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[ CAS No. 1040377-12-5 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 1040377-12-5
Chemical Structure| 1040377-12-5
Chemical Structure| 1040377-12-5
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Product Details of [ 1040377-12-5 ]

CAS No. :1040377-12-5 MDL No. :MFCD13195616
Formula : C9H11BrN2O Boiling Point : -
Linear Structure Formula :- InChI Key :RHEDZKKCXNVSPI-UHFFFAOYSA-N
M.W : 243.10 Pubchem ID :51063918
Synonyms :

Calculated chemistry of [ 1040377-12-5 ]

Physicochemical Properties

Num. heavy atoms : 13
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.44
Num. rotatable bonds : 1
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 57.66
TPSA : 25.36 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.22
Log Po/w (XLOGP3) : 1.63
Log Po/w (WLOGP) : 1.3
Log Po/w (MLOGP) : 1.38
Log Po/w (SILICOS-IT) : 2.12
Consensus Log Po/w : 1.73

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.65
Solubility : 0.545 mg/ml ; 0.00224 mol/l
Class : Soluble
Log S (Ali) : -1.78
Solubility : 4.08 mg/ml ; 0.0168 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.07
Solubility : 0.207 mg/ml ; 0.000853 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 2.19

Safety of [ 1040377-12-5 ]

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

Application In Synthesis of [ 1040377-12-5 ]

* 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.

  • Downstream synthetic route of [ 1040377-12-5 ]

[ 1040377-12-5 ] Synthesis Path-Downstream   1~44

  • 1
  • [ 35980-77-9 ]
  • [ 1040377-12-5 ]
YieldReaction ConditionsOperation in experiment
56% To the ice-bath cooled solution of 26b (6.61g, 36.9) in a mixture of 98% H2SO4 (3O8mL) and H2O (189mL) was added a solution OfNaNO2 (2.55g, 36.9mmol) in H2O (137mL) drop-wise. The resulting mixture was stirred for 30min at O0C, was then added CuBr (6.09, 42.4mmol) and 48%HBr (10OmL, 80.91mmol). After being stirred for 15min at 00C and 30min at 6O0C, the mixture was cooled to room temperature, neutralized to pH=8 and extracted with EtOAc. The organic phase was dried over Na2SO4, concentrated under vacua and purified by column chromatograph on silica gel (EA: PE=I : 10) to give 26c (5.03, 56%).
  • 2
  • [ 110-91-8 ]
  • [ 128071-98-7 ]
  • [ 1040377-12-5 ]
YieldReaction ConditionsOperation in experiment
90% With caesium carbonate In N,N-dimethyl-d<SUB>6</SUB>-formamide at 20 - 100℃; for 12h; Sealed tube; 7.1; 24.4 Step 4. 4 -(4 -bromopyridin -2 -yl jmorpholine 4-Bromo-2-fluoropyridine (1.0 g, 5.68 mmol) was dissolved in 5 mL DMF and morpholine (0.60 mL, 6.82 mmol) and Cs2C03 (3.70 g, 11.36 mmol) were added at room temperature. The mixture was stirred in a sealed vial at 100 °C overnight. The mixture was portioned between H20 and EtOAc. The phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic layers washed with brine (lx), dried over anhydrous Na2S04 and evaporated to dryness. The crude material was purified via column chromatography on a 50 g silica gel column using as eluent a gradient of EtOAc in cyclohexane from 0 to 50%. The desired fractions were collected together to afford the title compound (1.24 g, 5.10 mmol, 90% yield) as a white solid. NMR (400 MHz, DMSO-d6) d 8.01 (d, J=5.3 Hz, 1H), 7.06 (d, J=l .3 Hz, 1H), 6.88 (dd, J=l .5, 5.3 Hz, 1H), 3.73 - 3.62 (m, 4H), 3.54 - 3.42 (m, 4H). MS-ESI (m/z) calcd for C9Hi2BrN20 [M+H]+: 243.01. Found 243.09/245.10.
75% With caesium carbonate at 100℃; for 12h; 278.1 Step 1: 4-(4-Bromopyridin-2-yl)morpholine To a solution of 4-bromo-2-fluoropyridine (2 g, 11.36 mmol) in 10 mL of DMF was added morpholine (1.19 g, 13.64 mmol) and Cs2CO3 (7.41 g, 22.73 mmol) at 20 °C and the mixture was stirred at 100 °C for 12 hrs. The reaction mixture was diluted with 40 mL of H2O and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (2.13 g, 75%) as a white solid. MS-ESI (m/z) calcd for C9H12BrN2O [M+H]+: 243.0/245.0. Found 243.0/245.0.
75% With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 12h; 39.1 Step 1: 4-(4-bromopyridin-2-yl)morpholine To a solution of 4-bromo-2-fluoro-pyridine (2 g, 11.36 mmol) in DMF (10 mL) was added morpholine (1.19 g, 13.64 mmol, 1.20 mL) and C52CO3 (7.41 g, 22.73 mmol) at 20 °C.The mixture was stirred at 100 °C for 12 hrs. The reaction mixture was then diluted with H20 and extracted with EtOAc (3x), the combined organic layers were dried over Na2SO4 and evaporated to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash column) using a 0-8% EtOAc/petroleum ether gradient eluent to afford the title compound (2.13 g, 75%) as a white solid. MS-ESI (m/z) calc’d forC9H12BrN2O [M+Hj: 243.0/245.0. Found 243.0/245.0.
