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Structure of 1032759-30-0

Chemical Structure| 1032759-30-0

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Product Details of [ 1032759-30-0 ]

CAS No. :1032759-30-0
Formula : C12H20BN3O2
M.W : 249.12
SMILES Code : CC1(C)C(C)(C)OB(C2=CN=C(N(C)C)N=C2)O1
MDL No. :MFCD07368238
InChI Key :RMPRVJCNMPFBCX-UHFFFAOYSA-N
Pubchem ID :16414215

Safety of [ 1032759-30-0 ]

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

Computational Chemistry of [ 1032759-30-0 ] Show Less

Physicochemical Properties

Num. heavy atoms 18
Num. arom. heavy atoms 6
Fraction Csp3 0.67
Num. rotatable bonds 2
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 72.71
TPSA ?

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

47.48 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

1.65
Log Po/w (WLOGP)?

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

0.84
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.

0.26
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

0.39
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.63

Water Solubility

Log S (ESOL):?

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

-2.54
Solubility 0.721 mg/ml ; 0.00289 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.

-2.26
Solubility 1.37 mg/ml ; 0.00549 mol/l
Class?

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

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

-3.37
Solubility 0.107 mg/ml ; 0.000429 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.

-6.65 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)

3.01

Application In Synthesis of [ 1032759-30-0 ]

* 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 [ 1032759-30-0 ]

