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Chemical Structure| 72287-26-4 Chemical Structure| 72287-26-4
Chemical Structure| 72287-26-4

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CAS No.: 72287-26-4

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Wilms, Gerrit ; Schofield, Kevin ; Maddern, Shayna , et al.

Abstract: Small-molecule-induced protein degradation has emerged as a promising pharmacological modality for inactivating disease-relevant protein kinases. DYRK1A and DYRK1B are closely related protein kinases that are involved in pathological processes such as neurodegeneration, cancer development, and adaptive immune homeostasis. Herein, we report the development of the first DYRK1 proteolysis targeting chimeras (PROTACs) that combine a new ATP-competitive DYRK1 inhibitor with ligands for the component cereblon (CRBN) to induce ubiquitination and subsequent proteasomal degradation of DYRK1A and DYRK1B. The lead compound (DYR684) promoted fast, efficient, potent, and selective degradation of DYRK1A in cell-based assays. Interestingly, an enzymatically inactive splicing variant of DYRK1B (p65) resisted degradation. Compared to competitive kinase inhibition, targeted degradation of DYRK1 by DYR684 provided improved suppression of downstream signaling. Collectively, our results identify DYRKs as viable targets for PROTAC-mediated degradation and qualify DYR684 as a useful chemical probe for DYRK1A and DYRK1B.

Purchased from AmBeed: ; ; ;

Lish, Matthew S ; McKeon, Jillian EM ; Palmentiero, Caroline M , et al.

Abstract: Primary amoebic meningoencephalitis (PAM) is a human brain infection caused by Naegleria fowleri with a 97% mortality rate. Quinazolinones resulting from a Mannich-coupled domino rearrangement were recently identified as inhibitors of the amoeba. Herein, we resolved the effective concentrations for 25 pilot compounds and then, using the Mannich protocol and a key late-stage, N-demethylation/functionalization, we synthesized 53 additional analogs to improve potency, solubility and microsomal stability. We established an antiamoebic quinazolinone pharmacophore, culminating in (±)-trans-57b which featured the best combination of potency, selectivity index, solubility, and microsomal stability. Enantiomeric separation afforded (4aS,13bR)-57b (BDGR-20237) with a 41-fold potency advantage over its enantiomer. ADME and mouse pharmacokinetic profiling for BDGR-20237 revealed high brain penetrance but a limited half-life which did not statistically enhance the mouse survival in a pilot efficacy study. The pharmacophoric model, supported by 88 quinazolinones, several of which exhibit subnanomolar potency, will guide further scaffold optimization.

Purchased from AmBeed: ; ; ;

Smolkova, Denisa ; Gregus, Michal ; Cmelik, Richard , et al.

Abstract: This work focuses on profiling N-linked glycans by capillary electrophoresis coupled to mass spectrometry using a novel fluorescent and mass spectrometry (MS) active derivatization tag. The label is based on 2-phenylpyridine bearing tertiary amine and hydrazide functionalities. It provides efficient labeling via hydrazone formation chemistry, promising fluorescence properties, and ionization efficiency in the positive ion MS mode. Electrophoretic analysis in a neutral-coated capillary allowed baseline separation of maltooligosaccharides with limits of detection in nanomolar concentrations. The developed labeling method was successfully applied to the analyses of N-linked glycans released from several glycoproteins such as bovine ribonuclease B, human immunoglobulin G, or chicken albumin.

Keywords: Oligosaccharides ; Glycans ; Labeling ; Phenylpyridine ; Capillary electrophoresis ; Mass spectrometry

Purchased from AmBeed: ; ;

Togo, Takaya ; Tram, Linh ; Denton, Laura G. , et al.

Abstract: Heteroaromatic stacking interactions are important in drug binding, supramolecular chemistry, and materials science, making protein-ligand model systems of these interactions of considerable interest. Here we studied 30 congeneric ligands that each present a distinct heteroarene for stacking between tyrosine residues at the dimer interface of procaspase-6. Complex X-ray crystal structures of 10 analogs showed that stacking geometries were well conserved, while high-accuracy computations showed that heteroarene stacking energy was well correlated with predicted overall ligand binding energies. Empirically determined KD values in this system thus provide a useful measure of heteroarene stacking with tyrosine. Stacking energies are discussed in the context of torsional strain, the number and positioning of heteroatoms, tautomeric state, and coaxial orientation of heteroarene in the stack. Overall, this study provides an extensive data set of empirical and high-level computed binding energies in a versatile new protein-ligand system amenable to studies of other intermolecular interactions.

Purchased from AmBeed: ; ; ;

Mixdorf, Jason Craig ;

Abstract: Allylic fluorides are ubiquitous scaffolds in pharmaceuticals, agrochemicals, materials chemistry, and positron emission tomography (PET) imaging. Recently, it has been shown that transition metal complexes can catalyze the formation of allylic carbon-fluoride bonds. This dissertation describes the development of a new procedure for the synthesis of enantioenriched allylic fluorides utilizing an iridium complex as the catalyst. A detailed study using both computational and laboratory experiments was conducted leading to insights about this unique mechanism of the iridium-catalyzed allylic fluorination reaction. Additionally, the allylic fluorination methodology was translated for the production of allylic [18F]fluorides for potential use as radiotracers for qualitative and quantitative assessment of disease state.

