]
[ 1146950-60-8 ]
[ 1122520-91-5 ]
Yield
Reaction Conditions
Operation in experiment
With caesium fluoride; In methanol; dichloromethane; ethyl acetate;
The tert-butyl 4-[4-(5-amino-6-formyl-pyrazin-2-yl)pyrazol-1-yl]piperidine-1-carboxylate used as starting material was made as follows: 1,1'-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.245 g) was added to a mixture of caesium fluoride (18.85 g), <strong>[6966-01-4]methyl 3-amino-6-bromopyrazine-2-carboxylate</strong> (14.4 g) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (30.4 g) in methanol (450 ml). The resulting mixture was stirred at 60 C. for 1 hour at which time a further portion of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (15.0 g) was added. The resultant mixture was stirred for a further 3 hours at 60 C. The reaction mixture was concentrated under reduced pressure and redissolved in ethyl acetate (500 ml), then washed twice with water (2*250 ml). The organic extract was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The material so obtained was purified by flash silica chromatography on Flash 75 equipment, elution gradient 0 to 4% methanol in dichloromethane. There was thus obtained methyl 3-amino-6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxylate (24.98 g); Mass Spectrum: M-H+ 401; RT 2.09 min; NMR Spectrum: (DMSOd6) 8.44 (s, 1H), 7.95 (s, 1H), 7.92 (s, 1H), 6.37 (brs, 2H), 4.30 (m, 1H), 3.98 (s, 3H), 2.93 (t, 2H), 2.18 (d, 2H), 1.98 (m, 2H), 1.66 (s, 2H), 1.50 (s, 9H).
With isopropylmagnesium chloride; In tetrahydrofuran; at -10 - 30℃; for 9h;Inert atmosphere; Large scale;
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 81%
44%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 0.166667h;Inert atmosphere;
C. 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 44% yield (10 g). 1H NMR (400 MHz, CDC13) delta 7.79 (s, 1H), 7.72 (s, 1H), 4.32-4.13 (m, 3H), 2.95-2.80 (m, 2H), 2.15-2.05 (m, 2H), 1.93-1.82 (m, 2H), 1.47 (s, 9H), 1.31 (s, 12H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;
As shown in step 3-iii of Scheme 3, tert-butyl 4-(4-bromo-lH-pyrazol-l- yl)piperidine-l-carboxylate (Compound 1014, 10.52 g, 31.86 mmol), 4,4,5, 5-tetramethyl-2- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (9.71 g, 38.23 mmol), and potassium acetate (9.38 g, 95.58 mmol) were taken up in 105 mL of 1,4-dioxane. The mixture was flushed with nitrogen for 20 minutes and PdCl2(dppf) (1.3 g, 1.59 mmol) was added. The reaction was heated at 900C for 11 hours. The reaction was cooled to room temperature and filtered through a plug of Florisil, which was subsequently rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford a dark brown oil that was dissolved in hexanes and eluted through a second plug of Florisil with 1 :2 EtOAc/hexanes. The filtrate was concentrated under reduced pressure to give a tan oil, which was triturated with hexanes and stirred at 00C until a white precipitate formed. The precipitate was collected by vacuum filtration, washed with hexanes, and dried to afford 6.79 g of tert-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)piperidine- 1-carboxylate (Compound 1015).
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; Sealed tube;
d) tert-Butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yl)piperidine- 1 -carboxylateTo a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- (1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10 % ethyl acetate in hexane) to give the product in 59 % yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3[(M+H]+ (RT: 1.83 min).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 80℃; for 10h;Inert atmosphere;
General procedure: To a solution of 4-bromo-1-(oxan-4-yl)-1H-pyrazole 26a (1.00 g, 4.33 mmol) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.32 g, 5.19 mmol) in 10 mL of DMF was added potassium acetate (1.27 g, 12.98 mmol), followed by 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (177 mg, 0.22 mmol) under argon. The resulting mixture was stirred at 80 C for 10 h and then diluted with 40 mL of water. The mixture was extracted with EA (3 × 30 mL). The combined organic phase was washed with water (3 × 30 mL), brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA/PE, 1:4) to afford 25c as white solid in 68% yield.