72% With potassium carbonate In N,N-dimethyl-formamide at 100℃; Inert atmosphere; 4.1 Step 1-Preparation of 4-(4-bromopyridin-2-yl)morpholine A mixture of 4-bromo-2-fluoropyridine (3.1 mL, 30.0 mmol), morpholine (2.6 mL, 30.0 mmol) and potassium carbonate (4.15 g, 30.0 mmol) in DMF (30 mL) is heated at 100° C. overnight under nitrogen. The DMF was removed under reduced pressure and EtOAc (100 mL) was added. The reaction is washed with water (50 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography using 0-20% hexanes-EtOAc to give 4-(4-bromopyridin-2-yl)morpholine (5.56 g, 72% yield). ESI-MS m/z calc. 242.01, found 243.0 (M+H)+.
62% With triethylamine In tetrahydrofuran at 100℃; for 2h;
46% With triethylamine at 100℃; for 12h; Inert atmosphere; 1 Step 1 - 4-(4-Dromo-2-pyridyl)morpholine To a mixture of 4-bromo-2-fluoro-pyridine (5.00 g, 28.4 mmol, CAS 128071-98- 7) in morpholine (2.48 g, 28.4 mmol, 2.50 mL, CAS 110-91-8) was added TEA (2.87 g, 28.4 mmol, 3.95 mL) at 25 °C. The reaction mixture was stirred at 100 °C for 12 hours. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography ((SiO2, PE: EA = 30:1 to 10:1) to give the title compound (3.20 g, 46% yield) as white solid.1H NMR (400 MHz, DMSO-d6) d 8.00 (d, J = 5.2 Hz, 1H), 7.05 (d, J = 1.2 Hz, 1H), 6.90 - 6.83 (m, 1H), 3.68 - 3.64 (m, 4H), 3.49 - 3.43 (m, 4H).
With triethylamine at 100℃; for 66h; 62 Synthesis of 4-(4-bromopyridin-2-yl)morpholine Synthesis of 4-(4-bromopyridin-2-yl)morpholine To a solution of triethylamine (1.0 equiv.) and 2-fluoro-4-bromopyridine (1.0 equiv.) at RT was added morpholine (1.0 equiv) in one portion, the resulting mixture was then heated in an oil bath at 100° C. for 66 hr. LCMS analysis indicated the formation of the desired product (m/z=244.9, Rt=0.36 min). The reaction mixture was concentrated in vacuo to yield 4-(4-bromopyridin-2-yl)morpholine as a light brown solid, (>100%, TEA impurity). LCMS (m/z) (M+H)=244.9, Rt=0.36 min. 1H NMR (400 MHz, ) δ ppm 3.39-3.55 (m, 4H) 3.59-3.75 (m, 4H) 6.87 (dd, J=5.28, 1.37 Hz, 1H) 7.05 (d, J=1.17 Hz, 1H) 8.00 (d, J=5.48 Hz, 1H).

Reference: [1]Current Patent Assignee: EVOTEC AG; ESCAPE BIO - WO2019/222173, 2019, A1 Location in patent: Page/Page column 62-63; 85-87
[2]Current Patent Assignee: E SCAPE BIO - WO2021/7477, 2021, A1 Location in patent: Page/Page column 442; 443
[3]Current Patent Assignee: E SCAPE BIO - WO2021/178780, 2021, A1 Location in patent: Page/Page column 169
[4]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - US2021/340139, 2021, A1 Location in patent: Paragraph 0125; 0126
[5]Nishiguchi, Gisele A.; Rico, Alice; Tanner, Huw; Aversa, Robert J.; Taft, Benjamin R.; Subramanian, Sharadha; Setti, Lina; Burger, Matthew T.; Wan, Lifeng; Tamez, Victoriano; Smith, Aaron; Lou, Yan; Barsanti, Paul A.; Appleton, Brent A.; Mamo, Mulugeta; Tandeske, Laura; Dix, Ina; Tellew, John E.; Huang, Shenlin; Mathews Griner, Lesley A.; Cooke, Vesselina G.; Van Abbema, Anne; Merritt, Hanne; Ma, Sylvia; Gampa, Kalyani; Feng, Fei; Yuan, Jing; Wang, Yingyun; Haling, Jacob R.; Vaziri, Sepideh; Hekmat-Nejad, Mohammad; Jansen, Johanna M.; Polyakov, Valery; Zang, Richard; Sethuraman, Vijay; Amiri, Payman; Singh, Mallika; Lees, Emma; Shao, Wenlin; Stuart, Darrin D.; Dillon, Michael P.; Ramurthy, Savithri [Journal of Medicinal Chemistry, 2017, vol. 60, # 12, p. 4869 - 4881]
[6]Current Patent Assignee: KYMERA THERAPEUTICS INC - WO2020/113233, 2020, A1 Location in patent: Paragraph 00962; 003640-003642
[7]Current Patent Assignee: NOVARTIS AG; Barsanti, Paul A.; Burger, Matthew; Lou, Yan; Nishiguchi, Gisele; Polyakov, Valery; Ramurthy, Savithri; Rico, Alice; Setti, Lina; Smith, Aaron; Taft, Benjamin; Tanner, Huw; DiPesa, Alan; Yusuff, Naeem - US2014/275003, 2014, A1 Location in patent: Paragraph 0393; 0394
  • 3
  • [ 1040377-12-5 ]
