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Chemical Structure| 1228014-10-5 Chemical Structure| 1228014-10-5

Structure of 1228014-10-5

Chemical Structure| 1228014-10-5

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Product Details of [ 1228014-10-5 ]

CAS No. :1228014-10-5
Formula : C17H30BNO3Si
M.W : 335.32
SMILES Code : CC(C1=NC=C(B2OC(C)(C)C(C)(C)O2)C=C1)(O[Si](C)(C)C)C
MDL No. :MFCD12198135
InChI Key :GQSLZAFZAPLKEY-UHFFFAOYSA-N
Pubchem ID :53398358

Safety of [ 1228014-10-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 1228014-10-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 23
Num. arom. heavy atoms 6
Fraction Csp3 0.71
Num. rotatable bonds 4
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 98.55
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

40.58 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

0.0
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.54
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.36
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.3
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.44
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.93

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-4.08
Solubility 0.028 mg/ml ; 0.0000835 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-4.08
Solubility 0.0281 mg/ml ; 0.0000838 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-5.42
Solubility 0.00127 mg/ml ; 0.00000378 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

GI absorption?

Gatrointestinal absorption: according to the white of the BOILED-Egg

High
BBB permeant?

BBB permeation: according to the yolk of the BOILED-Egg

Yes
P-gp substrate?

P-glycoprotein substrate: SVM model built on 1033 molecules (training set)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

Yes
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.83 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

1.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.84

Application In Synthesis of [ 1228014-10-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 1228014-10-5 ]