5.4 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 12h;Inert atmosphere;
To a (N2 bubbling) solution of the compound of Intermediate Example 5(c) (8 g, 24.2 mmol) in 1,4-dioxane (100 ml) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane) (7.36 g, 29 mmol, 1.2 eq.), Pd(dppf)Cl2 (2 g, 2.42 mmol, 0.1 eq.) and potassium acetate (8 g, 82.4 mmol, 3.4 eq.) using the procedure of Intermediate Example 1(b). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 10% ethyl acetate in hexane) to give the product in 59% yield (5.4 g). LC-MS (ESI): Calculated mass: 377.29; Observed mass: 378.3 [(M+H]' (RT: 1.83 min).
<strong>[911434-05-4]5-bromo-2-methyl-3-nitropyridine</strong> (4.6 g, 21 mmol, 1.0 eq) and 424 mg of Pd(PPh3)4 were stirred in dimethoxyethane (DME) (17 ml) at r.t. for 20 min, and then tert-butyl 4-[4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl]piperidine-l-carboxylate (prepared as in Example 15) in isopropanol (21 ml) was added followed by a 2.0 M solution Of K2CO3 (15 ml). The reaction mixture was stirred at 850C overnight, the mixture was cooled to room temperature and evaporated. The mixture was purified with ISCO (MeOH/DCM 1 :20) to a yellow solid, 7.75 g, in 95% yield.
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; acetonitrile; at 160℃; for 0.08333330000000001h;microwave irradiation;
In a 10 mL microwave vial, propane- 1 -sulfonic acid [3-(5-bromo- 1 H-pyrrolo[2,3-b]pyridine-3- carbonyl)-2,4-difluoro-phenyl]-amide (9, 51.0 mg, 0.1 1 1 mmol) and 4-[4-(4,4,5,5-tetramethyl- [l ,3,2]dioxaborolan-2-yl)-pyrazol- l -yl]-piperidine-l -carboxylic acid tert-butyl ester (34, 84.2 mg, 0.223 mmol) are combined with 0.680 mL of acetonitrile and potassium carbonate (0.34 mL, 1.00 M in water). l, r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.3 mg, 0.01 1 mmol) is added and the mixture is heated at 160 C in the microwave for 5 minutes, then diluted with water and extracted with ethyl acetate. The organic layer is washed with water, brine, and dried with magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1001, 47 mg). MS (ESI) [M+H+]+ = 629.0.
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; dimethyl sulfoxide; at 100℃; for 0.0333333h;Inert atmosphere;
Example 4. Preparation of N-(2,4-difluoro-3-(5-(l-(piperidin-4-yl)-lH-pyrazol-4- yl) - 1 H-p yrrolo 2 , 3 -bl pyridine- 3 -carbon yl)phenyl)propane- 1 -sulfonamide.[0045] Step 1 : Preparation of ferf-butyl 4-(4-(3-(2,6-difluoro-3-(propylsulfonamido)benzoyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-lH-pyrazol-l-yl)piperidine-l- carboxylate. A mixture of ferf-butyl 4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)piperidine-l-carboxylate (360 mg, 0.95 mmol, 1.8 eq), and N-(3-(5-bromo-lH- pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-l-sulfonamide (236 mg, 0.52 mmol, 1.0 eq), and K2CO3 (351 mg, 2.5 mmol, 4.9 eq) under a nitrogen atmosphere was treated with DMSO (20 mL), water (8 mL), and Pd(dppf)Cl2 (37 mg, 0.051 mmol, 0.1 eq). The mixture was purged with bubbling nitrogen for 2 minutes, and then stirred at 100 C overnight. The reaction was cooled to room temperature, poured into water (100 mL), and extracted with ethyl acetate (6 x 50mL). The combined organic layers were washed with brine, dried(MgS04), filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel to give the product ferf-butyl 4-(4-(3-(2,6- difluoro- 3 - (propylsulf onamido)benzoyl) - 1 H-pyrrolo [2,3 -b]pyridin-5 -yl) - 1 H-pyrazol- 1 - yl)piperidine-l-carboxylate (220 mg).
