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Chemical Structure| 74-11-3 Chemical Structure| 74-11-3

Structure of 4-Chlorobenzoic acid
CAS No.: 74-11-3

Chemical Structure| 74-11-3

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Product Citations

Product Citations

Eduardo Ramirez ;

Abstract: Alzheimer’s (AD) and Parkinson’s (PD) are the most common debilitating disorders to affect the geriatric population. There are two pathological hallmarks which correlate with the manifestation of AD: the first is the formation amyloid-β plaques (Aβ plaques) in the extracellular space and the second is the aggregation of hyperphosphorylated tau protein (p-tau) which develops into neurofibrillary tangles (NFTs) in the interneuron. PD results from the misfolding of α-synuclein (α-syn) which then aggregates to form Lewy bodies. In over 50% of AD cases aggregated α-syn_x005f_x0002_containing Lewy bodies are presently displayed. My research projects focus on the dual targeting of small molecules to abrogate aberrant α-syn, tau (2N4R), and p-tau (1N4R) aggregation and to reduce the spread of AD and related dementias. Not very many drug discovery programs focus on the specific isoforms of the tau protein. We set out to establish two series of aminoindole compounds connected by a carboxamide or triazine linker to evaluate the effectiveness of both families in decreasing the amount of misfolded α-syn and tau protein. Biophysical methods such as thioflavin T (ThT) fluorescence assays, photoinduced cross-linking of unmodified proteins (PICUP), and transmission electron microscopy (TEM) were deployed to assess the anti_x005f_x0002_aggregation potential of our aminoindole derivatives. M17D intracellular inclusion assay was used to detect the potency of our best compounds in reducing α-syn inclusions. We found that compounds A2, A8, and A17 from the amide series and compound T10 from the triazine series were effective in reducing the formation of α-syn and tau isoform 2N4R fibrils and oligomers in a dose-dependent manner. This was observed through the use of ThT fluorescence and PICUP assays and was validated with TEM. These same compounds reduced the development of α-syn inclusions in M17D neuroblastoma cells. Compounds A8 of the amide project and T10 of the triazine series were the most effective in preventing α-syn and tau isoform 2N4R aggregation. Compound T10 also showed reduction of ex vivo Aβ plaques and paired helical filaments (PHFs) in the brain tissue of a deceased AD patient showcasing its translational potential. These results demonstrate the potential of 4-aminoindole derivatives in preventing the aggregation α-syn and tau (2N4R isoform) proteins. The triazine derivatives series demonstrates the effectiveness of N_x005f_x0002_linked triazines in reducing misfolding of α-syn and tau in contrast to O-linked triazines and display the importance of symmetry in drug design.

Keywords: Alzheimer's disease ; Amide ; alpha-synuclein (synuclein alpha) ; fibril oligomer ; tau isoform 2n4r ; anti-aggregation compounds ; hyperphosphorylated protein tau ; paired helical filaments ; drug discovery ; triazine compound

Purchased from AmBeed: ; ; ;

Alternative Products

Product Details of [ 74-11-3 ]

CAS No. :74-11-3
Formula : C7H5ClO2
M.W : 156.57
SMILES Code : O=C(O)C1=CC=C(Cl)C=C1
MDL No. :MFCD00002531
InChI Key :XRHGYUZYPHTUJZ-UHFFFAOYSA-N
Pubchem ID :6318

Safety of [ 74-11-3 ]

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

Computational Chemistry of [ 74-11-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 10
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 38.41
TPSA ?

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

37.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.44
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

2.65
Log Po/w (WLOGP)?

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

2.04
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.

2.2
Log Po/w (SILICOS-IT)?

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

1.86
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.04

Water Solubility

Log S (ESOL):?

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

-2.86
Solubility 0.217 mg/ml ; 0.00139 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.

-3.08
Solubility 0.129 mg/ml ; 0.000823 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

-2.37
Solubility 0.663 mg/ml ; 0.00424 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

No
CYP2C19 inhibitor?

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

No
CYP2C9 inhibitor?

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

No
CYP2D6 inhibitor?

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

No
CYP3A4 inhibitor?

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

No
Log Kp (skin permeation)?

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

-5.37 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

1.0
Bioavailability Score?

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

0.56

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)

1.0

Application In Synthesis of [ 74-11-3 ]

* 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 [ 74-11-3 ]