Purchased from AmBeed: ;

Alternative Products

Product Details of [ 72287-26-4 ]

CAS No. :72287-26-4
Formula : C34H28Cl2FeP2Pd
M.W : 731.70
SMILES Code : [Cl-][Pd+2]1([Cl-])[P](C=2C=CC=CC2)(C=3C=CC=CC3)[C-]45[CH]6=[CH]7[CH]8=[CH]4[Fe+2]789%10%11%1265[CH]=%13[CH]%12=[CH]%11[C-]%10([CH]%139)[P]1(C=%14C=CC=CC%14)C=%15C=CC=CC%15
MDL No. :MFCD00015757

Safety of [ 72287-26-4 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P264-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P362-P403+P233-P501

Calculated chemistry of [ 72287-26-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 40
Num. arom. heavy atoms 24
Fraction Csp3 0.06
Num. rotatable bonds 8
Num. H-bond acceptors 0.0
Num. H-bond donors 0.0
Molar Refractivity 171.8
TPSA ?

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

27.18 ?2

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

9.52
Log Po/w (WLOGP)?

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

9.2
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.

7.92
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

7.39
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

6.8

Water Solubility

Log S (ESOL):?

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

-10.29
Solubility 0.0000000375 mg/ml ; 0.0000000001 mol/l
Class?

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

Insoluble
Log S (Ali)?

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

-10.0
Solubility 0.000000073 mg/ml ; 0.0000000001 mol/l
Class?

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

Insoluble
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

-11.0
Solubility 0.0000000074 mg/ml ; 0.0 mol/l
Class?

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

Insoluble

Pharmacokinetics

GI absorption?

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

 Low
BBB permeant?

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

 No
P-gp substrate?

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

 Yes
CYP1A2 inhibitor?

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

 No
CYP2C19 inhibitor?

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

 No
CYP2C9 inhibitor?

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

 No
CYP2D6 inhibitor?

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

 Yes
CYP3A4 inhibitor?

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

 No
Log Kp (skin permeation)?

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

-4.0 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

 2.0
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

 1.0
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

 2.0
Bioavailability Score?

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

0.17

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

2.0 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<3.0
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)

 6.66

Application In Synthesis [ 72287-26-4 ]

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

  • Downstream synthetic route of [ 72287-26-4 ]

