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Chemical Structure| 618-89-3 Chemical Structure| 618-89-3

Structure of Methyl 3-bromobenzoate
CAS No.: 618-89-3

Chemical Structure| 618-89-3

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Product Details of [ 618-89-3 ]

CAS No. :618-89-3
Formula : C8H7BrO2
M.W : 215.04
SMILES Code : O=C(OC)C1=CC=CC(Br)=C1
MDL No. :MFCD00017777
InChI Key :KMFJVYMFCAIRAN-UHFFFAOYSA-N
Pubchem ID :12070

Safety of [ 618-89-3 ]

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

Computational Chemistry of [ 618-89-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 11
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 45.42
TPSA ?

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

26.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.34
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

2.91
Log Po/w (WLOGP)?

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

2.24
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.

2.67
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

2.36
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.5

Water Solubility

Log S (ESOL):?

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

-3.28
Solubility 0.113 mg/ml ; 0.000527 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.

-3.12
Solubility 0.162 mg/ml ; 0.000753 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

-3.33
Solubility 0.0999 mg/ml ; 0.000465 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

No
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

Yes
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.

-5.55 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

0.0 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)

1.42

Application In Synthesis of [ 618-89-3 ]

* 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 [ 618-89-3 ]

[ 618-89-3 ] Synthesis Path-Downstream   1~55

  • 1
  • [ 618-89-3 ]
  • [ 75-16-1 ]
  • [ 30951-66-7 ]
YieldReaction ConditionsOperation in experiment
93% EXAMPLE 76; Preparation of N- [ (lS, 2R)-3- { [l- (3-bromophenyl)-l- methylethyl] amino}-1- (3, 5-difluorobenzyl)-2-hydroxypropyl] acetamide; 32 Scheme 8 O Br MeMgBr g NaN3 Br 'H Bu OMe OH Nh THF TFA THF 4 | kOH SOH 4 reflux H 19 H HOH H N, 1) TFA-0 zon F F 0 HCI 2) Ac-Im F 31 3) HCI 30 30 F 31 F NaOH HOH H Bu F 32 Step 1; Preparation of 2- (3-bromophenyl)-2-propanol 27; To 75 mmol of methylmagnesium bromide in 25 mL of ether stirring at 6 C is added, dropwise over 10 min, a solution of methyl-3-bromobenzoate (4.3 g, 20 mmol) in 25 mL of dry THF. The mixture is then allowed to warm to ambient temperature and stirred for 3.5 h, then cooled to 0C and quenched by dropwise addition of aqueous 10% HC1. The acidified mixture is extracted twice with ethyl acetate, and the combined organic phases are washed with 1 N NaHC03 and with brine. The solution is dried over Na2SO4, concentrated, and chromatographed over silica gel, eluting with 15% ethyl acetate in heptane, to afford 4.00 g (18.6 mmol, 93%) of 2- (3-bromophenyl)-2- propanol 27 as a pale yellow oil
80% In tetrahydrofuran; at 0 - 20℃; for 4h; General procedure: To a solution of 26 (7.41 mmol) in anhydrous tetrahydrofuran (30 mL) was added 3M methyl magnesium bromide (22.24 mmol) dropwise at 0 C. The mixture was stirred for 4 hours at rt and quenched with saturated NH4Cl solution at 0. The reaction mixture was partitioned between water (50 mL) and ether (30 mL×3). The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to give the product.
10% In tetrahydrofuran; at 20℃; for 2h;Cooling with ice; Methyl 3-bromobenzoate (2g, 9.30mmol)Dissolved in anhydrous tetrahydrofuran (30mL),Add methylmagnesium bromide dropwise under ice bath conditions(1M in THF, 11.6mL, 11.6mmol),The reaction was then reacted at room temperature for two hours and then quenched with saturated ammonium chloride solution.After extraction with ethyl acetate, the organic phases were combined, and the organic phases were washed with saturated brine and dried with anhydrous sodium sulfate. The solvent was evaporated to dryness under reduced pressure and column chromatography was used to obtain the target compound 39b (0.2 g, 10%).
2- (3-Bromo-phenyl)-propan-2-ol :; The 3-bromo-benzoic acid methyl ester (1.0 g, 4.7 mmol) in tetrahydrofuran (10 mL) was brought to-78 C followed by the addition of methyl magnesium bromide (7.7 mL, 10.81 mmol) and warmed to room temperature and stirred for 17 h. The mixture was poured into sat NH4Cl and extracted with ethylacetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate and chromatographed on silica gel using 04% methanol/dichloromethane to afford colorless oil.
14.9 g In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 2h; To a solution of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (15.0 g, 69.8 mmol) in THF (140 mL) at -78 C was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over Na2S04, filtered and concentrated to afford the corresponding alcohol (14.9 g) which was used without further purification.
14.9 g In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 2h; To a solution of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (15.0 g, 69.8 mmol) in THF (140 mL) at -78 C. was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to afford the corresponding alcohol (14.9 g) which was used without further purification.

