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[ CAS No. 851985-81-4 ] {[proInfo.proName]}

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Chemical Structure| 851985-81-4
Chemical Structure| 851985-81-4
Structure of 851985-81-4 * Storage: {[proInfo.prStorage]}
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Product Details of [ 851985-81-4 ]

CAS No. :851985-81-4 MDL No. :MFCD08063115
Formula : C15H18BNO2 Boiling Point : -
Linear Structure Formula :- InChI Key :CIXVOEJAOCHQKS-UHFFFAOYSA-N
M.W : 255.12 Pubchem ID :59296116
Synonyms :

Calculated chemistry of [ 851985-81-4 ]

Physicochemical Properties

Num. heavy atoms : 19
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.4
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 0.0
Molar Refractivity : 78.22
TPSA : 31.35 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : Yes
CYP3A4 inhibitor : Yes
Log Kp (skin permeation) : -5.6 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.0
Log Po/w (XLOGP3) : 3.18
Log Po/w (WLOGP) : 2.53
Log Po/w (MLOGP) : 1.71
Log Po/w (SILICOS-IT) : 2.35
Consensus Log Po/w : 1.95

Druglikeness

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

Water Solubility

Log S (ESOL) : -3.75
Solubility : 0.0455 mg/ml ; 0.000178 mol/l
Class : Soluble
Log S (Ali) : -3.51
Solubility : 0.0789 mg/ml ; 0.000309 mol/l
Class : Soluble
Log S (SILICOS-IT) : -5.3
Solubility : 0.00127 mg/ml ; 0.00000497 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.86

Safety of [ 851985-81-4 ]

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 [ 851985-81-4 ]

* 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 [ 851985-81-4 ]

[ 851985-81-4 ] Synthesis Path-Downstream   1~93

  • 1
  • [ 163485-84-5 ]
  • [ 73183-34-3 ]
  • [ 851985-81-4 ]
YieldReaction ConditionsOperation in experiment
81.3% With potassium acetate In 1,4-dioxane at 80℃; 36.B Potassium acetate (391 mg, 3.98 mmol) was added to a solution of quinolin-7-yl trifluoromethanesulfonate (370 mg, 1 .32 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi- 1 ,3,2-dioxaborolane (405 mg, 1.60 mmol), and [1 , 1 '-bis-(diphenylphosphino)ferrocene]- dichloropalladium (I I) dcm complex (325 mg, 0.40 mmol) in 1 ,4-dioxane (5.0 mL) in a 20 mL vial. The vial was capped and heated to 80°C and stirred at this temperature overnight. The reaction was allowed to cool, diluted with ethyl acetate (25 mL) and water (25 mL), filtered through celite (~1 inch) and the filter pad was washed with ethyl acetate (10 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2x30 mL). The combined organics were dried (MgS04), filtered, and concentrated. Crude material was purified via flash chromatography using an Analogix SF15-24g column and ethyl acetate in heptane (0-50%) as the eluant to afford the title compound as a white solid (277 mg, 81.3%). LC-MS m/z 256.5 (M+1 ). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (s, 12 H) 7.40 - 7.45 (m, 1 H) 7.81 (d, J=8.01 Hz, 1 H) 7.88 - 7.95 (m, 1 H) 8.12 - 8.18 (m, 1 H) 8.62 (d, J=0.78 Hz, 1 H) 8.83 - 9.01 (m, 1 H)
74% With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 100℃; for 2h; 1.h h) 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline A flask was charged with a suspension of 7-quinolinyl trifluoromethanesulfonate (8.66 mmol), bis(pinacolato)diboron (10.39 mmol), PdC12(dppf)-CH2C12 adduct (0.432 mmol), 1 , l'-bis(diphenylphosphino)ferrocene (0.433 mmol) and potassium acetate (26.0 mmol) in 1,4-dioxane (40 mL) and heated at 100 °C for 2 h. The resulting dark suspension was cooled to room temperature, taken up into ethyl acetate, washed with water (2x) and brine, dried (sodium sulfate), and evaporated to an oil (2.25 g). The oil was purified by flash chromatography (10-60% ethyl acetate in hexanes). The desired fractions were combined and evaporated to an oil that was taken up in dichloromethane and evaporated again in vacuo to afford the title product (1.72 g, 74% yield) as a pale yellow oil that solidified upon standing. MS(ES)+ m/e 256.2 [M+H]+ . 1H NMR (400 MHz, DMSO- 6) 5 ppm 1.34 (s, 12 H) 7.58 (dd, J=8.34, 4.04 Hz, 1 H) 7.80 (dd, J=8.08, 1.01 Hz, 1 H) 7.93 - 8.00 (m, 1 H) 8.34 (s, 1H) 8.36 - 8.41 (m, 1 H) 8.95 (dd, J=4.29, 1.77 Hz, 1 H).
74% With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 100℃; for 2h; 1.h h) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline A flask was charged with a suspension of 7-quinolinyl trifluoromethanesulfonate(8.66 mmol), bis(pinacolato)diboron (10.39 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.432 mmol), 1,1-bis(diphenylphosphino)ferrocene (0.433 mmol) and potassium acetate (26.0 mmol) in 1,4-dioxane (40 mL) and heated at 100 °C for 2 h. The resulting dark suspension was cooled to room temperature, taken up into ethyl acetate, washed with water (2x) and brine, dried (sodium sulfate), and evaporated to an oil (2.25 g). The oilwas purified by flash chromatography (10-60% ethyl acetate in hexanes). The desired fractions were combined and evaporated to an oil that was taken up in dichloromethane and evaporated again in vacuo to afford the title product (1 .72 g, 74% yield) as a pale yellow oil that solidified upon standing. MS(ES)+ m/e 256.2 [M+H]+ . 1H NMR (400 MHz, DMSO-d6) 6 ppm 1.34 (s, 12H) 7.58 (dd, J=8.34, 4.04 Hz, 1H) 7.80 (dd, J=8.08, 1.01Hz, 1H) 7.93 - 8.00 (m, 1H) 8.34 (s, 1H) 8.36 - 8.41 (m, 1H) 8.95 (dd, J=4.29, 1.77 Hz,1H).
74% With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate In 1,4-dioxane at 100℃; for 2h; 27.b b) 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline A flask was charged with a suspension of 7-quinolinyl trifluoromethanesulfonate (8.66 mmol), bis(pinacolato)diboron (10.39 mmol), l,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (0.432 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene (0.433 mmol) and potassium acetate (26.0 mmol) in 1,4- dioxane (40 mL) and heated at 100 °C for 2 h. The resulting dark suspension was cooled to room temperature, taken up into ethyl acetate, washed with water (2x) and brine, dried (sodium sulfate), and evaporated to an oil (2.25 g). The oil was purified by flash chromatography (10-60% ethyl acetate in hexanes). The desired fractions were combined and evaporated to an oil that was taken up in dichloromethane and evaporated again in vacuo to afford the title product (1.72 g, 74%) as a pale yellow oil that solidified upon standing. MS(ES)+ m/e 256.2 [M+H]+ . 1H NMR (400 MHz, DMSO- 6) δ ppm 1.34 (s, 12 H) 7.58 (dd, J=8.34, 4.04 Hz, 1 H) 7.80 (dd, J=8.08, 1.01 Hz, 1 H) 7.93 - 8.00 (m, 1 H) 8.34 (s, 1H) 8.36 - 8.41 (m, 1 H) 8.95 (dd, J=4.29, 1.77 Hz, 1 H).
With potassium acetate In 1,4-dioxane 11 Description 11; 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; To a mixture of Description 10 (8.7 g, 31.4 mmol), bis (pinacolato) diboron (8. 8 g, 34.5 mmol), and potassium acetate (9.25 g, 94.2 mmol) in anhydrous 1, 4-dioxane (150 ml) was added Pd (dppf) C12 (860 mg, 0.94 mmol). The mixture de-gassed three times and heated at 80OC overnight. The mixture was cooled and diluted with ethyl acetate (200 ml), washed with water (required a filtration through celite), sat. NaCl, dried over Na2SO4, filtered and evaporated to give the title compound as a brown oil which solidified on standing. 1H NMR (400 MHz, CDCl3) 1.39 (12 H, s), 7. 42 (1 H, dd, J8.2 and 3.9), 7.79 (1 H, d, J7.8), 7.90 (1 H, d, J9.0), 8.15 (1 H, dd, J8. 6 and 1. 2), 8. 61 (1 H, s), 8.90 (1 H, dd, J4. 3 and 2. 0).
With potassium acetate In 1,4-dioxane at 125℃; for 0.25h; Microwave irradiation; 7.b (b) 7-(4,4,5,5-Betramethyl-1,3,2-dioxaborolan-2-yl)quinoline. To a 20-mL microwave reaction tube was added 1,1'-bis(diphenylphosphino)ferrocene (0.106 g, 0.191 mmol, Aldrich), 1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium(ii) (0.141 g, 0.192 mmol, Aldrich), potassium acetate (1.134 g, 11.55 mmol, EMD Science), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.172 g, 4.617 mmol, Aldrich) and quinolin-7-yl trifluoromethanesulfonate (1.042 g, 3.760 mmol) in 10 mL of 1,4-dioxane. The tube was subjected to the microwave irradiation at 125° C. for 900 s. The reaction mixture was filtered through a pad of Celite and washed with 100 mL EtOAc. The organic phase was washed with water (1×100 mL) and saturated aqueous NaCl (1×100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a gray residue. The crude product was purified by flush column chromatography (eluent: EtOAc in hexanes 0%-60%) to afford 7-(4,4,5,5-betramethyl-1,3,2-dioxaborolan-2-yl)quinoline as brownish solid [MS (ESI, pos. ion) m/z: 256 (M+1)].
4.34 g With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 100℃; for 2h; Inert atmosphere; Sealed tube; 10.b (b) 7-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline A sealable reaction flask was charged with 7-quinolinyl trifluoromethanesulfonate (5.17 g, bis(pinacolato)diboron (4.74 g), Pd(dppf)CI2 (0.682 g), 1 , 1 '-bis(diphenylphosphino)ferrocene (0.517 g), potassium acetate (5.49 g) and 1 ,4-dioxane (100 mL). The flask was purged with nitrogen, sealed and heated to 100 °C. After 2 hours, the reaction was allowed to cool to room temperature and diluted with EtOAc. The mixture was filtered through a pad of Celite^ rinsing with EtOAc, and the filtrate was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 40-50%EtOAc/hexanes. The appropriate fractions were concentrated under reduced pressure and dried to constant weight over 36 hours to provide 4.34 g of the titled compound as an off- white solid. LCMS m/z 174.0 (M+H).