With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;
EXAMPLE 8: Synthesis of 2-(5-chloro-2-fluoro-phenyl)-4-[5-(1-piperidin-4-yl-1 H-pyrazol-4- -pyridin-3-ylH1.8]naPnthyridine dihydrochloride (no. 11)A slurry of 2.50 g (8.81 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 3.66 g (9.7 mmol) 4-[4-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidin-1 -carboxylic acid tert.butyl ester (synthesis described in WO 2007/066187) and 3.74 g (17.6 mmol) tri-potassium- phosphate-trihydrate in 30 ml 1 ,2-dimethoxyethane was heated to 80C under nitrogen. Then 6 8 mg (0.88 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride were added. The reaction mixture was stirred for 16 hours at 80C. The reaction mixture was partitioned between THF and brine. The organic phase was dried over sodium sulfate and evaporated yielding 4-[4-(5-bromo-pyridin-3-yl)-pyrazol-1 -yl]-piperidine-1 -carboxylic acid tert-butyl-ester as slightly yellow crystals; HPLC-MS: 2.28 min, [M+H] 407/409.
With potassium phosphate tribasic trihydrate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;
A slurry of 2.50 g (8.81 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 3.66 g (9.7 mmol) 4-[4- (4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidin-1-carboxylic acid tert.butyl ester (synthesis described in WO 2007/066187) and 3.74 g (17.6 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1 ,2-dimethoxyethane is heated to 80 C under nitrogen. Then 618 mg (0.88 mmol) bis-(triphenylphosphine)- palladium(ll)-chloride are added. The reaction mixture is stirred for 16 hours at 80 C. The reaction mixture is partitioned between THF and brine. The organic phase is dried over sodium sulfate and evaporated yielding 4-[4-(5-bromo-pyridin- 3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl-ester as slightly yellow crystals; HPLC-MS: 2.28 min, [M+H] 407/409.
With potassium phosphate tribasic trihydrate; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;
A suspension of 5.68 g (20.0 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 7.55 g (20.0 mmol) 4-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyrazol-1 -yl]-piperidin-1 - carboxylic acid tert-butyl ester (synthesis described in WO 2007/066 87) and 8.49 g (40.0 mmol) tri-potassium-phosphate-trihydrate in 40 ml 1,2- dimethoxyethane was heated to 80 C under nitrogen. Then 421 mg (0.60 mmol) bis-(triphenylphosphine)-palladium(ll)-chloride and 50 muIota (0.361 mmol) triethylamine were added. The reaction mixture was stirred for 6 hours at 80 C. The reaction mixture was partitioned between THF and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and evaporated. The residue was recrystallized from isopropanol yielding 4-[4-(5-bromo-pyridin-3-yl)- pyrazol-1-yl]-piperidine-1 -carboxylic acid tert-butyl-ester as slightly yellow crystals; HPLC-MS (A): 2.41 min, [M+H] 407/409.
With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate tribasic trihydrate; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;
A slurry of 2.50 g (8.81 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 3.66 g (9.7 mmol) 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidin-1-carboxylic acid tert.butyl ester (synthesis described in WO 2007/066187) and 3.74 g (17.6 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane was heated to 80 C. under nitrogen. Then 618 mg (0.88 mmol) bis-(triphenylphosphine)-palladium(II)-chloride were added. The reaction mixture was stirred for 16 hours at 80 C. The reaction mixture was partitioned between THF and brine. The organic phase was dried over sodium sulfate and evaporated yielding 4-[4-(5-bromo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl-ester as slightly yellow crystals; HPLC-MS: 2.28 min, [M-1-H] 407/409.
With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate tribasic trihydrate; In 1,2-dimethoxyethane; at 80℃; for 16h;Inert atmosphere;
1. A slurry of 2.50 g (8.81 mmol) <strong>[233770-01-9]3-bromo-5-iodo-pyridine</strong>, 3.66 g (9.7 mmol) 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidin-1-carboxylic acid tert.butyl ester (synthesis described in WO 2007/066187) and 3.74 g (17.6 mmol) tri-potassium-phosphate-trihydrate in 30 ml 1,2-dimethoxyethane is heated to 80 C. under nitrogen. Then 618 mg (0.88 mmol) bis-(triphenylphosphine)-palladium(II)-chloride are added. The reaction mixture is stirred for 16 hours at 80 C. The reaction mixture is partitioned between THF and brine. The organic phase is dried over sodium sulfate and evaporated yielding 4-[4-(5-bromo-pyridin-3-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl-ester as slightly yellow crystals; HPLC-MS: 2.28 min, [M+H] 407/409.