  • 2
  • [ 618-89-3 ]
  • [ 544-92-3 ]
  • [ 13531-48-1 ]
  • 3
  • [ 618-89-3 ]
  • [ 118062-05-8 ]
  • [ 125110-18-1 ]
YieldReaction ConditionsOperation in experiment
58% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃; (The following reaction is done in an N2 atmosphere.) To a solution of 2,3,4-Trimethoxyphenylboronic acid (32) (1.40g, 6.60mmol) in toluene (15.0mL) is added EtOH (2.0mL), Pd(PPh3)4 (208mg, 0.18mmol) and Na2CO3·10H2O (4.81g, 16.80mmol) in water (5.2mL). The resulting mixture is carefully degassed (5 times alternating vacuum and flushing with N2). A solution of Methyl-3-bromobenzoate (9) (1.29g, 6.00mmol) in toluene (9.0mL) is added by syringe, the resulting mixture is again carefully degassed and stirred overnight at 100C. Partition the mixture between brine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc (3x), wash the combined organic layer with brine, dry with Na2SO4 and remove solvent. Purify crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+5) to obtain 2',3',4'-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (33) as a yellowish oil (1.07g, 58%). 1H NMR (400MHz, CDCl3): 3.66 (s, 3 H); 3.89 (s, 3 H); 3.92 (s, 6 H); 6.74 (d, 1 H, J= 8.6Hz); 7.03 (d, 1 H, J = 8.6Hz); 7.44 (t, 1 H, J = 7.8Hz); 7.70 (d, 1 H, J = 7.6Hz); 7.97 (d, 1 H, J = 7.8Hz); 8.15 (br.s 1 H).
  • 4
  • [ 618-89-3 ]
  • [ 151-50-8 ]
  • [ 13531-48-1 ]
  • 5
  • [ 618-89-3 ]
  • [ 93-58-3 ]
YieldReaction ConditionsOperation in experiment
84%Chromat. With 1,2,3,4-tetrakis(carbazol-9-yl)-5,6-dicyanobenzene; triethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 1h;Inert atmosphere; Irradiation; General procedure: To a 10 mL photocatalytic reactor containing a solution of an aryl halide (0.5 mmol, 1equiv) and 5CzBN (0.01 mmol, 0.02 equiv) in dry NMP (3 mL) was added Et3N (0.8 mmol, 1.6 equiv) under nitrogen atmosphere. The solution was stirred under their radiation of 5 W blue LED for the indicated time until complete consumption of starting material as monitored by GC-MS analysis at rt. The yields were calculated from GC measurements using internal standards.
68%Chromat. With 1,2-dimethoxyethane; hydrogen; C51H53ClOP3Ru(1+)*ClO4(1-); at 120℃; under 60006.0 Torr; for 36h;Autoclave; General procedure: Under an atmosphere of nitrogen, a stainless steel 100 mL autoclave,equipped with a magnetic stir bar, was charged with Ru-Cat. (0.5 - 5.0mol) and the solvent to be used (5 mL). A solution of the substrates (0.5mmol) in the solvent (5 mL) was then added via a syringe. The autoclavewas purged by three cycles of pressurization/ venting with N2 (1 - 5 bar),and then pressurized with the desired pressure (40 ~ 80 bar). Theautoclave was heated to the desired temperature (100 ~ 160 C) and thecontents stirred. After the pre-determined reaction time, the autoclavewas cooled to room temperature and the pressure slowly released. Thereaction mixture was filtered through a plug of silica gel and thenanalyzed by GC and GC-MS. The mixture was concentrated underreduced pressure. The residue was purified by column chromatographyon silica gel (EtOAc in petroleum ether) to afford the correspondingreduced product.
  • 6
  • [ 618-89-3 ]
  • [ 1751-97-9 ]
YieldReaction ConditionsOperation in experiment
73% With bis(bipyridine)nickel(II) bromide; ethylene dibromide; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 2.5h;Electrochemical reaction; Inert atmosphere; General procedure: DMF (40 mL), NaI (375 mg, 2.5 mmol), and 1,2-dibromoethane (100μL, 1.16 mmol) were added to an undivided electrochemical cell, fitted with an iron/nickel (64/36) anode, and surrounded by a nickel foam as the cathode (surface: 40 cm2, porosity: 500 μm, Goodfellow).The mixture was electrolyzed under argon at a constant current intensityof 0.2 A at r.t. for 15 min. The current was then stopped, then NiBr2bpy (187 mg, 0.5 mmol) and aryl or heteroaryl halide (5 mmol),were sequentially added. The solution was electrolyzed at 0.2 A untilthe starting aryl or heteroaryl halide had been totally consumed (2-5h). Sat. aq EDTA-Na2 solution (50 mL) was added, and the resultingsolution was extracted either with EtOAc (for aryl halides) or withCH2Cl2 (for heteroaryl halides) (3 × 50 mL). The combined organic layerswere washed with brine (50 mL), dried (MgSO4), filtered, and concentratedunder vacuum. The crude product was purified by flashchromatography (silica gel, 70-200 μm).
  • 7
  • [ 618-89-3 ]
  • [ 557-21-1 ]
  • [ 13531-48-1 ]
  • 8
  • [ 618-89-3 ]
  • [ 105-53-3 ]
  • 2-(3-methoxycarbonylphenyl)malonic acid diethyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% With di-tert-butyl(neopentyl)phosphine; sodium hydride; bis(dibenzylideneacetone)-palladium(0); In toluene; mineral oil; at 70℃; for 24h; General procedure: Reactions were conducted using standard dry box techniques and all solvents were distilled over Reactions were conducted using standard dry box techniques and all solvents were distilled oversodium. Method A: To a screw capped vial was added Pd(dba)2 (0.010 mmol), DTBNpP(0.020mmol), and NaH (1.2 mmol). The vial was sealed with a septa screw cap and removed from the glove box. To the vial was added toluene (1.0 mL), aryl bromide (1.0 mmol), and diethyl malonate (1.2 mmol). The reaction mixture was stirred at 70 C for 24 hours and the conversion of the aryl bromide was then measured by GC. The crude reaction mixture was filtered through a plug of Celite and then concentrated in vacuo. The concentrate was thenpurified by column chromatography on silica gel.
  • 9
  • [ 618-89-3 ]
  • [ 13331-27-6 ]
  • [ 149506-24-1 ]
YieldReaction ConditionsOperation in experiment
26% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 20 - 80℃; for 5h;Inert atmosphere; [000408] Synthesis of methyl 3’-nitro-[l, 1’-biphenylj-3-carboxylate (515): To a stirred solution of <strong>[618-89-3]methyl 3-bromobenzoate</strong> 514 (2.5 g, 14.99 mmol) and (3-nitrophenyl) boronic acid 382 (3.8 g, 17.99 mmol) in toluene (20 mL) under inert atmosphere were added sodium carbonate (3.17 g, 29.99 mmol in 20 mL of H20) at RT and purged under argon atmosphere for 20 mm. To this was added Pd(PPh3)4 (693 mg, 0.59 mmol) and heated to 80 C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 515 (1 g, 26%) as yellow liquid. TLC: 15% EtOAc/ hexanes (R 0.5); 1H NMR (400 MHz, DMSO-d6): ö 8.48-8.46 (m, 1H), 8.30-8.25 (m, 2H), 8.22-8.18 (m, 1H), 8.11-8.07 (m, 1H), 8.04 (dt,J 7.8, 1.3 Hz, 1H),7.80 (t, J= 8.0 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 3.91 (s, 3H).
With palladium 10% on activated carbon; sodium carbonate; In methanol;Reflux; [0089] A mixture of (3-nitrophenyl)boronic acid and <strong>[618-89-3]methyl 3-bromobenzoate</strong> was placed into a reaction vessel with 10% palladium on carbon (Pd/C) and sodium carbonate (Na2C03) in methanol (MeOH). The reaction mixture was held at reflux until the starting materials had been converted into methyl 3'-nitro-[l1,1]-biphenyl]-3-carboxylate. The methyl 3'-nitro-[1,1]biphenyl]-3-carboxylate was maintained in the reaction vessel, used without purification, isopropyl acetate was added to the reaction vessel and the mixture subsequently reacted with 10% Pd/C in a hydrogen atmosphere to yield methyl 3'-amino-[1,1]-biphenyl]- 3-carboxylate.
  • 10
