Home Cart 0 Sign in  

[ CAS No. 877399-74-1 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
Chemical Structure| 877399-74-1
Chemical Structure| 877399-74-1
Structure of 877399-74-1 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 877399-74-1 ]

Related Doc. of [ 877399-74-1 ]

Alternatived Products of [ 877399-74-1 ]

Product Details of [ 877399-74-1 ]

CAS No. :877399-74-1 MDL No. :MFCD11112131
Formula : C19H32BN3O4 Boiling Point : -
Linear Structure Formula :- InChI Key :QSQWENQPOSRWLP-UHFFFAOYSA-N
M.W :377.29 Pubchem ID :45480279
Synonyms :

Calculated chemistry of [ 877399-74-1 ]

Physicochemical Properties

Num. heavy atoms : 27
Num. arom. heavy atoms : 5
Fraction Csp3 : 0.79
Num. rotatable bonds : 5
Num. H-bond acceptors : 5.0
Num. H-bond donors : 0.0
Molar Refractivity : 109.64
TPSA : 65.82 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -6.78 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 2.56
Log Po/w (WLOGP) : 2.37
Log Po/w (MLOGP) : 1.31
Log Po/w (SILICOS-IT) : 0.74
Consensus Log Po/w : 1.4

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.6
Solubility : 0.095 mg/ml ; 0.000252 mol/l
Class : Soluble
Log S (Ali) : -3.59
Solubility : 0.097 mg/ml ; 0.000257 mol/l
Class : Soluble
Log S (SILICOS-IT) : -3.34
Solubility : 0.171 mg/ml ; 0.000454 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 3.8

Safety of [ 877399-74-1 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H332-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 877399-74-1 ]

* 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.

  • Upstream synthesis route of [ 877399-74-1 ]
  • Downstream synthetic route of [ 877399-74-1 ]

[ 877399-74-1 ] Synthesis Path-Upstream   1~17

  • 1
  • [ 877399-73-0 ]
  • [ 73183-34-3 ]
  • [ 877399-74-1 ]
YieldReaction ConditionsOperation in experiment
87.9% 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).

Reference: [1] Patent: WO2014/193647, 2014, A2, . Location in patent: Paragraph 0185
[2] Patent: CN104119331, 2018, B, . Location in patent: Paragraph 0382; 0390; 0391
[3] Patent: WO2010/68292, 2010, A1, . Location in patent: Page/Page column 85-86
[4] Patent: WO2014/89280, 2014, A1, . Location in patent: Page/Page column 50
[5] Patent: CN103833753, 2017, B, . Location in patent: Paragraph 0352; 0358; 0359
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4092 - 4108
[7] Journal of Medicinal Chemistry, 2013, vol. 56, # 6, p. 2294 - 2310
[8] Patent: US2008/300273, 2008, A1,
[9] Patent: US2008/293769, 2008, A1, . Location in patent: Page/Page column 6
[10] Patent: US2006/46991, 2006, A1, . Location in patent: Page/Page column 69-70
[11] Patent: WO2006/21881, 2006, A2, . Location in patent: Page/Page column 81; 82
[12] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[13] Patent: WO2013/17989, 2013, A1, . Location in patent: Page/Page column 67
[14] Patent: EP2764866, 2014, A1, . Location in patent: Paragraph 0054
[15] Patent: US2016/206608, 2016, A1, . Location in patent: Paragraph 0264; 0266
[16] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
  • 2
  • [ 877399-50-3 ]
  • [ 73183-34-3 ]
  • [ 877399-74-1 ]
YieldReaction ConditionsOperation in experiment
81% 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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 ]
YieldReaction ConditionsOperation 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] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[2] Patent: WO2014/20467, 2014, A2, . Location in patent: Page/Page column 20
  • 6
  • [ 877399-73-0 ]
  • [ 1195-66-0 ]
  • [ 877399-74-1 ]
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 ]
YieldReaction ConditionsOperation 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).
Reference: [1] Patent: CN105153211, 2017, B, . Location in patent: Paragraph 0020; 0023-0024
  • 9
  • [ 76-09-5 ]
  • [ 13675-18-8 ]
  • [ 2065-75-0 ]
  • [ 1196486-69-7 ]
  • [ 877399-74-1 ]
YieldReaction ConditionsOperation in experiment
8.8 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 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).
Reference: [1] Patent: CN105153211, 2017, B, . Location in patent: Paragraph 0015; 0018-0019
  • 10
  • [ 877399-50-3 ]
  • [ 1195-66-0 ]
  • [ 877399-74-1 ]
Reference: [1] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
  • 11
  • [ 109384-19-2 ]
  • [ 877399-74-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4092 - 4108
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 18, p. 6342 - 6363
[3] Organic Process Research and Development, 2011, vol. 15, # 5, p. 1018 - 1026
[4] Patent: WO2011/100502, 2011, A1,
[5] Patent: WO2011/143646, 2011, A1,
[6] Patent: US2012/165305, 2012, A1,
[7] Journal of Medicinal Chemistry, 2013, vol. 56, # 6, p. 2294 - 2310
[8] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 21, p. 6804 - 6820
[9] Patent: WO2013/17989, 2013, A1,
[10] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[11] Tetrahedron Letters, 2014, vol. 55, # 9, p. 1528 - 1531
[12] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299
[13] Patent: US2014/121200, 2014, A1,
[14] Patent: WO2014/89280, 2014, A1,
[15] Patent: EP2764866, 2014, A1,
[16] Patent: WO2014/193647, 2014, A2,
[17] Patent: US2015/11548, 2015, A1,
[18] Patent: WO2015/81257, 2015, A2,
[19] Bioorganic Chemistry, 2016, vol. 65, p. 146 - 158
[20] Patent: US2017/8889, 2017, A1,
[21] Patent: CN106336413, 2017, A,
[22] Patent: CN106317024, 2017, A,
[23] Patent: CN107417603, 2017, A,
[24] Patent: CN104119331, 2018, B,
[25] Patent: CN106831720, 2017, A,
[26] Patent: US2016/206608, 2016, A1,
[27] Patent: WO2013/53983, 2013, A1,
[28] Patent: CN103833753, 2017, B,
  • 12
  • [ 877399-50-3 ]
  • [ 185990-03-8 ]
  • [ 877399-74-1 ]
Reference: [1] Chemical Science, 2015, vol. 6, # 5, p. 2943 - 2951
  • 13
  • [ 5382-16-1 ]
  • [ 877399-74-1 ]
Reference: [1] Patent: US2015/11548, 2015, A1,
[2] Patent: CN107417603, 2017, A,
[3] Patent: WO2013/53983, 2013, A1,
  • 14
  • [ 24424-99-5 ]
  • [ 877399-74-1 ]
Reference: [1] Patent: US2015/11548, 2015, A1,
[2] Patent: WO2013/53983, 2013, A1,
  • 15
  • [ 73183-34-3 ]
  • [ 877399-74-1 ]
Reference: [1] Journal of the American Chemical Society, 2014, vol. 136, # 11, p. 4287 - 4299
  • 16
  • [ 79099-07-3 ]
  • [ 877399-74-1 ]
Reference: [1] Patent: CN105153211, 2017, B,
  • 17
  • [ 24608-52-4 ]
  • [ 877399-74-1 ]
Reference: [1] Patent: CN107417603, 2017, A,
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 877399-74-1 ]