[ 72287-26-4 ] Synthesis Path-Downstream   1~26

  • 1
  • [ 72287-26-4 ]
  • C23H24BClFNO3 [ No CAS ]
  • [ 29418-67-5 ]
  • 5-acetyl-3-chloro-9-fluoro-5,6-dihydro-8-[2-(1,3,4-oxadiazol-2-yl)phenyl]-dibenzo[b,f]azocine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 85℃; for 2h; To a solution of Example 246A (48 mg, 0.11 mmol) and Example 246B (25 mg, 0.11 mmol) in EtOH (1 mL) and toluene (1 mL) under an argon atmosphere were added 2M Na2CO3 (0.165 mL, 0.33 mmol) followed by Pd(PPh3)4 (13 mg, 0.011 mmol)). The resulting suspension was stirred under argon at 85° C. for 2 hours. The reaction was cooled to ambient temperature, concentrated and purified by preparative HPLC to give the title compound (8.8 mg). HPLC Rt=2.203 min. m/z=446.08.
  • 2
  • [ 72287-26-4 ]
  • [ 262433-06-7 ]
  • [ 73183-34-3 ]
  • [ 262433-07-8 ]
  • N1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-phenylbenzene]-1-benzenesulfonamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With potassium acetate; triethylamine; In n-heptane; dichloromethane; N,N-dimethyl-formamide; c) N1-[2-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-1-benzenesulfonamide. A mixture of the N1-(4-bromo-2-phenylbenzene)-1-benzenesulfonamide (0.388 g, 1.00 mmol), bis(pinacolato)diboron (0.305 g, 1.20 mmol), potassium acetate (0.294 g, 3.00 mmol) and [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (25 mg, 0.030 mmol) in DMF (10 ml) was heated under an atmosphere of nitrogen at 100° C. for 16.5 hours. The DMF was evaporated in vacuo and the residue purified by silica gel flash chromatography using methylene chloride/heptane 7:3 plus 2percent triethyl amine to provide N1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-phenylbenzene]-1-benzenesulfonamide (0.135 g) as an oil. tR=23.13 min (RP-HPLC, 25-100percent acetonitrile-0.1percent TFA, 25 min); low resolution MS m/e 434 (M-H+)
  • 3
  • [ 72287-26-4 ]
  • [ 118757-04-3 ]
  • [ 73183-34-3 ]
  • [ 262433-09-0 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate; In N,N-dimethyl-formamide; b) 1-(phenylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline. A mixture of the 5-bromo-1-(phenylsulfonyl)indoline (1.0 g, 3.07 mmol), bis(pinacolato)diboron (0.935 g, 3.68 mmol), potassium acetate (0.902 g, 9.202 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (88 mg, 0.092 mmol) in DMF (20 ml) was heated under an atmosphere of nitrogen at 100° C. for 16 hours. The DMF was evaporated in vacuo and the residue triturated with toluene (20 ml) then the solids were removed by filtration through celite. The filtrate was washed with water (3*15 ml) then dried over MgSO4, filtered and evaporated to a residue which was used crude in the next step. 1H NMR (DMSO-d6, 400 MHz) delta 7.83 (2H, d), 7.43-7.68 (6H, m), 3.94 (2H, t), 2.94 (2H, t), 1.26 (12H, s); tR=21.23 min (RP-HPLC, 25-100percent acetonitrile-0.1N ammonium acetate, 25 min;
  • 4
  • [ 72287-26-4 ]
  • [ 262433-11-4 ]
  • [ 73183-34-3 ]
  • [ 262433-12-5 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate; In N,N-dimethyl-formamide; c) N1-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N1-methyl-1-benzenesulfonamide. A mixture of the N1-(4-bromo-2-chlorophenyl)-N1-methyl-1-benzenesulfonamide (0.5 g, 1.389 mmol), bis(pinacolato)diboron (0.423 g, 1.66 mmol), potassium acetate (0.408 g, 4.167 mmol) and [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) (34 mg, 0.042 mmol) in DMF (20 ml) was heated under an atmosphere of nitrogen at 100° C. for 16 hours. The DMF was evaporated in vacuo and the residue triturated with toluene (15 ml) then filtered through celite to give N1-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N1-methyl-1-benzenesulfonamide (0.25 g) as a dark oil which was used crude in the next step. 1H NMR (DMSO-d6, 400 MHz) delta 7.93 (2H, d), 7.57-7.75 (5H, m), 7.07 (1H, d), 3.12 (3H, s), 1.29 (12H, s)
  • 5
  • [ 72287-26-4 ]
  • [ 474111-60-9 ]
  • [ 618-89-3 ]
  • argon [ No CAS ]
  • [ 497-19-8 ]
  • [ 474111-79-0 ]
YieldReaction ConditionsOperation in experiment
3.83 g (77%) In water; ethyl acetate; toluene; EXAMPLE 85 Preparation of Methyl 3-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate Argon was bubbled through a solution of the compound of Example 81 (5 g, 8 mmol) in toluene (100 mL) for 10 minutes. Then, [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (460 mg, 0.56 mmol) and methyl 3-bromobenzoate (2.6 g, 12 mmol) were added in a single portion. The resulting reaction mixture was degassed with argon for an additional 5 minutes before aqueous Na2CO3 (2M, 40 mL, 80 mmol) was added and the solution was heated at 85° C. overnight. The product mixture was allowed to cool to room temperature, water was added and the biphasic mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated and purified with a Biotage column, gradient 10-30percent ethyl acetate/hexanes to obtain 3.83 g (77percent) of the title compound. MH+=633.5
  • 6
  • [ 72287-26-4 ]
  • [ 477251-79-9 ]
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloronickel [ No CAS ]
  • [ 1450-75-5 ]
  • [ 497-19-8 ]
  • [ 73183-34-3 ]
  • [ 477252-06-5 ]
YieldReaction ConditionsOperation in experiment