  • 2
  • [ 851985-81-4 ]
  • [ 852062-26-1 ]
  • 2-(morpholin-4-ylmethyl)-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With caesium carbonate In 1,4-dioxane at 140℃; for 0.5h; 109 Example 109; 2- (Morpholin-4-vlmethvl)-6-auinolin-7-vl-N [4-trifluoromethyl phenyllpyrimidin-4-amine; A mixture of Description 130 (122 mg, 0.327 mmol), Description 11 (167 mg, 0.654 mmol), Pd (dppf) Cl2 (12 mg, 0.016 mmol) and 2M sodium carbonate (654 ffi 1.31 mmol) in dioxane (3 ml) was degassed and heated at 140°C for 30 mins. The cooled mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5 % MeOH in 1: 1 isohexane- ethyl acetate increasing polarity to 10 % MeOH in 1: 1 isohexane-ethyl acetate. The product was then recrystallised from toluene to give a beige coloured solid (40 mg, 26 %). 1H NMR (500 MHz, DMSO-d6) 2.66 (4 H, m), 3.66 (4 H, m), 3.76 (2 H, s), 7.41 (1 H, s), 7.61 (1 H, dd, J8. 2 and 4. 1), 7.71 (2 H, d, J8. 6), 8.06 (2 H, d, J 8.5), 8.15 (1 H, d, J8. 6), 8.26 (1 H, dd, J8.5 and 1.4), 8.45 (1 H, d, J8.0), 8.69 (1 H, s), 9.00 (1 H, dd, J4.1 and 1.5), 10.15 (1 H, s) ; m/z (ES+) 466 (M+H+).
  • 3
  • [ 851985-81-4 ]
  • [ 852062-31-8 ]
  • 6-quinolin-7-yl-2-trifluoromethyl-N-[4-trifluoromethylphenyl]-pyrimidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With sodium carbonate In 1,4-dioxane at 160℃; for 2h; Microwave irradiation; 119 Example 119; 6-Quinolin-7-yl-2-trifluoromethyl-N-[4-trifluoromethylphenyl]- pyrimidin-4-amine; Description 136 (0.5 g, 1.46 mmol), Description 11 (0.41 g, 1.61 mmol), [1, 1'- Bis (diphenylphosphino) ferrocene] palladium (II) chloride (53 mg, 0.073 mmol) and 2M Na2CO3 (aq) (1.6 ml) were suspended in dioxane (5ml) and the mixture was heated at 1600C for 15 mins in a microwave reactor (Personal Chemistry-Emrys OptimizerNo.). The mixture was filtered through celite, washing the residue with EtOAc and water. The layers were separated, and the organic phase was dried (sodium sulfate) and concentrated to give a brown oily residue, which was triturated with DCM followed by diethyl ether to give a white crystalline solid. (250 mg, 39%). 1H NMR (500 MHz, CDCI3) 7.26 (1 H, s), 7.43 (1 H, s), 7. 49 (1 H, dd, J8.6 and 4.2), 7.65 (2 H, d, J8.6), 7. 72 (2 H, d, J8.6), 7.96 (1 H, d, T8.-Q) v 8. 22 (1 H, d, J7.8), 8. 36 (1 H, dd, J8.6 and 1.7), 8.70 (1 H, s), 8.99 (1 H, dd, J4.1 and. 1.6) ; mlz (ES+) 435 (M+H+).
  • 4
  • [ 851985-81-4 ]
  • [ 851985-88-1 ]
  • 5-nitro-6-quinolin-7-yl-N-[4-trifluoromethylphenyl]pyrimidin-4-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
4% With sodium carbonate In ethanol; toluene Heating / reflux; 28 Example 28; 5-Nitro-6-quinolin-7-vl-N- [4-trifluoromethvlphenvl] pyrimidin-4- amine; To a mixture of Description 29 (2.01 g, 6.3 mmol) and Description 11 (2.41 g, 9.45 mmol) in a mixture of toluene (50 ml) and ethanol (10 ml) was added 2M sodium carbonate (3.15 ml, 6.3 mmol) and Pd (PPh3) 4 (364 mg, 0.315 mmol). The mixture was de-gassed three times and heated at reflux overnight. The cooled mixture was diluted with EtOAc (100 ml) and washed with water (200 ml), sat. NaCl (100 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica: (eluent 1% MeOH in DCM +0, 5% NHs) then a second column (eluent 20% EtOAc in iso-hexanes). The product triturated with diethyl ether to give the title compound as a pale yellow solid (100 mg, 4%). 1H NMR (500 MHz, CDC13) 7.50 (1 H, dd, J8.3 and 4.2), 7.70 (2 H, d, J 8.1), 7.72 (1 H, dd, J8. 6 and 1. 7), 7.81 (2 H, d, J8.1), 7.95 (1 H, d, J8.6), 8.24 (1 H, d, J7. 6), 8.36 (1 H, s), 8.87 (1 H, s), 9.00 (1 H, dd, J4.2 and 1.7) ; m/z (ES+) 412 (M+H+).
  • 5
  • [ 6299-25-8 ]
  • [ 851985-81-4 ]
  • [ 852062-30-7 ]
YieldReaction ConditionsOperation in experiment
64% With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 16h; Description 134; 7- [6-Chloro-2-methvlthiopvrimidin-4-yl] quinoline; 4, 6-Dichloro-2-methylthiopyrimidine (0.99 g, 5.09 mmol), Description 11 (0.65 g, 2.54 mmol), [1, l'-Bis (diphenylphosphino) ferrocene] palladium (II) chloride (93 mg, 0.12 mmol) and 2M Na2CO3 (aq) (2.54 ml) were suspended in 1,4-dioxane (20 ml) and heated to 100°C for 16 hours under nitrogen. After cooling to room temperature the mixture was filtered through a pad of Celite (g), washing the residue ethyl acetate. The filtrate was concentrated under-reduced pressure to give a brown residue, which was partitioned between water and ethyl acetate. The aqueous phase was washed with ethyl acetate, the combined organic phases were washed (brine), dried (sodium sulfate) and concentrated to give a dark- brown oil, which was purified by flash chromatography using a Biotage-HorizonNo. HPFC system (40S cartridge, gradient elution from 0-50percent ethyl acetate/ isohexane) to give a pale yellow solid (0.47 g, 64percent). 1H NMR (400 MHz, CDCl3) 2.70 (3 H, s), 7.49 (1 H, dd, J8.3 and 4.2), 7.57 (1 H, s), 7.95 (1 H, d, J8.6), 8.22- 8.28 (2 H, m), 8.81 (1 H, s), 9.00 (lH, dd, J4. 2 and 1. 7).
  • 6
  • [ 851985-81-4 ]
  • [ 352-34-1 ]
  • [ 889687-03-0 ]
YieldReaction ConditionsOperation in experiment
50% With sodium carbonate In 1,4-dioxane; water at 80℃; for 18h; 29.1 Step 1: 7-(4-Fluorophenyl)quinoline hydrochloride; A mixture of 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline [prepared by the method ofHollingworth et al, WO 2005047279] (7.6 g, 30 mmol), 4-fluoro-l-iodobenzene (3.4 mL, 30 mmol), 2 M aqueous sodium carbonate (50 mL) and [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.22 g, 1.5 mmol) in 1,4-dioxane (150 mL) was degassed then stirred at 800C (oil bath temperature) under nitrogen for 18 hours. The reaction mixture was filtered and the filter cake washed with ethyl acetate. Water (150 mL) was added to the filtrate and the mixture extracted with ethyl acetate (2 x 250 mL). The extracts were washed with brine (100 mL), combined, dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with dichloromethane then 5% ethyl acetate/dichloromethane, to afford a tan solid (3.42 g). This solid was dissolved in dichloromethane (30 mL) and the solution diluted with diethyl ether (30 mL). IM Hydrogen chloride in diethyl ether (18 mL) was added with swirling to precipitate a solid. The mixture was further diluted with diethyl ether (42 mL) and left to stand for 20 minutes. The solid was collected under suction, washed with 25% dichloromethane/diethyl ether and dried in vacuo to afford 7-(4-fluorophenyl)quinoline hydrochloride (3.90 g, 50%). 1H NMR (500 MHz,CD3OD) δ 9.24 (2H, d, J 6.5 Hz), 8.44 (IH, d, J 8.6 Hz), 8.41 (IH, s), 8.31 (IH, dd, J 1.6, 8.6 Hz), 8.10(IH, m), 7.95-7.93 (2H, m), 7.34 (2H, t, J 8.7 Hz).
  • 7
  • [ 153034-86-7 ]
  • [ 851985-81-4 ]
  • [ 942947-22-0 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate In water; toluene at 90℃; for 20h; 7.c (c) 7-(2-Chloropyridin-4-yl)quinoline. To a solution of 4-iodo-2-chloro pyridine (0.300 g, 1.25 mmol, Alfa Aesar) and (t-4)-tetrakis(triphenylphosphine)-palladium (0.145 g, 0.125 mmol, Strem Chemicals) in toluene (4 mL) in a 150-mL round-bottomed flask under N2 was added 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.352 g, 1.38 mmol) followed by Na2CO3 (0.159 g, 1.50 mmol, Mallinckrodt) in 1 mL of water. The reaction mixture was stirred at 90° C. for 20 h. The reaction was allowed to cool to room temperature and partitioned between EtOAc (10 mL) and saturated NaCl (10 mL). The aqueous layer was back extracted with EtOAc (3×10 mL) and the combined EtOAc layers were dried over Na2SO4, filtered, and concentrated. The crude material was purified by normal phase column chromatography (gradient: 5%-50% EtOAc/Hexanes) to yield 7-(2-chloropyridin-4-yl)quinoline as a yellow solid [MS (ESI, pos. ion) m/z: 241 (M+1)].
  • 8
  • [ 4965-36-0 ]
  • [ 73183-34-3 ]
  • [ 851985-81-4 ]
YieldReaction ConditionsOperation in experiment
60% With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 20 - 80℃;Inert atmosphere; To a solution of <strong>[4965-36-0]7-bromoquinoline</strong> (520 mg, 2.5 mmol) in DMSO (50 mL) was added KOAc (750 mg, 7.5 mmol), bis(pinacolato)diboron (690 mg, 2.75 mmol) and PdCl2(dppf) (85 mg, 0.125 mmol) at room temperature. The reaction mixture was stirred overnight at 8O0C under N2 protection. The resulted mixture was diluted with EA and washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EA:PE=1 :5) to afford 7-(4,4,5,5-tetramethyl-l,3,2 -dioxaborolan-2-yl)quinoline (380 mg, 60%) as yellow solid. MS (m/z) (M~+H): 255 (ester) and 173 (acid).
58% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 5h;Inert atmosphere; A mixture of <strong>[4965-36-0]7-bromoquinoline</strong> (CAS 4965-36-0, 2 g, 9.60 mmol), 4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl-4',4',5',5'-tetramethyl-1,3,2-dioxaborolane (2.68 g, 10.5 mmol), potassium acetate (2.83g, 28.8 mmol) and bis(diphenylphosphino)ferrocene]dichloropalladium (351 mg, 0.48 mmol) in dry dioxane (50 mL) was degassed under argon. The mixture was heated at 110C for 5 h. This mixture was filtered through celite, washed with ethyl acetate and the filtrate was concentrated under vacuum to give 4.2 g of the crude product (50% pure by 1H NMR). 2.9 g of the crude product was purified by using isolera (80g column, eluent: heptane-ethyl acetatee, 1:9, 5CV, 10-60% gradient 10CV) to give 1.5 g of the desired product (95% purity, 58% yield). (1019) LC-MS (Method 5): Rt = 0.69 min; MS (ESIpos): m/z = 256 [M+H]+ 1H NMR (400 MHz, CDCl3) [ppm]: 1.37 (s, 12H), 7.39-7.42 (m, 1H), 7.79 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 8.61 (s, 1H), 8.92 (d, 1H).
52% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃;Inert atmosphere; 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (66a) (0311) 7-Bromoquinoline (500 mg, 2.36 mmol, 1.0 equiv), bis(pinacolato)diboron (671 mg, 2.64 mmol, 1.1 equiv), potassium acetate (707 mg, 7.20 mmol, 3.1 equiv) and Pd(dppf)Cl2 (52.7 mg, 72.0 mumol, 0.03 equiv) were dissolved under Argon atmosphere in 7 ml DMSO and the mixture was stirred at 80 C. over night. Water was added and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to dryness. The raw product was purified by flash chromatography; yield: 52% (316 mg). 1H NMR (300 MHz, acetone-d6): delta 8.93 (dd, J=4.1, 1.7 Hz, 1H), 8.49 (s, 1H), 8.35-8.27 (m, 1H), 7.97-7.83 (m, 2H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 1.39 (s, 12H).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 130℃;Inert atmosphere; Under an argon atmosphere, 600 mg (2.884 mmol) of <strong>[4965-36-0]7-bromoquinoline</strong> [Butler et al., J. Heterocycl. Chem. 1975, 12, 1015] was dissolved in 25 ml dioxane. Then 509 mg (5.19 mmol) potassium acetate, 188 mg (0.231 mmol) of l,l'-bis-(diphenylphosphino)ferrocene palladium(IT) chloride-dichloromethane complex and 805 mg (3.17 mmol) of 4,4,4'4'5,5,5'5'-octamethyl-2,2'-bi- 1,3,2-dioxaborolan were added. The reaction mixture was stirred overnight at 1300C oil bath temperature. After cooling, dioxane was added to the reaction mixture and it was filtered on kieselguhr. It was washed again with ethyl acetate. The filtrate was concentrated in a rotary evaporator at reduced pressure and dried under high vacuum. We obtained 1100 mg of 7-(4 ,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline as raw product. This was reacted subsequently without further purification.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere; Compound A3-1 (105mg, 0.51mmol) was dissolved in dioxane (10mL), was added bis (pinacolato) diboron (191mg, 0.75mmol),KOAc (147mg, 1.50mmol), Pd(dppf)2Cl2 (20mg, 0.024mmol), purged with nitrogen, stirred overnight at 90 deg. C, cooled to room temperature, withCelite filtration, the filtrate was spin-dried to obtain a crude black oil (360mg), was used directly in the next step.