  • 2-methyl-2'-morpholino-[3,4'-bipyridin]-5-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 2: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 0.25 h / 110 °C / Microwave irradiation
  • 4
  • [ 1040377-12-5 ]
  • 2-(2-cyanopropan-2-yl)-N-(2-methyl-2′-morpholino-[3,4′-bipyridin]-5-yl)isonicotinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium acetate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 2: sodium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / 1,2-dimethoxyethane / 0.25 h / 110 °C / Microwave irradiation 3: 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 4 h / 20 °C
  • 5
  • [ 1040377-12-5 ]
  • [ 73183-34-3 ]
  • [ 888721-86-6 ]
YieldReaction ConditionsOperation in experiment
56% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In N,N-dimethyl-formamide at 80℃; Inert atmosphere; 62 Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine Synthesis of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine 4-(4-bromopyridin-2-yl)morpholine (1.10 equiv), bis(pinacolato)diboron (1.0 equiv.), potassium acetate (4.0 equiv), and PdCl2(dppf)CH2Cl2 (0.05 equiv.) were added to a rb flask which was purged with nitrogen. DMF (0.20 M) was added and the mixture was heated to 80° C. overnight. The reaction was cooled to rt, quenched with water, and the product was extracted into EtOAc (3*). The combined organics were dried over Na2SO4, filtered, and concentrated. The crude was loaded onto silica gel and purified via ISCO to yield 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine as a light brown foam (56%). 1H NMR (400 MHz, ) δ ppm 1.33 (s, 12H) 3.49-3.55 (m, 4H) 3.79-3.83 (m, 4H) 6.98 (d, J=4.70 Hz, 1H) 7.03 (s, 1H) 8.21 (d, J=4.70 Hz, 1H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 80℃; for 12h; Inert atmosphere; 7.2 Step 2. 4-(4-(4, 4, 5, 5-Tetramethyl-J 3, 2-dioxaborolan-2-yl)pyridin-2-yl )morpholine A mixture of 4-(4-bromo-2-pyridinyl)-morpholine (1.5 g, 6.17 mmol), (0516) bis(pinacolato)diboron (1.88 g, 7.40 mmol), KOAc (1.51 g, 15.43 mmol), and Pd(dppf)Cl2 (451 mg, 617.03 pmol) in dioxane (15 mL) was degassed and purged with N2 (3x); then the mixture was stirred at 80 °C for 12 h under N2 atmosphere. LC-MS showed 4-(4-bromo-2- pyridinyl)-morpholine was completely consumed and the desired mass was detected. The mixture was filtered and concentrated under reduced pressure to give the title compound (1.28 g, crude) as a black oil.
  • 6
  • [ 876322-58-6 ]
  • [ 1040377-12-5 ]
  • N-(4-methyl-3-(2-morpholinopyridin-4-yl)phenyl)-3-(trifluoromethyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,2-dimethoxyethane; water at 120℃; for 0.333333h; Microwave irradiation;
16% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate In 1,2-dimethoxyethane at 120℃; for 0.333333h; Microwave irradiation; 62 Synthesis of N-(4-methyl-3-(2-morpholinopyridin-4-yl)phenyl)-3-(trifluoromethyl)benzamide. Synthesis of N-(4-methyl-3-(2-morpholinopyridin-4-yl)phenyl)-3-(trifluoromethyl)benzamide. To a solution of 4-(4-bromopyridin-2-yl)morpholine (1.0 equiv.) and Intermediate A (1.2 equiv.) in DME and 2M sodium carbonate (3:1, 0.08 M) was added PdCl2(dppf)-DCM adduct (0.1 equiv.) in a microwave vial equipped with a stir bar. The reaction was heated to 120° C. for 20 min in the microwave. The reaction was quenched with water and extracted with ethyl acetate. The combined organic phase was dried with sodium sulfate, filtered and concentrated. The crude material was purified via preparative reverse phase HPLC. Upon lyophilization of the pure fractions, N-(4-methyl-3-(2-morpholinopyridin-4-yl)phenyl)-3-(trifluoromethyl)benzamide was isolated as the TFA salt in 16% yield.LCMS (m/z) (M+H)=442.3, Rt=0.76 min. 1H NMR (400 MHz, ) δ ppm 2.25 (s, 3H) 3.44-3.59 (m, 5H) 3.64-3.87 (m, 22H) 6.82 (d, J=5.48 Hz, 1H) 7.00 (s, 1H) 7.27-7.41 (m, 1H) 7.67-7.82 (m, 3H) 7.90-8.03 (m, 1H) 8.17 (d, J=5.48 Hz, 1H) 8.26 (d, J=7.83 Hz, 1H) 8.30 (s, 1H) 10.40-10.61 (m, 1H).