[ 1032759-30-0 ] Synthesis Path-Downstream   1~27

  • 1
  • [ 1032759-30-0 ]
  • [ 1034303-30-4 ]
  • [ 1034303-40-6 ]
YieldReaction ConditionsOperation in experiment
80% With potassium carbonate;[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl) palladium(II) dichloride; In 1,4-dioxane; at 60.0℃; for 16h; Compound H .21A mixture of [C2] (100mg, 0.29mmol), [1 ,3-bis(2,6.diisopropylphenyl)imidazol-2-ylidene](3- chloropyridyl)palladium(ll) dichloride (PEPPSI) (5mg, 0.01 mmol), 2- dimethylaminopyrimidine-5-boronic acid pinacol ester (78mg, 0.31 mmol) and potassium carbonate (119mg, O.deltadeltammol) in 1 ,4-dioxane (5ml) under argon, was heated at 6O0C for 16 hours. The mixture was evaporated and the residue subjected to column chromatography over silica, eluting with an ethyl acetate/heptane gradient to give 5-(2-dimethylamino- pyrimidin-5-yl)-1-(2-fluoro-phenyl)-4-formyl-1 H-pyrazole-3-carboxylic acid cyclohexylamide(100mg, 0.23mmol, 80%).LCMS: RT = 2.779min. (M+H)+ = 437.
  • 2
  • [ 1032759-30-0 ]
  • [ 1206195-35-8 ]
  • [ 1206194-28-6 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; at 90.0℃; <strong>[1032759-30-0]2-dimethylamino-pyrimidine-5-boronic acid pinacol ester</strong> (2eq.) was added to a solution of N-[4-(5-bromo-[l,2,4]triazolo[l,5-a]pyridin-2-ylamino)-phenyl]-acetamide in dioxan/water (5:1) (or EtOH). K2CO3 (2 eq.) and PdC^dppf (cat.) were added to the mixture. The resulting mixture was heated in an oil bath at 900C for 4 to 16 h until the reaction went to completion (monitored by LCMS). Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous MgStheta4 and evaporated in vacuo to yield the crude product. The crude product was then purified by preparative HPLC.
  • 3
  • [ 1032759-30-0 ]
  • [ 1221165-86-1 ]
  • [ 1221165-87-2 ]
YieldReaction ConditionsOperation in experiment
65% With potassium phosphate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 120.0℃; for 0.25h;Microwaves; A mixture of 3A (70mg, 0.20 mmol), <strong>[1032759-30-0]2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester</strong>, (98mg, 0.39 mmol), Pd(dppf)CI2-CH2Cl2 (16mg, 0.02 mmol), K3PO4 (125mg, 0.59 mmol) in 3:1 DME-H2O (2 ml_) were microwaved at 120 C for 15 min. The reaction was diluted with EtOAc and washed with water (3x). The organic layer were dried over Na2SO4, concentrated and chromatographed (2% of NH3-MeOH/DCM) to give 3B (50mg, 65%) as a yellow solid. LCMS m/z 399 (MH+).
  • 4
  • [ 944401-95-0 ]
  • [ 1032759-30-0 ]
  • [ 1254697-45-4 ]
  • 5
  • [ 38696-21-8 ]
  • [ 73183-34-3 ]
  • [ 1032759-30-0 ]
YieldReaction ConditionsOperation in experiment
60% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; 1,2-dimethoxyethane; at 150.0℃; for 0.25h;Inert atmosphere; Microwave irradiation; A mixture of 5-bromo-N,N-dimethylpyrimidin-2-amine (0.966 g, 4.78 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.46 g, 5.74 mmol), PdCl2dppf(DCM) (0.114 g, 0.14 mmol) and KOAc (1.407 g, 14.34 mmol) were placed under Ar in a 20 mL microwave flask. Anhydrous 1,2-dimethoxyethane (16 mL) was added and the flask was irradiated at 150 oC for 15 minutes. The reaction was filtered through celite, concentrated and slurried in EtOAc. The reaction was filtered through celite again and the organics were concentrated and purified by column chromatography 0 to 30 % EtOAC in Hexanes. The material was isolated as a light teal solid (0.718 g, 60 % yield). 1H NMR (400 MHz, CDCl3) delta 8.59 (s, 2H), 3.21 (s, 6H), 1.31 (s, 12H).13C NMR (100 MHz, CDCl3) delta 164.1, 83.7, 77.4, 37.2, 25.2, 24.9. HRMS (EI+) m/z calculated for C12H12BN3O2 [M+H]+: 250.1721, found: 250.17189.
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100.0℃; for 12h;Inert atmosphere; PdCl2(dppf)-CH2Cl2 adduct (323 mg, 0.396 mmol) was added to a solution of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1207 mg, 4.75 mmol), 5-bromo- N,N-dimethylpyrimidin-2-amine (800 mg, 3.96 mmol) and potassium acetate (1 166 mg, 1 1 .88 mmol) in 1 ,4-dioxane (10 ml_) at room temperature under an atmosphere of nitrogen. The resulting solution was stirred at 100 C for 12 hr. The reaction was filtered and the filtrate was concentrated to afford crude product.