  • 9
  • [ 851985-81-4 ]
  • [ 1209485-74-4 ]
  • [ 1210047-83-8 ]
YieldReaction ConditionsOperation in experiment
22% With potassium phosphate In 1,4-dioxane at 100℃; Inert atmosphere; 76A.2 Under an argon atmosphere, 202 mg of the 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline raw product thus obtained, together with 150 mg (0.468 mmol) of example 69A, 13 mg (0.045 mmol) of tricyclohexylphosphine, 19 mg (0.019 mmol) of tris(dibenzylidene- acetone)-dipalladium and 0.637 ml (0.637 mmol) of IM potassium phosphate solution, was taken up in 5 ml dioxane. Then it was reacted overnight at 1000C. The solid constituents were separated by filtration, the solvent was removed in a rotary evaporator and the reaction mixture was purified by HPLC (Puriflash Analogix: 4OS: isohexane / ethyl acetate = 95 / 5 → isohexane / ethyl acetate = 10 / 90). We obtained 37 mg (22% of theor.) of the target compound.LC-MS (method 4): R, = 1.27 min; MS (EIpos): m/z = 449 [M+H]+.IH-NMR (400 MHz, DMSO-D6): δ [ppm] = 2.18 (s, 3H), 2.47 (s, 3H), 3.79 (s, 3H), 6.48 (d, IH), 6.59 (t, IH), 7.16 (t, IH), 7.23 (m, IH), 7.27-7.36 (m, 2H), 7.43 (d, IH), 7.47 (dd, IH), 7.65 (dd, IH), 7.71 (dd, IH), 7.92 (d, IH), 8.04 (s, IH), 8.29 (d, IH), 8.85 (d, IH), 9.21 (s, IH).
  • 11
  • [ 851985-81-4 ]
  • [ 1366767-95-4 ]
  • [ 1366767-62-5 ]
YieldReaction ConditionsOperation in experiment
25% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; 101 Example 1017-[4-(4- [ 1 -(cyclopropylcarbonyl)-3-azetidinyl]methyl}-4H- 1 ,2,4-triazol-3-yl)-3- fluorophenyl] quinolineA mixture of 3-(4-bromo-2-fluorophenyl)-4-[l-(cyclopropylcarbonyl)-3- azetidinyl]methyl}-4H-l,2,4-triazole (100 mg, 0.264 mmol), 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (US2007/149513A1; 75 mg, 0.294 mmol), and PdCl2(dppf) (20 mg, 0.024 mmol) in 1,4-dioxane (2 mL) and 2 M aq. K2C03 (1.0 mL) was stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature and the 1,4-dioxane layer was filtered through a plug of Celite and Na2S04, rinsing with 1,4-dioxane (2 mL). The combined 1 ,4-dioxane layers were concentrated in vacuo and the residue was purified by reverse phase HPLC (10-70% CH3CN/water with 0.1% NH4OH) and then reverse phase HPLC (2-40% CH3CN/water with 0.1% ammonia) to afford the title compound (28 mg, 25%) as a solid. MS(ES)+ m/e 428.0 [M+H]+.
  • 12
  • [ 851985-81-4 ]
  • [ 1332332-73-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / water; propan-1-ol / 22 h / 130 °C 1.2: 5 h / 100 °C 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.03 h / Inert atmosphere 2.2: 1 h / 20 °C
  • 13
  • [ 851985-81-4 ]
  • [ 1332332-74-7 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: potassium carbonate / water; propan-1-ol / 22 h / 130 °C 1.2: 5 h / 100 °C 2.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 1.5 h / 20 °C / Inert atmosphere
  • 14
  • [ 851985-81-4 ]
  • [ 1332333-33-1 ]
  • [ 1332333-95-5 ]
YieldReaction ConditionsOperation in experiment
69% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; Inert atmosphere; Sealed tube; 200.a Example 2005 - { [(3 S)- 1 -(4-morpholinylcarbonyl)-3 -pyrrolidinyljmethyl} -4- [4-(7-quinolinyl)phenyl] - 2,4-dihydro-3H-l,2,4-triazol-3-onea) l,l-dimethylethyl (3S)-3-({5-oxo-4-[4-(7-quinolinyl)phenyl]-4,5-dihydro-lH-l,2,4- triazol-3-yl}methyl)-l-pyrrolidinecarboxylateA solution of 1,1-dimethylethyl (3S)-3-[4-(4-bromophenyl)-5-oxo-4,5-dihydro- lH-l,2,4-triazol-3-yl]methyl}-l-pyrrolidinecarboxylate (1.181 mmol) in dioxane (6 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (1.215 mmol), dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (50 mg), and 2M aq potassium carbonate (3 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110 °C for 1 h. The solution was cooled to room temperature and the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (6 mL). All dioxane filtrates were combined and concentrated in vacuo. Silica gel chromatography (0-20% methanol: ethyl acetate) was utilized in purifying the title compound (386 mg, 69%). MS(ES)+ m/e 472.2 [M+H]+.
  • 15
  • [ 851985-81-4 ]
  • [ 1332333-53-5 ]
  • [ 1332333-74-0 ]
YieldReaction ConditionsOperation in experiment
31% Stage #1: N-(4-bromo-2-fluorophenyl)-2-[1-(cyclopropylcarbonyl)-3-azetidinyl]acetyl}hydrazinecarboxamide With potassium carbonate In propan-1-ol; water at 130℃; for 22h; Stage #2: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline In 1,4-dioxane; propan-1-ol; water at 100℃; for 5h; 166.a Example 1663-({4-[2-fluoro-4-(7-quinolinyl)phenyl]-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl}methyl)-N,N-dimethyl- 1 -azetidinecarboxamidea) 5-(3-azetidinylmethyl)-4-[2-fluoro-4-(7-quinolinyl)phenyl]-2,4-dihydro-3H- 1 ,2,4- triazol-3-one In a round bottom flask equipped with reflux condenser, a mixture of N-(4-bromo- 2-fluorophenyl)-2-[l-(cyclopropylcarbonyl)-3-azetidinyl]acetyl}hydrazinecarboxamide (4.77 mmol) and potassium carbonate (23.84 mmol) in 1-propanol (10 mL) and water (100 mL) was stirred at vigorous reflux (oil bath, 130 °C) for 22 h. The pale yellow solution was cooled to room temperature and concentrated in vacuo. Water (12 mL) was added to the flask followed by 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (5.24 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.24 mmol) and 1,4-dioxane (30 mL). The flask containing the reaction mixture was equipped with stir bar and reflux condenser, and the reaction was stirred at 100 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (50 mL), and the layers were separated. The aqueous layer was adjusted to pH ~5 using IN HC1 solution and extracted with ethyl acetate (2 x 100 mL). The organic layers were combined, dried over magnesium sulphate, and concentrated in vacuo. The aqueous layer was lyophilized to give a solid, which was taken up into methanol (25 mL), dichloromethane (25 mL) and ethyl acetate (25 mL) and filtered to remove the salts. The mother liquor was concentrated in vacuo. Methanol (5 mL) was added and a precipitate formed. The precipitate was filtered off and the mother liquor was concentrated in vacuo to provide the title compound as an oil (815 mg, 67% pure, 31% yield). MS(ES)+ m/e 376.0 [M+H]+.
  • 16
  • [ 851985-81-4 ]
  • [ 1332333-76-2 ]
  • [ 1332332-75-8 ]
YieldReaction ConditionsOperation in experiment
33% With caesium carbonate In 1,4-dioxane; water at 100℃; for 15h; Microwave irradaiation; Inert atmosphere; 168.c c) 4-[5-chloro-2-fluoro-4-(7-quinolinyl)phenyl]-5-[(35)-l-(cyclopropylcarbonyl)-3- pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-oneTo a microwave vial were added 4-(4-bromo-5-chloro-2-fluorophenyl)-5-[(35)- l-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (0.124 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.16 mmol), cesium carbonate (0.37 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.0062 mmol). The mixture was purged with nitrogen and suspended in 1,4-dioxane (1 mL) and water (0.5 mL). The mixture was heated for 15 h at 100 °C. Analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water + 0.1%) TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH~6 with IN aq HC1. The aqueous phase was extracted with ethyl acetate (3x), and the combined organics were washed with brine, dried over Na2S04, and concentrated to afford the title product as an off-white solid (20 mg, 33%). MS(ES)+ m/e 492.2, 494.0 [M+H]+.
  • 17
  • [ 851985-81-4 ]
  • [ 1332333-78-4 ]
  • [ 1332332-77-0 ]
YieldReaction ConditionsOperation in experiment
84% With caesium carbonate In 1,4-dioxane; water at 100℃; for 15h; Inert atmosphere; Sealed tube; Microwave irradiation; 170.c c) 5-[(35)-l-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-5-methyl-4-(7- quinolinyl)phenyl]-2,4-dihydro-3H- 1 ,2,4-triazol-3-oneTo a microwave vial were added 4-(4-bromo-2-fluoro-5-methylphenyl)-5-[(35)- l-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (0.160 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.20 mmol), cesium carbonate (0.39 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (0.0062 mmol). The mixture was purged with nitrogen and suspended in 1,4-dioxane (1 mL) and water (0.5 mL). The mixture was heated for 15 h at 100 °C. Analysis by LCMS indicated desired product formation and consumption of starting material. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water + 0.1%) TFA). The desired fractions were collected and added to a separatory funnel containing ethyl acetate. The aqueous phase was adjusted to pH~6 with IN aq HC1. The aqueous phase was extracted with ethyl acetate (3x), and the combined organics were washed with brine, dried over Na2S04, and concentrated to afford the title product as a white solid (52 mg, 84%). MS(ES)+ m/e 472.2 [M+H]+.
  • 18
  • [ 851985-81-4 ]
  • [ 1332333-82-0 ]
  • [ 1332332-92-9 ]
YieldReaction ConditionsOperation in experiment
33% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; Inert atmosphere; Sealed tube; 185.c c) 5-[(3S)-l-acetyl-3-pyrrolidinyl]methyl}-4-[4-(7-quinolinyl)phenyl]-2,4-dihydro-3H- 1 ,2,4-triazol-3-oneA solution of 5-[(3S)-l-acetyl-3-pyrrolidinyl]methyl}-4-(4-bromophenyl)-2,4- dihydro-3H-l,2,4-triazol-3-one (0.211 mmol) in dioxane (2 mL) was treated with 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.216 mmol), dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (20 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HC1, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water + 0.1% NH4OH) was utilized to purify the title compound (29 mg, 33%). MS(ES)+ m/e 413.8 [M+H]+.
  • 19
  • [ 851985-81-4 ]
  • [ 1332333-83-1 ]
  • 5-[(3S)-1-propanoyl-3-pyrrolidinyl]methyl}-4-[4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; Inert atmosphere; Sealed tube; 186.b b) 5-[(3S)-l-propanoyl-3-pyrrolidinyl]methyl}-4-[4-(7-quinolinyl)phenyl]-2,4-dihydro- 3H-l,2,4-triazol-3-oneA solution of 4-(4-bromophenyl)-5-[(3S)-l-propanoyl-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (0.171 mmol) in dioxane (2 mL) was treated with 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.176 mmol), dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (15 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water + 0.1% NH4OH) was utilized to purify the title compound (44 mg, 59%). MS(ES)+ m/e 427.8 [M+H]+.
  • 20
  • [ 851985-81-4 ]
  • [ 1332333-84-2 ]
  • [ 1332332-94-1 ]
YieldReaction ConditionsOperation in experiment
42% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; Inert atmosphere; Sealed tube; 187.b b) (3S)-N,N-dimethyl-3-({5-oxo-4-[4-(7-quinolinyl)phenyl]-4,5-dihydro-lH-l,2,4- triazol-3-yl}methyl)- 1 -pyrrolidinecarboxamideA solution of (3S)-3-[4-(4-bromophenyl)-5-oxo-4,5-dihydro-lH-l,2,4-triazol-3- yl]methyl}-N,N-dimethyl-l -pyrrolidinecarboxamide (0.342 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.353 mmol), dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (25 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Reverse phase HPLC (10-65% acetonitrile/water + 0.1% NH4OH) was utilized to purify the title compound (65 mg, 42%). MS(ES)+ m/e 442.8 [M+H]+.
  • 21
  • [ 851985-81-4 ]
  • [ 1332333-86-4 ]
  • 5-[(3S)-1-(2,2-dimethylpropanoyl)-3-pyrrolidinyl]methyl}-4-[4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; Inert atmosphere; Sealed tube; 189.b . b) 5- { [(3 S)- 1 -(2,2-dimethylpropanoyl)-3-pyrrolidinyl]methyl} -4-[4-(7- quinolinyl)phenyl]-2,4-dihydro-3H- 1 ,2,4-triazol-3-oneA solution of 4-(4-bromophenyl)-5-[(3S)-l-(2,2-dimethylpropanoyl)-3- pyrrolidinyl]methyl}-2,4-dihydro-3H-l,2,4-triazol-3-one (0.277 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.294 mmol), dichloro [ 1 , 1 ' -bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (20 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110 °C for 1 h. The reaction mixture was cooled to room temperature, diluted with water, neutralized with the dropwise addition of 6N aq HCl, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-70%) acetonitrile/water + 0.1% NH4OH) and then reverse phase HPLC (10-40% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA). The combined product fractions were concentrated in vacuo for 30 min to remove the acetonitrile. The aqueous solution was neutralized with the addition of saturated aqueous sodium bicarbonate and extracted with dichloromethane (2x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (49 mg, 38%> yield). MS(ES)+ m/e 456.0 [M+H]+.
  • 22
  • [ 851985-81-4 ]
  • [ 1332333-27-3 ]
  • [ 1332333-92-2 ]
YieldReaction ConditionsOperation in experiment
65% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; Inert atmosphere; Sealed tube; 194.a a) 1,1-dimethylethyl (3S)-3-({4-[2-fluoro-4-(7-quinolinyl)phenyl]-5-oxo-4,5-dihydro- lH-l,2,4-triazol-3-yl}methyl)-l-pyrrolidinecarboxylateA solution of 1,1-dimethylethyl (3S)-3-[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5- dihydro-lH-l,2,4-triazol-3-yl]methyl}-l-pyrrolidinecarboxylate (0.770 mmol) in dioxane (6 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.770 mmol), dichloro[ 1 , 1 '-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (50 mg), and 2M aq potassium carbonate (3 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110 °C for 1 h. The solution was cooled to room temperature and the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (6 mL). All dioxane filtrates were combined and concentrated in vacuo. Silica gel chromatography (0-20% methanol: ethyl acetate) was utilized in purifying the title compound (250 mg, 65%). MS(ES)+ m/e 490.2 [M+H]+.
  • 23
  • [ 851985-81-4 ]
  • [ 1332333-94-4 ]
  • [ 1332333-06-8 ]
YieldReaction ConditionsOperation in experiment
35% With potassium carbonate In 1,4-dioxane; water at 110℃; for 1h; Inert atmosphere; Sealed tube; 199.b b) (3S)-N-ethyl-3-({4-[2-fiuoro-4-(7-quinolinyl)phenyl]-5-oxo-4,5-dihydro-lH-l,2,4- triazol-3-yl}methyl)- 1 -pyrrolidinecarboxamideA solution of (3S)-3-[4-(4-bromo-2-fluorophenyl)-5-oxo-4,5-dihydro-lH-l,2,4- triazol-3-yl]methyl}-N-ethyl-l-pyrrolidinecarboxamide (0.179 mmol) in dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.180 mmol), dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (15 mg), and 2M aq potassium carbonate (1 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110 °C for 1 h. The solution was cooled to room temperature and the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (2 mL). All dioxane filtrates were combined and concentrated in vacuo. Reverse phase HPLC (10-70% acetonitrile/water + 0.1% NH4OH) was utilized in purifying the title compound (29 mg, 35%). MS(ES)+ m/e 461.2 [M+H]+.
  • 24
  • [ 851985-81-4 ]
  • [ 1426096-39-0 ]
  • [ 1426095-60-4 ]
YieldReaction ConditionsOperation in experiment
138 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 95℃; for 3h; 67 Example 67 2-[(3S)-1 -Cyclopropylcarbonyl)-3-pyrrolidinyl]-A -[2-fluoro-4-(7-quinolinyl)phenyl]-A - methylacetamideA 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2- [(3S)-1-Cyclopropylcarbonyl)-3-pyrrolidinyl]-N-methylacetamide (199 mg), 7-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline (199 mg), Pd(dppf)CI2-CH2CI2 adduct (21 .20 mg) and 2.0 M aqueous potassium carbonate (1.038 ml) in 1 ,4-dioxane (6.24 ml) and then capped. The reaction was heated in an aluminum block at 95 °C for 3 hours. The resulting dark slurry was diluted with water and extracted into ethyl acetate then the extracts were dried with sodium sulfate, treated with silica powder (~2g) and evaporated under reduced pressure to dryness. This was purified by silica gel flash chromatography eluting with a gradient of 0-7% MeOH/EtOAc, followed by preparative reverse phase HPLC. The desired HPLC fractions were combined and evaporated under reduced pressure to a brown-orange residue that was purified a second time by reverse phase HPLC. The desired fractions were combined, treated with saturated aqueous sodium bicarbonate (~10ml) then concentrated under reduced pressure. The resulting cloudy solution was extracted with DCM and the extracts were dried over sodium sulfate and evaporated under reduced pressure. The resulting colorless oil was dissolved in acetonitrile (1 ml) then water (2ml) was added and the solution was frozen and lyophilized to afford 138 mg of the titled compound as a white solid. LCMS m/z 432.3 (M+H).
  • 25
  • [ 851985-81-4 ]
  • [ 1426096-49-2 ]
  • [ 1426095-62-6 ]
YieldReaction ConditionsOperation in experiment
100 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; for 1h; 69 Example 69 2-[1 -Cyclopropylcarbonyl)-3-azetidinyl]-A -[2-fluoro-4-(7-quinolinyl)phenyl]-W- methylacetamideA 25 ml microwave vial was charged with a suspension of N-(4-bromo-2-fluorophenyl)-2-[1 - Cyclopropylcarbonyl)-3-azetidinyl]-N-methylacetamide (126 mg), 7-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)quinoline (131 mg), Pd(dppf)CI2-CH2CI2 adduct (13.93 mg) and 2.0 M aqueous potassium carbonate (0.683 ml) in 1 ,4-dioxane (2.73 ml) and then capped. The reaction was heated in an aluminum block at 100 °C for 1 hour. The resulting dark slurry was cooled to room temperature then diluted brine and extracted with ethyl acetate. The extracts were dried over sodium sulfate then treated with silica powder (~1 g) and evaporated under reduced pressure to dryness. This was placed purified by silica gel flash chromatography eluting with EtOAc and then 3% MeOH/EtOAc, followed by preparative reverse phase HPLC. The combined desired fractions were treated with saturated aqueous sodium bicarbonate (10 ml) then extracted into DCM. The extracts were dried over sodium sulfate and evaporated to a colorless residue. This was dissolved into acetonitrile (~1 ml) and diluted with water (~3ml) then frozen and lyophilized to afford 100 mg of the titled compound as a white solid. LCMS m/z 418.2 (M+H).