Tert-butyl-4-(4-iodo-1H-pyrazol-1-yl)piperidine-1-carboxylate 2(25.0 g, 0.036 mol) was dissolved in tetrahydrofuran (50 ml) at -10 Cand a solution of isopropyl magnesium chloride in tetrahydrofuran(60% w/w, 60 ml) was added under an atmosphere of nitrogen while keeping the temperature below 0 C. After the addition was completed,the mixture was heated up to 20 C and stirred for 2 h. Subsequently, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g, 0.087 mol)was dissolved in tetrahydrofuran (10 ml), and slowly added dropwise tothe above reaction system. Then the reaction was stirred at roomtemperature for 12 h. After completion of reaction indicated by TLC, themixture was pooled into saturated ammonium chloride solution(200 ml) and stirred for 20 min, and then extracted with ethyl acetate(200 ml×2), The organic layer was washed with water and brine,dried with anhydrous sodium sulfate, and concentrated under reducedpressure. The resulting residue was purified by column chromatography(eluent=dichloromethane:methanol=97:3) to afford 3 as a whitesolid (15.38 g, 61.5%). MS (ESI) m/z: 378.2 [M+H]+.
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 16h;Inert atmosphere;
ie f-Butyl 4-[4-(7/-/-pyrrolo[2,3-c]pyridazin-3-yl)-1 /-/-pyrazol-1 -yl]piperidine-1-carboxylateTo a well stirred suspension of 3-chloro-7/-/-pyrrolo[2,3-c]pyridazine (136 mg, 0.89 mmol), 4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-piperidine-1-carboxylic acid ie f-butyl ester (367 mg, 0.97 mmol, 1.1 eq), and cesium carbonate (526 mg, 1.62 mmol, 1.8 eq) in 20% aqueous dioxane (20 mL) was bubbled nitrogen for 15 min at room temperature. To the resulting mixture was added Pd(PPh3)4 (51 mg, 0.045 mmol), then the mixture was heated at 100 C for 16 h. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was partitioned between water and DCM (30 mL each), and the aqueous layer was extracted with more methylene chloride (2x15 mL). The combined organic layers were washed with water (20 mL) followed by brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 5 to 10% methanol in methylene chloride as eluent to yield the title compounds as off-white solid. 1H NMR (300 MHz, CDCI3): delta = 1.45 (s, 9H), 1 .81-2.35 (m, 4H), 2.78-3.05 (m, 4H), 4.12 (mc, 1 H), 6.62 (d, J = 3.3 Hz, 1 H), 7.62 (d, J = 3.3 Hz, 1 H), 7.93 (s, 1 H), 8.08 (s, 1 H), 8.20 (s, 1 H).
With n-butyllithium; In tetrahydrofuran; hexane; at -70 - 20℃; for 3h;
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).
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,2-dimethoxyethane at 130℃; for 2h; Microwave irradiation;
5
General procedure: The following Preparations were prepared according to Methods 9 or 10 (Preparations 3 or 4) above using the appropriate chloroisoquinoline and the appropriate cross-coupling partner as described. The Preparations were purified according to the methods described or as described below: Method A: Biotage silica gel column chromatography eluting with 30-35% EtOAc in cyclohexane. Method B: Biota e silica gel column chromatography eluting with 50% EtOAc in cyclohexane.