With potassium acetate; In hexane; N,N-dimethyl-formamide; Example 23 N-Isopropyl-1-[3-(3-Acetyl-4-Hydroxyphenyl)Phenyl]-1,4-Dihydro[1,8]Naphthyridin-4-One-3-Carboxamide A mixture of 5'-bromo-2'-hydroxyacetophenone, diboron pinacol ester (1.25 eq), potassium acetate (3 eq) and [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) in N,N-dimethylformamide (10 ml/mmol) was stirred at 80° C. for 3 hours and cooled down. A solution of N-Isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Example 1, Step 4 (0.75 eq) in N,N-dimethylformamide (7 ml/mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (8.5 eq) were added and the resulting mixture was stirred at 80° C. for 2.5 hours. The cooled mixture was partitioned between ethyl acetate and water and the product from the organic phase was chromatographed on silica gel eluding with 60percent ethyl acetate in hexane to afford the title compound as a light yellow solid. 1H NMR (Acetone-d6) delta 1.24 (d, 6H), 2.75 (s, 3H), 4.19 (m, 1H), 7.06 (d, 1H), 7.59-7.63 (m, 2H), 7.72 (t, 1H), 7.92 (d, 1H), 7.97 (d, 1H), 8.02 (s, 1H), 8.33 (s, 1H), 8.73 (m, 1H), 8.78 (dd, 1H), 8.90 (s, 1H), 9.65 (br, NH).
  • 7
  • [ 72287-26-4 ]
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloronickel [ No CAS ]
  • [ 702640-76-4 ]
  • [ 129013-83-8 ]
  • [ 497-19-8 ]
  • [ 477252-14-5 ]
YieldReaction ConditionsOperation in experiment
In dichloromethane; ethyl acetate; N,N-dimethyl-formamide; Step 3 N-Isopropyl-1-{3-[4-(Pyridin-3-yl)Phenyl]Phenyl}-1,4-Dihydro[1,8]Naphthyridin-4-One-3-Carboxamide A mixture of the boronate from Step 1, <strong>[129013-83-8]3-(4-bromophenyl)pyridine</strong> from Step 2 (1.5 eq), [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (5 eq) in N,N-dimethylformamide (7 ml/mmol) was stirred at 85° C. for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and water. The crude product from the organic phase was chromatographed on silica gel eluding with a 7:3 mixture of ethyl acetate and methylene chloride to afford the N-Isopropyl-1-{3-[4-(pyridin-3-yl)phenyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid. 1H NMR (CDCl3) delta 1.30 (d, 6H), 4.25 (m, 1H), 7.35 (m, 1H), 7.39-7.48 (m, 2H), 7.60-7.75 (m, 6H), 7.80 (d, 1H), 7.90 (d, 1H), 8.58 (d, 1H), 8.70 (m, 1H), 8.82 (d, 1H), 8.88 (s, 1H), 9.08 (s, 1H), 9.68 (br, NH).
  • 8
  • [ 72287-26-4 ]
  • [1,1'-bis(diphenylphosphino)ferrocene]dichloronickel [ No CAS ]
  • [ 589-87-7 ]
  • [ 497-19-8 ]
  • [ 129013-83-8 ]
YieldReaction ConditionsOperation in experiment
In hexane; ethyl acetate; N,N-dimethyl-formamide; Step 2 3-(4-Bromophenyl)Pyridine A mixture of pyridine-3-boronic acid 1,3-propanediol cyclic ester, 4-bromoiodobenzene (1.1 eq), [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (5 eq) in N,N-dimethylformamide (2 ml/mmol) was stirred at 85° C. for 4 hours. After quenching with saturated aqueous ammonium chloride solution, the mixture was partitioned between ethyl acetate and water, and the crude product from the organic phase was chromatographed on silica gel eluding with a 1:9 mixture of ethyl acetate and hexane to afford the 3-(4-Bromophenyl)pyridine compound as a solid.
  • 9
  • [ 72287-26-4 ]
  • [ 589-87-7 ]
  • [ 497-19-8 ]
  • [ 129013-83-8 ]
YieldReaction ConditionsOperation in experiment
In hexane; ethyl acetate; N,N-dimethyl-formamide; Step 1: 3-(4-Bromophenyl)pyridine. A mixture of pyridine-3-boronic acid 1,3-propanediol cyclic ester, 4-bromoiodobenzene (1.1 eq), [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (0.05 eq) and 2M aqueous sodium carbonate (5 eq) in N,N-dimethylformamide (2 mL/mmol) was stirred at 85° C. for 4 hours. After quenching with saturated aqueous ammonium chloride solution the mixture was partitioned between ethyl acetate and water and the crude product from the organic phase was chromatographed on silica gel eluding with a 1:9 mixture of ethyl acetate and hexane to afford the 3-(4-bromophenyl)pyridine compound as a solid.
  • 10
  • [ 72287-26-4 ]
  • 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one [ No CAS ]
  • [ 73183-34-3 ]
  • [ 179898-34-1 ]
  • [ 305800-55-9 ]
YieldReaction ConditionsOperation in experiment
33% With potassium acetate; sodium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide; A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassium acetate (1.5 g, 15.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol) in DMF (30 mL) was subject to a positive flow of nitrogen to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The reaction mixture was allowed to cool to ambient temperature, treated with 3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate (2 g, 19 mmol) in water (10 mL). The resulted solution was heated at 85° C. for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a flash silica gel column chromatography (THF:hexane/2:3) to yield 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as a white solid (0.6 g, 33percent): mp 252-253° C.; 1H-NMR (DMSO-d6) delta9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6 Hz), 7.82 (m,1H), 7.39 (s 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z 325 [M-H]-.