0.6 g With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100.0℃; for 4.5h; A mixture of 0.5 g (2.48 mmol) 5-bromo-N,N-dimethyl-pyrimidin-2-amine, 0.8 g (3.24 mmol) bis(pinacolato)diborone, 0.6 g (6.38 mmol) KOAc, 0.2 g (0.25 mmol) (0358) Pd(dppf)CI2 * DCM and dioxane is heated to 100C for 4.5 h. After cooling to RT, the reaction mixture is filtered through a pad of Celite and evorated, water is added and the mixture is extracted with EtOAc. The organic phases are pooled, dried and evaporated The crude product is purified by FC. (0359) Yield: 0.6 g (96%), ESI-MS: m/z = 250 (M+H)+, Rt(HPLC): 0.22 min (HPLC-A)
  • 6
  • [ 1032759-30-0 ]
  • [ 1310584-13-4 ]
  • [ 1310584-20-3 ]
YieldReaction ConditionsOperation in experiment
68% With potassium phosphate; (chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II)); In tetrahydrofuran; water; at 45.0℃; for 24h;Inert atmosphere; General procedure: Compound 4 0.05 mmol (1 equiv) and 0.15 mmol K3PO4 were placed in a Schlenk tube and dissolved in 16 ml of a degassed THF/H2O mixture (5:3). The solution was purged with N2 for further 30 min, followed by the addition of 0.15 mmol of the corresponding boronic acid (or ester, respectively) and 10 mol % of precatalyst 5. The Schlenk tube was sealed, and the reaction mixture was heated to 45 C and stirred for 24 h (unless not denoted differently for the specific reaction) under N2. After completion (TLC and ESI-MS monitoring), the reaction mixture was evaporated to dryness, the residue was dissolved in 30 ml of CHCl3 and washed twice with 10 ml of water. The organic phase was then dried over anhydrous Na2SO4, evaporated to dryness and purified via column chromatography (silica/varying eluents).
YieldReaction ConditionsOperation in experiment
26% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85.0℃;Inert atmosphere; General procedure: Step 34b: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (Compound 0602-107)[0334]To a solution of compound 0601-107 (2.5 g, 11.6 mmol) and bis(pinacolato)diboron (4.4 g, 17.5 mmol) in dioxane (100 mL) was added potassium acetate (3.4 g, 35 mmol) and PdCl2(dppf)2 (0.95 g, 1.1 mmol). The mixture was degassed with nitrogen and heated at 85 C. for overnight. The reaction mixture was concentrated under reduced pressure to afford the crude product, which purified by column chromatography (ethyl acetate in petroleum ether, 15% v/v) to give the compound 0602-107 (1.55 g, 51%) as a pink solid. LCMS: 262 [M+1]+. 1H NMR (400 MHz, DMSO-d6) delta 1.29 (s, 12H), 2.03 (s, 3H), 7.30 (s, 1H), 7.31 (d, J=2.0 Hz 1H), 7.73 (d, J=2.0 Hz, 1H), 7.89 (d, J=1.6 Hz, 1H), 9.93 (s, 1H).
26% With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 85.0℃;Inert atmosphere; General procedure: Compound in dioxane (100mL) 0601-107 (2.5g, 11.6mmol) and a solution of bis (pinacolato) diboron (4.4 g, 17.5 mmol), potassium acetate (3.4 g, 35 mmol) and and PdCl2 (dppf) 2 ( 0.95g, 1.1mmol) was added. The mixture was degassed with nitrogen and heated overnight at 85 C.. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether in ethyl acetate, 15% v / v) to give the compound 0602-107 as a pink solid obtained (1.55 g, 51%).
  • 8
  • [ 1032759-30-0 ]
  • [ 1332450-86-8 ]
  • [ 1332447-93-4 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 95.0℃; for 0.5h;Inert atmosphere; Example No. 31; Preparation of Compound No. 31[0328] A solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3- b]indole (100 mg, 0.282 mmol), <strong>[1032759-30-0]2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester</strong> (105.5 mg, 0.423 mmol) and potassium phosphate (149.7 mg, 0.706 mmol) in DMF (4 mL) - water (1 mL) was purged with nitrogen followed by addition ofdichlorobis(triphenylphosphine) palladium (II) (9.91 mg, 5 mol %). The reaction mixture was heated at 95 C for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water, extracted with EtOAc, the organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude which was purified by reverse phase HPLC to yield 9 mg of the title compound. 1H NMR (TFA salt, CD3OD) d (ppm): 8.03 (s, 1H), 7.98 (s, 1H), 7.60-7.68 (m, 3H), 7.43 (d, 1H), 7.30 (s, 1H), 7.0 (d, 1H), 6.80 (m, 1H), 4.78 (m, 2H), 4.40 (d, 2H), 3.70 (m, 1H), 3.40-3.51 (m, 1H), 3.11 (m, 9H), 2.40 (s, 3H).
