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Structure of 1002309-52-5

Chemical Structure| 1002309-52-5

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Product Details of [ 1002309-52-5 ]

CAS No. :1002309-52-5
Formula : C12H18BNO3
M.W : 235.09
SMILES Code : O=C1C=CC(B2OC(C)(C)C(C)(C)O2)=CN1C
MDL No. :MFCD11044683
InChI Key :IJUNZKOKAXJGRQ-UHFFFAOYSA-N
Pubchem ID :45480194

Safety of [ 1002309-52-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P261-P280-P305+P351+P338

Computational Chemistry of [ 1002309-52-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 17
Num. arom. heavy atoms 6
Fraction Csp3 0.58
Num. rotatable bonds 1
Num. H-bond acceptors 3.0
Num. H-bond donors 0.0
Molar Refractivity 68.44
TPSA ?

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

40.46 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

0.93
Log Po/w (WLOGP)?

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

0.68
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.

0.73
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

0.88
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.65

Water Solubility

Log S (ESOL):?

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

-2.08
Solubility 1.96 mg/ml ; 0.00834 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-1.37
Solubility 10.1 mg/ml ; 0.0431 mol/l
Class?

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

Very 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

-3.1
Solubility 0.187 mg/ml ; 0.000794 mol/l
Class?

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

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

No
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

No
Log Kp (skin permeation)?

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

-7.07 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)

2.97

Application In Synthesis of [ 1002309-52-5 ]

* 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 [ 1002309-52-5 ]

[ 1002309-52-5 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 81971-39-3 ]
  • [ 73183-34-3 ]
  • [ 1002309-52-5 ]
YieldReaction ConditionsOperation in experiment
23.6% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 2h;Microwave irradiation; A solution of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol), bis(pinacolato)diboron (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol), Pd (dppf)Cl2 (80 mg, 0.11 mmol) in dioxane (5 mL) was heated at 100° C. for 2 h under microwave. The mixture was filtered, washed with water and extracted with ethyl acetate (20 mL*3). The combined organics were dried over Na2SO4, filtered and concentrated to give the crude title compound (59.0 mg, 23.6percent). LCMS (M+H)+ 236.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 0.5h; To a solution of 5-bromo-1-methylpyridin-2(1H)-one (800 mg) in DMSO (21 ml) was added bis(pinacolato)diboron (1620 mg), potassium acetate (1253 mg) and 1,1'-bis(diphenyl-phosphino)ferrocene-palladium(II)dichloride dichloromethane adduct (213 mg). The reaction mixture was stirred at 80°C for 30 min. The reaction was diluted with water (20 ml) and extracted with EtOAc (3 x 30 ml). The organic layer was dried with Na2SO4 and solvents were reduced under reduced pressure. The crude product was purified by flash chromatography.
With sodium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 120 - 130℃; for 8.5h; 5-Bromo-l-methylpyridin-2 (IH) -one (0.100 g, 0.532 mmol) was suspended in dioxane (2 mL) then added 4,4,5,5- tetramethyl-2- (4,4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) - 1, 3, 2-dioxaborolane (0.203 g, 0.798 mmol), PdC12 (dppf) - CH2C12Adduct (0.0217 g, 0.0266 mmol) and sodium acetate (0.109 g, 1.33 mmol) . The reaction mixture was heated at 120 0C for 5.5 hours then at 130 0C for 3 hours. The reaction mixture was <n="119"/>filtered through a pad of Celite, washing with MeOH. The filtrate was concentrated under vacuum. The remaining black residue was then dissolved in dichloromethane and filtered through another pad of Celite, washing well with dichloromethane. The filtrate was concentrated under vacuum and the remaining black residue was further dried under high vacuum to afford l-methyl-5- (4,4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)pyridin-2 (IH) -one as a black solid. MS (ESI pos. ion) m/z: 236.1 (MH+).
With potassium acetate;palladium bis[bis(diphenylphosphino)ferrocene] dichloride; In dichloromethane; N,N-dimethyl-formamide; at 80℃; for 10h; Example 9N-(3-fluoro-4-(l-methyl-6-oxo-l,6-dihvdropyridin-3-yl)benzyl)-4-(pyrazin-2-yl)benzamideCompound 21[0174] Step 1: A mixture of 5-bromo-l-methylpyridin-2(lH)-one 21-1 (350 mg, 1.87 mmol), (4,4',4',5,5,5',5'-heptamethyl-[2,2'-bi(l,3,2-dioxaborolan)]-4-yl)methylium 21-2 (617 mg, 2.43 mmol), potassium acetate (550 mg, 5.61 mmol) and Pd(dppf)2Cl2 dichloromethane complex (82 mg, 0.1 mmol) in DMF (10 mL) was stirred at 80 °C for 10 hours. After cooling to room temperature, the mixture was filtered through celite, concentrated by evaporation under reduced pressure and then redistributed between ethyl acetate and water. The organic phase was dried over Na2S04 and concentrated by evaporation under reduced pressure. The resulting residue was subjected to silica gel column chromatography with 1: 1 ethyl acetate/hexanes as eluent to give l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one 21-3.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃;Inert atmosphere; Reflux; Preparation of Compound 2222a 22b To a dry flask was added 5-bromo-l-methylpyridin-2(lH)-one 22a (1.0 g, 5.32 mmol), potassium acetate (1.57 g, 15.96 mmol, 3.0 equiv), bis(pinacolato)diboron (1.49 g, 5.85 mmol, LI equiv) and 1,4-dioxane (25 mL). Nitrogen was bubbled through the solution for 10 minutes, at which time dichloro[l,l'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (217 mg 0.27 mmol, 0.05 equiv) was added. The reaction mixture was refluxed at 115 °C overnight under nitrogen. After cooling to room temperature, EtOAc (30 mL) was added and the resulting slurry was sonicated and filtered. Additional EtOAc (20 mL) was used to wash the solids. The combined organic extracts was concentrated and purified by flash chromatography (90percent EtOAc/ hexanes) to yield 22b (520 mg).Compound 22 was prepared analogous to the preparation of 2 but using compound 22b.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 110℃; for 0.5h; General procedure: A mixture of 3-bromo-1-methylpyridin-2(1H)-one (Step 1 of Example 25, 770 mg, 4.1 mmol),bis(pinacolato)diboron (1248 mg, 4.91 mmol), PdCI2(dppf)CH2CI2 complex (401 mg, 0.491mmol) and potassium acetate (1206 mg, 12.29 mmol) in dioxane (16 mL) was stirred for 2 h at 110 00. The reaction mixture was diluted with toluene, sonicated for 30 mm at 40°C and filtered (the filter cake was rinsed with hot toluene). The filtrate was concentrated to afford the title compound (1.7 g, purity 40percent) as a brown oil. The title compound was prepared using an analogous procedure to that described in Step 2 of Example 25 using 5-bromo-1-methylpyridin-2(1H)-one (ABCR, 1.05 g, 5.58 mmol) and stirringthe reaction mixture for 30 mm at 110°C. The title compound (2.75 g, purity 30percent) was used without purification. Rt: 0.83 mm (LC-MS 1); MS m/z: 236.2 [M+H] (boronic acid) (LC-MS 1).
160 mg With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In ethylene glycol; at 80℃; for 3h; To a stirred suspension of 5-bromo-l-methylpyridin-2(lH)-one (470 mg, 2.49 mmol), potassium acetate (736 mg, 7.49 mmol) and bis(pinacolato)diboron (952 mg, 3.74 mmol) in degassed polyethylene glycol-400 (15 mL) was added [1, 1 '- bis(diphenylphosphino)ferrocene]dichloropalladium (II) (204 mg, 0.24 mmol) at RT. The resultant suspension was stirred for 3 h at 80 °C. The reaction mixture was cooled to RT, diluted with ethyl acetate (100 mL) and washed with water (100 mL) followed by brine (100 mL). The organic layer was concentrated and the residue obtained purified by flash column chromatography to afford 160 mg of the titled product; 1H NMR (300 MHz, CDC13) delta 1.30 (s, 12H), 3.54 (s, 3H), 6.53 (d, J = 9.3 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.75 (s, 1H); APCI- MS (m/z) 236 (M+H)+.