5-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde[ No CAS ]
[ 877399-74-1 ]
[ 3215-64-3 ]
(E)-2-(2,6-dichlorophenyl)-3-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylonitrile[ No CAS ]
(Z)-2-(2,6-dichlorophenyl)-3-(5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acrylonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a mixed solution of CH3CN (5 mL) and Na2C03 aqueous solution (5 mL, 2 M) were added 3-(5-bromo-l-(phenylsulfonyl)-lH-pyrrolo[2,3-b]pyridin-3-yl)-2-(2,6- dichlorophenyl) acrylonitrile (a mixture of la and lb) (680 mg, 1.73 mmol), tert-butyl 4-(4- (4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- IH-pyrazol- 1 -yl)piperidine- 1 -carboxylate (849 mg, 2.25 mmol) and Pd(PPh3)2Cl2 (84 mg, 0.12 mmol). The mixture was microwaved at 150 C for 1 hour, then cooled to rt, poured into water (50 mL) and the resulted mixture was extracted with CH2CI2 (50 mL x 4). The combined organic layers were dried over anhydrous Na2S04, and concentrated in vacuo. The crude product was used in next step without further purification. [0205] The crude product was dissolved in CH2CI2 (40 mL), then a solution of HC1 in EtOAc (12 mL, 3M) was added. The mixture was stirred at rt for 5 hours, then filtered, and the filter cake was dissolved in water (100 mL). The resulted mixture was adjusted to pH=10 with saturated Na2C03 aqueous solution and extracted with CH2CI2 (200 mL x 4). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (CH2CI2/CH3OH/NH3 H2O (v/v/v) = 200/20/1) to give the title compound (a mixture of 2a and 2b) as an off-white solid (350 mg, 44%). MS (ESI, pos. ion) m/z: 463.0 (M+l).
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; water; at 80℃; for 2h;Inert atmosphere;
Methyl 2-amino-5-bromonicotinate 1a (40 g, 170 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl)piperidine-1-carboxylate 26 (71.8 g, 190 mmol), cesium carbonate (192 g, 588 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 g, 8.66 mmol) in dioxane (1 L) and water (250 mL) were stirred at 80 C for 2 hours under nitrogen. The reaction mixture was evaporated to dryness and redissolved in EtOAc (1 L), washed with water (2 x 500 mL), brine (2 x 300 mL). The organic layer was dried over MgSO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 5% of MeOH in DCM. The solvent were evaporated to dryness, the residue was triturated with diethyl ether (500 mL) to give a solid which was collected by filtration and dried under vacuum to afford methyl 2-amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazol-4-yl)nicotinate (48.3 g, 70%) as a pale white solid. A suspension of methyl 2-amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)pyrazol-4-yl)nicotinate (48.3 g, 120 mmol) in 4 N hydrogen chloride in dioxane (450 mL) was stirred at room temperature for 4 h. Diethyl ether (1 L) was added. The resulting precipitate was filtered off and dried to afford methyl 2-amino-5-(1-(piperidin-4-yl)pyrazol-4-yl)nicotinate hydrochloride (49.0 g) as an off-white solid. Methyl 2-amino-5-(1-(piperidin-4-yl)pyrazol-4-yl)nicotinate hydrochloride (49.0 g), DIPEA (63 mL, 360 mmol) and formaldehyde (9.8 mL, 130 mmol) were stirred in methanol (400 mL) at room temperature for 10 min. Sodium triacetoxyborohydride (25.5 g, 120 mmol) was added and the resulting solution was stirred 3 hours at room temperature. Additional formaldehyde and sodium triacetoxy borohydride were added to complete the reaction. The solution was stirred for 18 hours. The solvents were evaporated and the residue was taken-up in minimum DCM and 7 N ammonia in MeOH. The resulting salts were filtered off. The filtrate was evaporated to dryness and purified by chromatography on silica, eluting with 7 N ammonia in MeOH and DCM (5 : 95). The resulting product was stirred in 2 N aq. HCl (250 mL) at room temperature for 18 h. The pH was adjusted to 9 with sat. aq. NaHCO3. The mixture was extracted with DCM (2 x 500 mL). The organic layer was washed with brine, dried on MgSO4, filtered and concentrated to afford methyl 2-amino-5-(1-(1-methylpiperidin-4-yl)pyrazol-4-yl)nicotinate 1b (21.0 g, 55%) as an off-white solid.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 110℃; for 1.5h; Inert atmosphere; Microwave irradiation;
24 Synthesis of 2-(2-(3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-ethylphenyl) propan-2-yl)-1H-indole-6-carbonitrile (25)