[ 1228014-10-5 ] Synthesis Path-Downstream   1~15

  • 1
  • [ 1228014-10-5 ]
  • 7-bromo-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one [ No CAS ]
  • 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-((1r,4r)-4-methoxycyclohexyl)-3,4-dihydropyrazino-[2,3-b]pyrazin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
93% With sodium carbonate;PdCl2(AmPhos)3; In N,N-dimethyl-formamide; at 70℃; for 1.5h; Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4- methoxycyclohexanamine.hydrochloride (1.5 equiv), NMP and DIEA were combined and heated to 127 0C and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to 35 0C over 4 h. The batch was transferred to a mixture of ethyl acetate and 5 % brine. The aqueous layer was removed and the organic layer containing the batch was washed successively with 5 % brine and water. The organic layer containing the batch was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected by vacuum filtration. The filter cake was washed with MTBE and the product was dried in a vacuum to give 41% yield of ethyl 2-(5-bromo- 3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino) acetate. A mixture of ethyl 2-(5- bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino) acetate (1 equiv), water and 85 % phosphoric acid (3:1) was heated to 80 0C over 1 h. Heating was maintained for 18 h to effect reaction completion. Upon reaction completion, the mixture was cooled to 25 0C and filtered to give a crude product as tan solid. The resulting solids were washed with water, slurried in water and filtered. The filter cake was washed with water until the pH of the filtrate was between 4 and 8. The resulting material was dried under vacuum to give 89 % yield of 7-bromo-l-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin- 2(lH)-one. 7-Bromo-l-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin- 2(lH)-one (1 equiv), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-(2- (trimethylsilyloxy)propan-2-yl)pyridine (1 equiv), sodium carbonate (3 equiv) and PdCl2(AmPhOs)2 (0.003 equiv) were combined in isopropanol and heated at 70 0C for 1.5 h. Standard work-up and purification afforded the protected compound in 93 % yield. Deprotection using standard conditions for removal of a trimethylsilyl-group and isolation gave the title compound.
  • 2
  • [ 1228014-10-5 ]
  • 6-bromo-1-[2-(difluoromethoxy)benzyl]-5-fluoro-2-methyl-1H-benzimidazole [ No CAS ]
  • {1-[5-(1-[2-(difluoromethoxy)phenyl]methyl}-5-fluoro-2-methylbenzimidazol-6-yl)-pyridin-2-yl]-1-methylethoxy}(trimethyl)silane [ No CAS ]
YieldReaction ConditionsOperation in experiment
71% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 7h;Inert atmosphere; {1-[5-(1-[2-(Difluoromethoxy)phenyl]methyl}-5-fluoro-2-methylbenzimidazol-6-yl)-pyridin-2-yl]-1-methylethoxy}(trimethyl)silane Intermediate 147 (185 mg, 0.55 mmol) and Intermediate 50 (175 mg, 0.45 mmol) were dissolved in anhydrous 1,4-dioxane (8 mL) and 2M aqueous potassium carbonate solution (0.7 mL) was added. The mixture was degassed under nitrogen for 5 minutes. Pd(dppf)Cl2 complex with DCM (20 mg, 0.024 mmol) was added. The mixture was stirred at 100 C. under nitrogen for 7 h. The reaction mixture was allowed to cool, dried over sodium sulfate and concentrated under vacuum to give crude product as a dark oil (318 mg). This material was loaded onto a 10 g HP-silica cartridge and eluted on a Biotage Isolera 4, from a 0-70% ethyl acetate in heptane gradient, to afford the title compound (166 mg, 71%) as a colourless oil. deltaH (500 MHz, CDCl3) 8.61 (s, 1H), 7.85 (d, J 8.0 Hz, 1H), 7.72 (d, J 8.2 Hz, 1H), 7.53 (d, J 10.8 Hz, 1H), 7.37-7.29 (m, 1H), 7.21-7.14 (m, 2H), 7.13-7.06 (m, 1H), 6.80-6.45 (m, 2H), 5.43-5.37 (m, 2H), 2.61 (s, 3H), 1.65 (s, 6H), 0.17 (s, 9H).
  • 3
  • 5-bromo-2-{2-[(trimethylsilyl)oxy]propan-2-yl}pyridine [ No CAS ]
  • [ 73183-34-3 ]
  • [ 1228014-10-5 ]
YieldReaction ConditionsOperation in experiment
80% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 80 - 100℃; for 2h;Inert atmosphere; Sealed tube; 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{2-[(trimethylsilyl)oxy]propan-2-yl}pyridine In a pressure tube, a stirring solution of Intermediate 146 (200 mg, 0.69 mmol) in 1,4-dioxane (8 mL) was treated with bis(pinacolato)diboron (211 mg, 0.83 mmol) and potassium acetate (205 mg, 2.09 mmol). The stirring mixture was degassed with nitrogen for 10 minutes, then Pd(dppf)Cl2 complex with DCM (29 mg, 0.04 mmol) was added. The pressure tube was sealed and the contents were stirred at 80 C. for 1 h, then at 100 C. for 1 h. The reaction mixture was allowed to cool and then filtered through celite, washing with ethyl acetate (30 mL). The filtrate was concentrated under vacuum to give a dark brown oil, which was triturated in 2:1 ether:heptane (10 mL). The suspension was filtered and the filtrate concentrated in vacuo to give a brown oil which was loaded onto a 10 g HP-silica cartridge and eluted on a Biotage Isolera 4, from a 0-100% ethyl acetate in heptanes gradient, to afford the title compound (185 mg, 80%) as a light brown solid. deltaH (500 MHz, CDCl3) 8.85 (s, 1H), 8.03 (d, J 7.8 Hz, 1H), 7.64 (d, J 7.9 Hz, 1H), 1.61 (s, 6H), 1.34 (s, 12H), 0.14 (s, 9H).
  • 4
  • [ 624-28-2 ]
  • [ 1228014-10-5 ]
  • 5
  • [ 290307-40-3 ]
  • [ 1228014-10-5 ]
  • 6
  • [ 1228014-10-5 ]
  • 2-[5-(1-[2-(difluoromethoxy)phenyl]methyl}-5-fluoro-2-methylbenzimidazol-6-yl)-pyridin-2-yl]propan-2-ol [ No CAS ]
  • 7
  • [ 1228014-10-5 ]
  • 4-[(6-bromo-2-methylimidazo[1,2-a]pyridin-3-yl)methyl]-8-fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-one [ No CAS ]
  • 8-fluoro-4-({6-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-2-methylimidazo[1,2-a]pyridin-3-yl}methyl)-3,4-dihydro-2H-1,4-benzoxazin-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: Prepared from Intermediate 21 and 5 -(4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2- yl)-2- {2- [(trimethylsilyl)oxy]propan-2-yl} pyridine by a method analogous to that used to prepare Example 1, followed by treatment with TBAF at room temperature. H (500MHz, DMSO-d6) 8.82 (d,J2.2 Hz, 1H), 8.75 (s, 1H), 8.04 (dd,J8.3, 2.4 Hz, 1H), 7.78(d,J8.2 Hz, 1H), 7.63 (dd,J9.3, 1.7 Hz, 1H), 7.57 (d,J9.3 Hz, 1H), 7.19 (d,J8.3 Hz,1H), 7.06 (td,J8.3, 5.7 Hz, 1H), 7.00 (t,J8.7 Hz, 1H), 5.64 (s, 2H), 5.31 (s, 1H), 4.88 (s,2H), 2.39 (s, 3H), 1.50 (s, 6H). LCMS m/z 447.
  • 8
  • [ 1228014-10-5 ]
  • (4-{4-bromo-5-[(4-chlorophenyl)sulfanyl]-1,3-oxazol-2-yl}cyclohexyl)methanol [ No CAS ]
  • 2-(5-{5-[(4-chlorophenyl)sulfanyl]-2-[cis-4-(hydroxymethyl)cyclohexyl]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example B5.18 2-(5-{5-[(4-Chlorophenyl)sulfanyl]-2-[cis-4-(hydroxymethyl)cyclohexyl]-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-olTo a mixture of bromide (43.0 mg, 0.107 mmol), <strong>[1228014-10-5]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{2-[(trimethylsilyl)oxy]propan-2-yl}pyridine</strong> (40.5 mg, 0.160 mmol), tetrakis(triphenylphosphine)palladium(0) (12.3 mg, 10.7 mumol) in toluene (2000 mul) was added K2CO3 (267 mul, 0.534 mmol) and heated in oil bath at 120 C. for 12 h. The reaction was diluted with CH2Cl2, dried over Na2SO4, filtered and conc. The residue was dissolved in THF (1 mL) and treated with TBAF (107 mul, 0.107 mmol) for 1 h. The solvent was removed and the residue was purified by reverse-phase HPLC (C-18, 20-80% MeCN in H2O, with 0.05% TFA) to provide product as a white solid. 1H NMR (CDCl3, 400 MHz) delta 9.37 (s, 1H), 8.86-8.82 (m, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 2H), 4.24 (d, 6.0 Hz, 1H), 3.54 (d, J=6.0 Hz, 1H), 2.87-2.78 (m, 1H), 2.27-2.20 (m, 2H), 2.00-1.96 (m, 2H), 1.71 (s, 6H), 1.70-1.43 (m, 3H), 1.26-1.09 (m, 2H). FIRMS (ES) [M+1]+ calcd for C24H28ClN2O3S: 459.1504. Found: 459.1498.
  • 9
  • [ 1228014-10-5 ]
  • 5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazole [ No CAS ]
  • 2-(5-{5-[(4-chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-ol [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example B5.12-(5-{5-[(4-Chlorophenyl)sulfanyl]-2-(tetrahydro-2H-pyran-4-yl)-1,3-oxazol-4-yl}pyridin-2-yl)propan-2-olTo a mixture of B5 (540 mg, 1.44 mmol), tetrakis(triphenylphosphine)palladium(0) (83.0 mg, 0.0720 mmol), and <strong>[1228014-10-5]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-{2-[(trimethylsilyl)oxy]propan-2-yl}pyridine</strong> (438 mg, 1.73 mmol) in toluene (11.5 mL) was added 2.0 M aqueous solution of K2CO3 (2.2 mL). The resulting mixture was heated at 160 C. in a microwave for 1 h. The process was repeated three more times until the starting material consumed. The reaction mixture was diluted with dichloromethane, dried