  • 2
  • [ 445264-61-9 ]
  • [ 74-88-4 ]
  • [ 1002309-52-5 ]
YieldReaction ConditionsOperation in experiment
at 80℃; for 3h; X. l-Methyl-5-(4,4,5,5-tetramethyl-L3,2-dioxaborolan-2-yl)pyridin-2(lH)-one; A mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine(235 mg, 1.00 mmol) and CH3I (426 mg, 3.00 mmol) was heated at 800C for 3 hours. The mixture was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, and evaporated to dryness to afford l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one that was directly used in next step without further purification.
  • 3
  • [ 936727-68-3 ]
  • [ 1002309-52-5 ]
  • [ 1083167-72-9 ]
YieldReaction ConditionsOperation in experiment
72% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;microwave irradiation; AO. l-(2.2-Difluorobenzordipi.31dioxol-5-yl)-N-(5-methyl-6-(l-methyl-6-oxo-L6-dihvdropyridin-3-yl)pyridin-2-yl)cvclopropanecarboxamide; To a mixture of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one (68 mg, 0.30 mmol), N-(6-chloro-5-methylpyridin-2-yl)-l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)cyclopropanecarboxamide (88 mg, 0.24 mmol) in DME (1.5 mL) and 2 M Na2CO3 (0.24 mL) was added Pd(PPh3)4 (14 mg, 0.0030 mmol). The mixture was heated in microwave oven at 1200C for 30 min. The mixture was partitioned between ethyl acetate and H2O before the aqueous layer was extracted with ethyl acetate (3x). The combined <n="120"/>organic layers were washed with brine and dried over MgSO4. After the removal solvent, the residue was purified by column chromatography (10-20percent EtOAc -Hexane) to afford l-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)-N-(5-methyl-6-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)pyridin-2-yl)cyclopropanecarboxamide (67 mg, 72percent). 1H-NMR (400 MHz, CDCl3) delta 8.06 (d, J = 8.4 Hz, IH), 7.63 (s, IH), 7.57 (d, J = 8.4 Hz, IH), 7.53-7.48 (m, 2H), 7.24 (td, J = 10.0, 1.7 Hz, 2H), 7.12 (d, J = 8.2 Hz, IH), 6.61 (d, J = 9.2 Hz, IH), 3.60 (s, 3H), 2.33 (s, 3H), 1.77 (q, J = 3.6 Hz, 2H), 1.19 (q, J = 3.6 Hz, 2H). MS (ESI) m/e (M+H+) 440.2.
  • 4
  • [ 64-18-6 ]
  • [ 1002309-52-5 ]
  • [ 1162202-99-4 ]
  • [ 1347541-58-5 ]
YieldReaction ConditionsOperation in experiment
A degassed mixture of 2-bromo-3-(3-pyrrolidin-1-yl-prop-1-ynyl)-imidazo[1,2-a]pyridine-6-carboxylic acid bis-(3-methyl-butyl)amide (200 mg), intermediate 33a) (145 mg), and 2M aqueous sodium carbonate solution (0.8 ml) in DMF (4 ml) was treated with Pd(PPh3)4 (47.3 mg). The reaction mixture was transferred to a pre-heated oil bath (110°C) and stirred in a sealed tube at this temperature overnight. The mixture was diluted with diethyl ether (50 ml) and washed with water (1 x 20 ml). The aqueous layer was extracted with diethyl ether (2 x 20 ml). The combined organic extract was washed with brine (50 ml), dried over sodium sulfate, filtered, and evaporated. The crude product was purified by column chromatography followed by preparative LC-MS.
  • 5
  • [ 1002309-52-5 ]
  • [ 1225059-25-5 ]
  • [ 1225059-95-9 ]
YieldReaction ConditionsOperation in experiment
40% With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 110℃; for 2h; Example 11 : 5-(5-amino-6-(l-methyl-lH-benzo[dlimidazol-2-yl)pyrazin-2-yl)-l-methylpyridin- 2(lHVone (Compound 1-25) SCHEME XIMethod A Steps 1 -3 Compound 1-25Compound 1-25 was prepared using Method A, Steps 1-3 followed by Method K, Step 1.METHOD K: Step 1: 5-(5-amino-6-(6-methyl-lH-benzo[d]imidazol-2-yl)pyrazin-2-yl)-l- methylpyridin-2(lH)-one[00298] A mixture of 5-bromo-3-(6-methyl-lH-benzimidazol-2-yl)pyrazin-2-amine (100 mg, 0.3288 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (154.6 mg, 0.6578 mmol) , potassium carbonate (136.4 mg, 0.9867 mmol) and [1,1- bis(diphenylphosphino)ferrocene]dichloropalladium (26.86 mg, 0.03289 mmol) in DMF (3 mL) were heated to HO0C for 2 hours. The mixture was diluted with EtOAc, washed with water, and the organic layer concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC [Waters Sunfire C 18, lOuM, IOOA column, gradient 10percent - 95percentB (solvent A: 0.05percent TFA in water, solvent B: CH3CN) over 16 minutes at 25mL/min]. The fractions were collected and freeze-dried to give the title compound (47.4mg, 40percent Yield). MS (ES+) 333
YieldReaction ConditionsOperation in experiment
60% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; General procedure: A solution of Intermediate 2A (12.50 g, 55.10 mmol), bispinacolatodiboron (20.97 g, 83.00 mmol) and potassium acetate (16.21 g, 165.00 mmol) in dioxane (200 mL) was degassed with nitrogen for 20 minutes. PdCl2(dppf)2CH2Cl2 (4.50 g, 5.51 mmol) was added and the resulting mixture was degassed again for 10 minutes then was heated at 100 C for 12 h. The reaction was cooled to ambient temperature, filtered through Celite and the filtrate was concentrated under reduced pressure. The resultant residue was washed with nhexane to obtain Intermediate 2B (8.55 g, 56.70%) as a black solid. The compound was taken directly to the subsequent step without further purification.1H NMR (300 MHz, DMSOd6) G ppm 1.28- 1.43 (m, 12 H), 2.46 (s, 3 H), 5.41 (s, 2 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.72- 7.87 (m, 1 H). LCMS (MethodI): retention time 1.43 min, [M+H] 275.1.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃; for 3.5h;Inert atmosphere; General procedure: 1,3-Dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one J-1 5-Bromo-1,3-dimethyl-1H-pyridin-2-one C-1 (10.0 g; 48.0 mmol), bis(pinacolato)diboron (16.0 g; 63.0 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichlormethane (2.00 g; 2.376 mmol) and potassium acetate (9.423 g; 96.016 mmol) are introduced into a flask. 1,4-Dioxane (100.0 mL) is added and the flask is flushed with argon. The reaction is heated to 90 C. for 3 h. A second portion of bis(pinacolato)diboron (1.200 g; 4.726 mmol) is added and the solution is stirred for an additional 30 min. The reaction mixture is then cooled to RT and filtered through a plug of celite, washed with dioxane (2*100.0 mL). The filtrate is concentrated under reduced pressure. The residue is then dissolved in DCM (200.0 mL) and washed with water (1*100.0 mL). The water layer is extracted DCM (1*100.0 mL). The combined organic layer is dried with Na2SO4, filtered and concentrated under reduced pressure. The crude material is purified by silica gel chromatography Combiflash (Column Redisep Rf, 330 g; gradient: cyclohexane/EtOAc=100%/0% to 0%/100% over 16 column volumes; flow rate=200 mL/min; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduced pressure. The remaining catalyst is filtered off and washed with ethyl acetate. The filtrate is concentrated under reduced pressure to give the desired product as an oil, which crystallizes upon standing. HPLC-MS: (M+H)+=250; tRet=0.96 min; method M1