General procedure: A mixture of 23 (350 mg, 0.68 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (422 mg, 1.36 mmol), Pd(PPh3)4 (158 mg, 0.136 mmol), and Na2CO3 (2 M in water, 1.5 mL) in dioxane (4.5 mL) was degassed with nitrogen for 5 min and then heated at 110 °C under microwave for 1.5 h. After the completion of the reaction, the mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated and purified by chromatograph (petroleum/acetoacetate) to afford a yellow solid (275 mg, 71% yield). The obtained solid was dissolved in toluene/TFA (5 mL/5 mL). The mixture was heated at 80 °C for 3 h under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was evaporated in vacuum, and basified with saturated sodium bicarbonate until pH > 7. After extraction with EtOAc, the combined mixture was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatograph (CHCl3/MeOH) to give the corresponding intermediate as a pale yellow solid (80 mg, 45%). The intermediate (80 mg, 0.22 mmol) was dissolved in 2 mL of pyridine. Ac2O (0.24 mL, 2.6 mmol) and DMAP (3 mg, 0.025 mmol) were added. The solution was stirred at room temperature overnight until the completion of the reaction. After removal of the solventunder vacuum, DCM (80 mL) was added and the solution was washed with diluted hydrochloric acid (1 N) followed by brine, dried over sodium sulfate, and then ltered. After evaporation of the solvent, the residue was puried by chromatograph (CHCl3/ MeOH) to yield the title product 25 as a white solid (81 mg, 91%yield) (29% overall yield in three steps)
With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 16h;Inert atmosphere; Large scale;
Measure 10L ethylene glycol dimethyl ether, added to the reactor,Then add 5L of water, stirring and mixing, then under a nitrogen atmosphere,To the kettle was added 10 g of palladium acetate and 50 g of1,1'-bis (diphenylphosphine)Ferrocene,Then 1kg of compound of formula 1 was added to the reaction kettle,Then 1.9 kg of the compound of formula 2 and then were added successively1.9kg of potassium carbonate, mix well,The contents of the reactor slowly heated up to 90 ,Then the reaction was continued at this temperature for 16 hours, HPLC monitoring the reaction was completed;After the post-treatment, the reaction solution after completion of the reaction was distilled under reduced pressure,The distilled ethylene glycol dimethyl ether was recovered and reused, 2 L of water was added to the residue after the ethylene glycol dimethyl ether was distilled off,Then the filtrate was filtered, and the filtrate was extracted with 1.5 L of ethyl acetate. The extracted aqueous phase was adjusted to pH 6 with 1 mol / L dilute hydrochloric acid, and a large amount of solid was precipitated. Then, the filtrate was collected by suction filtration,The resulting filter cake was dried in a vacuum oven to remove moisture,Then recrystallized from ethyl acetate to give a compound of formula 3,Yellow solid, 1.6 kg, purity 98%, yield 90%;
Take 1mol B1 dissolved in THF at room temperatureNitrogen protection drops to -25C,A THF solution containing 1 mol of isopropylmagnesium chloride is added dropwise thereto(Shaoxing Shangyu Hualun Chemical Co., Ltd., specification is 1.31mol/L),After the addition of insulation 2h,2 mol of trimethyl borate was added dropwise, and the temperature was raised to 5 C. and kept warm for 1 h after the addition was completed.Warm up to 10C and incubate for 1.5 hours.Finally add 1.2mol pinacol, react at 60 C for 2.5h, filter, concentrate,An isopropanol solution was added to the treatment solution and a solid precipitated. It was tert-butyl 4-(4-iodo-1H-pyrazol-1-yl)-1-piperidinecarboxylate B1.Concentration gives 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine 1-tert-butyl formate, denoted as C1; the collected <strong>[877399-73-0]4-(4-iodo-1H-pyrazol-1-yl)-1-piperidinecarboxylic acid tert-butyl ester</strong> B1 precipitated during the post-reaction treatment and recovered. Use as a raw material,Continue to be used in this reaction to form a recovery cycle and eventually improve4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]Piperidine-1-Formic acidButyl esterYield of C1, while 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1- The tert-butyl piperidine-1-carboxylic acid C1 is an important intermediate for the synthesis of crizotinib, if its yield increases,It will increase the yield in the entire synthesis process
tert-butyl bis-4-(1H-pyrazolyl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83.2%
With bis-triphenylphosphine-palladium(II) chloride; tetrabutylammomium bromide; caesium carbonate; In water; toluene; at 70℃; for 5.5h;Inert atmosphere;
Take 1molB11.6mol C14mol of barium carbonateWith 0.1mol tetrabutylammonium bromide dissolved in toluene/water at room temperature,The reaction system was replaced with nitrogen three times, and 0.005 mole of bistriphenylphosphine dichloride palladium catalyst was added.After reacting at 70C for 5.5 hours, the organic phase was separated at the end of the reaction, and a 2:3 volume ratio of methanol/ethyl acetate was added thereto to crystallize the target product.which isTert-butyl bis-4-(1H-pyrazolyl)piperidine-1-carboxylate;The tert-butyl bis-4-(1H-pyrazol-1-yl)piperidine-1-carboxylate synthesized in this Example was analyzed and calculated.The yield of this target product was 83.2%.