33% With potassium acetate; sodium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide; A mixture of 6-bromo-8-methoxy-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (1.6 g, 5.6 mmol), bis(pinacolato)diboron (1.6 g, 6.3 mmol), potassium acetate (1.5 g, 15.3 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol) in DMF (30 mL) was subject to a positive flow of nitrogen to remove oxygen and then heated at 85° C. under a blanket of nitrogen for 18 hours. The reaction mixture was allowed to cool to ambient temperature, treated with 3-bromo-5-fluoro-benzonitrile (1.2 g, 6 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]palladium (II) chloride (1:1 complex with methylene chloride, 0.5 g, 0.6 mmol), and sodium carbonate (2 g, 19 mmol) in water (10 mL). The resulted solution was heated at 85° C. for 3 hours under a blanket of nitrogen, cooled to rt, and treated with brine (50 mL). Ethyl acetate (100 mL) was added, organic layer was separated, dried (MgSO4), and evaporated. The residue was purified by a flash silica gel column chromatography (THF:hexane/2:3) to yield 3-(4,4-dimethyl-8-methoxy-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-5-fluorobenzonitrile as a white solid (0.6 g, 33percent): mp 252-253° C.; 1H-NMR (DMSO-d6) delta9.76 (s, 1H), 8.21 (s, 1H), 8.07 (d, 1H, J=10.6 Hz), 7.82 (m, 1H), 7.39 (s 1H), 7.36 (s, 1H), 3.93 (s, 3H), 1.66 (s, 6H). MS (ESI) m/z 325 [M-H]-.
  • 11
  • [ 72287-26-4 ]
  • [ 387866-37-7 ]
  • [ 1765-93-1 ]
  • [ 497-19-8 ]
  • [ 387866-32-2 ]
YieldReaction ConditionsOperation in experiment
280 mg (89%) In N,N-dimethyl-formamide; Step 7 3-(4-Fluorophenyl)-6-methyl-4-(4-methylthio)phenyl-pyran-2-one A mixture of 3-bromo-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one (300 mg, 0.96 mmol), 4-fluorophenylboronic acid (270 mg, 1.9 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), dichloromethane complex (50 mg, 0.06 mmol) and 2M aqueous Na2CO3 (1.5 mL, 3 mmol) in DMF (8 mL) was heated at 80° C. for 2 h. After cooling to r.t., the mixture was diluted with H2O and extracted with EtOAc. The EtOAc extract was washed with H2O, dried (anhydrous MgSO4) and concentrated. Chromatography over silica gel and elution with hexanes:EtOAc (3:1) yielded 280 mg (89percent) of title compound as a yellow foam. 1H NMR (Acetone-d6) delta 7.20-6.90 (m, 8H), 6.33 (s, 1H), 2.46 (s, 3H), 2.31 (s, 3H).
  • 12
  • [ 72287-26-4 ]
  • tert-butyl (7BR,11AS)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate [ No CAS ]
  • [ 1735-53-1 ]
  • tert-butyl (7BR,11AS)-6-[4-cyano-2-(trifluoromethyl)phenyl]-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
130 mg (88%) With sodium carbonate; In water; N,N-dimethyl-formamide; Part C. tert-butyl (7bR,11aS)-6-[4-cyano-2-(trifluoromethyl)phenyl]-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate. To a solution of tert-butyl (7bR,11aS)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate (0.135 g, 0.28 mmol) in 15 mL of DMF and 2 mL of water was added 4-bromo-3-(trifluoromethyl)benzonitrile (0.143 g, 0.57 mmol) and sodium carbonate (0.15 g, 0.1.43 mmol). The mixture was degassed with a stream of nitrogen for 20 min and then there was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (20 mg, 0.028 mmol) and the mixture was stirred at 80° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with sat'd aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo to afford 130 mg (88percent) of the title compound, which was used without purification. LRMS (ES+): 516.1 (M+H)+.
130 mg (88%) With sodium carbonate; In water; N,N-dimethyl-formamide; Part C. tert-butyl (7bR,11aS)-6-[4-cyano-2-(trifluoromethyl)phenyl]-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate. To a solution of tert-butyl (7bR,11aS)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate (0.135 g, 0.28 mmol) in 15 mL of DMF and 2 mL of water was added 4-bromo-3-(trifluoromethyl)benzonitrile (0.143 g, 0.57 mmol) and sodium carbonate (0.15 g, 0.1.43 mmol). The mixture was degassed with a stream of nitrogen for 20 min and then there was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (20 mg, 0.028 mmol) and the mixture was stirred at 80° C. for 16 h. The reaction was allowed to cool to ambient temperature and was diluted with ethyl acetate, washed with sat'd aqueous sodium bicarbonate and brine, dried (MgSO4), filtered through Celite and concentrated in vacuo to afford 130 mg (88percent) of the title compound, which was used without purification. LRMS (ES+): 516.1 (M+H)+.
  • 13
  • [ 72287-26-4 ]
  • potassium phosphate [ No CAS ]
  • [ 395101-69-6 ]
  • [ 98437-24-2 ]
  • [ 395101-94-7 ]
YieldReaction ConditionsOperation in experiment
62% In dimethylethylene glycol ether; dichloromethane; A. 3-benzo[b]Furan-2-yl-1-Perhydro-2H-Pyran-2-Yl-1H-Indazole-5-Carbonitrile To a flask containing 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.30 mmol) in dimethyl glycol ether (15 mL) was added potassium phosphate (2.75 g), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (106 mg, 0.130 mmol), and benzo[b]furan-2-boronic acid (315 mg, 1.95 mmol). The reaction mixture was brought to 90° C. under nitrogen conditions for 18 hours. The mixture was condensed and extracted with water (25 mL) and ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified by chromatography (SiO2, 20percent ethyl acetate/hexanes) to afford the title compound (278 mg, 62percent). ES-MS (m/z) 344[M+1]+.