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 2h; General procedure: To a stirred solution of 5-bromo-1-isopropylpyridin-2(1 H)-one (Step A1.1 - method A) (10 g, 46.3 mmol) in Dioxane (150 ml.) were added Bis(pinacolato)diboron (14.1 g, 55.5 mmol), KOAc (6.08 g, 93 mmol) and PdCI2(dppf) (3.39 g, 4.63 mmol). The reaction mixture was heated up and stirred at 90C for 2 hr. Solvent was partially evaporated under reduced pressure, passed through a pad of Celite; the pad was washed with EtOAc and the resulting filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc and aqueous NaHC03 solution, both phases separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated under reduced pressure to afford, without further purification, the title product (20.69 g, 39.3 mmol, 85% yield) as a dark oil. Rt = 0.98 min (UPLC-MS); ESI-MS = 264.2 [M+1]+ (UPLC-MS).
  • 7
  • [ 1002309-52-5 ]
  • [ 1352152-85-2 ]
  • [ 1352152-86-3 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; acetonitrile; at 90℃; for 3h;Inert atmosphere; (ii) (S)-tert-Buty\\ l-(l-amino-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phoxopropan-2-ylcarbamoyl)cycloheptylcarbamate(S)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2- ylcarbamoyl)cycloheptylcarbamate (Example 35, step (i), 400 mg), l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (213 mg) and potassium acetate (148 mg) in a mixture of acetonitrile (15 mL) and water (10 mL) and under a nitrogen atmosphere was treated with 1,1 3/4z5(di-tert-butylphosphino)ferrocene palladium dichloride (16 mg) and the mixture stirred and heated at 90 °C for 3h. The reaction mixture was cooled and diluted with water (100ml). The products were extracted into ethyl acetate (2x 100ml) and the combined extracts washed with 10percent aq potassium cabonate (50ml) followed by 5percent> aq citric acid (50 mL). The organic phase was dried and concentrated to dryness to afford the sub-titled compound (320 mg). m/e (APCI+) 512 [M+H]
  • 8
  • [ 1002309-52-5 ]
  • [ 1352151-91-7 ]
  • [ 1352152-06-7 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate;dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In water; acetonitrile; at 85℃; for 18h;Inert atmosphere; (i) (S)-tert- utyl l-(l-amino-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)-l- oxopropan-2-ylcarbamoy])cyclohexylcarbamate (iS)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (1.5 g) and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (684 mg) in acetonitrile (8 mL) and water (lmL) with potassium acetate (571 mg) was bubbled through with nitrogen and then 1 , 1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5mg) was added and the mixture was heated at 85°C for 18 h. The reaction mixture was allowed to cool to room temperature and absorbed onto silica for purification bychromatography on silica eluting with ethyl acetate, then ethyl acetate / methanol (2:98) as eluent to afford the subtitled compound. m/e (APCI+) 497 [M+H]
  • 9
  • [ 1002309-52-5 ]
  • [ 1354355-52-4 ]
  • 10
  • [ 1002309-52-5 ]
  • [ 1354353-66-4 ]
  • 11
  • [ 1002309-52-5 ]
  • [ 1354355-48-8 ]
  • [ 1354355-49-9 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 96℃;Inert atmosphere; [0176] Step 3: A mixture of l-methyl-5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2- yl)pyridin-2(lH)-one 21-3 (78 mg, 0.33 mmol), tert-butyl 4-chloro-3-fluorobenzylcarbamate 21-5 (94 mg, 0.36 mmol), Pd(PPh3)4 (38 mg, 0.033 mmol) and K3P04 (140 mg, 0.66 mmol) in dioxane (1.2 mL) and water (0.1 mL) was stirred at 96 °C under argon overnight. After cooling to room temperature, the mixture was filtered through celite and concentrated by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography to give crude tert-butyl 3-fluoro-4-(l-methyl-6-oxo- l,6-dihydropyridin-3-yl)benzylcarbamate 21-6.
  • 12
  • [ 1002309-52-5 ]
  • [ 1211533-83-3 ]
  • [ 1375711-15-1 ]
YieldReaction ConditionsOperation in experiment
37% With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 80℃; for 1h;Inert atmosphere; Example 43a5-(6-Amino-2-methoxypyridin-3-yl)-1-methylpyridin-2(1H)-one1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (CAS 1002309-52-5, 1.088 g, 4.63 mmol), 5-bromo-6-methoxypyridin-2-amine (CAS 1211533-83-30, 94 g, 4.63 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)chloride dichloromethane complex (0.113 g, 0.14 mmol) and potassium carbonate (aqueous 2M) (6 mL, 12.00 mmol) in dioxane (10 mL) were heated under argon to 80° C. for 1 h.The mixture was allowed to cool and was filtered through a short pad of Celite.The pad was washed with EtOAc (100 mL).The filtrate was collected and the solvent was removed by rotary evaporation.The crude product was added to a silica gel column and was eluted with 0-3percent MeOH in DCM.The collected fractions were combined and the solvent was removed by rotary evaporation.The residue was redissolved in DCM and the mixture was washed with saturated aqueous Na2CO3, dried over K2CO3, filtered and the solvent was removed by rotary evaporation to yield the title compound (0.402 g, 37percent).1H NMR (500 MHz, DMSO-d6) delta ppm 3.44 (s, 3H) 3.78 (s, 3H) 5.98 (s, 2H) 6.07 (d, 1H) 6.37 (d, 1H) 7.33 (d, 1H) 7.56 (dd, 1H) 7.72 (d, 1H). MS (ES+) m/z 232.1 [M+H]+.