  • 9
  • [ 1032759-30-0 ]
  • [ 1332450-87-9 ]
  • [ 1332448-10-8 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 0.75h;Inert atmosphere; Reflux; Example No. 40Preparation of Compound No. 40[0337] To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K2C03 (110 mg, 0.77 mmol) and purged solution with N2. Pd(PPh3)4 (20 mg, 0.017 mmol) and 2-(dimethylamino) pyrimidine-5-boronic acid pinacol ester (140 mg, 0.563 mmol) were added to the reaction mixture, which was refluxed under N2 for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3x6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. 1H NMR (TFA salt, CD3OD) d (ppm): 8.0 (m, 3H), 7.80 (dd, 1H), 7.38 (s, 1H), 7.0 (m, 1H), 6.82 (m, 1H), 4.77 (d, 1H), 4.40 (d, 1H), 3.80 (m, 1H), 3.58 (m, 1H), 3.20 (s, 6H), 3.18 (s, 3H), 3.0 (m, 1H), 2.76 (m, 1H), 2.40 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 0.75h;Inert atmosphere; Example No. 40: Preparation of Compound No. 40[0328] To a solution of 5-(4-bromothiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.25 mmol) in DME (2 mL) were added water (1 mL) and K2C03 (110 mg, 0.77 mmol) and purged solution with N2. Pd(PPh3)4 (20 mg, 0.017 mmol) and 2- (dimethylamino) pyrimidine-5-boronic acid pinacol ester (140 mg, 0.563 mmol) were added to the reaction mixture, which was refluxed under N2 for 45 min. The reaction mixture was cooled to RT and diluted with EtOAc. Aqueous layer was extracted with EtOAc (3x6 mL) and the combined organic layer dried over sodium sulfate. The solvent was removed under reduced pressure to afford crude material, which was purified by reverse phase HPLC. 1H NMR (TFA salt, CD3OD) delta (ppm): 8.0 (m, 3H), 7.80 (dd, IH), 7.38 (s, IH), 7.0 (m, IH), 6.82 (m, IH), 4.77 , 7/ (d, in;, <4-.<4-u ^a, iH), 3.80 (m, 1H), 3.58 (m, 1H), 3.20 (s, 6H), 3.18 (s, 3n;, j.u ^m, in;, z. /o(m, 1H), 2.40 (s, 3H).
  • 10
  • [ 1032759-30-0 ]
  • [ 1332450-89-1 ]
  • [ 1332448-14-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 0.75h;Inert atmosphere; Reflux; Example No. 42; Preparation of Compound No. 42[0339] To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), <strong>[1032759-30-0]2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester</strong> (140 mg, 0.561 mmol) and K2C03 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)- yl)phenyl)-N,N-dimethylpyrimidin-2-amine. 1H NMR (TFA salt, CD3OD) d (ppm): 8.8 (s, 2H), 7.6-7.77 (m, 3H), 7.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 6.97 (d, 1H), 4.77 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.3 (s, 6H), 3.1 (m, 4H), 3.0 (m, 1H), 2.4 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90.0℃; for 0.75h; Example No. 42: Preparation of Compound No. 42[0330] To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), <strong>[1032759-30-0]2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester</strong> (140 mg, 0.561 mmol) and K2C03 (120 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh )4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 5-(3-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)phenyl)-N,N- dimethylpyrimidin-2-amine. 1H NMR (TFA salt, CD3OD) delta (ppm): 8.8 (s, 2H), 7.6-7.77 (m, 3H), 7.4 (d, 1H), 7.3 (s, 1H), 7.1 (d, 1H), 6.97 (d, 1H), 4.77 (d, 1H), 4.4 (d, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.3 (s, 6H), 3.1 (m, 4H), 3.0 (m, 1H), 2.4 (s, 3H).
  • 11
  • [ 1032759-30-0 ]
  • [ 1332450-92-6 ]