  • [ 201230-82-2 ]
  • [ 618-89-3 ]
  • [ 6638-79-5 ]
  • N-methoxy-N-methyl-isophthalamic acid methyl ester [ No CAS ]
  • 11
  • [ 618-89-3 ]
  • [ 108-95-2 ]
  • [ 50789-43-0 ]
YieldReaction ConditionsOperation in experiment
73% With thio-xanthene-9-one; (2,2'-bipyridine)nickel(II) dibromide; N-tert-butylisopropylamine; In acetonitrile; for 72h;Inert atmosphere; Irradiation; Green chemistry; Methyl 3-bromobenzoate (0.2 mmol), phenol (0.6 mmol), TXO (20 mol %), Ni(bpy)Br2 (10 mol %), t-BuNH(i-Pr) (0.4 mmol) and MeCN (3 mL) was added to a dry reaction tube with a magnetic stir bar, then the reaction tube was replaced with N2 3 times, and the reaction was stirred for 72 hours under 45 W CFL irradiation. After the reaction, 5 mL of water was added, then extracted with 3×5 mL of ethyl acetate, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and separated by silica gel column chromatography to obtain The target product (73% yield).
  • 12
  • [ 618-89-3 ]
  • [ 63503-60-6 ]
  • [ 168618-92-6 ]
YieldReaction ConditionsOperation in experiment
89% General procedure: A solution of sodium carbonate (0.55mmol) in water (1.75mL) and EtOH (1.25mL) was prepared and degassed. In a 10mL vial Tetrakis (triphenylphosphine) palladium (0.055mmol) was added to a solution of 4a-e (0.275mmol) in DME (5mL) in a 10mL vial. Argon was bubbled into the DME solution with stirring for 10min. The boronic acid (1.650mmol) was added to the vial followed by the addition of the sodium carbonate mixture. The vial was sealed under argon and heated to 80C while stiring for 12h. The mixture was diluted in water and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The mixture was concentrated in vacuo to give the product as an oil. The product was purified in by column chromatography and characterized by 1H and 13C NMR.
  • 13
  • [ 93138-55-7 ]
  • [ 618-89-3 ]
  • N-(3-Methoxycarbonylbenzyl)-3-(piperidinomethyl)aniline [ No CAS ]
YieldReaction ConditionsOperation in experiment
72% With sodium hydride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 50℃; for 3.5h; 1-(3-Aminobenzyl)piperidine (0.52 g) obtained by the known process (WO99/32100) was dissolved in tetrahydrofuran (4.0 mL) and N,N-dimethylformamide (1.0 mL), and methyl 3-(bromomethyl)benzoate (0.63 g) and a 60% dispersion (0.013 g) of sodium hydride in mineral oil were added thereto, followed by stirring at 50 C. for 3.5 hours. The mixture was allowed to stand for cooling to room temperature, and then a saturated aqueous sodium bicarbonate solution and water were added thereto, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=5:1) to give Compound X (0.67 g, 72%) as a pale yellow oily substance. [0583] 1H NMR (270 MHz, CDCl3) δ8.03 (1H, m), 7.91 (1H, m), 7.56 (1H, m), 7.38 (1H, t), 7.08 (1H, t), 6.71 (1H, m), 6.65 (1H, brd), 6.51 (1H, brdd), 4.48 (1H, brs), 4.37 (2H, brs), 3.89 (3H, s), 3.49 (2H, brs), 2.45 (4H, m), 1.61 (4H, m), 1.43 (2H, m).
  • 14
  • [ 618-89-3 ]
  • [ 62-53-3 ]
  • [ 6025-56-5 ]
YieldReaction ConditionsOperation in experiment
82% With caesium carbonate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 20h; Methyl 3-bromobenzoate (1000 mg, 4.65 [MMOL),] Pd2 (dba) 3 (53 mg, 0.058 mmol), [CS2CO3] (2120 mg, 1.4 mmol) [AND N-[2'-(DICYCLOHEXYLPHOSPHINO)-1, 1'-BIPHENYL-2-YL]-] [N,] N-dimethylamine (27mg, 0.07 mmol) were placed in a 100ml one-necked round bottom flask. The system was evacuated and filled with argon several times. Then aniline (519 mg, 5.58 mmol) was added, followed by the addition of toluene (50 ml). The solution was heated at [100C] for 20h, the solvent was removed in vacuo and residue was purified by silica gel chromatography [(ETOAC/HEPATANE] [1/3)] to get 180 mg (18%) of methyl ester as a yellow solid, which was hydrolyzed by [LIOH] (50 mg) ) in THF (4 [ML)] and water (1 [ML)] to afford 140 mg (82%) of 3-Anilinobenzoic acid as a white [SOLID. 1H] NMR (400 MHz, DMSO-d6) 8 8.02 (s, 1 H), 7.65 (s, 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.19 (t, J= 8.3 Hz, 2 H), 7.10 (d, J= 7.7 Hz, 1H), 7.03 (d, J= 7.6 Hz, 2 H), 6.96 [(M,] [1] H), 6.76 (t, J= 7.3 Hz, [1] [H)
  • 15
  • [ 108-22-5 ]
  • [ 618-89-3 ]
  • [ 74998-19-9 ]
YieldReaction ConditionsOperation in experiment
Preparation 65: methyl [3-(2-oxopropyl)phenyl]acetate Tributyltin methoxide (80.3ml, 279mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5g, 249mmol), isopropenyl acetate (39.4ml, 358mmol), palladium(II)acetate (2.6g, 11.6mmol) and tri-o -tolylphosphine (7.1 g, 23.2mmol) were stirred together in toluene (350ml) at 100C under nitrogen for 18 hours. After cooling, the reaction was treated with 4M aqueous potassium fluoride solution (560ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200ml) and filtered through celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by flash column chromatography on silica gel eluding with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3g) as an orange oil. 1H NMR (400MHz, CDCl3): δ = 7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 215, [M-H]- 191.
Tributyltin methoxide (80.3 mL, 279 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium (11) acetate (2.6 g, 11.6 mmol) and tri-ortho-tolylphosphine (7.1 g, 23.2 mmol) were stirred together in toluene (350 mL) at 100 C under nitrogen for 18 hours. After cooling, the reaction was treated with potassium fluoride solution (4M, 560 ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200 mL) and filtered through Celite No., washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by chromatography eluting with ethylacetate : pentane 10 : 90 to 20: 80 to give the title compound (45.3 g) as an orange oil- 'H NMR-(400MHz, CDCI3) ã : 2.18 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 7.43-7. 37 (2H, m), 7.87 (1H, s), 7.95-7. 93 (1H, d); LRMS ESI m/z 215 [M+Na] +, 191 [M- H]-.
Tributyltin methoxide (80.3 ml, 279 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium(II)acetate (2.6 g, 11.6 mmol) and tri-o-tolylphosphine (7.1 g, 23.2 mmol) were stirred together in toluene (350 ml) at 100 C. under nitrogen for 18 hours. After cooling, the reaction was treated with 4M aqueous potassium fluoride solution (560 ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200 ml) and filtered through celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3 g) as an orange oil. 1H NMR (400 MHz, CDCl3): δ=7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm. LRMS (electrospray): m/z [M+Na]+215, [M-H]-191.
Tributyltin methoxide (80.3ml, 279mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5g, 249mmol), isopropenyl acetate (39.4ml, 358mmol), palladium(ll)acetate (2.6g, 11.6mmol) and tri-o-tolylphosphine (7.1g, 23.2mmol) were stirred together in toluene (350ml) at 100C under nitrogen for 18 hours. After cooling, the reaction was treated with 4M aqueous potassium fluoride solution (560ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200ml) and filtered through Celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced invacua. The residue was purified by flash column chromatography on silica gel eluting with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3g) as an orange oil.1H NMR (400MHz, CDCI3): 8 = 7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm.LRMS (electrospray): m/z [M+Na]+ 215, [M-H]' 191.