  • 13
  • [ 1002309-52-5 ]
  • [ 1383474-79-0 ]
  • [ 1383472-05-6 ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; N,N-dimethyl-formamide; at 90℃;Inert atmosphere; Step B: Preparation of N-(3 -methyl- 1 -((6-methylpyridin-2-yl methvQ- 1 H- indazol-4-yl)-7-(l-methyl-6-oxo-l,6-dihvdropyridin-3-yl)imidazori,2-a1pyridine-3- carboxamide: 7-Bromo-N-(3 -methyl- 1 -((6-methylpyridin-2-yl)methyl)- 1 H-indazol-4- yl)imidazo[l,2-a]pyridine-3-carboxamide (0.05 g, 0.12 mmol) was dissolved in dimethoxyethane:dimethylformamide (1 : 1, 0.8 mL) in a 2 dram vial, and l-Methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (0.04 g, 0.17 mmol), PdCl2(dppf)*dcm (0.005 g, 0.006 mmol), and 2 M sodium carbonate (0.17 mL, 0.34 mmol) were added. Nitrogen was bubbled through the reaction mixture for 5 minutes before capping the vial and heating in a sand bath at 90 °C overnight. The reaction mixture was diluted with ethyl acetate and water. A greenish precipitate formed and was collected. The crude material was purified by preparatory thin layer chromatography (silica, 20 x 20 cm, 0.5 mm) developed in a chamber with 10percent MeOH/DCM. The UV active band with Rf = 0.1 was isolated and the silica washed with 10percent MeOH/DCM. The filtrate was concentrated to give N-(3 -methyl- l-((6-methylpyridin-2-yl)methyl)-lH-indazol-4-yl)-7-(l-methyl-6-oxo-l, 6- dihydropyridin-3-yl)imidazo[l,2-a]pyridine-3-carboxamide as a beige solid (31 mg).
  • 14
  • [ 1054483-78-1 ]
  • [ 74-88-4 ]
  • [ 1002309-52-5 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In acetonitrile; at 50℃; for 16h;Sealed vial; Step 2: l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one [00346] Iodomethane (0.283 mL, 4.52 mmol) was added to a mixture of 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-ol (0.500 g, 2.262 mmol) and potassium carbonate (1.563 g, 11.31 mmol) in acetonitrile (10 mL). The reaction vial was sealed and stirred at 50 °C for 16 h. The resulting mixture was filtered to remove the inorganic salt and the filter cake rinsed with ethyl acetate. The filtrate was concentrated, treated with ethyl acetate (20 mL) and dichloromethane (20 mL), and filtered to remove the residual inorganic salt. The filtrate was concentrated and dried under vacuum to give crude l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one as white solid (399.4 mg). This material was used in subsequent Suzuki coupling reactions without further purification. 1H NMR (400 MHz, chloroform-if) delta ppm 7.76 (d, J=2.0 Hz, 1H), 7.60 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=9.0 Hz, 1H), 3.55 (s, 3H), 1.31 (s, 12H).
  • 15
  • [ 1002309-52-5 ]
  • [ 1400580-94-0 ]
  • [ 1400578-44-0 ]
YieldReaction ConditionsOperation in experiment
44% With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In water; N,N-dimethyl-formamide; at 90℃; for 3h;Inert atmosphere; Sealed tube; Step 3: 4-(((3S,4S)-l-(5-cyanopyrimidin-2-yl)-4-ethylpyrrolidin-3-yl)amino)-6-(l- methyl-6-oxo- 1 ,6-dihydropyridin-3-yl)pyrrolo[l ,2-b]pyridazine-3-carboxamide (Example159) [00347] A mixture of 6-bromo-4-(((3S,4S)-l-(5-cyanopyrimidin-2-yl)-4- ethylpyrrolidin-3-yl)amino)pyrrolo[l,2-b]pyridazine-3-carboxamide (20 mg, 0.044 mmol, from Step 1), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (31.0 mg, 0.132 mmol, from Step 2), and PdCl2(dppf)-CH2Ci2 adduct (7.17 mg, 8.79 muiotaetaomicron) was pumped under vacuum and backfilled with nitrogen three times. A 2 M aqueous solution of potassium phosphate tribasic (0.066 mL, 0.132 mmol) and N,N- dimethylformamide (0.5 mL) were added. The mixture was immediately pumped under vacuum and backfilled with nitrogen three times, sealed and placed in a 90 °C heating block for 3 h, then cooled to room temperature. The mixture was filtered to remove the insoluble material. The filtrate was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100percent B over 25 minutes, then a 5-minute hold at 100percent B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (9.4 mg, 44percent yield). 1H NMR (500 MHz, DMSO-i/6) delta ppm 1 1.16 (d, J=7.4 Hz, 1H), 8.77 (d, J=3.0 Hz, 1H), 8.67 (d, J=3.0 Hz, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.00 - 7.90 (m, 1H), 7.25 (d, J=1.5 Hz, 1H), 6.48 (d, J=9.4 Hz, 1H), 5.09 - 4.91 (m, 1H), 4.09 - 3.94 (m, 2H), 3.85 (d, J=12.4 Hz, 1H), 3.51 (s, 3H), 2.66 - 2.55 (m, 1H), 1.64 (quin, J=7.4 Hz, 2H), 0.96 (t, J=7.4 Hz, 3H); MS (ES+) m/z: 484.2 (M+H); LC retention time: 1.19 min (analytical LCMS Method I).
  • 16
  • [ 1002309-52-5 ]
  • [ 1407830-61-8 ]
  • [ 1407831-31-5 ]
YieldReaction ConditionsOperation in experiment
34.9% With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; for 16h; Example 52. Synthesis of (R)-5-(6-(4-chlorophenyl)-l,4-dimethyl-5,6-dihydro- 4H-benzo[b][l,2,4]triazolo[4,3-d][l,4]diazepin-8-yl)-l-methylpyridin-2(lH)-one (Compound 62). To a mixture of (R)-8-bromo-6-(4-chlorophenyl)-l,4-dimethyl-5,6-dihydro- 4H-benzo[b][l,2,4]triazolo[4,3-d][l,4]diazepine (40.2 mg, 0.1 mmol), l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin-2(lH)-one (44.2 mg, 0.2 mmol),tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol), cesium carbonate (98 mg, 0.3 mmol), toluene (2 mL), ethanol (1 mL) and water (3 drops) was stirred at 100°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 * 20 mL). The combined organic layers were washed with water (3 * 20 mL), brine (3 * 20 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuum, and then the residue was purified by column chromatography (silica gel, dichloromethane/methanol= 15:1) to give (R)-5-(6-(4-chlorophenyl)-l,4-dimethyl-5,6-dihydro- 4H-benzo[b][l,2,4]triazolo[4,3- d][l,4]diazepin-8-yl)-l-methylpyridin-2(lH)-one as a white solid (15 mg, 34.9percent).
  • 17
  • [ 1002309-52-5 ]
  • [ 1420830-57-4 ]