Organoboron

Chemical Structure| 877399-31-0

[ 877399-31-0 ]

tert-Butyl 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 1175275-00-9

[ 1175275-00-9 ]

1-Cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.81

Chemical Structure| 1002309-48-9

[ 1002309-48-9 ]

1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.79

Chemical Structure| 552846-17-0

[ 552846-17-0 ]

tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate

Similarity: 0.77

Chemical Structure| 1040377-03-4

[ 1040377-03-4 ]

1-(Tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.77

Amides

Chemical Structure| 877399-31-0

[ 877399-31-0 ]

tert-Butyl 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 552846-17-0

[ 552846-17-0 ]

tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate

Similarity: 0.77

Chemical Structure| 1083326-46-8

[ 1083326-46-8 ]

2-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide

Similarity: 0.69

Chemical Structure| 864771-44-8

[ 864771-44-8 ]

tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate

Similarity: 0.67

Chemical Structure| 1121057-77-9

[ 1121057-77-9 ]

tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate

Similarity: 0.66

Related Parent Nucleus of
[ 877399-74-1 ]

Pyrazoles

Chemical Structure| 877399-31-0

[ 877399-31-0 ]

tert-Butyl 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate

Similarity: 0.92

Chemical Structure| 1175275-00-9

[ 1175275-00-9 ]

1-Cyclohexyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.81

Chemical Structure| 1002309-48-9

[ 1002309-48-9 ]

1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.79

Chemical Structure| 552846-17-0

[ 552846-17-0 ]

tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate

Similarity: 0.77

Chemical Structure| 1040377-03-4

[ 1040377-03-4 ]

1-(Tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

Similarity: 0.77

Piperidines

Chemical Structure| 877399-50-3

[ 877399-50-3 ]

tert-Butyl 4-(4-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate

Similarity: 0.66

Chemical Structure| 1029413-55-5

[ 1029413-55-5 ]

tert-Butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

Similarity: 0.66

Chemical Structure| 877399-73-0

[ 877399-73-0 ]

1-Boc-4-(4-Iodo-1H-pyrazol-1-yl)piperidine

Similarity: 0.63

Chemical Structure| 956136-85-9

[ 956136-85-9 ]

tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylate

Similarity: 0.62

Chemical Structure| 889865-34-3

[ 889865-34-3 ]

tert-Butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine-1-carboxylate

Similarity: 0.60