  • [ 1332449-33-8 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90.0℃; for 2h;Inert atmosphere; Example No. 104; Preparation of Compound No. 138[0401] To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5- tetrahydro-lH-pyrido[4,3-b]indole (100 mg, 0.280 mmol), 2-(dimethylamino)pyrimidine-5- boronic acid pinacol ester (139 mg, 0.557 mmol) and K2CO3 (116 mg, 0.839 mmol) in mixture of DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 2h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by reverse HPLC to yield 5-(6-(2,8-dimethyl-3,4-dihydro- lH-pyrido[4,3-b]indol-5(2H)-yl)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine as the TFA Salt. 1H NMR (CD3OD, TFA salt) d (ppm): 8.8 (s, IH), 8.71 (s, 2H), 8.24 (d, IH), 7.68 (d, IH), 7.48 (d, IH), 7.37 (s, IH), 7.17 (d, IH), 4.7 (d, IH), 4.3 (d, IH), 3.81 (bs, IH), 3.4-3.6 (m, 3H), 3.3 (s, 6H), 3.18 (s, 3H), 2.42 (s, 3H).
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90.0℃; for 2h; Example No. 104: Preparation of Compound No. 138[0392] To a de-aerated solution of 5-(5-bromopyridin-2-yl)-2,8-dimethyl-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole (100 mg, 0.280 mmol), <strong>[1032759-30-0]2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester</strong> (139 mg, 0.557 mmol) and K2C03 (116 mg, 0.839 mmol) in mixture of DME (4 mL) and water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90 C for 2h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by reverse HPLC to yield 5-(6-(2,8-dimethyl-3,4-dihydro-lH-pyrido[4,3-b]indol-5(2H)- yl)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine as the TFA Salt. 1H NMR (CD3OD, TFA salt) delta (ppm): 8.8 (s, IH), 8.71 (s, 2H), 8.24 (d, IH), 7.68 (d, IH), 7.48 (d, IH), 7.37 (s, IH), 7.17 (d, IH), 4.7 (d, IH), 4.3 (d, IH), 3.81 (bs, IH), 3.4-3.6 (m, 3H), 3.3 (s, 6H), 3.18 (s, 3H), 2.42 (s, 3H).
  • 12
  • [ 1032759-30-0 ]
  • [ 1382994-99-1 ]
  • [ 1382995-32-5 ]
YieldReaction ConditionsOperation in experiment
50% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100.0℃;Inert atmosphere; Step 2. 1-{5-Chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethanone A biphasic solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.10 g, 0.36 mmol) and <strong>[1032759-30-0]N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine</strong> (0.11 g, 0.43 mmol) in 1,4-dioxane (1.2 mL) and 10% sodium carbonate in water (0.57 mL, 0.54 mmol) was bubbled with N2 to degas. After tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.014 mmol) was added, the mixture was bubbled with N2 for 5 min. and heated at 100 C. overnight. The mixture was cooled to r.t. and diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with more ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column, eluting with 0-30% of ethyl acetate in hexane, to give the desired product (60 mg, 50%). LCMS calculated for C16H19ClN3O2 (M+H)+: m/z=320.1. found: 320.1.
  • 13
  • [ 1032759-30-0 ]
  • [ 1332450-86-8 ]
  • C25H27N5 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 95.0℃; for 0.5h;Inert atmosphere; Example No. 31: Preparation of Compound No. 31[0319] A solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH-pyrido[4,3- b]indole (100 mg, 0.282 mmol), <strong>[1032759-30-0]2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester</strong> (105.5 mg, 0.423 mmol) and potassium phosphate (149.7 mg, 0.706 mmol) in DMF (4 mL) - water (1 mL) was purged with nitrogen followed by addition of dichlorobis(triphenylphosphine) palladium (II) (9.91 mg, 5 mol %). The reaction mixture was heated at 95 C for 30 min under ^ ^ ^nitrogen amiospnere. The reaction mixture was diluted with water, extracted wim m c, me organic layer dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude which was purified by reverse phase HPLC to yield 9 mg of the title compound. 1H NMR (TFA salt, CD3OD) delta (ppm): 8.03 (s, 1H), 7.98 (s, 1H), 7.60-7.68 (m, 3H), 7.43 (d, 1H), 7.30 (s, 1H), 7.0 (d, 1H), 6.80 (m, 1H), 4.78 (m, 2H), 4.40 (d, 2H), 3.70 (m, 1H), 3.40-3.51 (m, 1H), 3.11 (m, 9H), 2.40 (s, 3H).
  • 14
  • [ 1032759-30-0 ]
  • [ 1000342-95-9 ]
  • [ 76-05-1 ]