  • 26
  • [ 851985-81-4 ]
  • [ 1426050-09-0 ]
  • [ 1426050-08-9 ]
YieldReaction ConditionsOperation in experiment
72% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 23.b b) Methyl 3-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3-(2-fluoro-4- (quinolin-7-yl)phenyl)propanoate A solution of methyl 3-(4-bromo-2-fluorophenyl)-3-(4-cyclopropyl-3-oxo-l-oxa- 4,9-diazaspiro[5.5]undecan-9-yl)propanoate (1.924 mmol) in 1,4-dioxane (6 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (2.116 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.096 mmol) and 2M aq potassium carbonate (5.77 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The resulting black mixture was diluted with water (50 mL) and extracted with dichloromethane three times. The combined organic layer was treated with Silicycle Si-thiol (100 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-7% methanol/ dichloromethane) afforded the title compound as a brown solid (802 mg, 72% yield). MS(ES)+ m/e 518.4 [M+H]+.
  • 27
  • [ 851985-81-4 ]
  • [ 1426050-11-4 ]
  • [ 1426050-10-3 ]
YieldReaction ConditionsOperation in experiment
38 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 24.c c) 4-cyclopropyl-9-(2-oxo- 1 -(4-(quinolin-7-yl)phenyl)propyl)- 1 -oxa-4,9- diazaspiro[5.5]undecan-3-one A solution of the crude 9-(l-(4-bromophenyl)-2-oxopropyl)-4-cyclopropyl-l-oxa- 4,9-diazaspiro[5.5]undecan-3-one from Example 24b in 1,4-dioxane (1.5 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.245 mmol), PdCl2(dppf)- CH2C12 adduct (0.0113 mmol), and 2M aq potassium carbonate (0.668 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The resulting black mixture was diluted with water (50 mL) and extracted with dichloromethane three times. The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-6% methanol/dichloromethane) followed by reverse phase HPLC (20-60% acetonitrile/water with 0.1% NH4OH) afforded the title compound as a beige solid (38 mg, 34% yield over the two steps). MS(ES)+ m/e 470.3 [M+H]+.
  • 28
  • [ 851985-81-4 ]
  • [ 1426050-16-9 ]
  • (+)-4-cyclopropyl-9-( 1-(2-fluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • (-)-4-cyclopropyl-9-( 1-(2-fluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 12% 2: 11% Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl acetate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; Stage #2: With ethanol at 50℃; 25.e; 26.a e) 4-cyclopropyl-9-( 1 -(2-fluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)- 1 -oxa-4,9- diazaspiro[5.5]undecan-3-one A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)ethyl acetate (0.345 mmol) in 1,4-dioxane (1.5 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.380 mmol), PdCi2(dppf)-CH2Ci2 adduct (0.017 mmol), and 2M aq potassium carbonate (1.035 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The mixture was then concentrated to dryness in vacuo. The brown residue was diluted with ethanol (2 mL) and the solution was stirred in an oil bath at 50 °C overnight, after which the reaction was concentrated to dryness under a stream of nitrogen. The crude material was suspended in water (50 mL) and was extracted three times with ethyl acetate. The aqueous layer was further diluted with brine (20 mL) and was extracted once more with tetrahydrofuran. The organic layers (ethyl acetate and tetrahydrofuran) were combined, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-6% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol) afforded the title compound as a white solid in >98% ee (21 mg, 12% yield). MS(ES)+ m/e 476.1 [M+H]+. aD = +20 deg (c = 0.04, methanol). Example 26 (-)-4-cyclopropyl-9-(l -(2-fluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)- 1 -oxa-4,9- diazaspiro[5.5]undecan-3-one a) From Example 25 e, the title product was isolated as a white solid in >98% ee using chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (1 mL) (20 mg, 11% yield). MS(ES)+ m/e 476.1 [M+H]+. aD = -22 deg (c = 0.03, methanol).
  • 29
  • [ 851985-81-4 ]
  • [ 1426050-22-7 ]
  • (+)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N-methylacetamide [ No CAS ]
  • (-)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N-methylacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 25% 2: 28% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 27.d; 28.a d) (+)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4- (quinolin-7-yl)phenyl)-N-methylacetamide A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)-N-methylacetamide (0.366 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.403 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.018 mmol), and 2M aq potassium carbonate (1.099 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The resulting black mixture was diluted with water (50 mL) and brine (20 mL), and extracted with dichloromethane four times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The material was triturated with hexanes and the hexane solution was discarded. Purification of the residue by chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/ 25% acetonitrile) afforded the title compound as a beige solid in >98% ee (50 mg, 25% yield). MS(ES)+ m/e 503.1 [M+H]+. aD = +34 deg (c = 0.04, methanol). Example 28 (-)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4- (quinolin-7-yl)phenyl)-N-methylacetamide a) From Example 27d, the title product was isolated as a beige solid in >98%> ee using chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/ 25% acetonitrile) (55 mg, 28% yield). MS(ES)+ m/e 503.1 [M+H]+. aD = -34 deg (c = 0.03, methanol).
  • 30
  • [ 851985-81-4 ]
  • [ 1426050-30-7 ]
  • (+)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-2-(4-(1-(hydroxymethyl)cyclopropyl)-3-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetamide [ No CAS ]
  • (-)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-2-(4-(1-(hydroxymethyl)cyclopropyl)-3-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 16% 2: 17% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 29.i; 30.a i) (+)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-2-(4-(l -(hydroxymethyl)cyclopropyl)-3-oxo- 1 - oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide A solution of crude (85% purity) 2-(4-bromo-2-fluorophenyl)-2-(4-(l- (hydroxymethyl)cyclopropyl)-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (0.488 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (0.537 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.024 mmol), and 2M aq potassium carbonate (1.464 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. Additional portions of 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.117 mmol) and PdCl2(dppf)-CH2Ci2 adduct (0.012 mmol) were added. The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 5 min. The resulting black mixture was diluted with water (50 mL) and brine (20 mL) and was extracted with ethyl acetate three times. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was purified by reverse phase HPLC (20-60% acetonitrile/water with 0.1% NH4OH). Fractions containing the desired product were selected, combined and concentrated to dryness in vacuo. Further purification by chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/ 25% acetonitrile) afforded the title compound as a white solid in >98% ee (43 mg, 16% yield). MS(ES)+ m/e 519.3 [M+H]+. aD = +47 deg (c = 0.05, methanol). Example 30 (-)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-2-(4-(l -(hydroxymethyl)cyclopropyl)-3-oxo- 1 - oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide a) From Example 29i, the title product was isolated as a white solid in >98% ee using chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/ 25% acetonitrile) (46 mg, 17% yield). MS(ES)+ m/e 519.3 [M+H]+. aD = -32 deg (c = 0.05, methanol).
  • 31
  • [ 851985-81-4 ]
  • [ 1426050-39-6 ]
  • [ 1426050-40-9 ]
YieldReaction ConditionsOperation in experiment
81% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 36.e e) Methyl 2-(4-cyclopropyl-3-oxo- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4- (quinolin-7-yl)phenyl)acetate A solution of methyl 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-l-oxa- 4,9-diazaspiro[5.5]undecan-9-yl)acetate (2.53 mmol) in 1,4-dioxane (8 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (2.78 mmol), PdCl2(dppf)- CH2CI2 adduct (0.126 mmol), and 2M aq potassium carbonate (7.58 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The resulting black mixture was diluted with water (100 mL) and brine (20 mL) and was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-5% methanol/dichloromethane) afforded the desired product, which was dissolved with dichloromethane and concentrated in vacuo three times to afford the title compound as a brown gel (1.21 grams, 81% yield). MS(ES)+ m/e 504.1 [M+H]+.
  • 32
  • [ 851985-81-4 ]
  • [ 1426050-47-6 ]
  • (+)-4-cyclopropyl-9-(1-(2,6-difluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • (-)-4-cyclopropyl-9-(1-(2,6-difluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 15% 2: 17% Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; 2-(4-bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl acetate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.333333h; Inert atmosphere; Microwave irradiation; Stage #2: With water In ethanol at 80℃; 38.f; 39.a f) (+)-4-cyclopropyl-9-( 1 -(2,6-difluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)- 1 -oxa- 4,9-diazaspiro[5.5]undecan-3-one A solution of crude (80%> purity) 2-(4-bromo-2,6-difluorophenyl)-2-(4-cyclopropyl- 3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)ethyl acetate (0.361 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.397 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.018 mmol), and 2M aq potassium carbonate (1.083 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The reaction was cooled at which point additional portions of 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.08 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.006 mmol) were added. The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 5 min. The black reaction mixture was then concentrated to minimal volume (-0.5 mL) under a stream of nitrogen at which point it was diluted with a mixture of ethanol and water (2 mL, 1 : 1). This mixture was stirred in an oil bath at 80 °C overnight. The resulting solution was concentrated to dryness under a stream of nitrogen and then diluted with water (50 mL) and brine (20 mL). This aqueous mixture was extracted four times with ethyl acetate. The combined organic layers were treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-7% methanol/dichloromethane) and chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/ 25%o acetonitrile) afforded the title compound as a white solid in >99%> ee (29 mg, 15%> yield). MS(ES)+ m/e 494.1 [M+H]+. aD = +4 deg (c = 0.06, methanol). Example 39 (-)-4-cyclopropyl-9-(l-(2,6-difluoro-4-(quinolin-7-yl)phenyl)-2-hydroxyethyl)-l-oxa-4,9- diazaspiro[5.5]undecan-3-one a) From Example 38f, the title product was isolated as a white solid in >98%> ee using chiral HPLC (Chromegachiral CC4, methanol) followed by lyophilization from water (w/ 25% acetonitrile) (32 mg, 17% yield). MS(ES)+ m/e 494.1 [M+H]+. aD = -5 deg (c = 0.09, methanol).
  • 33
  • [ 851985-81-4 ]
  • [ 1426050-61-4 ]
  • (+)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N-methoxyacetamide [ No CAS ]
  • (-)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)-N-methoxyacetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 11% 2: 10% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; ethanol at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 50.b; 51.a b) (+)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4- (quinolin-7-yl)phenyl)-N-methoxyacetamide A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)-N-methoxyacetamide (0.170 mmol) in dry 1,4-dioxane (1 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.187 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.52 μιηοΐ) and 2M aq potassium carbonate (0.511 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The resulting black mixture was diluted with water (50 mL) and brine (20 mL) and was extracted four times with chloroform. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (20-50% acetonitrile/water with 0.1% NH4OH) followed by chiral HPLC (Chromegachiral CC4, methanol) and lyophilization from water (w/ 25% acetonitrile) afforded the title compound as a white solid (11 mg, 11%). MS(ES)+ m/e 519.3 [M+H]+, >99% ee, aD = +11 deg (c = 0.03, methanol). Example 51 (-)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4- (quinolin-7-yl)phenyl)-N-methoxyacetamide a) From Example 50b, the title product was isolated as a white solid in >99%> ee using chiral HPLC (Chiralpak Chromegachiral CC4, methanol) followed by lyophilization from water (w/ 25% acetonitrile) (10 mg, 10% yield). MS(ES)+ m/e 519.3 [M+H]+. aD = -10 deg (c = 0.03, methanol).
  • 34
  • [ 851985-81-4 ]
  • [ 1375107-47-3 ]
  • [ 1426050-70-5 ]
  • [ 76-05-1 ]
  • 2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4-(quinolin-7-yl)phenyl)acetamide trifluoroacetate salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
9% Stage #1: 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride; 2-bromo-2-(4-bromo-2,6-difluorophenyl)acetamide With potassium carbonate In water; N,N-dimethyl-formamide at 40℃; Stage #2: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 110℃; for 0.416667h; Stage #3: trifluoroacetic acid In water; acetonitrile 56.d d) 2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4- (quinolin-7-yl)phenyl)acetamide A solution of 4-cyclopropyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (45.0 mg, 0.18 mmol) in N,N-dimethylformamide (0.5 mL) was treated with 2M aq potassium carbonate (0.1 mL, 0.2 mmol), followed by the 2-bromo-2-(4-bromo-2,6- difluorophenyl)acetamide (60 mg, 0.18 mmol). The reaction mixture was stirred at 40 °C for overnight, at which point it had proceeded to completion. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were dried and concentrated to dryness to afford the crude intermediate. To a solution of this crude intermediate, 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)quinoline (23.3 mg, 0.09 mmol), and 2M aq potassium carbonate (0.1 mL, 0.2 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (6 mg, 7.3 μιηοΐ). The reaction mixture was purged with nitrogen, sealed, and irradiated in the microwave at 110 °C for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HC1. The organic phase was then washed with brine (5 mL), dried over anhydous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (5-45% acetonitrile + 0.1 %TFA:water + 0.1% TFA). The appropriate fractions were collected and evaporated to yield the title compound as a trifiuoroacetate salt (11 mg, 9%). MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 0.61 - 0.71 (m, 2 H) 0.78 - 0.89 (m, 2 H) 1.98 - 2.06 (m, 4 H) 2.69 - 2.79 (m, 2 H) 2.90 (br. s., 1 H) 3.21 (s, 3 H) 3.38 (br. s., 2 H) 4.01 (s, 2 H) 5.96 (br. s., 1 H) 7.16 (br. s., 1 H) 7.54 (d, J=9.35 Hz, 2 H) 7.91 (dd, J=8.34, 5.05 Hz, 1 H) 8.09 (dd, J=8.72, 1.64 Hz, 1 H) 8.26 (d, J=8.59 Hz, 1 H) 8.76 - 8.85 (m, 2 H) 9.28 (dd, J=5.18, 1.64 Hz, 1 H).
  • 35
  • [ 851985-81-4 ]
  • [ 1426050-64-7 ]
  • (+)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetamide [ No CAS ]