over Na2SO4 and filtered. The filtrate was concentrated and dissolved in THF (10.7 mL) and treated with TBAF (1.1 mL, 1M in THF) at room temperature for 1 h. The solvent was removed and the residue was purified by silica gel flash chromatography (5-70% EtOAc in hexanes), followed by reverse-phase HPLC (C-18, 20-90% MeCN in H2O, with 0.05% TFA) and a final purification by silica gel flash chromatography (10-70% EtOAc in hexanes) to provide the title compound as a clear oil. The product turned into a white solid after converting to the HCl salt foam. 1H NMR (CDCl3, 400 MHz) delta 9.18 (dd, J=1.2, 2.0, Hz, 1H), 8.33 (dd, J=2.0, 8.4 Hz, 1H), 7.42 (dd, J=1.2, 8.4 Hz, 1H), 7.29-7.238 (m, 2H), 7.16-7.13 (m, 2H), 4.85 (s, 1H), 4.06 (td, J=3.6, 8.4 Hz, 2H), 3.55 (dt, J=3.2, 10.8 Hz, 2H), 3.12 (m, 1H), 2.07-1.94 (m, 4H), 1.56 (s, 6H). HRMS (ES) [M+1]+ calcd for C22H24ClN2O3S: 431.1191. Found: 431.1198.
  • 10
  • [ 1228014-10-5 ]
  • (7R,14R)-11-chloro-1-(difluoromethoxy)-10-fluoro-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one [ No CAS ]
  • (7R,14R)-1-(difluoromethoxy)-10-fluoro-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine tetrafluoroborate; In 1,4-dioxane; water; at 20 - 105℃; for 1h; A degassed mixture of Example 10 (299 mg, 0.56 mmol), 6-(2-(trimethylsilyloxy)propan- 2-yl)pyridine-3-boronic acid pinacol ester (295 mg, 0.84 mmol),tris(dibenzylideneacetone)dipalladium(0) (26.0 mg, 0.03 mmo 1), potassium phosphate tribasic (296 mg, 1.40 mmol), and tricyclohexylphosphonium tetrafluoroborate (26.0 mg, 0.07 mmol) in 1,4-dioxane (4.5 mL) and water (0.5 mL) was heated to 105 C overnight. The reaction mixture was cooled to r.t, diluted with EtOAc (50 mL) and washed with water (2 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated invacuo. The residues were dissolved in DCM (4 mL) and 4M HC1 solution (1.5 mL) was added. The solution was stirred at r.t for 1 hour. Saturated aqueous sodium carbonate solution (50 mL) was added, and the aqueous layer separated. The organic layer was washed with brine (50 mL), dried (Na2504), filtered and concentrated in vacuo to give a crude oil. The crude material was purified by column chromatography, eluting with 0-100% EtOAc in DCM, followed by 0-10% MeOH in EtOAc to give the title compound as an off-white powder (105 mg, 38% yield).1H NMR (400 MHz, DMSO) oe 9.15 (d, 1 H, J = 6.8 Hz), 8.61 (s, 1 H), 8.26-8.21 (m, 1 H), 7.90 (dt, 1 H, J = 1.9, 8.2 Hz), 7.77 (d, 1 H, J= 8.2 Hz), 7.61 (t, 1 H, J = 75 Hz), 7.61 (d, 1 H, J 11.5 Hz), 7.52-7.50 (m, 3 H), 6.34 (d, 1 H, J 7.1 Hz), 5.27 (s, 1 H), 4.91 (t,1 H, J = 6.8 Hz), 3.52-3.45 (m, 1 H), 2.75 (d, 1 H, J = 13.4 Hz), 1.49 (s, 6 H). LCMS Method 3 ESI MH+ 495.1
  • 11
  • [ 1228014-10-5 ]
  • (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one [ No CAS ]
  • (7R,14R)-1-(difluoromethoxy)-11-[6-(2-trimethylsilyloxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine tetrafluoroborate; In 1,4-dioxane; water; at 105℃;Inert atmosphere; Example 11 (750 mg, 2.00 mmol), 6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3- boronic acid pinacol ester (1.41 g, 4.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (94 mg, 0.1 mmol) and tricyclohexylphosphonium tetrafluoroborate (91 mg, 0.24 mmol,97 mass%) were added to a round bottom flask, evacuated & refilled with nitrogen and1 ,4-dioxane (10 mL) added followed by potassium phosphate (1.27 g, 6.00 mmol) in water (1 mL). The mixture was degassed, placed under nitrogen and heated to 105C overnight. The mixture was partitioned between EtOAc and water, the organic layer dried over sodium sulphate, filtered and concentrated in vacuo. The crude material was purifiedby chromatography, (EtOAc to 15% MeOH gradient). The product fractions were concentrated in vacuo to give the title compound as an off-white solid, (1.05 g, 96% yield). LC/MS Method 3: RT 1.61 minutes, mlz 549.
  • 12
  • [ 1228014-10-5 ]
  • (7R,14R)-11-chloro-1-(difluoromethoxy)-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5(14H)-one [ No CAS ]
  • (7R,14R)-1-(difluoromethoxy)-11-[6-(2-hydroxypropan-2-yl)pyridin-3-yl]-6,7-dihydro-7,14-methanobenzimidazo[1,2-b][2,5]benzodiazocin-5 (14H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