  • N,N-dimethyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyrimidin-2-aminne trifluoroacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% EXAMPLE 247: N,N-dimethyl-5-(6-(trifiuoromethyl)-lH-indazol-4-yl)pyrimidin-2- amine [0786] A vial was charged with a mixture of 4-bromo-6-(trifluoromethyl)-lH-indazole (0.1 g, 0.377 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2- amine (0.122 g, 0.491 mmol) and PdCl2(dppf) (0.014 g, 0.019 mmol) in dioxane (8 mL) and aqueous saturated NaHC03 (2 mL). The resulting light brown suspension was heated at 140°C for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated and the crude residue was purified by preparative HPLC, eluting with a gradient of 30-40percent ACN (containing 0.035percent TFA) in H20 (containing 0.05percent TFA) over a period of 8 minutes. The product-containing fractions were combined and the volatiles removed in vacuo to give a TFA salt of the title compound as a light brown solid (68 mg, 59percent). 1H NMR (400 MHz, OMSO-de) delta ppm 3.23 (s, 6 H), 7.48 (d, J=1.01 Hz, 1 H), 7.89 (s, 1 H), 8.40 (d, J=0.76 Hz, 1 H), 8.82 (s, 2 H); ESI-MS m/z [M+H]+ calc'd for d4Hi2F3N5, 308.1; found 308.15.
  • 15
  • [ 1032759-30-0 ]
  • 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-N-((4-methyl-2-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-1-yl)methyl)benzamide [ No CAS ]
  • 3-(2-(dimethylamino)pyrimidin-5-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-N-((1-methyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridin-4-yl)methyl)benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% Example 123:3-(2-(Di methylami no)pyrimidi n-5-yl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)ami no)-N-((1 -methyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c] pyridi n-4- yl)methyl)benzamideTo a solution of the compound of example 118 (100 mg, 0.199 mmol) in1,4-dioxane (10 mL) were added PdCI2(dppf)- CH2Cl2adduct (16.25 mg, 0.020mmol) and N,N-dimethyl-5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrimidin- 2-amine (64.5 mg, 0.259 mmol). The reaction mixture was stirred for 5 mm, a solution of sodium carbonate (63.3 mg, 0.597 mmol) in water (2.0 mL) was added and the mixture was stirred at 100 C for 5h. After completion of the reaction, thereaction mixture was filtered through celite, and the filtrate was distilled under vacuum.To the residue, water was added and the resulting mixture was extracted with ethyl acetate. The compound was adsorbed on silica and purified by column chromatography (silica gel, 10-20 % ethyl acetate in petroleum ether) to yield the title compound.Yield: 40 mg (37.0 %); 1H NMR (DMSO-d6, 300 MHz): 6 11.27 (5, 1 H), 8.65(5, 2H), 8.24 (5, 1 H), 7.39 (5, 1 H), 7.20 (5, 1 H), 4.23 - 4.21 (m, 1 H), 3.84 - 3.81(m, 2H), 3.28-3.25 (m, 2H), 3.21 (5, 5H), 3.16 -3.06 (m, 3H), 2.87-2.86 (m, 2H),2.73 - 2.72 (m, 1 H), 2.71 - 2,68 (m, 2H), 2.27 - 2.26 (m, 3H), 2.09 (5, 2H), 2.00 -1.91 (m, 2H), 1.56 - 1.45 (m, 2H), 0.81 (t, 3H); MS (ESl+): m/z 531.3 [M+H]HPLC Purity: 97.97 %.
  • 16
  • [ 1032759-30-0 ]
  • 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4, 3-b]indole [ No CAS ]
  • [ 1393915-40-6 ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 90.0℃; for 0.75h; Example 213 Preparation of Compound No. 303 (1431) To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), <strong>[1032759-30-0]2-(dimethylamino)pyrimidine-5-boronic acid pinacol ester</strong> (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90 C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 5-(2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)cyclopent-1-enyl)-N,N-dimethylpyrimidin-2-amine. 1H NMR (CD3OD, TFA salt) delta (ppm): 7.8 (d, 2H), 7.3 (s, 1H), 6.98-7.1 (m, 2H), 4.7 (m, 1H), 4.38 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 2.78-3.1 (m, 15H), 2.4 (s, 3H), 2.2 (m, 2H).
  • 17
  • [ 1032759-30-0 ]
  • trifluoro-methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-methyl-vinylester [ No CAS ]