  • [ 1420829-98-6 ]
YieldReaction ConditionsOperation in experiment
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,4-dioxane; water; at 90℃; under 760.051 Torr; for 2h;Inert atmosphere; General procedure: Compound 102 (0.45 mmol, 1.0 equiv), 1-methyl-6-oxo-1,6-dihydropyridin-3-ylboronic acid, pinacol ester (0.9 mmol, 2.0 equiv), and Na2C03 (0.9 mmol, 2.0 equiv) were dissolved in dioxane/water (4: 1 v/v, 4 mL). The mixture was bubbled with Ar for 5 min, then charged with PdCl2(amphos)2 (10 molpercent), further purged with Ar, and then heated to 90 °C for 2h. The reaction was then cooled and partitioned in ethyl acetate and saturated sodium bicarbonate. The layers were separated and the water layer was extracted with ethyl acetate (lx). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to provide the product which was purified using flash silica gel chromatography (gradient of 0-50percent ethyl acetate/hexanes followed by 0-7percent methanol/methylene chloride) to provide compound 103. ESI-MS m/z: 473.2 [M+H]+.
  • 18
  • [ 1002309-52-5 ]
  • [ 1425049-13-3 ]
  • [ 1425043-73-7 ]
YieldReaction ConditionsOperation in experiment
With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); sodium carbonate; In 1,4-dioxane; water; for 4h;Reflux; [1118] A mixture of compound 329 (10.40 g, 27.2 mmol), <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (9.58 g, 40.7 mmol), sodium carbonate (5.76 g, 54.3 mmol) and PdCl2(Amphos)2 (0.962 g, 1.358 mmol)) in dioxane/water (4:1, 208 mL)) was heated to reflux for 4 h. The mixture was cooled to room temperature and water (200 mL) was added. The solid was filtered, washed with water, and dried overnight. The solid was purified by column chromatography eluting with 0-10percent MeOH/dichloromethane to give compound 359. ESI-MS m/z: 456.2 [M+H]+
  • 19
  • [ 1002309-52-5 ]
  • N-[3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]methanesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 110℃; for 0.5h;Microwave irradiation; A mixture of 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-lH-pyridine-2-one (Synchem Inc. 0.056 g, 0.24 mmol), the product from Example 261C (0.068 g, 0.2 mmol), tetrakis(tiriphenylphosphine) palladium(O) (0.012 g, 0.01 mmol) and sodium carbonate 2M (0.2 mL, 0.40 mmol) in toluene (1 mL), ethanol (0.25 mL) and water (0.5 mL) was heated by microwave at 110 °C for 30 minutes. The reaction mixture was filtered through a 0.45muiotaeta Nylon filter disk to remove solids and the filtrate was partitioned between ethyl acetate and brine. The organic layer was separated and concentrated. Purification by reverse phase HPLC (C 18, 0- 100 percent CH3CN/water (0.1 percent TFA)) afforded the title compound (0.028 g, 37percent). 1H NMR (300 MHz, DMSO-d6) delta 9.73 (s, 1 H) 7.88 (d, J=2.38 Hz, 1 H) 7.56 (dd, J=9.52, 2.78 Hz, 1 H) 7.28 - 7.36 (m, 2 H) 7.26 (d, J=2.78 Hz, 1 H) 7.16 - 7.22 (m, 1 H) 7.05 (t, J=7.34 Hz, 1 H) 7.00 (d, J=8.73 Hz, 1 H) 6.90 (d, J=7.93 Hz, 2 H) 6.35 - 6.40 (m, 1 H) 3.44 (s, 3 H) 3.03 (s, 3 H). MS (ESI+) m z 371 (M+H)+.
  • 20
  • [ 1159607-48-3 ]
  • [ 124-63-0 ]
  • [ 1002309-52-5 ]
YieldReaction ConditionsOperation in experiment
75% Example 261B (2.86 g, 10.8 mmol) and triethylamine (6.03 mL, 43.3 mmol) were stirred in dichloromethane (48.1 mL) at ambient temperature. Methanesulfonyl chloride (2.53 mL, 32.4 mmol) was added dropwise and the solution stirred at ambient temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, dioxane (24 mL) and sodium hydroxide (10 percent w/v, 12 mL, 0.427 mmol) were added, and the solution was heated to 70 °C for 1 hour. The solution was neutralized to a pH of 7 with saturated aqueous NH4CI (200 mL). The aqueous phase was extracted with ethyl acetate (3x125 mL). The combined organics were washed with brine, dried (MgSC^), filtered, then concentrated. The residue was purified by flash chromatography (silica gel, 0-25percent ethyl acetate/hexane gradient,) to afford the title compound (2.79 g, 75percent).
  • 21
  • [ 1002309-52-5 ]
  • N-[2-methyl-5-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]methanesulfonamide [ No CAS ]
  • 22
  • [ 1002309-52-5 ]
  • 1-methyl-5-(4-methyl-5-nitro-2-phenoxyphenyl)pyridin-2(1H)-one [ No CAS ]
  • 23
  • [ 1002309-52-5 ]
  • 5-(5-amino-4-methyl-2-phenoxyphenyl)-1-methylpyridin-2(1H)-one [ No CAS ]
  • 24
  • [ 1002309-52-5 ]
  • [ 224185-19-7 ]
  • 5-(2-fluoro-4-methyl-5-nitrophenyl)-1-methylpyridin-2(1H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
99% With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; 4-bromo-5- fluoro-2-nitrotoluene (Aldrich, 0.234 g, 1.0 mmol), l-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)-1H-pyridin-2-one (Synchem, Inc.0.235 g, 1.0 mmol), bis(triphenylphosphine)palladium(II) chloride (0.035 g, 0.05 mmol) and sodium carbonate 2M (1.5 mL, 3.0 mmol) were combined in DME (4 mL) and water (4.0 mL), sparged with nitrogen and heated by microwave at 120 °C for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (Na2SO4), treated with mercaptopropyl silica gel for 30 minutes, filtered and concentrated to afford the title compound (0.262 g, 99percent).
99% With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Inert atmosphere; Microwave irradiation; Example 257A 5-(2-fluoro-4-methyl-5-nitrophenyl)-1-methylpyridin-2(1H)-one [1076] 4-bromo-5-fluoro-2-nitrotoluene (Aldrich, 0.234 g, 1.0 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaboralan-2-yl)-1H-pyridin-2-one (Synchem, Inc. 0.235 g, 1.0 mmol), bis(triphenylphosphine)palladium(II)chloride (0.035 g, 0.05 mmol) and sodium carbonate 2M (1.5 mL, 3.0 mmol) were combined in DME (4 mL) and water (4.0 mL), sparged with nitrogen and heated by microwave at 120° C. for 30 minutes. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried (Na2SO4), treated with mercaptopropyl silica gel for 30 minutes, filtered and concentrated to afford the title compound (0.262 g, 99percent).