62% In dimethylethylene glycol ether; dichloromethane; A. 3-benzo[b]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile To a flask containing 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.30 mmol) in dimethyl glycol ether (15 mL) was added potassium phosphate (2.75 g), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (106 mg, 0.130 mmol), and benzo[b]furan-2-boronic acid (315 mg, 1.95 mmol). The reaction mixture was brought to 90° C. under nitrogen conditions for 18 hours. The mixture was condensed and extracted with water (25 mL) and ethyl acetate. The extracts were dried over sodium sulfate, filtered and concentrated. The residue was then purified by chromatography (SiO2, 20percent ethyl acetate/hexanes) to afford the title compound (278 mg, 62percent). ES-MS (m/z) 344[M+1]+.
  • 14
  • [ 72287-26-4 ]
  • [ 110-71-4 ]
  • [ 395101-69-6 ]
  • [ 395101-70-9 ]
YieldReaction ConditionsOperation in experiment
77% D. 3-(4-Methoxyphenyl)-1-Perhydro-2H-Pyran-2-Yl-1H-Indazole-5-Carbonitrile A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 223 mg (1.47 nmmol, 1.50 equiv.) of 4-methoxyphenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1'-bis (diphenylphosphino)-ferrocene} dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2* sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20-30percent EtOAc in hexanes affording the title compound (251 mg, 77percent yield): ES-MS (m/z) 334 [M+1]+.
77% D. 3-(4-Methoxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile A flask was charged with 300 mg (0.98 mmol) of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile, 223 mg (1.47 mmol, 1.50 equiv.) of 4-methoxyphenylboronic acid, 80.3 mg (0.098 mmol, 0.100 equiv.) of [1,1'-bis (diphenylphosphino)-ferrocene} dichloropalladiuin (II) complex with dichloromethane (Aldrich), 1.04 g (4.90 mmol, 4.98 equiv.) of powdered potassium phosphate (K3PO4), and 4.90 mL of anhydrous 1,2-dimethoxyethane (DME). The mixture was refluxed under nitrogen for 19 h. The mixture was diluted with CH2Cl2, washed with 2*sat. aq. NaHCO3, and dried (Na2SO4). The crude material was purified by silica gel chromatography using 20-30percent EtOAc in hexanes affording the title compound (251 mg, 77percent yield): ES-MS (m/z) 334 [M+1]+.
  • 15
  • [ 72287-26-4 ]
  • 3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine [ No CAS ]
  • [ 7486-35-3 ]
  • 3-(1-BOC-2-(S)-Azetidinylmethoxy)-6-ethenylpyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% In toluene; 201c. 3-(1-BOC-2-(S)-azetidinylmethoxy)-6-ethenylpyridine To a solution of 3-(1-BOC-2-(S)-azetidinylmethoxy)-6-chloropyridine (1.8 g, 6.04 mmol) in toluene (25 mL) was added vinyltributyltin (2.7 mL, 9.06 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (180 mg). After heating at reflux for 16 h, the resulting mixture was cooled to room temperature and the solvent was removed. The residue was chromatographed (silica gel; hexane/EtOAc, 10:1) to afford the title compound (1.49 g, 85percent): 1 H NMR (CDCl3, 300 MHz) delta 1.40 (s, 9H), 2.25-2.30 (m, 2H), 3.85-3.90 (m, 2H), 4.16 (m, 1H), 4.35 (m, 1H), 4.54 (m, 1H), 5.35 (dd, 1H, J=1.0, 12.0 Hz), 6.05 (dd, 1H, J=1.0, 18.0 Hz), 6.80 (dd, 1H, J=12.0, 18.0 Hz), 7.20-7.26 (m, 2H), 8.35 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 291 (M+H)+, 319 (M+NH4)+.
  • 16
  • [ 72287-26-4 ]
  • [ 317830-16-3 ]
  • [ 55552-70-0 ]
  • [ 317826-94-1 ]
YieldReaction ConditionsOperation in experiment
2-[1-(3-Nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-(furan-3-yl)pyrimidine The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine and furan-3-boronic acid according to the precedure described in EXAMPLE 306, Step C and using [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(H) as catalyst. Mass spectrum (CH3CN/TFA/NH4O2CH/ESI) 427.0 (M+1).
  • 17
  • [ 72287-26-4 ]
  • [ 317830-16-3 ]
  • [1,1'-Bis(diphenylphosphino)ferrocene]dichloro-pallidium [ No CAS ]
  • [ 16419-60-6 ]
  • [ 317826-93-0 ]
YieldReaction ConditionsOperation in experiment
Step C: 2-[1-(3-Nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-(2-methylphenyl)pyrimidine The title compound was prepared from 2-[1-(3-nitrophenyl)ethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine and 2-methylphenylboronic acid according to the precedure described in EXAMPLE 306, Step C and using [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) as catalyst. Mass spectrum (CH3CN/TFA/NH4O2CH/ESI) 451.3 (M+1).
  • 18
  • [ 72287-26-4 ]
  • [ 299893-93-9 ]
  • [ 24850-33-7 ]
  • [ 228867-90-1 ]
YieldReaction ConditionsOperation in experiment
57% In toluene; 187c. 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-6-ethenyl-5-methylpyridine 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-6-chloro-5-methylpyridine (830 mg, 2.57 mmol) in toluene (10 mL) was added [1,1'-bis(diphenyl-phosphino)ferrocene]dichloropalladium(U) (83 mg) and allyltributyltin (1.3 mL, 5.1 mmol). The mixture was stirred and refluxed for 16 h. Solvent was evaporated and the residue was chromatographed (silica gel; hexane/EtOAc, 10:1 to 3:2) to afford an oil (450 mg, 57percent): 1 H NMR (CDCl3, 300 MHz) delta 1.47 (s, 9H), 1.62 (m, 1H), 1.86 (m, 1H), 2.00-2.10 (m, 2H), 2.34 (s, 3H), 3.30-3.46 (m, 2H), 3.90 (m, 1H), 4.04-4.20 (m, 2H), 5.37 (d, 1H, J=11.0 Hz), 6.20 (d, 1H, J=17.0 Hz), 6.94 (dd, 1H, J=11.0, 17.0 Hz), 7.02 (br s, 1H), 8.14 (d, 1H, J=2.5 Hz); MS (CI/NH3) m/z 319 (M+H)+.