  • (-)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 13% 2: 15% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 110℃; for 0.416667h; Inert atmosphere; Microwave irradiation; 58.b; 59.a b) (+)-2-(4-ethyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7- yl)phenyl)acetamide To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetamide (214 mg, 0.5 mmol), 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (127 mg, 0.5 mmol) and 2M aq K2C03 (0.55 mL, 1.1 mmol) in 1,4-dioxane (2.5 mL) was added PdCi2(dppf)-CH2Cl2 adduct (20.4 mg, 0.025 mmol). The reaction mixture was purged with nitrogen and the vessel was sealed and irradiated in the microwave at 110 °C for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HC1. The organic phase was then washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (5-65% acetonitrile: water with 0.1 % NH4OH) afforded the title product as a racemate, which was resolved by chiral HPLC (Chromegachiral CC4, methanol) to yield the title product in >98%> ee (31 mg, 13%>). α,ο = +21 deg (c = 0.06, methanol); MS(ES)+ m/e 477 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.65 - 1.74 (m, 1 H) 1.75 - 1.80 (m, 1 H) 1.89 - 2.01 (m, 2 H) 2.31 - 2.41 (m, 1 H) 2.58 - 2.70 (m, 2 H) 2.78 (br. s., 1 H) 3.19 (s, 2 H) 3.41 (q, J=7.33 Hz, 2 H) 3.97 - 4.08 (m, 2 H) 4.54 (s, 1 H) 5.65 (br. s., 1 H) 7.27 (br. s., 1 H) 7.43 - 7.48 (m, 2 H) 7.55 (d, J=1.77 Hz, 1 H) 7.64 (dd, J=7.96, 1.89 Hz, 1 H) 7.87 (dd, J=8.59, 2.02 Hz, 1 H) 7.98 (d, J=8.59 Hz, 1 H) 8.25 (dd, J=8.34, 1.01 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 8.97 (dd, J=4.04, 1.77 Hz, 1 H). Example 59 (-)-2-(4-ethyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7- yl)phenyl)acetamide a) From Example 58b, the title product was also isolated in >98% ee using chiral HPLC (Chromegachiral CC4, methanol) followed by concentration in vacuo and lyophilization (36 mg, 15% yield). aD = -22 deg (c = 0.04, methanol); MS(ES)+ m/e 477 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 1.13 (t, J=7.20 Hz, 3 H) 1.68 - 1.80 (m, 2 H) 1.90 - 2.02 (m, 2 H) 2.31 - 2.40 (m, 1 H) 2.65 (t, J=12.63 Hz, 2 H) 2.80 (d, J=12.13 Hz, 1 H) 3.19 (s, 2 H) 3.41 (d, J=7.07 Hz, 2 H) 4.02 (d, J=1.77 Hz, 2 H) 4.54 (s, 1 H) 5.63 (br. s., 1 H) 7.27 (br. s., 1 H) 7.43 - 7.53 (m, 2 H) 7.55 (d, J=1.77 Hz, 1 H) 7.64 (dd, J=7.96, 1.89 Hz, 1 H) 7.87 (dd, J=8.46, 1.89 Hz, 1 H) 7.98 (d, J=8.34 Hz, 1 H) 8.26 (d, J=8.34 Hz, 1 H) 8.36 (s, 1 H) 8.97 (dd, J=4.29, 1.77 Hz, 1 H).
  • 36
  • [ 851985-81-4 ]
  • [ 1426050-75-0 ]
  • [ 76-05-1 ]
  • ethyl 2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin-7-yl)phenyl)acetate trifluoroacetate salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
31 mg Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; ethyl 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 110℃; for 0.416667h; Inert atmosphere; Microwave irradiation; Stage #2: trifluoroacetic acid In water; acetonitrile 57.b b) ethyl 2-(4-ethyl-3-oxo- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin- 7-yl)phenyl)acetate To a solution of tert-butyl 4-ethyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecane-9- carboxylate (1 g, 3.35 mmol) in dichloromethane (10 mL) was added TFA (0.775 mL, 10.05 mmol). The reaction mixture was stirred at room temperature overnight, at which point the deprotection had proceeded to completion. The reaction mixture was concentrated in vacuo, dichloromethane was added, and the solution was concentrated in vacuo again. The residue was dissolved with N,N-dimethylformamide (12 mL). To this solution was added potassium carbonate (0.463 g, 3.35 mmol) and ethyl 2-bromo-2-(4- bromophenyl)acetate (1.079 g, 3.35 mmol). The reaction mixture was stirred at 40 °C for overnight, at which point the reaction had proceeded to completion. The reaction mixture was poured into water (120 mL) and was extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried and concentrated in vacuo. Crude ethyl 2-(4-bromo-2- fluorophenyl)-2-(4-ethyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate was obtained (590 mg) and was used directly in the next step. MS(ES)+ m/e 457 [M+H]+. To a solution of the crude ethyl 2-(4-bromo-2-fluorophenyl)-2-(4-ethyl-3-oxo-l- oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetate (590 mg), 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (329 mg, 1.29 mmol) and 2M aq K2CO3 (1.4 mL, 2.8 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (53 mg, 0.065 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in the microwave at 110 °C for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HC1. The organic phase was washed with brine (5 mL), dried over anhydous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. The crude product was purified with reverse phase HPLC (25-55% acetonitrile + 0.1 %TFA:water + 0.1 % TFA). The appropriate fractions were collected and evaporated to yield the title compound as a trifiuoroacetate salt (31 mg, 2% over the two steps). MS(ES)+ m/e 506 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 1.14 (t, J=7.20 Hz, 3 H) 1.28 (t, J=7.07 Hz, 3 H) 2.14 (s, 1 H) 2.11 (s, 1 H) 2.28 - 2.38 (m, 2 H) 3.05 (t, J=l 1.75 Hz, 1 H) 3.22 (t, J=13.26 Hz, 1 H) 3.30 (s, 2 H) 3.44 (d, J=7.07 Hz, 2 H) 3.62 (d, J=10.11 Hz, 1 H) 3.76 (d, J=13.89 Hz, 1 H) 4.06 (s, 2 H) 4.29 - 4.41 (m, 2 H) 5.43 (s, 1 H) 7.71 - 7.82 (m, 3 H) 7.89 - 7.96 (m, 1 H) 8.13 (d, J=8.59 Hz, 1 H) 8.26 (d, J=8.59 Hz, 1 H) 8.79 - 8.84 (m, 2 H) 9.27 - 9.32 (m, 1 H).
  • 37
  • [ 851985-81-4 ]
  • [ 1426050-95-4 ]
  • [ 76-05-1 ]
  • 2-(2,6-difluoro-4-(quinolin-7-yl)phenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide trifluoroacetate salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
47% Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; 2-(4-bromo-2,6-difluorophenyl)-2-(4-ethyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 110℃; for 0.416667h; Inert atmosphere; Microwave irradiation; Stage #2: trifluoroacetic acid In water; acetonitrile 70.g g) 2-(2,6-difluoro-4-(quinolin-7-yl)phenyl)-2-(4-ethyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetamide To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-(4-ethyl-3-oxo- 1 -oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetamide (252 mg, 0.57 mmol), 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (144 mg, 0.57 mmol) and 2M aq K2C03 (0.62 mL, 1.24 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (23 mg, 0.03 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in the microwave at 110 °C for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HC1. The organic phase was washed with brine (5 mL), dried over anhydous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. Purification of the residue by reverse phase HPLC (25-55% acetonitrile + 0.1 %TFA: water + 0.1 % TFA) afforded the title product as a trifluoroacetate salt (163 mg, 47% yield). MS(ES)+ m/e 495 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 1.12 (t, J=7.20 Hz, 3 H) 1.69 - 1.81 (m, 2 H) 1.92 - 2.04 (m, 2 H) 2.31 - 2.39 (m, 1 H) 2.64 - 2.74 (m, 1 H) 2.75 - 2.83 (m, 1 H) 2.87 (d, J=12.38 Hz, 1 H) 3.17 (s, 2 H) 3.41 (q, J=7.07 Hz, 2 H) 3.99 (s, 2 H) 4.79 (s, 1 H) 5.65 (d, J=4.04 Hz, 1 H) 7.39 - 7.46 (m, 3 H) 7.49 (dd, J=8.34, 4.29 Hz, 1 H) 7.85 (dd, J=8.46, 1.89 Hz, 1 H) 8.00 (d, J=8.59 Hz, 1 H) 8.26 (dd, J=8.46, 1.14 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 8.99 (dd, J=4.29, 1.77 Hz, 1 H).
  • 38
  • [ 851985-81-4 ]
  • [ 1426049-75-3 ]
  • [ 1426049-74-2 ]
YieldReaction ConditionsOperation in experiment
32% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; ethanol at 120℃; for 0.166667h; Inert atmosphere; Microwave irradiation; 1.i i) 2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(4-(quinolin-7- yl)phenyl)acetic acid A solution of 2-(4-bromophenyl)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetic acid (0.402 mmol) in 1,4-dioxane (2 mL) and ethanol (0.2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.442 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.020 mmol) and 2M aq potassium carbonate (0.602 mL). The vessel was purged with nitrogen, sealed and the reaction irradiated in a Biotage Initiator microwave at 120 °C for 10 min. The resulting black solution was then diluted with water (50 mL) and brine (10 mL), and the aqueous solution was sequentially extracted with dichloromethane and tetrahydrofuran. Only the tetrahydrofuran layer contained the product. The aqueous layer was concentrated in vacuo and the resulting solid was triturated with ethanol. The ethanol solution was filtered and added to the tetrahydrofuran layer. This organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the crude material by reverse phase HPLC (10-35% acetonitrile/water with 0.1 % NH4OH) afforded the title compound as a white solid (32%). MS(ES)+ m/e 472.4 [M+H]+.
  • 39
  • [ 851985-81-4 ]
  • [ 1426050-99-8 ]
  • (+)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4-(quinolin-7-yl)phenyl)acetamide [ No CAS ]
  • (-)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4-(quinolin-7-yl)phenyl)acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 22% 2: 21% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 110℃; for 0.416667h; Inert atmosphere; Microwave irradiation; 73.b; 74.a b) (+)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4- (quinolin-7-yl)phenyl)acetamide To a solution of 2-(4-bromo-2,6-difluorophenyl)-2-(4-cyclopropyl-3-oxo-l-oxa- 4,9-diazaspiro[5.5]undecan-9-yl)acetamide (246 mg, 0.54 mmol), 7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline (137 mg, 0.54 mmol) and 2M aq K2C03 (0.59 mL, 1.18 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (21.9 mg, 0.03 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in the microwave at 110 °C for 25 min, at which point the reaction had proceeded to completion. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with 5 mL of 1M aq HC1. The organic phase was washed with brine (5 mL), dried over anhydous sodium sulfate, filtered through a pad of celite, and concentrated in vacuo. Purification of the residue with reverse phase HPLC (10-70% acetonitrile: water with 0.1 % NH4OH) followed by chiral HPLC (Lux Cell 4, methanol) afforded the title product in 99.9% ee (61 mg, 22% yield). aD = +30 deg (c=0.1, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) 5 ppm 0.58 - 0.71 (m, 2 H) 0.76 - 0.87 (m, 2 H) 1.65 (dd, J=l 1.12, 4.29 Hz, 1 H) 1.71 - 1.81 (m, 1 H) 1.95 (s, 1 H) 1.92 (s, 1 H) 2.29 - 2.38 (m, 1 H) 2.64 - 2.75 (m, 2 H) 2.75 - 2.84 (m, 1 H) 2.84 - 2.96 (m, 1 H) 3.14 (s, 2 H) 3.98 (s, 2 H) 4.78 (s, 1 H) 5.68 (br. s., 1 H) 7.40 - 7.47 (m, 3 H) 7.49 (dd, J=8.21, 4.17 Hz, 1 H) 7.85 (dd, J=8.59, 2.02 Hz, 1 H) 8.00 (d, J=8.59 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.36 (s, 1 H) 8.99 (dd, J=4.29, 1.77 Hz, 1 H). Example 74 (-)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2,6-difluoro-4- (quinolin-7-yl)phenyl)acetamide a) Following Example 73b, the title product was also isolated in 99.3%> ee using chiral HPLC (Lux Cell 4, methanol) (59 mg, 21% yield). aD = -33.3 deg (c=0.3, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2C12) δ ppm 0.61 - 0.66 (m, 2 H) 0.77 - 0.86 (m, 2 H) 1.66 - 1.78 (m, 2 H) 1.86 - 1.97 (m, 2 H) 2.32 (t, J=10.61 Hz, 1 H) 2.63 - 2.75 (m, 2 H) 2.75 - 2.82 (m, 1 H) 2.87 (d, J=11.12 Hz, 1 H) 3.14 (s, 2 H) 3.98 (s, 2 H) 4.78 (s, 1 H) 5.85 (d, J=4.29 Hz, 1 H) 7.39 - 7.46 (m, 3 H) 7.49 (dd, J=8.34, 4.29 Hz, 1 H) 7.85 (dd, J=8.59, 1.77 Hz, 1 H) 8.00 (d, J=8.59 Hz, 1 H) 8.26 (dd, J=8.46, 0.88 Hz, 1 H) 8.34 - 8.39 (m, 1 H) 8.99 (dd, J=4.17, 1.64 Hz, 1 H).
  • 40
  • [ 851985-81-4 ]
  • 4-cyclopropyl-9-((2-fluoro-4-(quinolin-7-yl)phenyl)(4H-1,2,4-triazol-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one trifluoroacetate salt [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 2 h / 100 °C / Inert atmosphere 2.1: 105 °C 2.2: 2 h / 110 °C
Multi-step reaction with 3 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; ethanol / 0.25 h / 120 °C / Inert atmosphere; Microwave irradiation 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 20 °C 2.2: 20 °C 3.1: 105 °C 3.2: 2 h / 110 °C
  • 41
  • [ 851985-81-4 ]
  • (+)-4-cyclopropyl-9-((2-fluoro-4-(quinolin-7-yl)phenyl)(4H-1,2,4-triazol-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • (-)-4-cyclopropyl-9-((2-fluoro-4-(quinolin-7-yl)phenyl)(4H-1,2,4-triazol-3-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 2 h / 100 °C / Inert atmosphere 2.1: 105 °C 2.2: 2 h / 110 °C 3.1: Lux Cell 4 / methanol / Resolution of racemate
Multi-step reaction with 4 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; ethanol / 0.25 h / 120 °C / Inert atmosphere; Microwave irradiation 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 20 °C 2.2: 20 °C 3.1: 105 °C 3.2: 2 h / 110 °C 4.1: Lux Cell 4 / methanol / Resolution of racemate
  • 42
  • [ 851985-81-4 ]
  • [ 1426050-05-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; ethanol / 0.17 h / 120 °C / Inert atmosphere; Microwave irradiation 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 20 °C 2.2: 20 °C
  • 43
  • [ 851985-81-4 ]
  • [ 1426049-77-5 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; ethanol / 0.17 h / 120 °C / Inert atmosphere; Microwave irradiation 2: 2-chloro-1,3-dimethylimidazolinium chloride; N-ethyl-N,N-diisopropylamine / dichloromethane; N,N-dimethyl-formamide / 0.17 h / 20 °C
  • 44
  • [ 851985-81-4 ]
  • [ 1426049-78-6 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; ethanol / 0.17 h / 120 °C / Inert atmosphere; Microwave irradiation 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 20 °C 2.2: 19 h / 20 °C
  • 45
  • [ 851985-81-4 ]
  • [ 1426049-81-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 0.25 h / 120 °C / Inert atmosphere; Microwave irradiation 2: ethanol; lithium hydroxide / 96 h / 20 °C
  • 46
  • [ 851985-81-4 ]
  • (+)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-[2-fluoro-4-(7-quinolinyl)phenyl]acetamide [ No CAS ]
  • (-)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-[2-fluoro-4-(7-quinolinyl)phenyl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 2 h / 100 °C / Inert atmosphere 2: Chromegachiral CC4 / methanol / Resolution of racemate
Multi-step reaction with 3 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; ethanol / 0.25 h / 120 °C / Inert atmosphere; Microwave irradiation 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 20 °C 2.2: 20 °C 3.1: Chromegachiral CC4 / methanol / Resolution of racemate
  • 47
  • [ 851985-81-4 ]
  • [ 1426049-98-0 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 0.33 h / 120 °C / Inert atmosphere; Microwave irradiation 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 75 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 20 °C
  • 48
  • [ 851985-81-4 ]
  • [ 1426050-00-1 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; water / 0.33 h / 120 °C / Inert atmosphere; Microwave irradiation 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / tetrachloromethane / 75 °C / Inert atmosphere
  • 49
  • [ 851985-81-4 ]
  • [ 1426049-88-8 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate / 1,4-dioxane; ethanol / 0.25 h / 120 °C / Inert atmosphere; Microwave irradiation 2.1: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 0.17 h / 20 °C 2.2: 20 °C
  • 50
  • [ 32017-76-8 ]
  • [ 851985-81-4 ]
  • [ 1375142-88-3 ]
  • [ 1426050-07-8 ]
YieldReaction ConditionsOperation in experiment
3% Stage #1: (+/-)-2-(4-bromophenyl)oxirane; 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one With nickel diacetate In isopropyl alcohol at 20℃; Stage #2: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 22.a 4-cyclopropyl-9-(2 -hydroxy- 1 -(4-(quinolin-7-yl)phenyl)ethyl)- 1 - diazaspiro[5.5]undecan-3-o a) A solution of 4-cyclopropyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.951 mmol) and 2-(4-bromophenyl)oxirane (0.951 mmol) in isopropanol (3 mL) was treated with nickel (II) acetate (0.048 mmol) (see Synlett 2004, 5, 846-850). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated to dryness in vacuo, and the residue was purified by silica gel chromatography (0-9% methanol/dichloromethane). The desired intermediate was isolated as a 1 :3 mixture (according to 1H NMR) of regioisomers (109 mg, 0.266 mmol total). This mixture was diluted with 1,4-dioxane (2 mL) and was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.264 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.012 mmol) and 2M aq potassium carbonate (0.720 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The reaction mixture was diluted with water (50 mL) and its pH was adjusted to 3 using IN aq HC1. The aqueous mixture was washed twice with ethyl acetate to remove some non-polar impurities before the pH of the aqueous layer was adjusted to -10 with 30%> w/v aq ammonium hydroxide. The resulting basic solution was extracted three times with dichloromethane. The dichloromethane layers were combined, treated with Silicycle Si-thiol (50 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the regioisomeric mixture by chiral HPLC (Chiralpak AS-H column, acetonitrile:methanol 9: 1) followed by reverse phase HPLC (20- 50% acetonitrile/water with 0.1% NH4OH) afforded the racemic title compound as a solid (13 mg, 3% yield). MS(ES)+ m/e 458.4 [M+H]+.
  • 51
  • [ 851985-81-4 ]
  • [ 1426049-80-0 ]
  • [ 1426049-79-7 ]
YieldReaction ConditionsOperation in experiment
61% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 5.c c) methyl 3-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-3-(4-(quinolin- 7-yl)phenyl)propanoate A solution of methyl 3-(4-bromophenyl)-3-(4-cyclopropyl-3-oxo-l-oxa-4,9- diazaspiro[5.5]undecan-9-yl)propanoate (0.399 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.439 mmol), PdCi2(dppf)- CH2CI2 adduct (0.020 mmol) and 2M aq potassium carbonate (1.196 mmol). The reaction vessel was purged with nitrogen and the reaction irradiated in a Biotage Initiator microwave at 120 °C for 15 minutes. The black reaction mixture was then diluted with water (50 mL) and extracted with dichloromethane three times. The combined organic layer was treated with Silicycle Si-thiol (30 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (15-60%) acetonitrile/water with 0.1% NH4OH) afforded the title compound as a yellow oil, which was subsequently lyophilized from 1 mL of water and then triturated with hexanes and dried under a nitrogen stream to afford the title compound as a white solid (61%). MS(ES)+ m/e 500.3 [M+H]+.