  • 16
  • [ 431052-64-1 ]
  • [ 618-89-3 ]
  • [ 780800-90-0 ]
YieldReaction ConditionsOperation in experiment
17% EXAMPLE 36 COMPOUND 36: 3-(2-[(4-Amino-butyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-benzoic acid methyl ester (HBr salt) A stirred solution of 3-Tributylstannanyl-pyridine-2-carbaldehyde (256 mg, 0.65 mmol) and <strong>[618-89-3]methyl 3-bromobenzoate</strong> (128 mg, 0.59 mmol) in DMF (2.1 mL) was degassed with Ar for 5 minutes, after which PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuO (34 mg, 0.43 mmol) was added and the mixture heated to 110 C. overnight. The reaction was cooled to room temperature, and diluted with saturated aqueous NaHCO3 (15 mL) and EtOAc (40 mL). The organic phase was separated, washed with brine (3*15 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 60:40) gave 3-(2-Formyl-pyridin-3-yl)-benzoic acid methyl ester (25 mg, 17%) as a white solid. 1H NMR (CDCl3) δ 3.92 (s, 3H), 7.47-7.56 (m, 2H), 7.58 (d, 1H, J=4.9 Hz), 8.03 (s, 1H), 8.07-8.20 (m, 1H), 8.86 (dd, 1H, J=4.9, 1.8 Hz), 10.08 (s, 1H).
  • 17
  • [ 201230-82-2 ]
  • [ 618-89-3 ]
  • [ 1877-71-0 ]
YieldReaction ConditionsOperation in experiment
82% With methanol; triethylamine;palladium diacetate; 1,3-bis-(diphenylphosphino)propane; at 100℃; under 25858.1 Torr; for 15h; The following were introduced into a vessel: [10.] Og (40.3 mmol) of <strong>[618-89-3]methyl 3-bromobenzoate</strong>, 2.5g (mmol) of 1, 3-bis (diphenylphosphino) propane ("DPPP"), 14 mL of triethylamine, 0.905 g of palladium acetate, and 140 ml of methanol. The vessel was sealed and pressurized with carbon monoxide to a pressure of 500 psi. The vessel was heated to [100 C] for 15 hours. The mixture was then cooled and concentrated on a rotary evaporator before partitioning between EtOAc and 2M HC1. The layers were separated, and the aqueous layer was extracted with EtOAc [(LX).] The organic extracts were combined and washed with saturated aqueous [NACL] solution and dried [(MGSO4).] Concentration provided a solid, which is slurred in hexane and filtered. The material is dried in a vacuum oven at- 10mmHg at [70 C] ; yield 5.9g [(82%).] NMR: [DMSO'H 8] (ppm) 3.54 (3H, s); 7. [18-7.] 21 [(1H,] m); 7. [34- 7.] 40 [(1H,] m); 7. 46- 7.49 (1H m); 7. [87- 7.] 89 [(1H,] m).
  • 18
  • [ 618-89-3 ]
  • [ 81290-20-2 ]
  • [ 655-26-5 ]
YieldReaction ConditionsOperation in experiment
65% With tetrabutyl ammonium fluoride; In toluene; at -78 - 20℃; In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution TO-78 C, TBAF (232 UL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgS04), concentrated in vacuo, and resulting crude oil was purified using Si02 flash chromatography (elution: 5-20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow OIL. 1H-NMR (CDC13 ; 400 MHz) δ 8. 18 (br s, 1H), 7. 98-8. 00 (m, 1H), 7.82-7. 85 (m, 1H), 7.42-7. 46 (m, 1H). 19F-NMR (CDC13 ; 400 M HZ) δ -72. 06 (s).
With hydrogenchloride; tetrabutyl ammonium fluoride; In ethyl acetate; toluene; a 1-(3-Bromo-phenyl)-2,2,2-trifluoro-ethanone In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution to -78 C., TBAF (232 μL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgSO4), concentrated in vacuo, and resulting crude oil was purified using SiO2 flash chromatography (elution: 5-20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz) δ 8.18 (br s, 1H), 7.98-8.00 (m, 1H), 7.82-7.85 (m, 1H), 7.42-7.46 (m, 1H).
  • 19
  • [ 618-89-3 ]
  • [ 104013-60-7 ]
  • 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
43% With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 100℃; for 18h; Combine 1 - [4-(3 -amino-benzyloxy)-2-hydroxy-3 -propyl-phenyl] -ethanone (500 mg, 1.67 mmol), 3-bromo-benzoic acid methyl ester (326 mg, 1.52 mmol) and cesium carbonate (693 mg, 2.13 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2'-Bis(diphenyl-phosphino)-l,l'-binaphthyl] (142 mg, 0.228 mmol), and palladium acetate (34 mg, 0.152 mmol). Purge reaction vessel with argon. Heat to 100 0C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with ethyl acetate :hexanes to yield the title compound as a white solid (280 mg, 43%): 1H NMR (DMSO-^6) δ 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.82 (s, 3H), 5.23 (s, 2H), 6.71 (d, IH), 6.95 (d, IH), 7.01 (d, IH), 7.19 (m, IH), 7.28-7.41 (m, 4H), 7.65 (m, IH), 7.81 (d, IH), 8.49 (bs, IH), 12.84 (s, IH).
  • 20
  • [ 618-89-3 ]
  • [ 78782-27-1 ]
  • [ 25692-41-5 ]
YieldReaction ConditionsOperation in experiment
82% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; 74A: 3-Styryl-benzoic acid methyl ester; Methyl 3-bromobenzoate (458 mg, 2 mmol), 1-styreneboronic acid pinacoyl ester (484 mg, 2.1 mmol), Na2CO3 (222 mg, 2.1 mmol), tetrakis(triphenylphosphino)palladium (116 mg, 0.1 mmol), water (4 mL) and 1,2-dimethoxyethane (6 mL) were stirred with reflux conditions for one hour, under nitrogen. The reaction mixture was diluted with water andwas extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by trituration with Et2O. White crystals were obtained (393 nig, 82 %). NMR 1U (ppm, CDC13): 8.19 (t, / = 1.6 Hz, 1H), 7.91 (dt, / = 7.7 Hz, / = 1.3 Hz, 1H), 7.67 (d, J3 = 7.8 Hz, 1H), 7.52 (d, J3 = 7.3 Hz, 2H), 7.42 (t, J3 = 7.9 Hz, 1H), 7.36 (t, J3 = 7.4 Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J3 = 16.3 Hz, 1H), 7.11 (d, / = 16.4 Hz, 1H), 3.06 (s, 3H).
82% With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 1h;Heating / reflux; 74A: 3-Styryl-benzoic acid methyl ester; Methyl 3-bromobenzoate (458 mg, 2 mmol), 1-styreneboronic acid pinacoyl ester (484 mg, 2.1 mmol), Na2CO3 (222 mg, 2.1 mmol), tetrakis(triphenylphosphino)palladium (116 mg, 0.1 mmol), water (4 mL) and 1,2-dimethoxyethane (6 mL) were stirred with reflux conditions for one hour, under nitrogen. The reaction mixture was diluted with water and was extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by trituration with Et2O. White crystals were obtained (393 mg, 82%). NMR 1H (ppm, CDCl3): 8.19 (t, J4=1.6 Hz, 1H), 7.91 (dt, J3=7.7 Hz, J4=1.3 Hz, 1H), 7.67 (d, J3=7.8 Hz, 1H), 7.52 (d, J3=7.3 Hz, 2H), 7.42 (t, J3=7.9 Hz, 1H), 7.36 (t, J3=7.4 Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J3=16.3 Hz, 1H), 7.11 (d, J3=16.4 Hz, 1H), 3.06 (s, 3H).
  • 21
  • [ 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
  • 22
  • dimethylformamide [DMF] [ No CAS ]
  • 2,2-Dimethyl-7-methoxy-4-tributylstannyl-2,3-dihydrobenzofuran [ No CAS ]
  • [ 618-89-3 ]
  • 2,2-Dimethyl-7-methoxy-4-[3-(methoxycarbonyl)phenyl]-2,3-dihydrobenzofuran [ No CAS ]
YieldReaction ConditionsOperation in experiment
69.5% With sodium carbonate;palladium diacetate; In water; N,N-dimethyl-formamide; EXAMPLE 146 2,2-Dimethyl-7-methoxy-4-[3-(methoxycarbonyl)phenyl]-2,3-dihydrobenzofuran (Compound 146) A solution (30 ml) of Compound 144a obtained in Step A of Example 144 in DMF was added to a mixture of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (1.67 g), palladium acetate (0.18 g), sodium carbonate (2.10 g), and dimethylformamide (DMF) (70 ml), followed by stirring at 80 C. for one hour. A small amount of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/20) to give Compound 146 (1.69 g, 69.5%) as pale-yellow crystals. Melting point: 89-91 C. NMR(DMSO-d6, δ, ppm): 1.42(s, 6H), 3.12(s, 2H), 3.80 (s, 3H), 3.88(s, 3H), 6.90(d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.58(dd, J=7.4 Hz, 1H), 7.76(dd, 7.76(dd, J=7.9 Hz, 1.5 Hz, 1H), 7.91(d, J=7.4 Hz, 1H), 7.99(d, J=1.5 Hz, 1H) IR(KBr, cm-1): 1716
  • 23
  • [ 585-76-2 ]
  • [ 618-89-3 ]
YieldReaction ConditionsOperation in experiment