  • 25
  • [ 1002309-52-5 ]
  • [ 904326-92-7 ]
  • N-(3-(6-fluoro-5-methylpyridin-3-yl)-4-phenoxyphenyl)methanesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
82% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 110℃; for 0.5h;Microwave irradiation; A mixture of <strong>[904326-92-7]2-fluoro-3-methylpyridine-5-boronic acid</strong> (Combi-Blocks 0.088 g, 0.566 mmol), the product from Example 261C (0.149 g, 0.435 mmol), tetrakis(tiriphenylphosphine) palladium(O) (0.025 g, 0.022 mmol) and sodium carbonate (0.435 mL, 0.871 mmol) in toluene (2.4 mL), ethanol (0.62 mL) and water (1.24 mL) was heated by microwave at 110 °C for 30 minutes. The reaction mixture was filtered through a 0.45um Nylon filter disk to remove solids and the filtrate was partitioned between ethyl acetate and brine. The organic layer was separated and concentrated. Purification by chromatography (silica gel, 0-60percent ethyl acetate in hexane) afforded the title compound (0.133 g, 82percent). MS (ESI+) m/z 373 (M+H)+.
  • 26
  • [ 1002309-52-5 ]
  • [ 1445994-12-6 ]
  • N-[3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]methanesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In ethanol; water; toluene; at 110℃; for 0.5h;Microwave irradiation; Example 224 N-[3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-phenoxyphenyl]methanesulfonamide [1000] A mixture of <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridine-2-one</strong> (Synchem Inc. 0.056 g, 0.24 mmol), the product from Example 261C (0.068 g, 0.2 mmol), tetrakis(tiriphenylphosphine)palladium(0) (0.012 g, 0.01 mmol) and sodium carbonate 2M (0.2 mL, 0.40 mmol) in toluene (1 mL), ethanol (0.25 mL) and water (0.5 mL) was heated by microwave at 110° C. for 30 minutes. The reaction mixture was filtered through a 0.45 mum Nylon filter disk to remove solids and the filtrate was partitioned between ethyl acetate and brine. The organic layer was separated and concentrated. Purification by reverse phase HPLC (C18, 0-100percent CH3CN/water (0.1percent TFA)) afforded the title compound (0.028 g, 37percent). 1H NMR (300 MHz, DMSO-d6) delta 9.73 (s, 1H) 7.88 (d, J=2.38 Hz, 1H) 7.56 (dd, J=9.52, 2.78 Hz, 1H) 7.28-7.36 (m, 2H) 7.26 (d, J=2.78 Hz, 1H) 7.16-7.22 (m, 1H) 7.05 (t, J=7.34 Hz, 1H) 7.00 (d, J=8.73 Hz, 1H) 6.90 (d, J=7.93 Hz, 2H) 6.35-6.40 (m, 1H) 3.44 (s, 3H) 3.03 (s, 3H). MS (ESI+) m/z 371 (M+H)+
  • 27
  • [ 1002309-52-5 ]
  • [ 1414570-28-7 ]
  • [ 1414581-58-0 ]
YieldReaction ConditionsOperation in experiment
59% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; Preparation G 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)- 1 -methylpyridin-2( 1 H)-one1005491 3 -bromo-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine [Preparation F] (763 mg,3.03 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 nimol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mE) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOHJDCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H).
59% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; Intermediate 5 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3-yl)- 1 -methylpyridin-2( 1 H)-one1003011 3-Bromo-4-methyl-1-phenyl-1H-pyrazol-5-amine [Intermediate 4] (763 mg,3.03 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mE) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mE) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) mz = 281.2 (M+I{).
59% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; Intermediate 5 5-(5-amino-4-methyl- 1 -phenyl- 1 H-pyrazol-3 -vD- 1 -methylpyridin-2( 1 HVone [00359] 3-Bromo-4-methyl-l -phenyl- lH-pyrazol-5-amine [Intermediate 4] (763 mg, 3.03 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H).
59% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; 1004931 Step C: Preparation of 5-(5-amino-4-methyl-1-phenyl-1H-pyrazol-3-yl)-1- methylpyridin-2( 111)-one: 3-bromo-4-methyl- 1 -phenyl- 1 H-pyrazol-5-amine (763 mg, 3.03 mmol), 1 -methyl-5-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mE), water (5 mL) and EtOH (2.5 mL). The reaction mixture was heated to 95°C in a sealed tube for 16 hours. The mixture was cooled, filtered and the filtrate was concentrated. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic layer was removed and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with saturated NaC1 (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography eluting with 2percent MeOHJDCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) mlz = 281.2 (M+H).
59% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; 3-Bromo-4-methyl-l -phenyl- lH-pyrazol-5 -amine (763 mg, 3.03 mmol), l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H).
59% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; Intermediate 8 5-(5-amino-4-methyl- 1 -phenyl- 1 FI-pyrazol-3-yl)- 1 -methylpyridin-2(1 H)-one (006691 3-Bromo-4-methyl-l-phenyl-1H-pyrazol-5-amine [Intermediate 7] (763 mg, 3.03 mmol), 1 -methyl-5-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)pyridin-2( 1 H)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography eluting with 2percent MeOFI/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) mz = 281.2 (M+H).
59% With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 95℃; for 16h;Sealed tube; 3-bromo-4-methyl-l-phenyl-lH-pyrazol-5-amine (763 mg, 3.03 mmol), l-methyl-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)one (1.42 g, 6.05 mmol), K2C03 (1.67 g, 12.1 mmol) and Pd(PPh3)4 (350 mg, 0.30 mmol) were combined in toluene (10 mL), water (5 mL) and EtOH (2.5 mL) and warmed to 95 °C in a sealed tube for 16 hours. The cooled mixture was filtered and the filtrate partitioned between water (30 mL) and EtOAc (30 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine (20 mL), dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2percent MeOH/DCM to afford the title compound (504 mg, 59percent yield) as a yellow foam. MS (apci) m/z = 281.2 (M+H).