  • 52
  • [ 851985-81-4 ]
  • [ 1426049-86-6 ]
  • [ 1426049-88-8 ]
YieldReaction ConditionsOperation in experiment
91% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 100℃; for 2h; Inert atmosphere; 9.c c) (+)-2-(4-cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undec-9-yl)-2-[2-fluoro-4-(7- quinolinyl)phenyl]acetamide Argon was bubbled through a suspension of 2-(4-bromo-2-fluorophenyl)-2-(4- cyclopropyl-3-oxo-l-oxa-4,9-diazaspiro[5.5]undec-9-yl)acetamide (4.61 mmol), 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (5.76 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.138 mmol), and 2.0 M aqueous potassium carbonate (18.44 mmol) in 1,4- dioxane (36.9 mL) for 10 minutes then the reaction was heated at 100 °C for 2 hours. The reaction was cooled, treated with silica powder (~10g) then evaporated under reduced pressure to dryness. Purification of the residue on silica gel by flash chromatography (ethyl acetate, then 10% methanol/ethyl acetate) followed by combination of the product fractions and concentration to a residue that was taken into dichloromethane, filtered through celite, and concentrated in vacuo afforded the title product racemate (2.27 g, 91 > yield) as a light tan solid. MS(ES)+ m/e 489.5 [M+H]+.
  • 53
  • [ 851985-81-4 ]
  • [ 1426049-92-4 ]
  • [ 1426049-91-3 ]
YieldReaction ConditionsOperation in experiment
18% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 150℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 13.c c) 4-cyclopropyl-9-(l-(4-(quinolin-7-yl)phenyl)ethyl)-l-oxa-4,9-diazaspiro[5.5] undecan- 3 -one A solution of 9-[l-(4-bromophenyl)ethyl]-4-cyclopropyl-l-oxa-4,9- diazaspiro[5.5]undecan-3-one (0.297 mmol) in 1,4-dioxane (1.5 mL) was treated with 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.329 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.015 mmol) and 2M aq potassium carbonate (0.892 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture was irradiated in a Biotage Initiator Microwave at 150 °C for 20 min. The resulting black mixture was diluted with water (50 mL) and extracted three times with dichloromethane. The combined organic layers were treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (4-10% methanol/dichloromethane) and then by reverse phase HPLC (5-35% acetonitrile with 0.1% TFA/water with 0.1% TFA). Fractions containing the desired product were combined and the pH of the resulting mixture was adjusted to ~11 with 30% w/v ammonium hydroxide solution. This mixture was concentrated to a minimal volume in vacuo and was then extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Lyophilization of the resulting semisolid from water yielded the title compound as a white solid (26 mg, 18%). MS(ES)+ m/e 442.1 [M+H]+.
  • 54
  • [ 851985-81-4 ]
  • [ 16532-79-9 ]
  • [ 1426049-99-1 ]
YieldReaction ConditionsOperation in experiment
64% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 17.a a) 2-(4-(quinolin-7-yl)phenyl)acetonitrile A solution of 2-(4-bromophenyl)acetonitrile (2.55 mmol) in 1,4-dioxane (5 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (2.64 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.083 mmol), and 2M aq potassium carbonate (5.10 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 20 min. The resulting black mixture was diluted with water (100 mL) and extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by silica gel chromatography (0-100% ethyl acetate/hexanes) afforded the title compound as a yellow solid (424 mg, 64%). MS(ES)+ m/e 245.3 [M+H]+.
  • 55
  • [ 851985-81-4 ]
  • [ 1426050-02-3 ]
  • [ 1426050-01-2 ]
YieldReaction ConditionsOperation in experiment
63% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; ethanol at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 18.b b) 2-(4-cyclopropyl-3-oxo- 1 -oxa-4,9-diazaspiro[5.5]undecan-9-yl)-2-(2-fluoro-4-(quinolin- 7-yl)phenyl)acetic acid A solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo- 1 -oxa-4,9- diazaspiro[5.5]undecan-9-yl)acetic acid (0.408 mmol) in 1,4-dioxane (2 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.449 mmol), PdCl2(dppf)- CH2C12 adduct (0.020 mmol) and 2M aq potassium carbonate (1.224 mmol). The reaction vessel was purged with nitrogen and sealed, and the mixture irradiated in a Biotage Initiator Microwave at 120 °C for 15 min. The reaction mixture was diluted with methanol (10 mL), treated with Silicycle Si-thiol (20 mg), dried over sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-40%) acetonitrile/water with 0.1% NH4OH) followed by lyophilization from water afforded the title compound as a white solid (134 mg, 63%). MS(ES)+ m/e 490.3 [M+H]+.
  • 56
  • [ 851985-81-4 ]
  • [ 1429790-83-9 ]
  • [ 1429790-84-0 ]
YieldReaction ConditionsOperation in experiment
46% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane at 130℃; for 0.416667h; Microwave irradiation; 23.b 4-cyclopropyl-9-[2,3,6-trifluoro-4-(7-quinolinyl)phenyl]methyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A 20 mL microwave vial equipped with a stirbar was charged with 9-[(4-bromo-2, 3,6-trifluorophenyl)methyl]-4-cyclopropyl- 1 -oxa-4, 9-diazaspi ro[5 .5]undecan-3-one (0.750 g, 1.731 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.071 g, 0.087 mmol), and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (0.442 g, 1.731 mmol). The solids were taken up in 1,4-dioxane (6.92 mL) and the suspension treated with 2M aq potassium carbonate (1.731 mL, 3.46 mmol). The reaction mixture was subjected to microwaveirradiation at 130 °C for 25 mm on the very high absorption setting. The reaction mixture was then cooled to room temperature, diluted with 20 mL dichloromethane and 2 mL methanol, and the resulting suspension filtered through a pad of celite. The filtrate was diluted with 10 mL of water and the mixture extracted. The organic phase was isolated and the aqueous re-extracted with an additional 10 mL of dichloromethane. Theorganics were pooled, dried over sodium sulfate, filtered, and concentrated to a residue. The residue was purified by flash chromatography (0.2-9.5% methanol:dichloromethane). Fractions containing the desired material were pooled and concentrated to afford the title compound as an oil (405 mg, 0.799 mmol, 46% yield). MS(ES)+ m/e 482.0 [M+H]+.
  • 57
  • [ 851985-81-4 ]
  • [ 1429790-71-5 ]
  • [ 1429790-72-6 ]
YieldReaction ConditionsOperation in experiment
55% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane at 90℃; for 4h; 1.i i) 4-cyclopropyl-9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A 250 mL round bottom flask equipped with a stirbar was charged with 9-[(4-bromo-2-fluorophenyl)methyl]-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (6 g, 15.10 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (4.25 g, 16.66 mmol), and PdCl2(dppf)CH2CI2 adduct (0.493 g, 0.604 mmol). The solids were taken up in 1,4-dioxane (97 mL) and the suspension treated with 2M aq potassium carbonate(15.10 mL, 30.2 mmol). The flask was fitted with a needle-vented septum stopper and the suspension was heated to 90 °C with stirring for 4 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite, and the pad was washed with 100 mL 10% methanol/dichloromethane. The reaction mixture was then partitioned between water (200 mL) and an additional 100 mL of dichloromethane and the layers were separated. The organic layer was isolated and the aqueous layer re-extracted withan additional 200 mL of dichloromethane. The organics were then pooled, dried over sodium sulfate, filtered, and concentrated to a residue which was purified by reverse phase preparative HPLC (75:25 300 mM aq ammonium formate (pH 4):acetonitrile) to afford the title compound as an off white solid (3.81 g, 8.26 mmol, 55% yield). MS(ES) me 446.2 [M+H]+.
55% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 90℃; for 4h; 27.c c) 4-cyclopropyl-9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-1-oxa-4,9- diazaspiro[5.5]undecan-3-one A 250 mL round bottom flask equipped with a stir bar was charged with 9-[(4- bromo-2-fluorophenyl)methyl]-4-cyclopropyl- 1 -oxa-4,9-diazaspiro[5.5]undecan-3-one (6 g, 15.10 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (4.25 g, 16.66 mmol), and l, -bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.493 g, 0.604 mmol). The solids were taken up in 1,4-dioxane (97 mL) and the suspension treated with a 2M aqueous solution of potassium carbonate (15.10 mL, 30.2 mmol). The flask was fitted with a septum stopper and venting needle and the resulting suspension was heated to 90 °C with stirring for 4 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite and the pad washed with 10% methanol in dichloromethane (100 mL). The reaction mixture was then partitioned between water (200 mL) and an additional 100 mL of dichloromethane and the desired material extracted into the organic layer. The aqueous layer was extracted with dichloromethane (200 mL) and the organic layers were pooled. The organic solution was then dried over sodium sulfate and concentrated to a residue. The residue was purified by preparative chiral HPLC (Chiralpak AS-H, 95:5 acetonitrile:methanol) to afford the title compound as an off- white solid (3.81 g, 55%). MS(ES)+ m/e 446.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.56 - 0.71 (m, 4 H) 1.53 - 1.64 (m, 2 H) 1.66 - 1.76 (m, 2 H) 2.30 (t, J=11.12 Hz, 2 H) 2.52 - 2.62 (m, 2 H) 2.70 - 2.78 (m, 1 H) 3.11 (s, 2 H) 3.59 (s, 2 H) 3.96 (s, 2 H) 7.50 - 7.58 (m, 2 H) 7.70 (s, 1 H) 7.71 - 7.74 (m, 1 H) 7.99 (dd, J=8.59, 1.77 Hz, 1 H) 8.09 (d, J=8.59 Hz, 1 H) 8.31 - 8.34 (m, 1 H) 8.40 (dd, J=8.34, 1.52 Hz, 1 H) 8.95 (dd, J=4.29, 1.77 Hz, 1 H).
  • 58
  • [ 851985-81-4 ]
  • [ 1429790-82-8 ]
  • (+)-9-[2,6-difluoro-4-(7-quinolinyl)phenyl]methyl}-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecane-3,8-dione [ No CAS ]
  • (-)-9-[2,6-difluoro-4-(7-quinolinyl)phenyl]methyl}-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecane-3,8-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
1: 36% 2: 37% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane at 130℃; for 0.416667h; Microwave irradiation; 21.f; 22.a (+)-9-[2,6-difluoro-4-(7-quinolinyl)phenyl]methyl}-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecane-3,8-dione A 5 mL microwave vial was charged with 9-(4-bromo-2,6-difluorobenzyl)-4-ethyl- 1-oxa-4,9-diazaspiro[5.5]undecane-3,8-dione (120 mg, 0.288 mmol), 7-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)quinoline (88 mg, 0.345 mmol), and PdCI2(dppf)- CH2CI2 adduct (16.44 mg, 0.020 mmol). The solids were taken up in 1 ,4-dioxane (2588pL) and treated with 2M aq potassium carbonate (288 pL, 0.575 mmol). The mixture was then subjected to microwave irradiation at 130 °C for 25 mm. The reaction was then cooled to room temperature, diluted with -10 mL dichloromethane and then filtered through a stacked pad of sodium sulfate and celite to afford a dark brown solution. The solution was concentrated to a residue under a nitrogen stream at 70 °C, and the residuewas purified by flash chromatography (0.3-7% methanol:dichloromethane). Fractions containing the desired material were pooled and concentrated to afford the racemate, which was resolved by chiral HPLC (Chiralpak AS-H, 95:5 acetonitrile:methanol) to afford the title compound in 100% ee as an off-white solid (48 mg, 0.103 mmol, 36% yield). MS(ES)+ m/e 466.3 [M+H]+. αD = +4 deg (c = 0.1, 95:5 acetonitrile:methanol). From Example 21f, the title product was also isolated via chiral HPLC (Chiralpak ASH, 95:5 acetonitrile:methanol) as an off white solid in 100% ee (37% yield). MS(ES)+ m/e 466.3 [M+H]+. αD = -4 deg (c = 0.02, 95:5 acetonitrile:methanol).
  • 59
  • [ 851985-81-4 ]
  • [ 1534373-32-4 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; 1,4-dioxane / 0.5 h / 100 °C / Inert atmosphere; Microwave irradiation 2: phosphorus tribromide / 1,2-dichloro-benzene / 0 - 20 °C / Inert atmosphere
  • 60
  • [ 851985-81-4 ]
  • [ 1534371-87-3 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium carbonate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 / water; 1,4-dioxane / 0.5 h / 100 °C / Inert atmosphere; Microwave irradiation 2: phosphorus tribromide / 1,2-dichloro-benzene / 0 - 20 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.33 h / 120 °C / Microwave irradiation
  • 61
  • [ 851985-81-4 ]
  • [ 1534373-25-5 ]
  • [ 1534371-60-2 ]
YieldReaction ConditionsOperation in experiment
25% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.333333h; Sealed tube; Microwave irradiation; 29.d d) 4-cyclopropyl-9-[2,6-difluoro-4-(7-quinolinyl)phenyl]methyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one-d2 A 20 mL microwave vial equipped with a stir bar was charged with 9-[(4-bromo-2,6- difluorophenyl)methyl]-4-cyclopropyl- 1 -oxa-4,9-diazaspiro[5.5]undecan-3-one-+. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50 - 0.74 (m, 4 H) 1.48 - 1.63 (m, 2 H) 1.63 - 1.77 (m, 2 H) 2.31 (t, J=10.74 Hz, 2 H) 2.59 (d, J=11.37 Hz, 2 H) 2.73 (m, J=7.39, 7.39, 4.04, 3.66 Hz, 1 H) 3.09 (s, 2 H) 3.95 (s, 2 H) 7.57 (dd, J=8.21, 4.17 Hz, 1 H) 7.62 - 7.73 (m, 2 H) 8.02 (dd, J=8.59, 1.77 Hz, 1 H) 8.10 (d, J=8.59 Hz, 1 H) 8.40 (br. s., 1 H) 8.42 (dd, J=8.84, 1.26 Hz, 1 H) 8.97 (dd, J=4.17, 1.64 Hz, 1 H).
  • 62
  • [ 851985-81-4 ]
  • [ 1534373-27-7 ]
  • [ 1534371-68-0 ]
YieldReaction ConditionsOperation in experiment
33% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 130℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 33.e e) 9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-4-(1-methylcyclopropyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (176 mg, 0.692 mmol) and 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (26.9 mg, 0.033 mmol) were added to a 5 mL microwave reaction tube. To this was added 9- [(4-bromo-2-fluorophenyl)methyl]-4-(l -methylcyclopropyl)- 1 -oxa-4,9- diazaspiro[5.5]undecan-3-one (271 mg, 0.659 mmol) inl,4-dioxane (3 mL) followed by 2M aqueous potassium carbonate solution (0.725 mL, 1.450 mmol). The reaction tube was purged with nitrogen, sealed, and irradiated in a microwave reactor at 130 °C for 20 minutes. The reaction mixture was diluted with water (5 mL) and dichloromethane (30 mL). The organic layer was separated, washed with 5% aqueous sodium bicarbonate solution (10 mL) and brine (10 mL), dried over sodium sulfate and evaporated to dryness to afford the crude product. Purification by reverse phase HPLC (70:30 300 mM aqueous ammonium formate (pH 4) : acetonitrile) afforded the title compound (101 mg, 33%). MS(ES)+ m/e 460.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.56 - 0.66 (m, 2 H) 0.70 - 0.79 (m, 2 H) 1.22 (s, 3 H) 1.62 (br. s., 1 H) 1.65 (d, J=3.79 Hz, 1 H) 1.70 (br. s., 2 H) 2.32 (br. s., 2 H) 2.61 (s, 1 H) 2.58 (s, 1 H) 3.21 (s, 2 H) 3.60 (s, 2 H) 3.93 (s, 2 H) 7.51 - 7.61 (m, 2 H) 7.72 (d, J=9.60 Hz, 2 H) 8.00 (dd, J=8.59, 2.02 Hz, 1 H) 8.10 (d, J=8.59 Hz, 1 H) 8.33 (s, 1 H) 8.42 (d, J=8.34 Hz, 1 H) 8.95 (dd, J=4.17, 1.64 Hz, 1 H).
  • 63
  • [ 851985-81-4 ]
  • [ 1534373-33-5 ]
  • [ 1534371-88-4 ]
YieldReaction ConditionsOperation in experiment
61% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In ethanol; water at 80℃; for 1h; Inert atmosphere; Microwave irradiation; 43.c c) 4-cyclopropyl-9-((5-(quinolin-7-yl)pyridin-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one In a 5 mL microwave vial was placed 9-((5-bromopyridin-2-yl)methyl)-4- cyclopropyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (100 mg, 0.263 mmol), 7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (67.1 mg, 0.263 mmol), potassium carbonate (145 mg, 1.052 mmol), and l, -bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (20 mg, 0.024 mmol). A premade degassed solution of 3 : 1 ethanol: water (2.67 mL total) was added to the vial. The vial was capped and the contents were purged with nitrogen. The reaction was stirred at 80 °C for 1 h. After cooling to room temperature, the solution was diluted with dichloromethane (30 mL) and washed with water (20 mL). The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate (with a small amount of Si-thiol resin), filtered, and concentrated in vacuo. This was purified via flash chromatography (0-10% MeOH/CH2Cl2) to afford the title compound (69 mg, 61%). MS(ES)+ m/e 429.0 [M+H]+.
  • 64
  • [ 851985-81-4 ]
  • trans-9-(4-bromo-2-fluorobenzyl)-4-cyclopropyl-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • trans-4-cyclopropyl-7-fluoro-9-(2-fluoro-4-(quinolin-7-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