  • 7
  • [ 1040377-12-5 ]
  • C10H12N2O [ No CAS ]
  • 4-(4-(6-isopropoxy-1H-indazol-1-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With copper(l) iodide; (±)-N,N-dimethyl-trans-1,2-diaminocyclohexane at 120℃; for 6h; Microwave irradiation; 4 Synthesis of 4- (4- (6-isopropoxy- 1 H-indazol- 1 -yl)pyridin-2-yl)morpholine A mixture of lH-indazol-6-ol (124 mg, 0.96 mmol) and Cs2C03 (804 mg, 2.47 mmol) in DMF (3 mL) was added 2-iodopropane (157 mg, 0.93 mmol), stirred at rt for 6h and at 50 °C for 1 h, followed by addition of copper(I) iodide (23 mg, 0.12 mmol) and trans-N, N- dimethylcyclohexane-l,2-diamine (35 mg, 0.25 mmol) . The resulting mixture was microwaved at 120 °C for 6 h. The filtration removed the solid. After washing with DCM, the combined filtrate was concentrated in vacuo. The residue was purified by ISCO flash chromatography (eluted with 0-100% EtOAc / hexane) to provide 4-(4-(6-isopropoxy-lH-indazol-l-yl)pyridin-2- yl)morpholine (150 mg) which was dissolved in EtOAc (3 ml), treated with 4N HCl in dioxane (3 mL) and stirred for 5 min. The volatiles were evaporated in vacuo and the residue was washed with ether. The filtration collected HCl salt (Example 4). LCMS (ESI) m/z 339 (Ret. - 2.03 min, LCMS method a); LRRK2 IC50: 122 nM.
  • 8
  • [ 1040377-12-5 ]
  • 6-(1-methyl-1H-imidazol-5-yl)-1H-indazole [ No CAS ]
  • 4-(4-(6-(1-methyl-1H-imidazol-5-yl)-1H-indazol-1-yl)pyridin2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With copper(l) iodide; (±)-N,N-dimethyl-trans-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 6h; Microwave irradiation; 6.2 Step 2 - Synthesis of 4-(4-(6-(l-methyl-lH midazol-5-yl)-lH-indazol-l-yl)pyridin-2- yljmorpholine A mixture of 6-(l -methyl- lH-imidazol-5-yl)-lH-indazole (155 mg, 0.78 mmol) , Cs2C( (510 mg, 1.56 mmol) , copper(I) iodide (30 mg, 0.16 mmol) and trans-N, N- dimethylcyclohexane-l,2-diamine (45 mg, 0.31 mmol) in DMF (3 mL) was microwaved at 120 °C for 6 h. The filtration removed the solid. After washing with DCM, the combined filtrate was concentrated in vacuo. The residue was purified by ISCO flash chromatography (eluted with 0- 100% EtOAc / hexane) to provide 4-(4-(6-(l-methyl-lH-imidazol-5-yl)-lH-indazol-l-yl)pyridin- 2-yl)morpholine (Example 6). LCMS (ESI) m/z 361 (Ret. - 1.65 min, LCMS method a); LRRK2 IC50: 119 nM.
  • 9
  • [ 1040377-12-5 ]
  • 6-(4-methoxypyridin-3-yl)-1H-indazole [ No CAS ]
  • 4-(4-(6-(4-methoxypyridin-3-yl)-1H-indazol-1-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tert-butyl XPhos In toluene at 85℃; for 4h; 17.2 Step 2 - Synthesis of 4-(4-(6-(4-methoxypyridin-3-yl)-lH4ndazol-l-yl)p ridin-2-yl)mo A mixture of 6-(4-methoxypyridin-3-yl)-lH-indazole (100 mg, 0.44 mmol), 4-(4-bromopyridin- 2-yl)morpholine (162 mg, 0.67 mmol), Pd2(dba)3 (41 mg, 0.04 mmol) , 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl (38 mg, 0.09 mmol) and sodium tert-butoxide (64 mg, 0.67 mmol) in toluene (3 mL) was heated to 85 °C and stirred for 4 h. The filtration removed the solid. After washing with DCM, the combined filtrate was concentrated in vacuo. The residue was purified by ISCO flash chromatography (eluted with 0-5% MeOH / DCM) to provide 4-(4-(6-(4-methoxypyridin-3 -yl)- 1 H-indazol- 1 -yl)pyridin-2-yl)morpholine (Example 17). LCMS (ESI) m/z 388 (Ret. = 1.73 min, LCMS method a); LRRK2 IC50: 43 nM. Rat PK Oral AUC: 10 +/- 2.5 μΜ-h.
  • 10
  • [ 1040377-12-5 ]
  • 6-(1-trityl-1H-pyrazol-4-yl)-1H-indazole [ No CAS ]
  • 4-(4-(6-(1-trityl-1H-pyrazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; tert-butyl XPhos In toluene at 80℃; 18.2 Step 2 - Synthesis of 4-(4-(6-(l -trUyl-1 H-pyrazol-4-yl)-l H-indazol-1 -yl)pyridin-2-yl)morpholine A mixture of 6-(l-trityl-lH-pyrazol-4-yl)-lH-indazole (344 mg, 0.81 mmol), 4-(4- bromopyridin-2-yl)morpholine (294 mg, 1.21 mmol), Pd2(dba)3 (148 mg, 0.16 mmol) , 2-di-tert- butylphosphino-2',4',6'-triisopropylbiphenyl (103 mg, 0.24 mmol) and sodium tert-butoxide (155 mg, 0.61 mmol) in tolune (8 mL) was heated to 80 °C and stirred overnight. The filtration removed the solid. After washing with DCM, the combined filtrate was concentrated in vacuo. The residue was purified by ISCO flash cliromatography (eluted with 0-5% MeOH / DCM) to provide 4-(4-(6-(l -trityl- 1 H-pyrazol-4-yl)- 1 H-indazol- 1 -yl)pyridin-2-yl)morpholine.