  • 28
  • [ 1002309-52-5 ]
  • (S)-N-(5-(4-bromobenzyl)-4-isopropyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide [ No CAS ]
  • (S)-2-(4-(ethylsulfonyl)phenyl)-N-(4-isopropyl-5-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-2-yl)acetamide hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
[00211] To a solution of 89 (60 mg, 0.11 mmol) in dioxane (2 mL) was added 1-methyl- 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyridin-2( 1H)-one (50 mg, 0.21 mmol), Pd(dppf)C12 (15 mg, 0.02 mmol), Cs2CO3 (98 mg, 0.33 mmol) and H20 (0.2 mL) under N2.The mixture was stirred at 100 °C for 8 h. The mixture was added with water (10 mL) andextracted with EtOAc (5 mL x 3). The combined organic layers were dried over sodiumsulfate, filtered, concentrated, purified by preparative TLC (petroleum ether: ethyl acetate= 1:8) and separated by HC1 preparative HPLC to afford the compound I-A19 (HC1 salt, 10.4 mg,15percent) as a white solid. LCMS: tR = 0.727 mm in 5-95AB_1.5min chromatography (MKRP18e 25-2mm), MS (ESI) m/z 591.1 [M+H]. ?H NMR (CD3OD): oe 8.12 (d, J= 2.0 Hz,1H), 7.95 (dd, J= 2.4, 9.2 Hz, 1H), 7.91 (d, J= 8.4 Hz, 2H), 7.73 (s, 4H), 7.65 (d, J= 8.4 Hz,2H), 6.68 (d, J= 9.6 Hz, 1H), 4.80-4.60 (m, 5H) , 3.97 (s, 2H), 3.69 (s, 3H), 3.23 (q, J= 7.2Hz, 2H), 2.13-2.00 (m, 1H), 1.24 (t, J= 7.2 Hz, 3H), 1.12 (d, J= 6.8 Hz, 3H), 0.89 (d, J= 6.8Hz, 3H). Isomer SFC tR = 3.807 mm in 8 mm chromatography (Column: AS-H; MethodName: AS-H_S_5_40_3 mL_8 mm_iS cm, ee = 96.10percent).
  • 29
  • [ 1002309-52-5 ]
  • [ 75092-25-0 ]
  • methyl 1-methyl-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 12h; 5.1.51 Methyl 1-methyl-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1H-pyrazole-3-carboxylate (36) To a mixture of <strong>[1002309-52-5]1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one</strong> (34, 2.3 g, 9.78 mmol) and methyl 4-iodo-1-methyl-1H-pyrazole-3-carboxylate (35, 1.25 g, 4.70 mmol) in DMF (40 mL) and water (10 mL) were added Pd(PPh3)4 (814 mg, 0.71 mmol) and Cs2CO3 (3.06 g, 9.40 mmol), and the mixture was stirred at 80 °C for 12 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0-5percent MeOH in CHCl3) to give 36 (812 mg, 70percent) as colorless solid. 1H NMR (DMSO-d6) delta 3.44 (s, 3H), 3.74 (s, 3H), 3.91 (s, 3H), 6.39 (d, 1H, J = 9.3 Hz), 7.51 (dd, 1H, J = 9.4, 2.6 Hz), 7.86 (d, 1H, J = 2.6 Hz), 7.94 (s, 1H); MS (ESI) m/z 248 [M+H]+.
  • 30
  • [ 1002309-52-5 ]
  • [ 75092-25-0 ]
  • 5-[3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl]-1-methylpyridin-2(1H)-one [ No CAS ]
  • 31
  • 5-bromo-1-methylpyridin-2-(1H)-one [ No CAS ]
  • [ 73183-34-3 ]
  • [ 1002309-52-5 ]
YieldReaction ConditionsOperation in experiment
64% With tris-(dibenzylideneacetone)dipalladium(0); potassium hydroxide; tricyclohexylphosphine; In 1,4-dioxane; at 80℃; for 5h;Inert atmosphere; To a mixture of 5-bromo-1-methylpyridin-2(1H)-one (1.0 g, 5.32 mmol), KOH (0.78 g, 7.98 mmol) and bis(pinacolato)diboron (0.162 g, 6.38 mmol) in 1 ,4-dioxane (20 mL), tricyclohexyiphosphine (149 mg, 0.532 mmol), Pd2dba3 (487 mg, 0.532 mmol) were added under N2 atmosphere. The mixture was stirred at about 80 °C for about 5 h. Then water was added, the aqueous layer was extracted with EtOAc (50 mL x 2), and the organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and the residue was purified by column chromatograph on silica gel to provide ]-methyl-5-(4, 4,5, 5-tetramethyl-], 3, 2-dioxaborolan-2-yl)pyridin-2(]H)-one (0.80 g, 64percent): ?H NMR (CDC13) 7.70 (s, 1 H), 7.54 (d, J= 8.8 Hz, 1 H), 6.47 (d, J= 8.8 Hz, 1 H), 3.49 (s, 3 H), 1.24(s, 12 H).