85% With sulfuric acid; In methanol; dichloromethane; ethyl acetate; Part A: 3-Bromobenzoic acid (1.1 g, 5.47 mmol) was dissolved in methanol (20 ml) in a 50 ml flask. Concentrated sulfuric acid (2 drops) was added and the mixture was refluxed under nitrogen for ten hours then concentrated under reduced pressure. The residue was mixed with dichloromethane (20 ml) and saturated sodium bicarbonate solution (10 ml). The organic material was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was flushed through silica gel with hexane/ethyl acetate (3:1), and concentrated which provided methyl 3-bromobenzoate (1.0 g, 85%).
  • 24
  • [ 893420-22-9 ]
  • [ 618-89-3 ]
  • [ 934280-95-2 ]
YieldReaction ConditionsOperation in experiment
62% With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 90 - 100℃; 5-Fluoro-4-(l-isopropyl-2-methyl-lH'-imidazol-5-yl)pyrimidin-2-amuie (obtained from Example l(b)) (99 mg, 0.42 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (97 mg, 0.45 mmol) and Cs2CO3 (230 mg, 0.71 mmol) were mixed in anhydrous 1,4-dioxane and the mixture was flushed with argon for 10 minutes before Pd2(dba)3 (23 mg, 0.025 mmol) and X-Phos (24 mg, 0.050 mmol) were added. The mixture was flushed with argon, then heated in a sealed tube at +90-100 C until the reaction was complete. The reaction mixture was diluted with CH2Cl2, filtered and evaporated. The residue was taken up in CH2Cl2 and the organic phase was washed with H2O. Residual water was removed from the organic phase by treatment with Na2SO4. The crude of the base product was purified using preparative HPLC to give s the title compound (97 mg, 62%) as a solid.1HNMR (400 MHz, DMSO-J6) δ ppm 9.73 (s, 1 H) 8.57 (d, 1 H) 8.19 (t, 1 H) 8.04 - 7.95 (m, 1 H) 7.59 - 7.52 (m, 1 H) 7.43 (t, 1 H) 7.37 (d, 1 H) 5.44 - 5.31 (m, 1 H) 3.84 (s, 3 H) 2.51 (s, 3 H) 1.42 (d, 3 H) 1.40 (d, 3 H); MS (ESI) m/z 370 (M+l).
62% With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 90 - 100℃; Example 18(a)Methyl 3-[5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}benzoate 5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (obtained from Example 1(b)) (99 mg, 0.42 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (97 mg, 0.45 mmol) and Cs2CO3 (230 mg, 0.71 mmol) were mixed in anhydrous 1,4-dioxane and the mixture was flushed with argon for 10 minutes before Pd2(dba)3 (23 mg, 0.025 mmol) and X-Phos (24 mg, 0.050 mmol) were added. The mixture was flushed with argon, then heated in a sealed tube at +90-100 C. until the reaction was complete. The reaction mixture was diluted with CH2Cl2, filtered and evaporated. The residue was taken up in CH2Cl2 and the organic phase was washed with H2O. Residual water was removed from the organic phase by treatment with Na2SO4. The crude of the base product was purified using preparative HPLC to give the title compound (97 mg, 62%) as a solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H) 8.57 (d, 1H) 8.19 (t, 1H) 8.04-7.95 (m, 1H) 7.59-7.52 (m, 1H) 7.43 (t, 1H) 7.37 (d, 1H) 5.44-5.31 (m, 1H) 3.84 (s, 3H) 2.51 (s, 3H) 1.42 (d, 3H) 1.40 (d, 3H); MS (ESI) m/z 370 (M+1).
  • 25
  • [ 618-89-3 ]
  • [ 57260-71-6 ]
  • [ 179003-10-2 ]
YieldReaction ConditionsOperation in experiment
85% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 12h;Inert atmosphere; A mixture of 86 (3.00 g, 14.0 mmol), /V-Boc-piperazine (2.73 g, 14.7 mmol), Pd(OAc)2(313 mg, 1.40 mmol), Cs2C03(9.09 g, 27.9 mmol) and BINAP (869 mg, 1.40 mmol) in toluene (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 C for 12 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 87 (3.80 g, 85%) as a pale yellow solid.1H N R (400 MHz, CDCI3) 7.60 (s, 1 H), 7.55 (d, J = 7.6 Hz, 1 H),7.33 (t, J - 8.0 Hz, 1 H), 7.13 (d, J - 2.4 Hz, 1 H), 3.91 (s, 3H), 3.60 (t, J = 4.4 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1 .49 (s, 9H). To a solution of 87 (1 .00 g, 3.12 mmol) in THF (20 mL) was added LiAIH4(1 18 mg,3.12 mmol). The mixture was stirred at 0 C for 1 h. The reaction mixture was quenched by sodium potassium tartrate (0.5 mL) at 15 C, and then filtered and concentrated under reduced pressure to give 88 (700 mg, 77%) as a pale yellow oil.1H NMR (400 MHz, CDCI3) 7.28-7.25 (m, 1 H), 6.96 (s, 1 H), 6.89-6.84 (m, 2H), 4.66 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). To a solution of 88 (293 mg, 1.00 mmol) and Et3N (304 mg, 3.00 mmol) in DCM (10 mL) was added MsCI (229 mg, 2.00 mmol). The mixture was stirred at 0 C for 2 h. The reaction mixture was quenched by addition H20 (20 mL) at 15 C, and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give crude 89 (200 mg, yellow solid) which was used in the next step without further purification. MS (ESI): mass calcd. for C17H26N205S 370.16, m/z found 371.2 [M+H]+. A mixture of 89 (300 mg, 810 umol), 6-003 (236 mg, 0.810 mmol) and K2C03(336 mg, 2.43 mmol) in DMF (5 mL) was stirred at 60 C for 1 h under N2atmosphere. The reaction mixture was quenched by H20 (10 mL) at 15 C, and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give crude 90 (400 mg, pale yellow oil) which was used in the next step without further purification. MS (ESI): mass calcd. for C3oH4oBN307565.30, m/z found 566.3 [M+H]+. To a solution of 90 (400 mg, 0.707 mmol) in EtOAc (10 mL) was added HCI/EtOAc (6 M, 1.18 mL). The mixture was stirred at 15 C for 1 h. After concentrated under reduced pressure, the reaction mixture was purified by prep. HPLC (column: Luna C18 100 x 30 mm; liquid phase: [A-HCI/H2O=0.040% v/v; B-ACN] B%: 13%-43%, 12 min]) to give 6-126 (102 mg, 28%) as a white solid.1H NMR (400 MHz, DMSO-d6) 9.17 (s, 2H), 8.58 (d, J = 7.2 Hz, 1 H),7.34 (d, J = 7.2 Hz, 1 H), 7.28-7.22 (m, 2H), 7.01 (s, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.88 (d, J = 7.2 Hz, 1 H), 5.13 (s, 2H), 4.97 (s, 2H), 4.34 (t, J = 7.2 Hz, 1 H), 3.36 (d, J = 5.2 Hz, 4H), 3.17 (d, J = 2.8 Hz, 4H), 2.44 (s, 3H), 2.20-2.11 (m, 6.8 Hz, 1 H), 0.958-0.942 (m, 6 H); ESI-MS m/z 466 [M+H]+; HPLC purity: 97.27% (220 nm), 96.92% (254 nm)
30% With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 0.25h;Inert atmosphere; A mixture of tert-butyl piperazine-1-carboxylate (1.0 eq), 17 (1.0 eq.), BINAP (5% mol) and sodium tert-butoxide (3.0 eq) were placed in two neck round bottom flask. Then anhydrous toluene was added to the mixture. The mixture was degassed and back-filled with dry nitrogen gas before suspension of palladium (II) acetate (5%mol) in dry toluene was added. The mixture reaction was stirred at 100 oC for 15min, cooled to room temperature, quenched by water. Normal extraction and purification was applied to get white solid, yield 30%.1H NMR (300MHz, CDCl3) δ 7.59 (s, 1H), 7.54 (d, J = 7.68 Hz, 1H), 7.33 (t, J = 8.04 Hz, 1H), 7.10 (d, J = 8.25 Hz, 1H), 3.91 (s, 3H), 3.59 (t, J = 4.95 Hz, 4H), 3.18 (t, J = 5.31 Hz, 4H), 1.49 (s, 9H).
23% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; for 18h;Inert atmosphere; Reflux; To a 250 mL round-bottom flask containing 40 mL of 1,4-dioxane, raw material 2-23 (<strong>[618-89-3]methyl m-bromobenzoate</strong>) (2.15 g, 10 mmol), BINAP (622 mg, 1 mmol), palladium acetate (45 mg, 0.2 mmol), cesium carbonate (6.5 g, 20 mmol), Boc-piperazine 2-24 (1.86 g, 10 mmol) were added in sequence, and reacted under argon atmosphere and reflux at 100 C for 18 hours, until TLC (PE: EA = 10: 1) detection showed the reaction was completed. Filtration was carried out with diatomite to remove solid(s). The filtrate was evaporated under reduced pressure and subjected to column chromatography (PE: EA = 10: 1) to give 720 mg of a light yellow oily product, yield: 23%.
With sodium t-butanolate;palladium diacetate; johnphos; In toluene; at 50℃; To a mixture containing piperazine-1-carboxyltc acid tert-butyl ester (400 mg, 2.16 mmol), 3-bromo-benzoic acid methyl ester (547 mg, 2.56 mmol), Pd(AcO) (32 mg, 0.14 mmol), 2-(di-f-butylphosphino)biphenyl (80 mg, 0.28 mmol) and sodium t- butoxide (400 mg, 4 mmol) in toluene (20 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified <n="183"/>using prep-HPLC to give desired product (250 mg, 37 % yield for two steps) as TFA salt.