  • 11
  • [ 1040377-12-5 ]
  • [ 1448429-59-1 ]
  • 4-(4-(6-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With copper(l) iodide; (±)-N,N-dimethyl-trans-1,2-diaminocyclohexane; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 6h; Microwave irradiation; 1.2 Step 2 - Synthesis of 4-(4-(6-(l-methyl-lH-pyrazol-4-yl)-lH-indazol-l-yl)pyridin-2- yl)morpholine A mixture of 6-(1-methyl- lH-pyrazol-4-yl)-lH-indazole (130 mg, 0.66 mmol), 4-(4- bromopyridin-2-yl)morpholine (319 mg, 1.31 mmol), copper(I) iodide (18 mg, 0.10 mmol) , trans-N, N-dimethylcyclohexane-l,2-diamine (28 mg, 0.20 mmol) and CS2CO3 (641 mg, 1.97 mmol) in DMF (3 mL) was microwaved at 120 °C for 6 h. The filtration removed the solid. After washing with DCM, the combined filtrate was concentrated in vacuo. The residue was purified by ISCO flash chromatography (eluted with 0-100% EtOAc / hexane) to provide 4-(4- (6-(l -methyl- lH-pyrazol-4-yl)-lH-indazol-l-yl)pyridin-2-yl)morpholine (Example 1). LCMS (ESI) m/z 361 (Ret. = 1.90 min, LCMS method a); LRRK2 IC50: 72 nM. Rat PK Oral AUC: 2.1 +/- 0.09 μΜ-h.
  • 12
  • [ 1040377-12-5 ]
  • 4,5,7,7-tetramethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) / ethanol; water / 12 h / 100 °C / Inert atmosphere 3: ammonium chloride; zinc / ethanol; water / 16 h / 80 °C 4: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 18.08 h / 0 - 20 °C
  • 13
  • [ 1040377-12-5 ]
  • 4-(4-(5-nitro-1H-indazol-3-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) / ethanol; water / 12 h / 100 °C / Inert atmosphere
  • 14
  • [ 1040377-12-5 ]
  • rac-4,5,7-trimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: caesium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran; water / 1 h / 100 °C / Inert atmosphere 2.1: ammonium chloride; iron / ethanol; water / 0.5 h / 80 °C 3.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 70 °C 4.1: hydrogenchloride / tetrahydrofuran; 1,4-dioxane / 1 h / 20 °C 4.2: 75 h / 20 - 70 °C
  • 15
  • [ 1040377-12-5 ]
  • 3-(2-morpholinopyridin-4-yl)-1H-indazol-5-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) / ethanol; water / 12 h / 100 °C / Inert atmosphere 3: ammonium chloride; zinc / ethanol; water / 16 h / 80 °C
Multi-step reaction with 2 steps 1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II)
  • 16
  • [ 1040377-12-5 ]
  • 4,5-dimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) / ethanol; water / 12 h / 100 °C / Inert atmosphere 3: ammonium chloride; zinc / ethanol; water / 16 h / 80 °C 4: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / dichloromethane / 12 h / 15 °C
  • 17
  • [ 1040377-12-5 ]
  • 3-[2-(morpholin-4-yl)pyridin-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-5-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran; water / 1 h / 100 °C / Inert atmosphere 2: ammonium chloride; iron / ethanol; water / 0.5 h / 80 °C
  • 18
  • [ 1040377-12-5 ]
  • (7R)-4,5,7-trimethyl-N-{3-[2-(morpholin-4-yl)pyridin-4-yl]-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-5-yl}-4H,7H-[1,2,3,4]tetrazolo[1,5 -a]pyrimidine-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran; water / 1 h / 100 °C / Inert atmosphere 2: ammonium chloride; iron / ethanol; water / 0.5 h / 80 °C 3: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 70 °C
  • 19
  • [ 1040377-12-5 ]
  • (7S)-4,5,7-trimethyl-N-{3-[2-(morpholin-4-yl)pyridin-4-yl]-1H-indazol-5-yl}-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]
  • (7R)-4,5,7-trimethyl-N-{3-[2-(morpholin-4-yl)pyridin-4-yl]-1H-indazol-5-yl}-4H,7H-[1,2,3,4]tetrazolo[1,5-a]pyrimidine-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: caesium carbonate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / tetrahydrofuran; water / 1 h / 100 °C / Inert atmosphere 2.1: ammonium chloride; iron / ethanol; water / 0.5 h / 80 °C 3.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0 - 70 °C 4.1: hydrogenchloride / tetrahydrofuran; 1,4-dioxane / 1 h / 20 °C 4.2: 75 h / 20 - 70 °C 5.1: Chiralpak AD-H (25 x 2.0 cm), 5 μ / ethanol; hexane; methanol / Resolution of racemate
  • 20
  • [ 1040377-12-5 ]
  • 5-nitro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[2-(trimethylsilyl) ethoxy]methyl}-1H-indazole [ No CAS ]
  • 3-[2-(morpholin-4-yl)pyridin-4-yl]-5-nitro-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
44% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 100℃; for 1h; Inert atmosphere; 24.5 Step 5. 3 -[2 -(morpholin -4 -yl)pyridin -4 -yl / -5 -nitro -1 -[ 2 -( trimethylsilyl) ethoxy] methyl } -1 H- indazole 5-Nitro-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-[2-(trimethylsilyl) ethoxy]methyl}-lH-indazole (crude, 1.0 mmol), 4-(4-bromopyridin-2-yl)morpholine (292 mg, 1.2 mmol) and Cs2C03 (977 mg, 3.0 mmol) were suspended in THF (5 mL) and H20 (1 mL). The mixture was purged with N2 for 5 min, and then Pd(dppf)Cl2 (73 mg, 0.1 mmol) was added. The reaction mixture was stirred at 100 °C for 1 h under nitrogen atmosphere. The mixture was portioned between H20 and EtOAc. The phases were separated, the aqueous layer was extracted with EtOAc (2x) and the combined organic layers washed with H20 (lx), dried over anhydrous Na2S04 and the solvent was removed under reduced pressure. The obtained crude was purified by flash chromatography on a 25 g silica gel column, eluting with a gradient of EtOAc in cyclohexane from 0 to 30%. Compound 5 (200 mg, 0.44 mmol, 44% yield over 2 steps) was obtained as a yellow oil. NMR (400 MHz, Chloroform-d) d 8.99 (d, J=2.0 Hz, 1H), 8.44 - 8.35 (m, 2H), 7.74 (d, J=9.2 Hz, 1H), 7.24 (dd, J= 1.3, 5.1 Hz, 1H), 7.21 (s, 1H), 5.85 (s, 2H), 3.94 - 3.88 (m, 4H), 3.70 - 3.61 (m, 6H), 0.99 - 0.88 (m, 2H), -0.03 (s, 9H). MS-ESI (m/z) calcd for C22H3oN504Si [M+H]+: 456.20. Found 456.36.
200 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 100℃; for 1h; Inert atmosphere;
YieldReaction ConditionsOperation in experiment
With caesium carbonate In dimethyl sulfoxide at 50℃; for 2h; 1-(5-bromopyridin-2-yl)-6-oxa-1-azaspiro[3.3]heptane (G2.A-1) General procedure: A mixture of 5-bromo-2-fluoropyridine (800 mg, 4.55 mmol, 468 uL), 6-oxa-1-azaspiro[3.3]heptane (655 mg, 2.27 mmol), Cs2CO3 (1.48 g, 4.55 mmol) in DMSO (10.0 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50°C for 2 hrs under N2 atmosphere. The reaction mixture was partitioned between H2O 10.0 mL and EtOAc (10.0 mL x 3). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO2, PE/EtOAc = 5/1) to give intermediate G2.A-1 (353 mg, 30.4% yield) as a yellow solid.
  • 22
  • [ 1040377-12-5 ]
  • 2-(2-morpholino-4-pyridyl)oxazole-4-carboxylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: caesium carbonate; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 2: methanol; water; lithium hydroxide monohydrate / tetrahydrofuran / 0.5 h / 25 °C / Inert atmosphere
  • 23
  • [ 1040377-12-5 ]
  • N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-2-(2-morpholino-4-pyridyl)oxazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: caesium carbonate; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 2: methanol; water; lithium hydroxide monohydrate / tetrahydrofuran / 0.5 h / 25 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 25 °C / Inert atmosphere
  • 24
  • [ 1040377-12-5 ]
  • N-[3-(difluoromethyl)-1-(4-formylcyclohexyl)pyrazol-4-yl]-2-(2-morpholino-4-pyridyl)oxazole-4-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: caesium carbonate; palladium diacetate; tris-(o-tolyl)phosphine / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 2: methanol; water; lithium hydroxide monohydrate / tetrahydrofuran / 0.5 h / 25 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.5 h / 25 °C / Inert atmosphere 4: Dess-Martin periodane / dichloromethane / 2 h / 25 °C / Inert atmosphere
  • 25
  • [ 23012-14-8 ]
  • [ 1040377-12-5 ]
  • ethyl 2-(2-morpholino-4-pyridyl)oxazole-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With palladium diacetate; caesium carbonate; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 70℃; for 12h; Inert atmosphere; 2 Step 2 - Ethyl 2-(2-morpholino-4-pyridyl)oxazole-4-carboxylate To a mixture of 4-(4-bromo-2-pyridyl)morpholine (3.00 g, 12.3 mmol) and ethyl oxazole-4- carboxylate (1.74 g, 12.3 mmol, CAS 170487-38-4) in DMF (50 mL) was added Pd(OAc)2 (277 mg, 1.23 mmol), Cs2CO3 (12.0 g, 37.0 mmol) and tris-o-tolylphosphane (751 mg, 2.47 mmol). The reaction mixture was stirred at 70 °C for 12 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE: EA = 10:1 to 5:1) to give the title compound (2.60 g, 69% yield) as white solid.1H NMR (400 MHz, DMSO-d6) d 8.99 (s, 1H), 8.28 (d, J = 5.2 Hz, 1H), 7.23 (s, 1H), 7.19 - 7.14 (m, 1H), 4.36 - 4.26 (m, 2H), 3.74 - 3.66 (m, 4H), 3.55 - 3.47 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H).