2-amino-5-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;
To a mixture of <strong>[52833-94-0]2-amino-5-bromonicotinic acid</strong> (1 g, 4.61 mmol) and (1-(1-(tert- butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester (2.6 g, 6.91 mmol) in 25 mL of 1,4-dioxane/ water (3/1) was added K2CO3 (1.9 g, 13.8 mmol) followed by Pd(PPh3)4 (0.26 g, 0.23 mmol). The reaction mixture was heated at 100 °C for 3 h, cooled to room temperature, and partitioned between water and ethyl acetate. Water layer was separated and adjusted to pH value around 5. The precipitate was collected by filtration and triturated in mixture of methanol and water. The precipitate was filtered. The wet cake was dried to afford 1.5 g of the title compound. The crude product was used for the next step without further purification. MS (ESI, m/z): 388.1 [M+H]+
With 5%-palladium/activated carbon; potassium carbonate; In water; toluene; at 70.0℃; for 4.0h;Inert atmosphere;
Under a nitrogen atmosphere, a compound 6 (45 g), TABA (2 g), and a toluene solution of the compound 5 (58 g) were sequentially added.Potassium carbonate (27.4g), 5% palladium carbon water content 50% (4.2g), water (240g), warmed to 70 C and kept for 4 hours,The temperature was lowered to room temperature, the catalyst was removed by filtration, and the aqueous layer was separated. Palladium silica gel (5 g) was added to the toluene layer and stirred at 60 C for 2 hours.Filtration, concentration of organic phase, n-heptane, and filtration to give 67.5 g (yield: 90%) of compound 7 white solid.The heavy metal palladium content is less than 1 ppm.
tert-butyl 4-(4-(7-((pivaloyloxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.4%
With bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; at 80℃; for 8h;Inert atmosphere;
A mixture of 3 (11.93 g, 0.032 mol), bistriphenylphosphine palladiumdichlorideand (0.67 g, 0. 95 mmol) and barium carbonate (9.3 g,0.095 mol) in anhydrous dioxane (200 ml) was heated at 80 C under anatmosphere of nitrogen for 8 h, After the reaction finished, the mixturewas poured in water and then extracted with DCM (200 ml×2). Theorganic layer was washed with water and brine, dried with anhydroussodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent=petroleumether:ethyl acetate=5:1) to afford 5 as a gray red solid (10.47 g,62.4%). MS (ESI) m/z: 483.3 [M+H]+.
tert-butyl 4-(4-(2-fluoro-4-nitrophenyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 110℃; for 20h;Inert atmosphere;
General procedure: Dioxane (40 mL), H2O (10 mL) and Na2CO3 (3.2 equiv.) were combined in a 250 mL round-bottomed flask equipped with a stir bar under argon atmosphere and then degassed using argon for about 15 min. Both <strong>[185331-69-5]1-bromo-2-fluoro-4-nitrobenzene</strong> (1.0 equiv.) and boronic esters (1.4 equiv.) were then added to the round-bottomed flask under argon and degassed for another 15 min. Finally Pd(PPh3)4 catalyst (0.033 equiv.) was added and after degassing for 5 min, the reaction placed in pre-heated oil bath to 110 C for 12 h with vigorous stirring. The reaction was cooled to room temperature, the mixture diluted with EtOAc (2 × 25 mL) and washed with water (100 mL) and brine (50 mL). The combined organic layers were dried (Na2SO4) and concentrated under vacuum in a rotary evaporator. The pure nitrobenzene intermediates were obtained by trituration using EtOAc and Hexanes.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous sodium carbonate In 1,4-dioxane at 90℃; for 2h; Sealed tube;
70a.1 Step 1.