  • 26
  • [ 42397-28-4 ]
  • [ 618-89-3 ]
  • [ 959706-81-1 ]
  • 27
  • [ 34713-70-7 ]
  • [ 618-89-3 ]
  • [ 959706-74-2 ]
  • 28
  • [ 618-89-3 ]
  • [ 128622-13-9 ]
  • methyl 3-[7-tert-butyldimethylsilyloxy-1-formylheptyl]benzoate [ No CAS ]
  • 29
  • [ 618-89-3 ]
  • [ 66-25-1 ]
  • [ 959706-81-1 ]
  • 30
  • [ 618-89-3 ]
  • [ 1035869-05-6 ]
YieldReaction ConditionsOperation in experiment
37.22% With Lawessons reagent; In toluene; at 140℃; for 4h;Microwave irradiation; To a solution of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (10 g, 46.50 mmol) in toluene (10 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4dithiadiphosphetane (20.69 g, 51.15 mmol). The mixture was stirred in a microwave reactor at 140 C for 4 h. After cooling to rt the solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give O-methyl 3-bromobenzenecarbothioate (4 g, 37.22% yield). 1H NMR (400 MHz, METHANOL-d4) d ppm 8.29 (t, J = 1.76, 1 H) 8.08 - 8.16 (m, 1 H) 7.70 - 7.77 (m, 1 H) 7.34 (t, J = 7.94, 1 H) 4.27 - 4.33 (m, 3 H).
  • 31
  • [ 618-89-3 ]
  • [ 98-80-6 ]
  • [ 35714-17-1 ]
YieldReaction ConditionsOperation in experiment
72% With potassium phosphate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃; for 1h; I. Methyl 3-benzylbenzoate; [00306] A solution of 3-bromomethylbenzoate (500 mg, 2.18 mmol), phenylboronic acid (290 mg, 2.40 mmol), PdCl2(PPh3)2 (46 mg, 0.07 mmol) and K3PO4 (1.16 g, 5.45 mmol) in DMF (10 mL) and water (2 mL) was heated at 8O0C for 1 hr and then cooled to room temperature and diluted with EtOAc. The reaction mixture was washed with water (3 times) and saturated NaCl, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 1 :19 EtOAc:hexanes to give a colorless oil (353 mg, 72%).
  • 32
  • [ 618-89-3 ]
  • [ 39115-96-3 ]
YieldReaction ConditionsOperation in experiment
With hydrazine; In methanol; water; at 50 - 55℃; for 3.33333h; To a 100 L round bottom flask under nitrogen was added DABCO (2.81 kg, 25.06 mol) and MeOH (35 L). 3-bromobenzoyl chloride 1 (5.0 kg, 22.78 mol) was charged over 30 min at 20 - 25 0C and an ice water bath was used to control the temperature. <n="33"/>The mixture was stirred at room temperature for 10 - 20 minutes. Hydrazine (64%, 8.8 L, 182 mol) was added over 20 minutes, and the reaction mixture was heated at 50 to 55 0C for 3 hours. Water (35 L) was added to crystallize the batch at room temperature over 1 hour. The resulting slurry was stirred at room temperature for 1 -2 hours and filtered. The wet cake was washed with water (3 x 15 L), and dried at room temperature under a vacuum/N2 sweep to afford hydrazide 3 as white solid. HPLC retention time of hydrazide 3 = 6.75 minutes, on Waters Symmetry C- 18 column, 5 micron, 4.6 x 250 mm; 20 0C, UV detection at 215 nm; gradient flow 1.0 mL/min; A = water with 0.1% H3PO4; B = acetonitrile; gradient elution: 0 minutes: 95% A/5% B; 5 minutes: 55% A/45% B; 10 minutes: 25% A/75% B; 13 minutes: 10% A/90% B; and 26 minutes: 10% A/90% B. IH NMR (DMSO-d6): 69.88 (IH, s), 7.98 (IH, m), 7.81 (IH, m), 7.70 (IH, m), 7.41 (IH, m), 4.52 (2H, s).
With hydrazine hydrate; In methanol; for 5h;Reflux; General procedure: Compounds 6a-t were synthesized from substituted benzoic acid via six steps according to the literature method as described. Various substituted benzoic acids 1a-t were treated with SOCl2 to give compounds 2a-t, which were reacted with CH3OH and EtN3 in CH2Cl2 at 0 to afford compounds 3a-t. Compounds 4a-t were prepared by the reaction of compounds 3a-t, hydrazine hydrate in CH3OH under reflux condition about 5h. Subsequently, compounds 5a-t were obtained by reaction of compounds 4a-t with CS2 and KOH in CH3OH. Compounds 6a-t were obtained by the cyclization reaction of compounds 5a-t in the presence of HCl at 0-5C.
With hydrazine hydrate; In ethanol; for 9h;Reflux; General procedure: Substituted benzoic acid (1.0 mmol) was dissolved in thionylchloride and refluxed for 2 h, then the solvent was removed underreduced pressure to obtain the white solid. The white solid in methanol was added concentrated sulfuric acid (1 mL) and themixture was refluxed for 4 h, the solvent was removed to obtaincrude solid. The crude solid was extracted with ethyl acetate andwater. The solvents were evaporated to afford the pure product.Finally, the pure product was dissolved in ethanol, and the hydrazinehydrate was added. The mixture was refluxed for 9 h, and thesolvent was removed
With hydrazine hydrate; In methanol; for 8h;Reflux; General procedure: To a solution of methyl ester of aromatic carboxylic acid 2 (0.1 mol) in methanol (30 mL), hydrazine hydrate (0.2 mol) was added drop wise with stirring. The resulting mixture was allowed to reflux for 8 h. After the completion of the reaction as monitored by TLC, the excess methanol was distilled off under reduced pressure. The resulting acid hydrazide 3 was washed with cold water, dried and recrystallized from ethanol.
With hydrazine hydrate; In methanol; at 65℃; for 4h; General procedure: To a solution of esters (2a~2t, 1.0 equiv.), furan-2-carbonyl chloride (7a, 1.0 equiv.) orthiophene-2-carbonyl chloride (7b, 1.0 equiv.) in MeOH (2 mL/1 mmol) was added hydrazine hydrate(1 mL/1 mmol), then the mixture was allowed to reach 65 C and stirred for 4 h. After completion(monitored by TLC), the organic solvent was removed and extracted three times with ethyl acetate,the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to givethe corresponding hydrazides (3a~3t, 8a, or 8b) in high yields, which were taken up for the next stepwithout any purification.
With hydrazine hydrate; In methanol; at 10 - 80℃; for 6h; General procedure: 13.5 mmol of the methyl benzoate derivatives were added to 100 mL of methanol at the 250 mL double-mouth bottle. Add 6.75 mL (108 mmol) of hydrazine hydrate to the reactive mixture gradually between 10 and 25 C over 2 h. Then the temperature increased to 80 C and refluxed for 4 h, subsequently lowered to room temperature. After the methanol is removed by decompression concentration, 300 mL of added water was mixed at 5 C to decrystallize, and the white solid (b) is obtained by filtration and drying.
With hydrazine hydrate; In methanol; at 0 - 20℃; for 4h; General procedure: Compound 2a was dissolved in methanol and the mixture was cooled in an ice bath. Hydrazine hydrate (3 eq.) was added dropwise at 0C. The resulting reaction mixture was stirred at room temperature for 4h. The reaction progress was monitored by TLC (MeOH/DCM=1:20) until it was completed. A crude solid 3a was obtained by filtering and washing with ice methanol, which was used to the next step without further purification. Preparation method of 3b∼3q was same as 3a.