  • 26
  • [ 1040377-12-5 ]
  • [ 73183-34-3 ]
  • [ 952206-85-8 ]
YieldReaction ConditionsOperation in experiment
90% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane; water at 80℃; for 12h; Inert atmosphere; 39.2 Step 2: (2-Morpholinopyridin-4-yl,)boronic acid A mixture of 4-(4-bromopyridin-2-yl)morpholine (1.08 g, 4.44 mmol),bis(pinacolato)diboron (1.35 g, 5.33 mmol), AcOK (1.09 g, 11.11 mmol), [1,1-bis(diphenylphosphino)ferrocenej dichloropalladium(II) (325.07 mg, 444.26 umol) in 1,4- dioxane (15 mL) was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 80 °C for 12 hrs under N2 atmosphere. The reaction mixture was filtered and the filtrate was evaporated to afford the title compound (2.1 g, 90%) as a black oil. MS-ESI (m/z)calc’d for C9H14BN203 [M+Hf: 209.1. Found 209.0.
0.85 g With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In 1,4-dioxane at 80℃; for 12h; Inert atmosphere; 278.2 Step 2: (2-Morpholinopyridin-4-yl)boronic acid A mixture of 4-(4-bromopyridin-2-yl)morpholine (1 g, 4.11 mmol), bis(pinacolato)diboron (1.25 g, 4.94 mmol), AcOK (1.01 g, 10.28 mmol), Pd(dppf)Cl2 (300.99 mg, 411.35 umol) in 15 mL of dioxane was degassed and purged with N2 (3x) at 20 °C, and then the mixture was stirred at 80 °C for 12 hrs under an N2 atmosphere. The mixture was filtered, the filtrate was concentrated under reduced pressure to afford the title compound (0.85 g) as black oil, which was used without further purification. MS-ESI (m/z) calcd for C9H14BN2O3 [M+H]+: 209.1. Found 209.2.
  • 27
  • [ 1040377-12-5 ]
  • (x)C2HF3O2*C25H23N7O2 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) / water; ethanol / 1 h / 90 °C / Inert atmosphere
  • 28
  • [ 1040377-12-5 ]
  • 6-chloro-5-cyano-3,4-dimethyl-N-(3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)picolinamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) 3: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / dichloromethane; ethyl acetate / 12 h / 15 °C
  • 29
  • [ 1040377-12-5 ]
  • 5-((3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) / water; ethanol / 24 h / 90 °C / Inert atmosphere
  • 30
  • [ 1040377-12-5 ]
  • 5-((3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [ No CAS ]
  • 5-((3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)amino)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate; bis(di-tert-​butyl(4-​dimethylaminophenyl)​phosphine)​dichloropalladium(II) / water; ethanol / 24 h / 90 °C / Inert atmosphere 3: DAICEL CHIRALPAK AS(250*30 mm, 10 um) / methanol / Resolution of racemate
  • 31
  • [ 1040377-12-5 ]
  • 4-(4-(5-bromo-1H-indazol-3-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate / water; ethanol / 12 h / 90 °C / Inert atmosphere
  • 32
  • [ 1040377-12-5 ]
  • 4-(4-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate / water; ethanol / 12 h / 90 °C / Inert atmosphere 3: methanesulfonic acid / chloroform / 12 h / 15 - 70 °C
  • 33
  • [ 1040377-12-5 ]
  • 4-(4-(1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate / water; ethanol / 12 h / 90 °C / Inert atmosphere 3: methanesulfonic acid / chloroform / 12 h / 15 - 70 °C 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,3-dioxane / 2 h / 100 °C
  • 34
  • [ 1040377-12-5 ]
  • 3-(2-morpholinopyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate / water; ethanol / 12 h / 90 °C / Inert atmosphere 3: methanesulfonic acid / chloroform / 12 h / 15 - 70 °C 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,3-dioxane / 2 h / 100 °C 5: sodium peroxoborate tetrahydrate / tetrahydrofuran; water / 1 h / 15 - 50 °C / Inert atmosphere
  • 35
  • [ 1040377-12-5 ]
  • 5-((3-(2-morpholinopyridin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate / water; ethanol / 12 h / 90 °C / Inert atmosphere 3: methanesulfonic acid / chloroform / 12 h / 15 - 70 °C 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,3-dioxane / 2 h / 100 °C 5: sodium peroxoborate tetrahydrate / tetrahydrofuran; water / 1 h / 15 - 50 °C / Inert atmosphere 6: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 1 h / 0 - 45 °C
  • 36
  • [ 1040377-12-5 ]
  • 5-((3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate / water; ethanol / 12 h / 90 °C / Inert atmosphere 3: methanesulfonic acid / chloroform / 12 h / 15 - 70 °C 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,3-dioxane / 2 h / 100 °C 5: sodium peroxoborate tetrahydrate / tetrahydrofuran; water / 1 h / 15 - 50 °C / Inert atmosphere 6: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 1 h / 0 - 45 °C 7: toluene-4-sulfonic acid / water; deuteromethanol / 3 h / 70 °C
  • 37
  • [ 1040377-12-5 ]
  • 5-((3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [ No CAS ]