  • 19
  • [ 72287-26-4 ]
  • [ 456-41-7 ]
  • [ 147269-69-0 ]
  • [ 147269-70-3 ]
YieldReaction ConditionsOperation in experiment
With zinc; In tetrahydrofuran; e. Ethyl 3-benzyloxycarbonylamino-5-(3-fluorobenzyl)-2-oxo-1,2-dihydro-1-pyridylacetate. To a solution of freshly activated zinc dust (0.39 g) was added 3-fluorobenzyl bromide (0.76 g) in tetrahydrofuran (10 mL), maintaining the temperature at 20° C. The solution was allowed to stir for 3 h and dichloro[1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) (0.076 g) was added followed by a solution of ethyl 3-benzyloxycarbonylamino-5-iodo-2-oxo-1,2-dihydro-1-pyridylacetate (0.46 g) in tetrahydrofuran (10 mL), which was added dropwise. The mixture was stirred at room temperature for 5 h, at 50° C. for 4.5 h, and at room temperature overnight. It was poured into 1N hydrochloric acid and partitioned into ethyl acetate. The organic extracts were dried, evaporated, and the resulting oil was purified using chromatography with ethyl acetate:dichloromethane (gradient, 100, 5:95, 10:90) to give ethyl 2-[3-benzyloxycarbonylamino-5-(3-fluorobenzyl)-2-oxo-1,2-dihydro-1-pyridyl]acetate (0.225 g).
  • 20
  • [ 72287-26-4 ]
  • [ 58305-26-3 ]
  • [ 147269-71-4 ]
  • [ 147269-72-5 ]
YieldReaction ConditionsOperation in experiment
With zinc; In tetrahydrofuran; b. tert-Butyl 3-benzyloxycarbonylamino-2-oxo-5-(4-pivaloyloxybenzyl)-1,2-dihydro-1-pyridylacetate. A solution of 4-pivaloyloxybenzyl bromide (1.6 g) in tetrahydrofuran (10 mL) was added dropwise to freshly activated zinc dust (0,576 g) with stirring, maintaining the temperature at about 20° C. After 1 h, dichloro[1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) (0,112 g) was added followed by a solution of tert-butyl 3-benzyloxycarbonylamino-5-iodo-2-oxo-1,2-dihydro-1-pyridylacetate (0.714 g) in tetrahydrofuran (10 mL). The mixture was heated at 45°-50° C. for 5 h, stirred at room temperature overnight, poured into cold 1N hydrochloric acid (100 mL) and extracted with ethyl acetate. The combined extracts were dried and evaporated. The resulting residue was purified by chromatography, eluding with ethyl acetate:dichloromethane (0:100, 10:90), to give tert-butyl 3-benzyloxycarbonylamino-2-oxo-5-(4-pivaloyloxybenzyl)-1,2-dihydro-1-pyridylacetate (0.35 g).
  • 21
  • petroleum [ No CAS ]
  • [ 72287-26-4 ]
  • [ 128-37-0 ]
  • [ 594-27-4 ]
  • [ 134394-05-1 ]
  • (+/-)-8-Acetyl-2-(dipropylamino)tetralin hydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
323 mg (44%) With lithium chloride;silica gel; In N-methyl-acetamide; Example 7 (-)-8-Acetyl-2-(dipropylamino)tetralin hydrochloride A mixture of (-)-2-(dipropylamino)-8-[(trifluromethylsulfonyl)oxyl]tetralin (910 mg, 2.4 mmol), tetramethylstannane (514 mg, 2.88 mmol), lithium chloride (315 mg, 7.44 mmol), dichloro[1,1'-bis(diphenylphosphino) ferrocene]-palladium(ii) [PdCl2 (dppf)] (12 mg, 0.144 mmol), molecular sieves (4 A; 240 mg), 2,6-di-t-butyl-4-methylphenol (catalyst) in dimethylformamide (20 ml) was stirred under an atmosphere of carbon monoxide for 18 h at 90° C. The catalyst was filtered off and the filtrate was partitioned between water and ether. The organic layer was dried (sodium sulfate) and concentrated. The residue was chromatographed on an alumina column eluted with ether/light petroleum 1:16. Pure fractions were pooled and concentrated. The resulting oil was converted into the hydrochloride which was recrystallized from chloroform and ether to afford 323 mg (44percent) of pure (-)-8-acetyl-2-(dipropylamino)tetralin hydrochloride, mp: 114°-116° C. [alpha]D:-123.2° C. (c 1.0, MeOH).
  • 22
  • [ 144550-76-5 ]
  • [ 72287-26-4 ]
  • [ 2386-64-3 ]
  • [ 123102-32-9 ]
YieldReaction ConditionsOperation in experiment
43.5% Zinc chloride; In tetrahydrofuran; diethyl ether; c. Methyl 2-amino-6-ethylbenzoate To a stirred mixture of zinc chloride (8.6 g, 63 mM, previously dried at 200° C. for 2 hr under high vacuum) in tetrahydrofuran (105 mL) under a nitrogen atmosphere was added dropwise a solution of ethyl magnesium chloride (63 mM) in diethyl ether (31.5 mL). After the addition was completed, dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (0.107 g, 0.126 mM) was added to the resulting stirred thick white mixture followed by the dropwise addition of methyl 2-amino-4-iodobenzoate (3.5 g, 12.6 mM) in tetrahydrofuran (15 mL). The resulting reaction mixture was stirred at room temperature for 2.5 hr and then poured slowly into water (300 mL). The water mixture was extracted with ethyl acetate and the combined extracts were dried (MgSO4), filtered and concentrated. The residue was chromatographed over silical gel (eluant: Hexanes/diethyl ether; 8.5/1.5) to provide the title ester (1.0 g, 43.5percent) as a pale yellow oil; MS(CI): 180 (M+H). 250-MHz 1 H NMR (DMSO-d6); 7.04 (t, J=7.8, 1H), 6.53 (d, J=8.2, 1H), 6.42 (d, J=7.1, 1H), 5.55 (s, 2H, exchangeable), 3.80 (s, 3H), 2.59 (q, J=7.5, 1H), 1.08 (t, J=7.5, 3H).
YieldReaction ConditionsOperation in experiment