  • 34
  • [ 3162-29-6 ]
  • [ 618-89-3 ]
  • 1-(1,3-benzodioxol-5-yl)-3-(3-bromophenyl)-propan-1,3-dione [ No CAS ]
YieldReaction ConditionsOperation in experiment
87% With sodium hydride; In dimethyl sulfoxide; at 15 - 23℃; for 16h;Inert atmosphere; A dry, 500-mL, three-necked flask is fitted with a Teflon-coated magnetic stirring bar, a rubber septum, a thermometer, and a reflux condenser to which is attached a T-tube connected to a source of pure nitrogen. The remaining joint of the T-tube is connected to a bubbling device so that the rate of nitrogen flow can be observed throughout of the reaction. The apparatus is arranged so that the flask may be cooled intermittently with a water bath. After the reaction vessel has been flushed with nitrogen a static nitrogen atmosphere is maintained in the reaction vessel for the remainder of the reaction. The flask is charged with ca. 60% dispersion of sodium hydride (5 g, 0.125 mole) in mineral oil (Note 1). The mineral oil is washed from the hydride with petroleum benzine 40/60 (3 x 40 ml.) (Note 2). The supernatant petroleum benzine layer is removed using a Luer-lock hypodermic syringe with a stainless-steel needle inserted through the rubber septum. The residual sodium hydride is mixed with 80 ml_ of dimethyl sulfoxide (Note 3), and the rubber septum is replaced with a pressure-equalizing dropping funnel. A solution of 16.4 g (0.1 mole) of 1-(1 ,3-benzodioxol-5- yl)ethanone (Note 4) and 26.9 g (0.125 mole) of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (Note 5) in 60 mL of dimethyl sulfoxide is placed in the dropping funnel. The funnel is stoppered, stirring is begun and the contents of the flask are cooled in a water bath to 15 0C. The solution of 1- (1 ,3-benzodioxol-5-yl)ethanone and <strong>[618-89-3]methyl 3-bromobenzoate</strong> is added slowly so that hydrogen evolution is maintained at the controllable rate and the temperature did not rise above 20 0C over a period of 60 minutes (Note 6). After the addition is completed, the bath is removed, and the reaction mixture is stirred at room temperature (23 0C) for 15 hours. The resulting red-brown homogeneous reaction mixture is poured slowly into 500 mL of an ice and water containing 5 mL of 85% orthophosphoric acid (Note 7) with stirring. After 1 hour stirring the product is removed by filtration (Note 8), washed by suction filtration with water (2 x 100 mL), and vacuum dried to constant weight at 40 0C for 6 hours to give 34.4 g of the crude (Note 9) product. Recrystallization from 200 mL of 99.9% ethanol and 200 mL ethyl acetate (Note 10) and drying in vacuum to constant weight at 40 C for 6 hours gives 28.5 g (82% yield) of pure (Note 11) 1-(1 ,3-benzodioxol-5-yl)-3-(3-bromophenyl)propane-1 ,3-dione, m.p. 136-137 0C. The filtrate is concentrated under reduced pressure to a volume ca. 30 mL, the crystalline solid that separates is collected on a filter, washed by suction filtration with ethanol (2 x 10 mL) and vacuum dried to constant weight at 40 0C for 6 hours, yielding an additional crop (3.15 g) of the crude product. The crude product is recrystallized twice from 20 mL of 99.9% ethanol and 20 mL ethyl acetate and vacuum dried to constant weight at 40 CC for 6 hours to afford additional 1.8 g (5% yield) of pure 1-(1 ,3-benzodioxol-5-yl)-3-(3- bromophenyl)propane-1 ,3-dione (Note 12). The total yield of the product is 30.3 g (87%).2. Notes1. Sodium hydride, 57-63% oil dispersion, order number 13431 available from Alfa Aesar GmbH & Co KG, Karlsruhe was used. 2. Petroleum benzine GR for analysis boiling range 40-60 0C, order number 101775 from Merck KGaA, Darmstadt was used.3. The dimethyl sulfoxide GR for analysis, order number 102952 from Merck KGaA, Darmstadt was used without further purification. 4. 1-(1 ,3-Benzodioxol-5-yl)ethanone, 98%, order number A13597 available from Alfa Aesar GmbH & Co KG, Karlsruhe was used.5. Methyl 3-bromobenzoate, 98%+, order number A16174 available from Alfa Aesar GmbH & Co KG, Karlsruhe was used.6. A foaming is observed during the addition of the solution. The usage of mechanical stirrer and an antifoaming agent like polyethylene glycol dimethyl ether may be necessary at the upscaling.7. The orthophosphoric acid, 85% w/w aq. solution, GR for analysis, order number 100573 from Merck KGaA, Darmstadt was used.8. The pH-value of the reaction mixture is pH = 7. By acidification with additionally 15 ml_ ortophosphoric acid to pH = 2, 1.3 g of 3-bromobenzoic acid may be obtained.9. Purity of the product determined by HPLC is 96.3%.10. The ethanol 99.9% absolute GR for analysis, order number 100983, and ethyl acetate GR for analysis, order number 109623 available from Merck KGaA, Darmstadt was used. 1 1. Purity of the product determined by HPLC is 99.3%. Analytical HPLC is performed by using a Waters HPLC system with a Waters 996 Photodiode Array Detector. All separations involved a mobile phase of 0.1% v/v trifluoroacetic acid (TFA) in water (solvent A) and 0.1% v/v TFA in acetonitrile (solvent B) by using a reversed phase (RP) column Eurospher RP 18, 100 A, 5 μm, 250 x 4.6 mm at flow rates of 1 mL/min. The compound is dissolved in acetonitrile GR for HPLC at a concentration 1 mg/mL. Peaks with retention times (RT) 20.9 and 10.3 min are enol and keto forms respectively ...
  • 35
  • [ 618-89-3 ]
  • [ 5720-06-9 ]
  • methyl 2'-methoxy(1,1'-biphenyl)-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
85% With potassium phosphate monohydrate; XPhos;palladium diacetate; In tetrahydrofuran; at 20℃; for 18h; Step a: A mixture of palladium acetate and X-phos in THF (3 mL) was degassed and stirred at rt. After 30 minutes, this solution was added to an heterogeneous mixture of methyl 3-bromo-benzoate (6.85g, 31.85 mmol), 2-methoxyphenyl boronic acid (7.26 g, 47.78 mmol) and Κ3Ρ04·Η20 (21.98 g, 95.56 mmol) in THF (32 mL). After stirring at rt for 18 h, the insolubles were removed by filtration through Celite and rinsed with EtOAc. The combined filtrates were concentrated under reduced pressure and the residue was purified by column chromatography (5% EtOAc in hexanes) to give a white solid (6.53 g, 85%); Rf = 0.5 (10% EtOAc in hexanes).
  • 36
  • [ 618-89-3 ]
  • [ 4518-10-9 ]
YieldReaction ConditionsOperation in experiment
75% With trimethylsilylazide; copper; ethanolamine; In N,N-dimethyl acetamide; at 95℃; for 24h;Inert atmosphere; General procedure: A mixture of copper powder (63.5 mg, 1.00 mmol), the aryl halide (500 μmol), 2-aminoethanol (74.9 μL, 1.25 mmol), and TMSN3 (133 μL, 1.00 mmol) in DMA (1 mL) in a 15 mL test tube was stirred under an Ar atmosphere (balloon) at 95 C using a Chemistation personal organic synthesizer (EYELA, Tokyo). After complete consumption of the aryl halide was confirmed by TLC analyses or after 24 h (if the reaction was incomplete within 24 h), the mixture was diluted with EtOAc (10 mL) and then filtered through a Celite pad. The pad was successively washed with EtOAc (20 mL), H2O (25 mL), and concd aq ammonia solution (5 mL). After the two layers were separated, the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography with n-hexane/EtOAc or n-pentane/Et2O as the eluent.
  • 37
  • [ 618-89-3 ]
  • cis-benzyl N-[3-methoxypiperidin-4-yl]carbamate [ No CAS ]
  • methyl cis-(+/-)-3-(4-[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate [ No CAS ]
YieldReaction ConditionsOperation in experiment
39% With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; N,N-dimethyl-formamide; at 100℃; for 17h; (42a) Methyl cis(+/-)-3-(4-[(benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)benzoate Benzyl cis(+/-)-4-(3-methoxypiperidin-4-yl)-carbamate obtained by the method described in Example (40b) (0.5 g, 1.89 mmol) was dissolved in dioxane (20 ml) and DMF (6 mL). Methyl 3-bromobenzoate (0.35 g, 1.63 mmol), palladium acetate (39 mg, 0.17 mmol), BINAP (214 mg, 0.34 mmol) and cesium carbonate (1.35 g, 4.14 mmol) were added, and the mixture was stirred at 100C for 17 hours. Aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Thereafter, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate = 90/10, 80/20, 0/100) to obtain 250.9 mg of the title compound as a yellow oily substance (39%). 1H NMR spectrum (400 MHz, CDCl3) δ ppm: 1.85-1.89 (1H, m), 2.01-2.13 (1H, m), 2.88-2.92 (2H, m), 3.41 (3H, s), 3.51 (1H, br s), 3.60-3.71 (1H, m), 3.85-3.89 (2H, m), 3.90 (3H, s), 5.12 (2H, s), 5.26-5.30 (1H, m), 7.12 (1H, dd, J = 8.02, 2.52 Hz), 7.25-7.40 (6H, m), 7.48-7.52 (1H, m), 7.59-7.63 (1H, m).
  • 38
  • [ 618-89-3 ]
  • [ 99-76-3 ]
  • [ 74302-27-5 ]
YieldReaction ConditionsOperation in experiment