  • 5-((3-(2-morpholinopyridin-4-yl)-1H-indazol-5-yl)oxy)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 8 steps 1: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; 1,4-dioxane / 12 h / 80 °C / Inert atmosphere 2: potassium acetate / water; ethanol / 12 h / 90 °C / Inert atmosphere 3: methanesulfonic acid / chloroform / 12 h / 15 - 70 °C 4: potassium acetate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,3-dioxane / 2 h / 100 °C 5: sodium peroxoborate tetrahydrate / tetrahydrofuran; water / 1 h / 15 - 50 °C / Inert atmosphere 6: tributylphosphine; 1,1'-azodicarbonyl-dipiperidine / tetrahydrofuran / 1 h / 0 - 45 °C 7: toluene-4-sulfonic acid / water; deuteromethanol / 3 h / 70 °C 8: ammonium hydroxide / ethanol
  • 38
  • [ 1040377-12-5 ]
  • [ 1066-54-2 ]
  • 4-(4-((trimethylsilyl)ethynyl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
100% With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine In tetrahydrofuran at 70℃; for 1h; Inert atmosphere; 4.2 Step 2-Preparation of 4-(4-((trimethylsilyl)ethynyl)pyridin-2-yl)morpholine A mixture of 4-(4-bromopyridin-2-yl)morpholine (5.32 g, 21.9 mmol), PdCl2(PPh3)2 (768 mg, 1.09 mmol), copper iodide (207 mg, 1.09 mmol), triethylamine (5.8 mL, 42.0 mmol) and TMS-acetylene (15.0 mL, 109.5 mmol) in THF (42 mL) under nitrogen was heated at 70° C. for 1 h. EtOAc (100 mL) was added and the reaction mixture was washed with water (50 mL) and brine (50 mL). After removal of the solvent, the crude residue was purified by silica gel column chromatography using 0-30% hexanes:EtOAc to give 4-(4-((trimethylsilyl)ethynyl)pyridin-2-yl)morpholine (5.96 g, 100% yield). ESI-MS m/z calc. 260.13, found 261.1 (M+H)+.
  • 39
  • [ 1040377-12-5 ]
  • 2-(2-morpholinopyridin-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 6 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C 4.1: acetonitrile; 1-methyl-pyrrolidin-2-one / 1.17 h / 20 °C 5.1: copper(l) iodide / 1-methyl-pyrrolidin-2-one / 4 h / 95 °C 5.2: 16 h / 90 °C / Inert atmosphere 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; ethanol / 18 h / 3087.28 Torr
Multi-step reaction with 6 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C 4.1: acetonitrile; 1-methyl-pyrrolidin-2-one / 1.17 h / 20 °C 5.1: copper(l) iodide / 1-methyl-pyrrolidin-2-one / 4 h / 95 °C 5.2: 20 °C 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; ethanol / 18 h / 3087.28 Torr
  • 40
  • [ 1040377-12-5 ]
  • 3-((2-morpholinopyridin-4-yl)ethynyl)-5-nitropyridin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C
  • 41
  • [ 1040377-12-5 ]
  • 2,2,2-trifluoro-N-(3-((2-morpholinopyridin-4-yl)ethynyl)-5-nitro-pyridin-2-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 4 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C 4.1: acetonitrile; 1-methyl-pyrrolidin-2-one / 1.17 h / 20 °C
  • 42
  • [ 1040377-12-5 ]
  • 4-(4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 5 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C 4.1: acetonitrile; 1-methyl-pyrrolidin-2-one / 1.17 h / 20 °C 5.1: copper(l) iodide / 1-methyl-pyrrolidin-2-one / 4 h / 95 °C 5.2: 16 h / 90 °C / Inert atmosphere
Multi-step reaction with 5 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C 4.1: acetonitrile; 1-methyl-pyrrolidin-2-one / 1.17 h / 20 °C 5.1: copper(l) iodide / 1-methyl-pyrrolidin-2-one / 4 h / 95 °C 5.2: 20 °C
  • 43
  • [ 1040377-12-5 ]
  • 4-(4-ethynylpyridin-2-yl)morpholine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2: potassium carbonate; methanol / 1 h / 20 °C
  • 44
  • [ 1040377-12-5 ]
  • [ 1616386-69-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 7 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C 4.1: acetonitrile; 1-methyl-pyrrolidin-2-one / 1.17 h / 20 °C 5.1: copper(l) iodide / 1-methyl-pyrrolidin-2-one / 4 h / 95 °C 5.2: 16 h / 90 °C / Inert atmosphere 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; ethanol / 18 h / 3087.28 Torr 7.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C
Multi-step reaction with 7 steps 1.1: bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine / tetrahydrofuran / 1 h / 70 °C / Inert atmosphere 2.1: potassium carbonate; methanol / 1 h / 20 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; XPhos; caesium carbonate / acetonitrile / 0.5 h 3.2: 20 h / 60 °C 4.1: acetonitrile; 1-methyl-pyrrolidin-2-one / 1.17 h / 20 °C 5.1: copper(l) iodide / 1-methyl-pyrrolidin-2-one / 4 h / 95 °C 5.2: 20 °C 6.1: 5%-palladium/activated carbon; hydrogen / tetrahydrofuran; ethanol / 18 h / 3087.28 Torr 7.1: N-ethyl-N,N-diisopropylamine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate / N,N-dimethyl-formamide / 16 h / 20 °C
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