  • 32
  • [ 13466-38-1 ]
  • [ 1002309-52-5 ]
  • 33
  • [ 1002309-52-5 ]
  • 2-bromo-1-(cyclopropylmethoxy)-4-methanesulfonylbenzene [ No CAS ]
  • 5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; water; at 90℃; for 0.333333h; General procedure: N-[3-(1-methyl-6-oxopyridin-3-yl)phenyl]methanesulfonamide A mixture of 5-bromo-1-methylpyridin-2-one (100 mg, 0.532 mmol), [3-(methanesulfonamido)phenyl]boronic acid (171.1 mg, 0.798 mmol), KOAc (130.0 mg, 1.326 mmol) and Pd(dppf)Cl2 (38.9 mg, 0.05 mmol) in dioxane/H2O (2 mL/0.5 mL) was stirred at 90° C. for 20 min. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE:EA=1:1) to give the title compound (30.0 mg, 20percent) as a brown solid. 1H NMR (CDCl3, 400 MHz) delta 7.65-7.60 (dd, J1=7.6 Hz, J2=2.4 Hz, 1H), 7.54 (d, J=2.4 Hz, 1H), 7.41 (t, J=8.0 Hz, 1H), 7.33 (s, 1H), 7.24 (d, J=7.6 Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 6.86 (brs, 1H), 6.67 (d, J=9.2 Hz, 1H), 3.65 (s, 3H), 3.05 (s, 3H). LCMS (M+H)+ 279.5-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-1-methylpyridin-2-one 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one was treated with 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene in a manner similar to Example 94 to give the title compound. 1H NMR (CDCl3, 400 MHz): delta 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.68-765 (m, 2H), 7.03 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.8 Hz, 1H), 3.95 (d, J=6.8 Hz, 2H), 3.64 (s, 3H), 3.07 (s, 3H), 1.28-1.25 (m, 1H), 0.69-0.65 (m, 2H), 0.34-0.38 (m, 2H). LCMS (M+H)+ 334.
  • 34
  • [ 1002309-52-5 ]
  • [ 1240287-78-8 ]
  • 5-(2-ethyl-5-methylsulfonylphenyl)-1-methylpyridin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
97% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 85℃;Inert atmosphere; The title compound of step 3 (62 mg, 0.2 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (57 mg, 0.24 mmol), K2CO3 (82 mg, 0.6 mmol), Pd(dppf)Cl2 (6.2 mg) in 1,4-dioxane/water (4:1) (5 mL) were heated at 85° C. under N2 overnight. Silica gel chromatography (PE:EA=1:1) gave the title compound (56.6 mg, 97percent) as a brown oil. 1H NMR (300 MHz, CDCl3): delta 1.66 (3H, t, J=6.0 Hz), 2.63-2.71 (2H, m), 3.05 (3H, s), 3.60 (3H, s), 6.64 (1H, d, J=9.0 Hz), 7.28-7.33 (2H, m), 7.48 (1H, d, J=9.0 Hz), 7.70 (1H, s), 7.82-7.85 (1H, m). LCMS: 292 (M+1)+
  • 35
  • [ 1002309-52-5 ]
  • 1-(2-cyclopropylethyl)-2-iodo-4-methylsulfonylbenzene [ No CAS ]
  • 5-[2-(2-cyclopropylethyl)-5-methylsulfonylphenyl]-1-methylpyridin-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 1h;Inert atmosphere; The title compound of step 3 (120 mg, 0.34 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (89 mg, 0.37 mmol), Na2CO3 (72 mg, 0.68 mmol) and Pd(dppf)Cl2 (15 mg) in DMF/H2O (6 ml/1.5 ml) under N2 were heated at 100° C. for 1 h. EA extractive work up and preparative TLC (PE:EtOAc=0:1) gave the title compound (62 mg, 55percent). 1H NMR (CD3OD, 400 MHz): delta 7.92 (dd, J1=2.4 Hz, J2=5.6 Hz, 1H), 7.81 (d, J=2 Hz, 1H), 7.78 (d, J=2.4 Hz, 1H), 7.65-7.61 (m, 2H), 6.69 (m, J=9.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.89-2.86 (m, 2H), 1.51-1.45 (m, 2H), 0.68-0.65 (m, 1H), 0.45-0.40 (m, 2H), 0.04-0.00 (m, 2H). LCMS: 332 (M+1)+
 

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Organoborons

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