With N,N-dimethylammonium chloride; caesium carbonate;copper(l) iodide; In 1,4-dioxane; at 90℃; for 15h;Sealed tube; Exam le OL-4Example OL-4, step aMethyl 3-bromobenzoate (5 g, 23.2 mmol), methyl 4-hydroxybenzoate (5.3 g, 34.87 mmol), cesium carbonate (15.12 g, 46.4 mmol), copper (I) iodide (0.44 g, 2.32 mmol) and Ν,Ν-dimethyl hydrochloride (0.97 g, 6.96 mmol) were combined in dioxane (100 ml) in a sealed tube and the resulting mixture was heated to 90 C for 15 h. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate/water (1 : 1, 200 mL). The organic layer was washed with saturated aq. sodium carbonate, water and brine, dried (MgSC^), filtered and concentrated in vacuo. The resulting material was purified by flash chromatography (silica gel, 5% ethyl acetate/hexanes) to provide OL-4a as a clear oil that solidified upon standing (5.8 g). ¾ NMR (500 MHz, DMSO-d6) δ ppm 3.83 (s, 6 H), 7.10 (d, J=8.55 Hz, 2 H), 7.43 (dd, J=8.09, 2.59 Hz, 1 H), 7.56 (s, 1 H), 7.61 (t, J=7.93 Hz, 1 H), 7.81 (d, J=7.63 Hz, 1 H), 7.98 (d, J=8.55 Hz, 2 H). LC (Cond. 2): RT = 1.53 minutes;LCMS: Anal. Calcd. for (M+l)+ Ci6H1505: 287.01; found: 287.23.
With caesium carbonate;copper(l) iodide; In 1,4-dioxane; at 90℃; for 15h;Sealed tube; Example OL-4; Methyl 3-bromobenzoate (5 g, 23.2 mmol), methyl 4-hydroxybenzoate (5.3 g, 34.87 mmol), cesium carbonate (15.12 g, 46.4 mmol), copper (I) iodide (0.44 g, 2.32 mmol) and N,N-dimethyl hydrochloride (0.97 g, 6.96 mmol) were combined in dioxane (100 ml) in a sealed tube and the resulting mixture was heated to 90 0C for 15 h. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate/water (1 :1, 200 niL), The organic layer was washed with saturated aq. sodium carbonate, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The resulting material was purified by flash chromatography (silica gel, 5% ethyl acetate/hexanes) to provide OL-4a as a clear oil that solidified upon standing (5.8 g). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.83 (s, 6 H), 7.10 (d, J=8.55 Hz, 2 H), 7.43 (dd, J=8.09, 2.59 Hz, 1 H)5 7.56 (s, 1 H), 7.61 (t, J-7.93 Hz5 1 H), 7.81 (d, J=7.63 Hz, 1 H)5 7.98 (d, J=8.55 Hz, 2 H). LC (Cond. 2): RT = 1.53 minutes; LCMS: Anal. Calcd. for (MH-I)+Ci6H15O5: 287.01; found: 287.23.
  • 39
  • [ 618-89-3 ]
  • [ 1569-16-0 ]
  • [ 1256347-57-5 ]
  • 40
  • [ 455-14-1 ]
  • [ 618-89-3 ]
  • [ 1284180-25-1 ]
YieldReaction ConditionsOperation in experiment
86% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃;Inert atmosphere; To a solution of bromide (or triflate) (1 equiv) in toluene (0.1 M) was added aniline (1.2 equiv), Cs2CO3 (1.4 equiv) BINAP (0.08 equiv), and Pd(OAc)2 (0.05 equiv) at room temperature. The reaction mixture was allowed to stir at 120 C for 4-48 h. Once the reaction appeared to be complete by consumption of the bromide (or triflate) by TLC analysis, the mixture was allowed to cool to room temperature, diluted with EtOAc, washed with 2M aq HCl (2x), brine, and dried over sodium sulfate. The solution was concentrated, loaded on silica gel, and purified by silica gel chromatography.
  • 41
  • [ 618-89-3 ]
  • [ 769-92-6 ]
  • [ 1284180-29-5 ]
YieldReaction ConditionsOperation in experiment
81% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃;Inert atmosphere; To a solution of bromide (or triflate) (1 equiv) in toluene (0.1 M) was added aniline (1.2 equiv), Cs2CO3 (1.4 equiv) BINAP (0.08 equiv), and Pd(OAc)2 (0.05 equiv) at room temperature. The reaction mixture was allowed to stir at 120 C for 4-48 h. Once the reaction appeared to be complete by consumption of the bromide (or triflate) by TLC analysis, the mixture was allowed to cool to room temperature, diluted with EtOAc, washed with 2M aq HCl (2x), brine, and dried over sodium sulfate. The solution was concentrated, loaded on silica gel, and purified by silica gel chromatography.
  • 42
  • [ 618-89-3 ]
  • [ 106-49-0 ]
  • 3-[N-(4-methylphenyl)amino]benzoic acid methyl ester [ No CAS ]
YieldReaction ConditionsOperation in experiment
69% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃;Inert atmosphere; To a solution of bromide (or triflate) (1 equiv) in toluene (0.1 M) was added aniline (1.2 equiv), Cs2CO3 (1.4 equiv) BINAP (0.08 equiv), and Pd(OAc)2 (0.05 equiv) at room temperature. The reaction mixture was allowed to stir at 120 C for 4-48 h. Once the reaction appeared to be complete by consumption of the bromide (or triflate) by TLC analysis, the mixture was allowed to cool to room temperature, diluted with EtOAc, washed with 2M aq HCl (2x), brine, and dried over sodium sulfate. The solution was concentrated, loaded on silica gel, and purified by silica gel chromatography.
  • 43
  • [ 618-89-3 ]
  • [ 106-47-8 ]
  • [ 1055975-68-2 ]
YieldReaction ConditionsOperation in experiment
52% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃;Inert atmosphere; To a solution of bromide (or triflate) (1 equiv) in toluene (0.1 M) was added aniline (1.2 equiv), Cs2CO3 (1.4 equiv) BINAP (0.08 equiv), and Pd(OAc)2 (0.05 equiv) at room temperature. The reaction mixture was allowed to stir at 120 C for 4-48 h. Once the reaction appeared to be complete by consumption of the bromide (or triflate) by TLC analysis, the mixture was allowed to cool to room temperature, diluted with EtOAc, washed with 2M aq HCl (2x), brine, and dried over sodium sulfate. The solution was concentrated, loaded on silica gel, and purified by silica gel chromatography.
  • 44
  • [ 618-89-3 ]
  • [ 99-92-3 ]
  • [ 1284180-24-0 ]
YieldReaction ConditionsOperation in experiment
84% With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 120℃;Inert atmosphere; To a solution of bromide (or triflate) (1 equiv) in toluene (0.1 M) was added aniline (1.2 equiv), Cs2CO3 (1.4 equiv) BINAP (0.08 equiv), and Pd(OAc)2 (0.05 equiv) at room temperature. The reaction mixture was allowed to stir at 120 C for 4-48 h. Once the reaction appeared to be complete by consumption of the bromide (or triflate) by TLC analysis, the mixture was allowed to cool to room temperature, diluted with EtOAc, washed with 2M aq HCl (2x), brine, and dried over sodium sulfate. The solution was concentrated, loaded on silica gel, and purified by silica gel chromatography.
  • 45
  • [ 618-89-3 ]
  • potassium ferrocyanide [ No CAS ]
  • [ 13531-48-1 ]
  • 46
  • [ 1001-26-9 ]
  • [ 618-89-3 ]
  • [ 1491168-33-2 ]
YieldReaction ConditionsOperation in experiment
71% With bis(tri-t-butylphosphine)palladium(0); dicyclohexylmethylamine; lithium chloride; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere; General procedure: A flask containing LiCl (980 mg,23.1 mmol), 2-bromo-4-fluoroanisole (1.0 mL, 7.7 mmol), DCMA (1.8 mL,8.4 mmol) and <strong>[1001-26-9]ethyl 3-ethoxyacrylate</strong> (3.3 mL, 23 mmol) in 1,4-dioxane(20 mL) was degassed by passing a stream of nitrogen through the mixturefor 10 min. Bis(tri-t-butylphosphine) palladium(0) (166 mg, 0.32 mmol) wasadded, and reaction mixture was heated at reflux under nitrogen for 16 h. Thebrown mixture was then cooled and partitioned between ethyl acetate andwater. The layers were separated, and the organic layer was washedsequentially with aqueous NH4Cl and brine, followed by drying over Na2SO4.The mixture was filtered, and the filtrate was concentrated under reducedpressure to give an oil which was purified by flash chromatography on silica(40 g, 10?50percent ethyl acetate in heptane) to afford 22c as an orange oil (1.93 g,92percent) as an inseparable mixture of E- and Z-isomers: 1H NMR (CDCl3, 500 MHz)alkene protons d: 5.21, 5.33 ppm (1:1 ratio); LCMS (ES): 269.2 (MH). HRMSCalcd for C14H17FO: 269.1184. Found: 269.1196.
  • 47
  • [ 1001-26-9 ]
  • [ 618-89-3 ]
  • 3-(3-methoxycarbonylphenyl)-3-oxopropanoic Acid Ethyl Ester [ No CAS ]
  • 48
  • [ 253-66-7 ]
  • [ 618-89-3 ]
  • [ 1562366-98-6 ]
  • 49
  • [ 618-89-3 ]
  • [ 10601-99-7 ]
  • 50
  • [ 618-89-3 ]
  • [ 197223-39-5 ]
  • methyl 3',5'-di-t-butylbiphenyl-3-carboxylate [ No CAS ]
  • 51
  • [ 618-89-3 ]
  • [ 75-86-5 ]
  • [ 13531-48-1 ]
  • 52
  • [ 568577-88-8 ]
  • [ 618-89-3 ]
  • methyl 4'-(morpholin-4-yl)biphenyl-3-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃; To a solution of methyl 3-bromobenzoate (31; 500 mg, 2.33 mmol) in DME (5.0 mL)/water (2.0 mL) were added 15 (700 mg, 2.42 mmol), Na2CO3 (739 mg, 6.98 mmol), and Pd(PPh3)4(80 mg, 0.069 mmol). The mixture was stirred at 80 C overnight. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with saturated NaHCO3 aqueous solution and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH) to afford methyl 4'-(morpholin-4-yl)biphenyl-3-carboxylate (531 mg, 77%). To a solution of methyl 4'-(morpholin-4-yl)biphenyl-3-carboxylate (531 mg, 1.79 mmol) in EtOH (10 mL) was added 1M NaOH aqueous solution (5.00 mL, 5.00 mmol). The mixture was stirred at 60 C for 3 h. After being cooled to room temperature, the mixture was neutralized with 1M HCl aqueous solution. The resulting precipitate was filtered to give the product (470 mg, 93%) as a solid.
  • 53
  • [ 557-21-1 ]
  • [ 618-89-3 ]
  • [ 13531-48-1 ]
  • 54
  • potassium hexacyanoferrate(II) trihydrate [ No CAS ]
  • [ 618-89-3 ]
  • [ 13531-48-1 ]
  • 55
  • [ 618-89-3 ]
  • [ 4385-77-7 ]
 

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