715 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In ethanol; water at 80℃; for 1h; Inert atmosphere; Microwave irradiation; 49.i i) (-)-trans-4-cyclopropyl-7-fluoro-9-(2-fluoro-4-(quinolin-7-yl)benzyl)-1-oxa-4,9- diazaspiro[5.5]undecan-3-one A microwave vial was charged in succession with trans-9-(4-bromo-2-fluorobenzyl)- 4-cyclopropyl-7-fluoro-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (606 mg, 1.459 mmol), 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (380 mg, 1.489 mmol), potassium carbonate (810 mg, 5.86 mmol), and 1 , l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (50 mg, 0.061 mmol). Then, a premade degassed solution of 3 : 1 ethanol: water (12 mL) was added. The vial was capped, purged with nitrogen, and stirred at 80 °C. After 1 h, the mixture was cooled to room temperature. The reaction mixture was diluted with dichloromethane (100 mL), transferred to a separatory funnel, and the layers were separated. The organic layer was washed with water (100 mL) and the aqueous layer was back-extracted with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate (with a small amount of Si-Thiol resin), filtered, and concentrated in vacuo. This was purified via flash chromatography (0-10% methanol/dichloromethane). The recovered material (715 mg), which is a mixture of trans diastereomers, was delivered for chiral separation. Chiral resolution by preparative HPLC (Chiralpak AS-H, 95% acetonitrile : 5% methanol) afforded the title compound (222 mg) as a single unknown enantiomer with known relative stereochemistry. MS (ES)+ m/e 464.4 [M+H]+; aD = -29° (c = 0.05, CH3CN:CH3OH- 95:5).
  • 65
  • [ 851985-81-4 ]
  • trans-9-(4-bromo-2,6-difluorobenzyl)-4-cyclopropyl-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • trans-4-cyclopropyl-9-(2,6-difluoro-4-(quinolin-7-yl)benzyl)-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
700 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In ethanol; water at 80℃; for 1h; Inert atmosphere; Microwave irradiation; 53.b b) (-)-trans-4-cyclopropyl-9-(2,6-difluoro-4-(quinolin-7-yl)benzyl)-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one The reaction was performed in two 10 mL microwave vials. Into each vial was placed tra/75-9-(4-bromo-2,6-difluorobenzyl)-4-cyclopropyl-7-fluoro-l-oxa-4,9- diazaspiro[5.5]undecan-3-one (350 mg, 0.808 mmol), 7-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)quinoline (225 mg, 0.882 mmol), potassium carbonate (450 mg, 3.255 mmol), 1 , 1 '-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.043 mmol), and a premixed and degassed 3 : 1 ethanokwater solution (8 mL total). Each vial was sealed, purged with nitrogen, and stirred at 80 °C. After 1 h, the solutions were cooled to room temperature and poured into a separatory funnel containing dichloromethane (100 mL) and water (50 mL). The organic layer was separated and the aqueous layer was washed with dichloromethane (30 mL). The combined organic layers were dried over sodium sulfate (with 50 mg of Si-thiol resin). After 10 minutes of drying, the solution was filtered and concentrated in vacuo. The crude material was purified via flash chromatography (0-10% methanokethyl acetate). The recovered racemic material (700 mg) was resolved by chiral preparative HPLC (Chiralpak AS-H, 95% acetonitrile : 5% methanol) to afford the title compound (269 mg) as a single unknown enantiomer with known relative stereochemistry. MS(ES)+ m/e 482.0 [M+H]+. aD = -24° (c = 0.1 , MeOH).
  • 66
  • [ 851985-81-4 ]
  • trans-9-(4-bromo-2,3,6-trifluorobenzyl)-4-cyclopropyl-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • trans-4-cyclopropyl-7-fluoro-9-(2,3,6-trifluoro-4-(quinolin-7-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In ethanol; water at 80℃; for 0.5h; Inert atmosphere; Microwave irradiation; 53.b b) (+)-tran5-4-cyclopropyl-7-fiuoro-9-(2,3,6-trifluoro-4-(quinolin-7-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A 5 mL microwave vial was charged, in succession, with tra/?s-9-(4-bromo-2,3,6- trifluorobenzyl)-4-cyclopropyl-7-fluoro- 1 -oxa-4,9-diazaspiro[5.5]undecan-3-one (335 mg, 0.742 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (200 mg, 0.784 mmol), potassium carbonate (410 mg, 2.97 mmol), and Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.037 mmol) followed by a premade degassed solution of 3 : 1 ethanokwater (4 mL total). The vial was sealed, purged with nitrogen, and stirred at 80 °C. After 30 minutes, the solution was cooled to room temperature and poured into a separatory funnel containing dichloromethane (40 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over sodium sulfate (with 5 mg of Si-thiol resin). After 10 minutes of drying, the mixture was filtered and concentrated in vacuo. Purification via flash chromatography (0- 10% methanol: ethyl acetate) afforded product as the trans racemate. Resolution by chiral preparative HPLC (Chiralpak AS-H, 95% acetonitrile:5% methanol) to afforded the title compound (65 mg) as a single unknown enantiomer with known relative stereochemistry. MS(ES)+ m/e 500.2 [M+H]+. aD = +35° (c = 0.05, CH3CN:CH3OH- 98:2).
  • 67
  • [ 851985-81-4 ]
  • trans-9-((5-bromo-3-fluoropyridin-2-yl)methyl)-4-cyclopropyl-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • trans-4-cyclopropyl-7-fluoro-9-((3-fluoro-5-(quinolin-7-yl)pyridin-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
26% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In ethanol; water at 80℃; for 1h; Inert atmosphere; Microwave irradiation; 55.c c) trans-4-cyclopropyl-7-fluoro-9-((3-fluoro-5-(quinolin-7-yl)pyridin-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A 5 mL microwave vial was charged in succession with tra/?s-9-((5-bromo-3- fluoropyridin-2-yl)methyl)-4-cyclopropyl-7-fluoro-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (197 mg, 0.473 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (140 mg, 0.549 mmol), potassium carbonate (262 mg, 1.893 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (30 mg, 0.037 mmol), and a premade degassed solution of 3 : 1 ethanol: water (4 mL total). The vial was capped, purged with nitrogen, and stirred at 80 °C. After 1 h, the solution was cooled to room temperature and brought to pH = 7 with a few drops of IN aq. HC1. The mixture was poured into a separatory funnel containing ethyl acetate (30 mL) and water (20 mL). The organic layer was removed and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate (with a small amount of Si-Thiol resin), filtered, and concentrated in vacuo. Purification via flash chromatography (0-10% methanohethyl acetate) then reverse phase HPLC (10-70% acetonitrile /water w/ 0.1% ΝΗ4ΟΗ) afforded the title compound as the trans racemate (56 mg, 26%). MS (ES)+ m/e 465.4 [M+H]+.
  • 68
  • [ 851985-81-4 ]
  • cis-9-(4-bromo-2,6-difluorobenzyl)-4-cyclopropyl-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • (+)-cis-4-cyclopropyl-9-(2,6-difluoro-4-(quinolin-7-yl)benzyl)-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 130℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 59.e e) (+)-cis-4-cyclopropyl-9-[2,6-difluoro-4-(7-quinolinyl)phenyl]methyl}-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A solution of c 5-9-[(4-bromo-2,6-difluorophenyl)methyl]-4-cyclopropyl-7-fluoro-l- oxa-4,9-diazaspiro[5.5]undecan-3-one (0.549 mmol) in 1,4-dioxane (4 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.604 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.027 mmol) and 2M aqueous potassium carbonate (0.824 mL). The reaction vessel was purged with nitrogen gas and irradiated at 130 °C for 20 minutes in a Biotage Initiator microwave. The resulting mixture was diluted with water (100 mL) and extracted with dichloromethane. The organic phase was treated with SiliaBond thiol (Si-thiol) (100 mg) for 30 minutes, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Purification by chiral HPLC (Chiralpak AS-H, 5% methanol in acetonitrile) afforded the title compound (22%) as a single unknown enantiomer with known relative stereochemistry as an off- white solid. MS(ES)+ m/e 481.9 [M+H]+. aD = +2° (c = 0.1, CH3CN:CH3OH- 95:5).
  • 69
  • [ 851985-81-4 ]
  • cis-9-(4-bromo-2-fluorobenzyl)-4-cyclopropyl-7-fluoro-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
  • cis-4-cyclopropyl-7-fluoro-9-(2-fluoro-4-(quinolin-7-yl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 130℃; for 0.333333h; Inert atmosphere; Microwave irradiation; 61.b b) (+)-cis-4-cyclopropyl-7-fluoro-9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A solution of cz5-9-[(4-bromo-2-fluorophenyl)methyl]-4-cyclopropyl-7-fluoro-l-oxa- 4,9-diazaspiro[5.5]undecan-3-one (0.313 mmol) in 1,4-dioxane (2 mL) was treated with 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.344 mmol), Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.016 mmol) and potassium carbonate (2M, aqueous) (0.470 mL). The reaction vessel was purged with nitrogen gas and irradiated at 130 °C for 20 minutes in a Biotage Initiator microwave. The resulting mixture was diluted with water (100 mL) and extracted with dichloromethane. The organic phase was treated with SiliaBond thiol (Si-thiol) (lOOmg) for 30 minutes, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Purification by chiral HPLC (Chiralpak AS-H, 5% methanol in acetonitrile) afforded the title compound (29%) as a single unknown enantiomer with known relative stereochemistry as an off-white solid. MS(ES)+ m/e 464.3 [M+H]+. aD = +9° deg (c = 0.02, CH3CN:CH3OH - 95:5).
  • 70
  • [ 851985-81-4 ]
  • [ 1534373-76-6 ]
  • [ 1534372-11-6 ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 120℃; for 0.25h; Inert atmosphere; Microwave irradiation; 63.k k) (-)-4-cyclopropyl-9-[2,6-difluoro-4-(7-quinolinyl)phenyl]methyl}-7,7-difluoro-1-oxa-4,9-diazaspiro[5.5 ]undecan-3-one A solution of 9-[(4-bromo-2,6-difluorophenyl)methyl]-4-cyclopropyl-7,7-difluoro-l- oxa-4,9-diazaspiro[5.5]undecan-3-one (0.146 mmol) in 1,4-dioxane (1.5 mL) was treated with 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.161 mmol), potassium carbonate (2M, aqueous) (0.219 mL) and 1 , l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (6 mg). The reaction vessel was purged with nitrogen gas and irradiated at 120 °C for 15 minutes in a Biotage Initiator microwave. The resulting mixture was diluted with water (50 mL) and extracted with dichloromethane. The aqueous phase was diluted with brine (20 mL) and extracted with tetrahydrofuran. The combined organic phase was treated with SiliaBond thiol (Si-thiol) (20 mg) for 30 minutes, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Purification by chiral HPLC (Chiralpak AS-H, 2% ethanol in heptane) and then trituration of the first eluting enantiomer with hexanes afforded the title compound (12%) as an off-white solid. MS(ES)+ m/e 500.2 [M+H]+. aD = -24° (c = 0.05, EtOH:heptane - 2:98).
  • 71
  • [ 851985-81-4 ]
  • [ 1534374-05-4 ]
  • [ 76-05-1 ]
  • [ 1534372-18-3 ]
YieldReaction ConditionsOperation in experiment
10% Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; 9-[(4-bromophenyl)methyl]-4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In 1,4-dioxane; water at 130℃; for 0.333333h; Inert atmosphere; Microwave irradiation; Stage #2: trifluoroacetic acid In water; dimethyl sulfoxide; acetonitrile 70.b b) 4-cyclopropyl-9-[4-(7-quinolinyl)phenyl]methyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one trifluoroacetate salt A 5 mL microwave reaction vial was charged with 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (135 mg), PdCl2(dppf)-CH2Cl2 adduct (22 mg), crude 9-[(4- bromophenyl)methyl]-4-cyclopropyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (200 mg) in 1,4-dioxane (2.5 mL) and then 2M aqueous potassium carbonate (0.58 mL). The vessel was flushed with nitrogen, sealed and then irradiated in a microwave reactor at 130 °C for 20 min. The reaction mixture was filtered, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with IN aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was dissolved in dimethyl sulfoxide, filtered and purified by reverse phase HPLC (0-30% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA). The appropriate fractions were combined and lyophilized to afford the title compound (29.4 mg, 10%). MS(ES)+ m/e 428.0 [M+H]+.
  • 72
  • [ 851985-81-4 ]
  • [ 1534374-22-5 ]
  • [ 76-05-1 ]
  • [ 1534372-97-8 ]
YieldReaction ConditionsOperation in experiment
6% Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; 9-[(4-bromo-2-fluorophenyl)methyl]-4-ethyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one With potassium carbonate In 1,4-dioxane; water at 130℃; for 0.333333h; Inert atmosphere; Microwave irradiation; Stage #2: trifluoroacetic acid In water; dimethyl sulfoxide; acetonitrile 104.e e) 4-ethyl-9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one trifluoroacetate salt A 5 mL microwave reaction vial was charged with 7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)quinoline (132 mg), crude 9-[(4-bromo-2-fiuorophenyl)methyl]-4-ethyl-l- oxa-4,9-diazaspiro[5.5]undecan-3-one (200 mg) in 1,4-dioxane (2.5 mL) and 2M aq. potassium carbonate (0.571 mL). The vessel was flushed with nitrogen, sealed then irradiated in a microwave reactor at 130 °C for 20 min. The reaction mixture was filtered, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with IN aq. sodium bicarbonate and brine, dried over sodium sulfate, and evaporated to dryness. The crude product was dissolved in DMSO, filtered and purified by reverse phase HPLC (2-32% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA) to afford the title compound (18.1 mg, 6%). MS(ES)+ m/e 434.2 [M+H]+.
  • 73
  • [ 851985-81-4 ]
  • [ 1534374-72-5 ]
  • [ 1534372-12-7 ]
YieldReaction ConditionsOperation in experiment
59 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 1h; Microwave irradiation; 65.e e) 9-[2,6-difluoro-4-(7-quinolinyl)phenyl]methyl}-4-[1-(hydroxymethyl)cyclopropyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A microwave vial was charged with a suspension of 4-[l- (hydroxymethyl)cyclopropyl]-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (0.300 mmol), 5- bromo-2-(bromomethyl)-l,3-difluorobenzene (0.300 mmol) and potassium carbonate (1.498 mmol) in anhydrous Ν,Ν-dimethylformamide (DMF) (3.0 ml) then sealed with a standard aluminum crimp cap. The vessel was heated on an aluminum block at 80 °C for 2 h to form the intermediate aryl bromide. The suspension was cooled, treated with 7-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (0.449 mmol), PdCL^dppfJ-CFLCb adduct (0.015 mmol), and water (500 μ) then resealed and heated at 100 °C. After 1 h the reaction was cooled, filtered through a teflon syringe adaptor and purified directly by reverse phase HPLC (10-35% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA). The combined fractions were treated with saturated aqueous sodium bicarbonate then concentrated under reduced pressure to remove the volatiles. The precipitated solids were collected by filtration, rinsed well with water then suction and vacuum dried to afford the title compound (59 mg, 40%>) as a white solid. MS(ES)+ m/e 494.2 [M+H]+. 1H NMR (400 MHz, DMSO- 6) δ ppm 0.62 - 0.86 (m, 4 H) 1.45 - 1.63 (m, 2 H) 1.64 - 1.76 (m, 2 H) 2.25 - 2.41 (m, 2 H) 2.53 - 2.62 (m, 2 H) 3.28 (s, 2 H) 3.44 (d, J=5.56 Hz, 2 H) 3.62 (s, 2 H) 3.93 (s, 2 H) 4.71 (t, J=5.68 Hz, 1 H) 7.57 (dd, J=8.21, 4.17 Hz, 1 H) 7.68 (d, J=8.34 Hz, 2 H) 7.99 - 8.06 (m, 1 H) 8.06 - 8.14 (m, 1 H) 8.36 - 8.47 (m, 2 H) 8.96 (dd, J=4.17, 1.39 Hz, 1 H).
  • 74
  • [ 851985-81-4 ]
  • [ 1206968-92-4 ]
  • [ 1534373-31-3 ]
YieldReaction ConditionsOperation in experiment
150 mg With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 0.5h;Inert atmosphere; Microwave irradiation; A microwave vial was charged, in succession, with (5 -bromo-3 -fluoropyridin-2- yl)methanol (100 mg, 0.485 mmol), 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (124 mg, 0.485 mmol), 1 , -bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.043 mmol), 1,4-dioxane (3 mL), and 2M aq. potassium carbonate (1.5 mL). The vial was capped, purged with nitrogen, and stirred at 100 C. After 30 minutes, the reaction mixture was cooled to room temperature, allowing the organic phase to separate from the aqueous. The organic layer was removed and filtered through a plug of Celite and sodium sulfate. The plug was washed with dioxane (10 mL). The organic filtrate was concentrated in vacuo. Purification via flash chromatography (0-10% methanol/dichloromethane) afforded the title compound (150 mg, 103%). Although the recovered weight exceeded the theoretical yield, the compound was used without further purification. MS(ES)+ m/e 255.2 [M+H]+.
  • 75
  • [ 851985-81-4 ]
  • [ 1534374-73-6 ]
  • 9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-4-{1-[(methyloxy)methyl]cyclopropyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