66% EXAMPLE 5 4-Amino-8-pentylquinoline-3-[N-(2-propenyl)]carboxamide (Formula I, Ra=pentyl, Rb=2-propenyl, Rc=Rd=hydrogen) The procedures of Examples 1b-1f were followed to obtain the quinoline carboxylic acid except that 2-pentylaniline (3.38 g) was used instead of 2-ethylaniline and was reacted with 4.48 g of diethylethoxymethylenemalonate to obtain a compound of formula II (3.52 g, 66percent) (Ra=pentyl, Rd=H, A=--COOH).
  • 24
  • [ 72287-26-4 ]
  • [ 1826-67-1 ]
  • methyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-vinylindazol-1-ylmethyl]-3-methoxybenzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
42% With hydrogenchloride; palladium; zinc dibromide; In tetrahydrofuran; ethyl acetate; (e) To a solution of zinc bromide (6.75 g) (dried at 180° at 67 Pa for 2 hours) in tetrahydrofuran (90 ml) at 0° was added 1M vinylmagnesium bromide (25 ml) in ether. The reaction was allowed to stir at room temperature for 15 minutes before dichloro[1,1'bis(diphenylphosphino)ferrocene]palladium (II) (183 mg) was added to the reaction, and the reaction was heated at 45° for 120 hours. Additional portions of the palladium reagent (each 183 mg) were added after 48 and 84 hours of stirring. The reaction mixture was cooled to 0°, and 1N hydrochloric acid (50 ml) and ethyl acetate (250 ml) were added. The mixture was stirred for 15 minutes before it was filtered through diatomaceous earth with ethyl acetate washings. The organic layer was washed with water and brine, dried (MgSO4), and evaporated. Flash chromatography of the residue over 200 g silica gel, eluding with methylene chloride (800 ml), 2.5:97.5 ethyl acetate:methylene chloride (500 ml), and 5:95 ethyl acetate:methylene chloride afforded a solid. Recrystallization from methylene chloride and petroleum ether yielded methyl 4-[6-(N-cyclopentylmethylcarbamoyl)-3-vinylindazol-1-ylmethyl]-3-methoxybenzoate as a colorless solid (944 mg, 42percent), mp 138°-140°, resolidifies and remelts at 168.0°-170.0° mass spectrum (chemical ionization) 448 (M+H).
  • 25
  • [ 72287-26-4 ]
  • 7-(cyclopentylacetamido)naphth-1-yl triflate [ No CAS ]
  • [ 70264-94-7 ]
  • methyl 4-[7-(cyclopentylacetamido)naphth-1-ylmethyl]-3-methoxybenzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
79% With zinc; In tetrahydrofuran; ethyl acetate; f. Methyl 4-[7-(cyclopentylacetamido)naphth-1-ylmethyl]-3-methoxybenzoate A mixture of activated zinc dust (806 mg), methyl 4-bromomethyl-3-methoxybenzoate (2.14 g) and tetrahydrofuran (15 ml) was stirred for 18 h. To the reaction was added dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (76 mg). After stirring for 15 min, 7-(cyclopentylacetamido)naphth-1-yl triflate (830 mg) in tetrahydrofuran (10 ml) was added and the mixture was stirred for 72 h. The mixture was added to 100 ml of ethyl acetate and the ethyl acetate solution was washed (1N HCl, brine), dried (MgSO4) and evaporated. The residue was flash chromatographed, eluding with ether:petroleum ether (2:8,4:6, and 1:4, successively), to give a white solid. Recrystallization from methylene chloride and petroleum ether gave the title compound as a colorless solid (705 mg, 79percent); mp 172.5°-174.5° C. Analysis for C27 H29 NO4: Calculated: C, 75.15; H, 6.77; N, 3.24. Found: C, 74.82; H, 6.78; N, 2.85.
  • 26
  • [ 72287-26-4 ]
  • potassium phosphate [ No CAS ]
  • [ 426842-84-4 ]
  • [ 280-64-8 ]
  • [ 146603-99-8 ]
  • ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; ethyl acetate; Ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate 1.4 g of ethyl 4-allyl-1-(tert-butyloxy-carbonyl)piperidine-4-carboxylate were cooled to a temperature in the region of -30° C. and 11 cm3 of a 0.5 M solution of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran were added, with stirring and under an inert atmosphere. After the addition, the temperature of the mixture was returned to about 20° C. The solution obtained was stirred for a further 4 hours, followed by addition of 0.09 g of palladium diphenylphosphinoferrocene chloride, 1.4 g of 4-iodo-3-fluoro-6-methoxyquinoline and 2.5 g of tribasic potassium phosphate. After stirring for 16 hours at a temperature in the region of 60° C., the reaction mixture was cooled to about 20° C. and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was taken up in ethyl acetate and water, the phases were separated by settling and the organic phase was dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography, under atmospheric pressure, on a column of silica gel (particle size 70-200 mu; diameter 4.5 cm; mass 125 g), eluding with a mixture of dichloromethane/ethyl acetate (98/2 by volume), and collecting 20-cm3 fractions. Fractions 98 to 170 were combined and then concentrated to dryness under the above conditions. 1.5 g of ethyl 4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-4-carboxylate were obtained in the form of a thick brown oil. 1H NMR Spectrum (300 MHz, (CD3)2SO-d6, 6 in ppm): 1.02 (t, J=7 Hz: 3H); 1.30 (mt:2H); 1.39 (s: 9H); from 1.45 to 1.70 (mt: 4H); 1.92 (broad d, J=13.5 Hz: 2H); 2.81 (mt: 2H); 3.05 (broad t, J=6.5 Hz: 2H); 3.69 (broad d, J=13.5 Hz: 2H); 3.95 (s: 3H); 4.00 (q, J=7 Hz: 2H); 7.34 (d, J=2.5 Hz: 1H); 7.40 (dd, J=9 and 2.5 Hz: 1H); 7.97 (d, J=9 Hz: 1H); 8.70 (d, J=1 Hz: 1H).
 

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