20% With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); tricyclohexylphosphine tetrafluoroborate; In 1,4-dioxane; water; at 105℃; for 18h;Microwave irradiation; Example 11 (140 mg, 0.373 mmol) and 6-(2-(trimethylsilyloxy)propan-2-yl)pyridine-3- boronic acid pinacol ester (171 mg, 0.484 mmol) were added to a small microwave tube and tris(dibenzylideneacetone)dipalladium(0) (17.6 mg, 0.0 186 mmol) and tricyclohexylphosphonium tetrafluoroborate (17.0 mg, 0.0447 mmol) were added withdioxane (2 mL), followed by K3P04 (158 mg, 0.745 mmol) in water (1 mL). The mixture was degassed and heated to 105C for 18 hours. The mixture was diluted with EtOAc (30 mL) and washed with water (10 mL). The organic was concentrated in vacuo, redissolved in DCM (10 mL) and 4.OM HC1 in dioxane (5 mL) added and the mixture was stirred at r.t for 1 hour. The mixture was partitioned between DCM and sodium carbonate(20 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo.Purification by preparative HPLC gave the title compound (35 mg, 20%) as a white solid.1HNMR: (d6-DMSO 300 MHz) oe:1.48 (s, 6 H), 2.74 (d, 1H, J=13.3 Hz), 3.49 (m, 1H),4.88 (t, 1H, J=6.7 Hz), 5.24 (s, 1H), 6.35 (d, 1H, J7.0 Hz), 7.49-7.53 (m, 3H), 7.69-7.72(m, 3H), 7.66 (t, 1H, JHF73.2Hz), 7.97 (dd, 1H, J = 5.6, 8.2 Hz), 8.21-8.24 (m, 1H),8.73 (d, 1H, J 1.8 Hz), 9.13 (d, 1H, 6.8 Hz). LC/MS Method 3: RT 1.76 mins (pH 10),mlz 477.
  • 13
  • [ 1228014-10-5 ]
  • 7-chloro-1-isopropyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]imidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]
  • 1-isopropyl-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl]-7-(6-{2-[(trimethylsilyl)oxy]propan-2-yl}pyridin-3-yl)imidazo[1,5-a]pyridine-5-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,6?-diisopropoxy-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) 2nd generation; In tetrahydrofuran; at 50℃; for 2h;Inert atmosphere; To a solution of 7-chloro- 1 -isopropyl-N- [(6-methyl-2-oxo-4-propyl- 1 ,2-dihydropyridin-3- yl)methyl]imidazo[1,5-a]pyridine-5-carboxamide (intermediate 202A) (250 mg, 0.62 mmol) and 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-2- { 2- [(trimethylsilyl)oxy]propan-2-yl }pyridine (241 mg, 0.75 mmol) in tetrahydrofuran (10 ml) under an atmosphere of nitrogen was added potassium phosphate (0.5 M, 4.2 ml), followed by a solution of (2?-aminobiphenyl-2- yl)(chloro)dicyclohexyl(2?,6?-diisopropoxybiphenyl-2-yl)palladium (2? generation Ruphos precatalyst) (98 mg, 125 mmol) in tetrahydrofuran (0.5 ml), and the reaction was stirred at 50 Cfor 2 h. Water was added, the phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was taken to the next step without purification.LCMS (conditions 2.4): Rt 1.40 mm; MS (ESI): [M + H] = 574.5.
  • 14
  • [ 1228014-10-5 ]
  • iupleE [ No CAS ]
  • 8-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-oxo-1,2,3,5-tetrahydroindolizine-6-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; water; sodium carbonate; In 1,4-dioxane; at 85℃; for 16h;Inert atmosphere; [0570] A mixture of crude Example 122c (150 mg, 0.3 mmol), Example d (100 mg, 0.3 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol) and Na2C03 (100 mg, 0.9 mmol) in Dioxane/H20(3 mL/1 mL) was exchange N2 for 3 times. After stirred at 85C for 16 h at N2, the mixture was concentrated under reduced pressure, which was purified by Pre-TLC (Petroleum DCM/MeOH = 10/1) to give Example 126 38 mg, yield 25%) as a yellow solid. LCMS [M+l] + = 500. [0571] 1H NMR (400 MHz, DMSO-d 6) delta 12.59 (s, 1H), 8.88 (s, 1H), 8.60 (d, J= 2.4 Hz, 1H), 8.48 (s, 1H), 8.36 (d, J= 8.3 Hz, 1H), 8.01 (t, J= 8.0 Hz, 1H), 7.90 (dd, J= 8.2, 2.4 Hz, 1H), 7.81 (d, J= 7.5 Hz, 1H), 7.74 (d, J= 8.2 Hz, 1H), 5.35-5.28(m,lH), 5.27 (s, 1H), 4.26 (t,J= 7.4 Hz, 2H), 3.34 (d, J= 2.7 Hz, 2H), 2.29 - 2.03 (m, 2H), 1.52 (d, J= 6.7 Hz, 6H), 1.46 (s, 6H).
  • 15
  • [ 1228014-10-5 ]
  • C17H17IN6O2 [ No CAS ]
  • C28H35N7O3Si [ No CAS ]
YieldReaction ConditionsOperation in experiment
34.26 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃;Inert atmosphere; [0435] A mixture of Example 66a (50 mg, 0.11 mmol), Example 66b (43.1 mg, 0.13 mmol) in Dioxane/H20 (2mL, 10: 1) was added Pd(dppf)Cl2 (5 mg, 0.0068 mmol) and Na2C03(34.26 mg, 0.33 mmol). Then the mixture was degassed by bubbling N2 through the solution for 2 min using a syringe needle. After that, the mixture was heated at 80Covernight. LCMS [M+l]+ = 546.1
 

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