  • [ 1572012-58-8 ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; for 0.75h;Inert atmosphere; Reflux; Example 159 Preparation of Compound No. 187 (1376) To a solution of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yl trifluoromethanesulfonate (100 mg, 0.257 mmol) in DME (4 mL) was added Pd(PPh3)4 (15 mg, 0.0128 mmol) and the solution was purged with nitrogen for 5 min. Potassium carbonate (36 mg, 0.257 mmol), water (2 mL) and <strong>[1032759-30-0]2-(dimethylamino)-pyrimidine-5-boronic acid pinacol ester</strong> (128 mg, 0.515 mmol) were added, the reaction mixture was purged with nitrogen and refluxed for 45 min. The reaction mixture was cooled to RT and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc and filtered. The filtrate was concentrated under reduced pressure and purified by reverse phase HPLC to obtain the desired product as its TFA salt. 1H NMR (CD3OD, TFA salt) delta (ppm): 8.78 (s, 2H), 7.31 (s, 1H), 7.10 (m, 3H), 4.78 (d, 1H), 4.38 (d, 1H), 3.82 (m, 1H), 3.59 (m, 1H), 3.38 (s, 6H), 3.10 (m, 5H), 2.41 (s, 3H), 1.97 (s, 3H).
  • 18
  • [ 1032759-30-0 ]
  • 3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
  • N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 110.0℃; for 1h;Microwave irradiation; Example 106A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(1H-tetrazol-5-yl)phenyl]-L-phenylalaninamide (200 mg, 0.32 mmol) and <strong>[1032759-30-0]N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine</strong> (87 mg, 0.35 mmol) were dissolved in dimethylformamide (3 ml), and 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium(II) (26 mg, 32 mumol), sodium carbonate (101 mg, 0.96 mmol) and water (0.48 ml, 27 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 60 min. The reaction mixture was concentrated and converted further as the crude product. LC-MS (Method 4): Rt=1.18 min; MS (ESIpos): m/z=669.4 [M+H]+.
  • 19
  • [ 1032759-30-0 ]
  • 3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide [ No CAS ]
  • N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 1.5h;Microwave irradiation; Example 156A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(3-oxo-2,3-dihydro-1H-indazol-6-yl)-L-phenylalaninamide and <strong>[1032759-30-0]N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine</strong> are dissolved in dimethyl sulphoxide, and tetrakis(triphenylphosphine)palladium(0), sodium carbonate and water are added. The reaction mixture is stirred at 110 C. in a microwave (Biotage Initiator) for 90 min, cooled, filtered and purified chromatographically by HPLC. This gives the title compound.
  • 20
  • [ 1032759-30-0 ]
  • 3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-L-phenylalaninamide [ No CAS ]
  • N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-L-phenylalaninamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
47% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 2h;Microwave irradiation; Example 129A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-[4-(3-chloro-4H-1,2,4-triazol-5-yl)phenyl]-L-phenylalaninamide (150 mg, 0.23 mmol) and <strong>[1032759-30-0]N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine</strong> (85 mg, 0.34 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (26 mg, 23 gmol), sodium carbonate (72 mg, 0.68 mmol) and water (0.34 ml, 19 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 120 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 74 mg (47% of theory) of the title compound. LC-MS (Method 4): Rt=1.27 min; MS (ESIpos): m/z=702.5 [M+H]+.
  • 21
  • [ 1032759-30-0 ]
  • 3-bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-L-phenylalaninamide [ No CAS ]
  • N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-L-phenylalaninamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
29% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; dimethyl sulfoxide; at 110.0℃; for 1.5h;Microwave irradiation; Example 109A N-alpha-[(trans-4-[(tert-Butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-3-[2-(dimethylamino)pyrimidin-5-yl]-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-L-phenylalaninamide 3-Bromo-N-alpha-[(trans-4-[(tert-butoxycarbonyl)amino]methyl}cyclohexyl)carbonyl]-N-(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)-L-phenylalaninamide (150 mg, 0.24 mmol) and <strong>[1032759-30-0]N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine</strong> (91 mg, 0.36 mmol) were dissolved in dimethyl sulphoxide (2 ml), and tetrakis(triphenylphosphine)palladium(0) (28 mg, 24 mumol), sodium carbonate (76 mg, 0.72 mmol) and water (0.36 ml, 20 mmol) were added. The reaction mixture was stirred at 110 C. in a microwave (Biotage Initiator) for 90 min, cooled, filtered and purified by chromatography via HPLC (Method 10). This gave 47 mg (29% of theory) of the title compound. LC-MS (Method 4): Rt=1.11 min; MS (ESIpos): m/z=657.4 [M+H]+.
  • 22
  • [ 1032759-30-0 ]
  • (2R)-4-(6-bromo-1-oxoisoquinolin2(1H)-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide [ No CAS ]
  • (2R)-4-(6-(2-(dimethylamino)pyrimidin-5-yl)-1-oxoisoquinolin2(1H)-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide [ No CAS ]
  • 23
  • [ 1032759-30-0 ]
  • (2R)-4-(6-bromo-1-oxoisoquinolin2(1H)-yl)-2-methyl-2-(methylsulfonyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)butanamide [ No CAS ]
  • C21H25N5O5S [ No CAS ]
  • 24
  • [ 1032759-30-0 ]
  • 5-[18F]fluoro-N,N-dimethylpyrimidin-2-amine [ No CAS ]
  • 25
  • [ 474706-74-6 ]
  • [ 1032759-30-0 ]
  • 5-(6-bromoimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
> 95% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 80.0℃; for 3.5h;Inert atmosphere; 6-Bromo-3-iodoimidazo[1,2-a]pyridine (0.1 g, 0.31 mmol), N,N-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidin-2-amine (0.073 g, 0.31 mmol), PdCl2dppf(DCM) (13 mg, 0.015 mmol) and K2CO3 (0.162 g, 1.174 mmol) were combined in a dried flask and placed under Ar. Dioxane (1.4 mL) and water (0.47 mL) were added and the reaction was heated to 80 oC and followed by TLC. The reaction was stirred for 3.5 hours. The reaction was diluted with EtOAc and filtered through a celite plug. The plug was washed with ~125 mL of EtOAc and concentrated. The material was then purified by combiflash (0 to 10 % MeOH in DCM) to give a beige solid (0.1033 g, > 95 % yield, the material could not be separated from pinacol and was used in the next step 14.5 % contamination).1H NMR (400 MHz, CDCl3) delta 8.42 (s, 2H), 8.19 (s, 1H), 7.59 (s, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.23 (dd, J = 2.0, 9.6 Hz, 1H), 3.25 (s, 6H).13C NMR (100 MHz, CDCl3) delta 161.8, 157.6, 154.9, 133.3, 127.8, 123.3, 121.1, 119.0, 110.0, 107.8, 37.3. HRMS (EI+) m/z calculated for C13H13BrN5 [M+H]+: 318.0349, found: 318.03431.
  • 26
  • [ 474706-74-6 ]
  • [ 1032759-30-0 ]
  • N-(5-(3-(2-(dimethylamino)pyrimidin-5-yl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide [ No CAS ]
  • 27
  • [ 1032759-30-0 ]
  • (R)-3-bromo-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridine [ No CAS ]
  • (R)-5-(5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-N,N-dimethylpyrimidin-2-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
15% With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; at 90.0℃; for 2h;Inert atmosphere; General procedure: A reaction solution of 3-bromo-5-((2,4-dichlorobenzyl)oxy)pyridine (12a) (150.00mg, 0.45mmol) and 1-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-2-yl)methyl)piperidine (13c) (138.27mg, 0.45mmol) in 1,4-dioxane (15.00mL) was purged with nitrogen. Then PdCl2(PPh3)2 (15.44mg, 0.022mmol) and 1.0M of Na2CO3 (143.08mg, 1.35mmol) aqueous solution were added. The resulting mixture was purged with nitrogen and stirred at 90C for 2h. The reaction mixture was filtered through a Celite pad and washed well with MeOH. The residue was partitioned between DCM and saturated aqueous NaHCO3 solution and brine. The organic layer was dried over MgSO4 and concentrated in vacuo and the resulting crude mixture was purified by a silica gel column, eluting with EA:Hexane (1:1) to collect the title product (15) as a yellow solid (116.00mg, 59%)
 

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