Into a 50 mL sealed-tube reactor containing a well-stirred solution of 6-bromo-4-methoxy- pyrazolo[1,5-a]pyridine-3-carbonitrile (1; 600 mg, 2.38 mmol) and tert-butyl 4-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (2; 987.87 mg, 2.62 mmol) in anhydrous 1,4-dioxane (10 mL) was added aqueous Na2CO3 (3.57 mL; 2M) at ambient temperature and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, Pd(dppf)Cl2.CH2Cl2 complex (194.39 mg, 238.03 mmol) was added to the reaction mixture and reaction mixture was heated to 90 °C for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (2 x 150 mL). Organic phases were combined and washed with brine (100 mL). Combined organic phases were dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to get a crude residue, which was purified by silica-gel (230-400 mesh) column with 80% EtOAc in pet ether to yield tert-butyl 4-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1- yl)piperidine-1-carboxylate (3; 630 mg, 1.35 mmol) as a yellow solid. Yield-56.8%; LC MS: ES+ (M - tBu + H) 367.2.
56.8%
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II) dichloromethane adduct; anhydrous sodium carbonate In 1,4-dioxane at 90℃; for 2h; Sealed tube;
70a.1 Step 1.
Into a 50 mL sealed-tube reactor containing a well-stirred solution of 6-bromo-4-methoxy- pyrazolo[1,5-a]pyridine-3-carbonitrile (1; 600 mg, 2.38 mmol) and tert-butyl 4-[4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (2; 987.87 mg, 2.62 mmol) in anhydrous 1,4-dioxane (10 mL) was added aqueous Na2CO3 (3.57 mL; 2M) at ambient temperature and the resulting mixture was degassed by bubbling nitrogen gas into the reaction mixture for 10 minutes. Subsequently, Pd(dppf)Cl2.CH2Cl2 complex (194.39 mg, 238.03 mmol) was added to the reaction mixture and reaction mixture was heated to 90 °C for 2 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to room temperature and poured into water (50 mL) and extracted with EtOAc (2 x 150 mL). Organic phases were combined and washed with brine (100 mL). Combined organic phases were dried (anhydrous Na2SO4), filtered and the filtrate was concentrated under reduced pressure to get a crude residue, which was purified by silica-gel (230-400 mesh) column with 80% EtOAc in pet ether to yield tert-butyl 4-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1- yl)piperidine-1-carboxylate (3; 630 mg, 1.35 mmol) as a yellow solid. Yield-56.8%; LC MS: ES+ (M - tBu + H) 367.2.
With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 90℃; for 16h; Inert atmosphere; Sealed tube;
Step 1: Preparation of tert-butyl 4-(4-(3-cyano-4-methoxypyrazolo[1,5-a]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate.
A solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine-3-carbonitrile (Intermediate PI; 5.00 g, 19.8 mmol) in 4:1 dioxane:water (200 mL) was treated sequentially with tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (7.86 g, 20.8 mmol), Pd(PPh3 (1.15 g, 0.992 mmol) and K2C03(S) (8.22 g, 59.5 mmol). The resulting mixture was sparged with A, before sealing the reaction vessel. The mixture then was stirred for 16 h at 90°C. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc, then sequentially washed with water (2x), and brine (lx). The organic extracts then were dried over anhydrous Na2S04-(S), filtered, and concentrated in vacuo. The crude residue was purified by silica chromatography (using 5-95% DCM-Acetone as the gradient eluent) to cleanly provide the title compound, which was carried directly into Step 2 (~8.5 g, quantitative yield assumed). MS (apci) m/z =423.1 (M+H).
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