79 mg Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; C20H26BrFN2O3 With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate In water; N,N-dimethyl-formamide at 100℃; for 1.5h; Microwave irradiation; Stage #2: With hydrogenchloride In 1,4-dioxane 67.d d) 9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-4-{1-[(methyloxy)methyl]cyclopropyl}-1-oxa-4,9-diazaspiro[5.5]undecan-3-one dihydrochloride A stirring suspension of 4-{l-[(methyloxy)methyl]cyclopropyl}-l-oxa-4,9- diazaspiro[5.5]undecan-3-one hydrochloride (0.272 mmol), 4-bromo-l-(bromomethyl)-2- fluorobenzene (0.285 mmol) and potassium carbonate (1.087 mmol) in anhydrous N,N- dimethylformamide (DMF) (3.0 ml) was heated at 100 °C for 2 h. The intermediate was cooled to room temperature then treated with 7-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)quinoline (0.408 mmol), PdCl2(dppf)-CH2Cl2 adduct (8.15 μιηο) and water (500 μ). The vessel was resealed and heated at 100 °C for 1.5 h. The resulting dark suspension was cooled and filtered through a teflon syringe adapter then the filtrate was purified by reverse phase HPLC (10-30% acetonitrile w/ 0.1% TF A/water w/ 0.1% TFA). The combined fractions were treated with saturated aqueous sodium bicarbonate, extracted with dichloromethane then dried (sodium sulfate) and evaporated in vacuo to afford the free base as a colorless glass. Treatment with 4N HCl in 1,4-dioxane (0.680 mmol) followed by vacuum drying afforded the title compound (79 mg, 50%) as a cream-colored solid. MS(ES)+ m/e 490.5 [M+H]+.
  • 76
  • [ 851985-81-4 ]
  • [ 1534373-94-8 ]
  • [ 1534372-15-0 ]
YieldReaction ConditionsOperation in experiment
72% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 100℃; for 6h; Inert atmosphere; Microwave irradiation; 68.f f) 4-cyclopropyl-9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-7-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one A microwave vial was charged with 9-[(4-bromo-2-fluorophenyl)methyl]-4- cyclopropyl-7-methyl-l-oxa-4,9-diazaspiro[5.5]undecan-3-one (210 mg, 0.511 mmol), 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (175 mg, 0.686 mmol), cesium carbonate (499 mg, 1.532 mmol), and dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (21 mg, 0.026 mmol). The vial was purged with nitrogen and then 1,4-dioxane (1.5 mL) and water (1.5 mL) were added. The reaction mixture was heated for 6 h on a hot plate at 100 °C. The mixture was filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water + 0.1% TFA). The desired fractions were collected and added to a separatory funnel containing dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with dichloromethane (3x) and the combined organics were washed with brine, dried over Na2S04, and concentrated in vacuo to afford the title compound (170 mg, 72%) as a white foam. MS(ES)+ m/e 460.3 [M+H]+.
  • 77
  • [ 851985-81-4 ]
  • [ 1534374-03-2 ]
  • [ 1534372-16-1 ]
YieldReaction ConditionsOperation in experiment
68% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In 1,4-dioxane; water at 100℃; for 4h; Inert atmosphere; Microwave irradiation; 69.i i) 2-cyclopropyl-9-[2-fluoro-4-(7-quinolinyl)phenyl]methyl}-2,9-diazaspiro[5.5]undecan-3-one A microwave vial was charged with 9-[(4-bromo-2-fluorophenyl)methyl]-2- cyclopropyl-2,9-diazaspiro[5.5]undecan-3-one (60 mg, 0.152 mmol), 7-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)quinoline (39 mg, 0.16 mmol), CS2CO3 (148 mg, 0.455 mmol), and dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg, 0.012 mmol) and purged with nitrogen. 1,4-Dioxane (1.0 ml) and water (1.0 ml) were added to the mixture and the reaction was stirred for 4 h on a hot plate at 100 °C. The mixture was cooled to room temperature, filtered through a syringe filter and purified by reverse phase HPLC (10-90% acetonitrile/water + 0.1% TFA). The desired fractions were collected and added to a separatory funnel containing dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated, the aqueous phase was extracted with dichloromethane (3x), and the combined organic layers were washed with brine, dried over Na2S04, and concentrated to afford the title product as an oil (46 mg, 68%>). MS(ES)+ m/e 444.4 [M+H]+.
  • 78
  • [ 851985-81-4 ]
  • [ 25334-12-7 ]
YieldReaction ConditionsOperation in experiment
93% With copper(l) iodide; potassium iodide In methanol; water at 20 - 80℃; for 1h; Sealed tube;
93% With copper(l) iodide; 1,10-Phenanthroline; potassium iodide In methanol; water at 80℃; for 1h; B The starting material (638 mg, 2.5 mmol) was dissolved in methanol (20 mL) , and the methanol solution was transferred to a 250 mL pressure vessel containing Cul (47.6 mg, 0.25 mmol, 10.0 mol%) , phenanthroline (90.0 mg, 0.5 mmol, 20.0 mol%) and KI (0.622 g, 3.76 mmol, 1.50 equiv) . The mixture was stirred at room temperature, and water (5 mL) was added. The flask was sealed under air, and the mixture was heated at 80 °C for 1 hour, over which time the reaction was monitored by TLC. The reaction was cooled to room temperature, water (25 mL) was added, and the mixture was extracted with Et20 (3 χ 25 mL) . The combined organic phases were washed with brine (25 mL) , dried with MgSO^, and concentrated in vacuo. After purification by column chromatography using hexanes/EtOAc (20/1) as the eluent, the product was obtained as a white solid (593 mg, 93%) [Partridge et al., Org. Lett. 15:140 (2013)]. Partridge et al., Org. Lett. 15:140 (2013) 7-Iodoquinoline 1H NMR (600 MHz, CDC13) δ 8.91 (dd, J= 4.2, 1.8 Hz, 1H) , 8.55-8.54 (m, 1H) , 8.13-8.11 (m, 1H) , 7.81 (dd, J = 8.4, 1.8 Hz, 1H) , 7.54 (d, J = 8.4 Hz, 1H) , 7.42 (dd, J" = 8.4, 4.2 Hz, 1H) ; 13C NMR (150 MHz, CDC13) δ 151.07, 148.94, 138.53, 135.99, 135.30, 128.90, 127.25, 121.60, 95.47; HRMS (ESI-TOF) Calcd for C9H7IN [M+H]+: 255.9618; found: 255.9621.
  • 79
  • [ 851985-81-4 ]
  • C21H17N3O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: copper(l) iodide; potassium iodide / water; methanol / 1 h / 20 - 80 °C / Sealed tube 2: palladium diacetate; silver(I) acetate; 2,6-dimethylpyridine / 36 h / 20 - 80 °C / Sealed tube
  • 80
  • [ 851985-81-4 ]
  • methyl (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(quinolin-7-yl)propanoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: copper(l) iodide; potassium iodide / water; methanol / 1 h / 20 - 80 °C / Sealed tube 2: palladium diacetate; silver(I) acetate; 2,6-dimethylpyridine / 36 h / 20 - 80 °C / Sealed tube 3: [bis(acetoxy)iodo]benzene / 3 h / 80 °C / Sealed tube
  • 81
  • [ 851985-81-4 ]
  • [ 100-58-3 ]
  • [ 29314-09-8 ]
YieldReaction ConditionsOperation in experiment
30% Stage #1: 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline; phenylmagnesium bromide In tetrahydrofuran at -78 - 20℃; for 2.33333h; Inert atmosphere; Stage #2: With trifluoroacetyl chloride In tetrahydrofuran at -78 - 4℃; for 15h; Inert atmosphere; Further stages;
  • 82
  • [ 851985-81-4 ]
  • C17H14ClFN4 [ No CAS ]
  • C26H20FN5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
40 mg With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; 1.3.2 2) Synthesis of A3 product The A1-4 (50mg, 0.15mmol), A3-2 (360mg, crude) was dissolved in dioxane / water (5mL / 1mL), was added potassium carbonate (84mg, 0.61mmol),Phosphorus tetrakistriphenylphosphine palladium (17mg, 0.015mmol), purged with nitrogen, stirred overnight at 100 deg.] C, cooled to room temperature, suction filtered through Celite, and the filtrate with ethyl acetate.(15mL) diluted with anhydrous sodium sulfate, and sodium sulfate was filtered, spin-dry the solvent, the residue was purified by column chromatography (dichloromethane: methanol = 100: 1-50: 1),To give a brown solid (40mg, 63%).
  • 83
  • [ 851985-81-4 ]
  • (5-bromo-thiophen-2-yl)(2,4,5-trifluoro-3-hydroxy-phenyl)methanone [ No CAS ]
  • (5-(quinolin-7-yl)thiophen-2-yl)(2,4,5-trifluoro-3-hydroxyphenyl)methanone [ No CAS ]
YieldReaction ConditionsOperation in experiment
5% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; toluene for 20h; Reflux; Inert atmosphere;
  • 84
  • [ 851985-81-4 ]
  • 2-chloro-3-(1-(cyclopentylmethyl)-1H-pyrazol-4-yl)-6-methoxypyridine [ No CAS ]
  • 7-(3-(1-(cyclopentylmethyl)-1H-pyrazol-4-yl)-6-methoxypyridin-2-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) In 1,4-dioxane; water at 90℃; for 18h; 1 Step 1 : 7-(3-(l-(cyclopentylmethyl)-lH-pyrazol-4-yl)-6-methoxypyridin-2-yl)quinoline l, l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (20.1 mg, 0.031 mmol) was added to a stirred mixture of 7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline (157 mg, 0.617 mmol), 2-chloro-3-(l-(cyclopentylmethyl)-lH-pyrazol-4-yl)-6-methoxypyridine (INTERMEDIATE H28, 180 mg, 0.617 mmol), K3PO4 (393 mg, 1.851 mmol) in dioxane (5 ml) and water (1 ml) and the mixture was stirred at 90 °C for 18 hours. The mixture was cooled, then solvent was evaporated under reduced pressure. The residue was diluted with DCM (10 mL) and washed with water (2x10 mL), dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by TLC eluting with petroleum ether/ethyl acetate (1 : 1) to give the title compound. MS(M+1): 385.7.
  • 85
  • [ 851985-81-4 ]
  • 5-(1-(cyclopentylmethyl)-1H-pyrazol-4-yl)-6-(quinolin-7-yl)pyridin-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 2 steps 1: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 18 h / 90 °C 2: chloro-trimethyl-silane; sodium iodide / acetonitrile / 18 h / 60 °C
  • 86
  • [ 851985-81-4 ]
  • 7-(6-chloro-3-(1-(cyclopentylmethyl)-1H-pyrazol-4-yl)pyridin-2-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 18 h / 90 °C 2: chloro-trimethyl-silane; sodium iodide / acetonitrile / 18 h / 60 °C 3: trichlorophosphate; N,N-dimethyl-formamide / 18 h / 60 °C
  • 87
  • [ 851985-81-4 ]
  • 7-(3-(1-(cyclopentylmethyl)-1H-pyrazol-4-yl)-6-(difluoromethoxy)pyridin-2-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; 1,4-dioxane / 18 h / 90 °C 2: chloro-trimethyl-silane; sodium iodide / acetonitrile / 18 h / 60 °C 3: potassium carbonate / N,N-dimethyl-formamide / 3 h / 90 °C
  • 88
  • [ 851985-81-4 ]
  • 6-chloro-5-(1H-pyrazol-4-yl)picolinonitrile [ No CAS ]
  • 5-(1H-pyrazol-4-yl)-6-(quinolin-7-yl)picolinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); potassium carbonate Inert atmosphere; Heating; 146.1 Step 1 : 3-methoxy-7-(6-methyl-3-(lH-pyrazol-4-yl)pyridin-2-yl)cinnoline General procedure: A mixture of Na2C03 (1.095 g, 10.33 mmol), 2-chloro-6-methyl-3-(lH-pyrazol-4-yl)pyridine (INTERMEDIATE E2, 2.00 g, 10.33 mmol), 3-methoxy-7-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)cinnoline (INTERMEDIATE M8, 3.25 g, 11.36 mmol), PdCl2(dppf) (0.756 g, 1.033 mmol) in THF (24 ml) and water (6 ml) was stirred at 100°C overnight under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2S04, filtered and concentrated. The crude product was purified by silica gel chromatography (PE:EA=10: 1-0: 1) to give the title compound. 1H NMR (500 MHz, DMSO-d6): δ 12.83 (s, 1H), 8.25 (s, 1H), 7.84 (m, 2H), 7.64 (m, 1H), 7.57 (s, 1H), 7.32 (m, 1H), 7.19 (s, 1H), 4.14 (s, 3H), 2.52 (s, 3H). EXAMPLE 146 in Table 7 was prepared by the same two step sequence utilizing l, l'-bis(di-tert- butylphosphino)ferrocene palladium dichloride and K2C03 with INTERMEDIATE E3 and 7- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline for the Suzuki coupling to give the C-2 functionalized compound, followed by NaH alkylation of the pyrazole with INTERMEDIATE A7 to give the diastereomeric mixture. Chiral SFC (Chiralpak AD-H 250x4.6mm ID., 5um Mobile phase: methanol (0.05% DEA) in C02 from 5% to 40%) provided the single diastereomer as the later eluting peak.
  • 89
  • [ 851985-81-4 ]
  • 6-chloro-5-(2-(3-fluoro-3-methylbutyl)oxazol-5-yl)picolinonitrile [ No CAS ]
  • 5-(2-(3-fluoro-3-methylbutyl)oxazol-5-yl)-6-(quinolin-7-yl)picolinonitrile [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium phosphate tribasic trihydrate In 1,4-dioxane; water at 60℃; for 2h; 103.4 Step 4: 5- (2- (3-fluoro-3-methylbutyl) oxazol-5-yl) -6- (quinolin-7-yl) picolinonitrile To a solution of 6-chloro-5- (2- (3-fluoro-3-methylbutyl) oxazol-5-yl) picolinonitrile (20 mg, 0.068 mmol) , 1, 1'-bis (diphenylphosphino) ferrocene-palladium (ii) dichloride dichloromethane complex (5.56 mg, 6.81 μmol) , and tri-potassium phosphate trihydrate (36.3 mg, 0.136 mmol) in 1, 4-dioxane (2 mL) and water (0.5 mL) was added 7- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) quinoline (17.37 mg, 0.068 mmol) at 20 . The resulting mixture was stirred at 60 for 2 h, the color of the reaction mixture was sepia. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3) . The combined organic layers were washed with brine (30 ml) , dried over sodium sulfate, filtered, and concentrated in vacuum. The residue was purified by prep. HPLC (TFA) to give the title compound. MS: 387 (M+1) .1HNMR (Methanol-d4, 400 MHz) : δ 9.07 (d, J 4.4 Hz, 1H) , 8.82 (d, J 8.4 Hz, 1H) , 8.40 (d, J 8.0 Hz, 1H) , 8.22-8.26 (m, 2H) , 8.04 (d, J 8.4 Hz, 1H) , 7.85-7.89 (m, 2H) , 6.89 (s, 1H) , 2.76 (t, J 8.4 Hz, 2H) , 1.67-1.76 (m, 2H) , 1.90 (d, J 21.2 Hz, 6H) .
  • 90
  • [ 851985-81-4 ]
  • 2-chloro-3-(1-(3-fluoro-3-methylbutyl)-1H-pyrazol-4-yl)pyridine [ No CAS ]
  • 7-(3-(1-(3-fluoro-3-methylbutyl)-1H-pyrazol-4-yl)pyridin-2-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
76% With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate In 2-methyltetrahydrofuran at 75℃; for 18h; Inert atmosphere;
  • 91
  • [ 851985-81-4 ]
  • 2-chloro-3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)pyridine [ No CAS ]
  • 7-(3-(1-((1-methylcyclopentyl)methyl)-1H-pyrazol-4-yl)pyridin-2-yl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
72.1% With dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); sodium carbonate In 2-methyltetrahydrofuran at 75℃; for 18h; Inert atmosphere;
  • 92
  • [ 851985-81-4 ]
  • ethyl 5-(4-bromophenoxy)-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate [ No CAS ]
  • C28H24N4O4 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,2-dimethoxyethane; water Reflux; Inert atmosphere; 250 Example 81005311 Synthesis of 4-((2-(3,4-dichlorophenyl)thiazol-4-yl)thio)- 1H-1 ,2,3-triazole-5- carboxylic acid (8) General procedure: A mixture of 2,4-dibromothiazole (Compound 8A) (3.9 g, 16 mmol), 3,4- dichlorophenylboronic acid (3.05 g, 16 mol), Pd(dppf)C12 (0.7 g, 0.87 mmol), and cesium carbonate (15 g, 46 mmol) in DME (120 mL) and water (10 mL) was heated at reflux under nitrogen overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 8B. LC-MS (ESI) m/z: 308 [M+H]t
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water Inert atmosphere; Reflux; 250 Synthesis of 4-((2-(3,4-dichlorophenyl)thiazol-4-yl)thio)-1H-1,2,3-triazole-5- carboxylic acid (8) General procedure: A mixture of 2,4-dibromothiazole (Compound 8A) (3.9 g, 16 mmol), 3,4- dichlorophenylboronic acid (3.05 g, 16 mol), Pd(dppf)Cl2 (0.7 g, 0.87 mmol), and cesium carbonate (15 g, 46 mmol) in DME (120 mL) and water (10 mL) was heated at reflux under nitrogen overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel (ethyl acetate in petroleum ether, from 0% to 10% v/v) to yield Compound 8B. LC-MS (ESI) m/z: 308 [M+H]+.
  • 93
  • 4-bromo-6-chloro-pyridazin-3(2H)-one [ No CAS ]
  • [ 851985-81-4 ]
  • [ 214360-73-3 ]
  • 6-(4-aminophenyl)-4-(quinolin-7-yl)pyridazin-3(2H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
Stage #1: 4-bromo-6-chloro-pyridazin-3(2H)-one; 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline With potassium carbonate In 1,4-dioxane; water for 0.166667h; Inert atmosphere; Stage #2: With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane; water at 90℃; for 7h; Stage #3: 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)aniline With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride In 1,4-dioxane; water at 100℃; for 16h; Intermediate 24-2 (1021) 6-(4-Aminophenyl)-4-(quinolin-7-yl)pyridazin-3(2H)-one A mixture of 4-bromo-6-chloropyridazin-3(2H)-one, (Intermediate 16-3, 1.00 g, 4.77 mmol), 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.22 g, 4.77 mmol), and potassium carbonate (989 mg, 7.16 mmol), in 1,4-dioxane (75.0 mL) and water (15.0 mL) was degassed with argon for 10 minutes. Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (174 mg, 0.24 mmol) was added and the mixture heated at 90C for 7 hours. 4-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.25 g 5.73 mmol), and bis(diphenylphosphino)ferrocene] dichloropalladium(II), 175 mg (0.24 mmol) were added. The mixture was heated at 100 C for 16 hours. The mixture was cooled to r.t.. The solid precipitated out was collected by filtration, washed with ethyl acetate and dried to give the desired product, 0.93 g (95% purity, 59% yield). The filtrate was concentrated and the residue was triturated with ethyl acetate-methanol to give the desired product, 0.75 g (67% purity, 33% yield). (1023) LC-MS (Method 3): Rt = 0.34 min; MS (ESIpos): m/z = 315 [M+H]+ (1024) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 5.45 (br s, 2H), 6.62 (d, 2H), 7.56 (q, 1H), 7.68 (d, 2H), 8.03 (d, 1H), 8.12-8.18 (m, 2H), 8.39 (d, 1H), 8.70 (s, 1H), 8.94 (d, 1H);
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