[ 74-11-3 ] Synthesis Path-Downstream   1~29

  • 1
  • [ 95-54-5 ]
  • [ 74-11-3 ]
  • [ 1019-85-8 ]
YieldReaction ConditionsOperation in experiment
95% With polyphosphoric acid; at 140℃; for 4h; General procedure: 2.0 g (18.5 mmol) of 1,2-phenylenediamine and 3.2 g (20.4 mmol) of 4-chlorobenzoic acid were added to 20 g polyphosphoric acid (PPA) and mixed homogeneously. The reaction mixture was heated at 140 oC for 4 h. Then the reaction mixture was cooled to room temperature and neutralized with 5N NaOH. The resulting solid was filtered, washed with water and dried in vacuo. The title compound was obtained by recrystallization using ethanol. (4.0g, 95%)1H NMR (300 MHz, DMSO-d6) δ 12.98 (br s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.60-7.65 (m, 4H), 7.20-7.25 (m, 2H): MS(m/e, M+): 228
93% With diphosphorus tetraiodide; In acetonitrile; at 80℃;Sealed tube; Inert atmosphere; General procedure: To amixture of ortho-substituted (-NH 2 or -SH or -OH) anilines(1 mmol) and aryl acids (1 mmol) in acetonitrile (2 mL) in asealed tube (10 mL) was added diphosphorus tetraiodide (0.2mmol) under nitrogen atmosphere. Then, the tube was cappedand the mixture heated in an oil bath at 80 C with stirringuntil the reaction was complete as monitored by TLC. Afterbeing cooled to room temperature, the reaction was quenchedwith aqueous NaHCO 3 solution and extracted with ethyl acetatethree times. The combined organic layer was washed withwater and brine and then dried over anhydrous Na 2 SO 4 . Thesolvent was removed under reduced pressure and the residuewas purified by chromatography on silica gel, eluting withpetroleum ether/ethyl acetate, to afford the correspondingproduct. The products obtained were known compounds andwere identified by melting point and 1 H NMR spectroscopy.The spectral data were compared with the literature values.2-Phenyl-1H-benzimidazole (Table-2, entry 1): m.p.:290-293 C (Lit. [21] 292-294 C); IR (KBr, ν max , cm -1 ): 3450,3045, 1620, 1580, 1458; 1 H NMR (400 MHz, DMSO-d 6 ): δ7.08-7.14 (m, 2H), 7.31-7.5 (m, 5H), 7.96 (d, 2H), 12.80 (s,1H); 13 C NMR (DMSO-d 6 , TMS): δ 116.5, 123.1, 127.4, 128.6,129.5, 130.7, 139.0, 152.7; MS (ESI) m/z: [M+H] + 195.1.
90% With Amberlyst-15; In water; at 90℃; for 1h;Irradiation; General procedure: To a solution of o-phenylenediamine 1a, o-amino phenol 1b or o-amino thiophenol 1c (1.0 mmol) and aromatic acid (2, 1.2 mmol) in water (5 mL) was added Amberlyst-15 (10%, w/w) and the mixture was irradiated with ultrasound (40 KHz) continuously at 90 C till the completion of the reaction(monitored by TLC) as indicated in Table 3. The solid separated was filtered, washed with diethyl ether (2 x 5 mL), dried and treated with EtOAc (15 mL). After stirring for 10 min the mixture was filtered to remove the insoluble catalyst. The filtrate was collected and concentrated under vacuum. The solid obtained was purified by recrystallization (column chromatography infew cases) to afford the desired products 3, 4 or 5.
77% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 160℃; for 0.5h;Microwave irradiation; Sealed tube; General procedure: A mixture of o-phenylenediamine (1 mmol), carboxylic acid (1 mmol), N,N-diisopropylethylamine (1.5 mmol) and propylphosphonic anhydride (1 mmol, 50% w/w in AcOEt) was irradiated for 30 min under microwave at 160 C in a sealed tube. It was diluted with H2O, followed by alkalinization with saturated aqueous NaHCO3 solution. The precipitate was collected by filtration and washed thoroughly with H2O to afford the respective benzimidazole. If necessary, simple recrystallization was carried out in EtOH/H2O.
65% With boric acid; In 5,5-dimethyl-1,3-cyclohexadiene; for 16h;Reflux; General procedure: To a stirred solution of benzene-1,2-diamine 1 (1.85 mmol)in xylenes (10 mL) were added carboxylic acid 2 (2.77 mmol)and boric acid (0.185 mmol). The resulting solution wasrefluxed for 16 h. After cooling to room temperature, the reactionwas concentrated under reduced pressure and diluted withEtOAc (50 mL). The organic phase was washed with saturatedNaHCO3 solution (2 50 mL), dried over anhydrous Na2SO4and then concentrated under reduced pressure. The residuewas purified by silica gel flash column chromatography (elutingwith 10-15% Ethyl acetate in hexanes) to afford the title compounds3a-y and 5.6.2.2 2-(4-Chlorophenyl)-1H-benzo[d]imidazole (3b) Yield 65%; Off white solid; mp 289-291 C; IR (KBr) 2747, 1448, 1428, 1278, 1089, 830, 742 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 13.00 (br s, 1H), 8.16-8.22 (m, 2H), 7.60-7.71 (m, 3H), 7.50-7.58 (m, 1H), 7.17-7.28 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 150.3, 143.9, 135.1, 134.6, 129.2, 129.2, 128.3, 128.2, 128.2, 122.9, 122.0, 119.1, 111.5; HRMS calcd for C13H9ClN2 m/z 228.0534, found 228.05131.
39.6% In ethanol; at 100℃; for 8h; General procedure: All substituted benzimidazole ligands were prepared by the previously reported procedure [17]. o-Phenylenediamine (0.25 mol) and appropriate carboxylic acid (0.34 mol) was heated on an oil bath at 100 C for 8 h. The completion of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and its pH was adjusted between 7-8 using 10% NaOH solution. The crude benzimidazole was filtered and washed with ice-cold water. The crude product was dissolved in 40 mL of boiling water and 2 g of carbon was added and digested for 15 min. The solution was filtered while hot, cooled the filtrate to about 10 C. The pure product obtained was filtered, washed with 25 mL of cold water and dried (Scheme-I).
With boric acid; N,N-dimethyl-aniline; at 195 - 205℃; for 3h; BD-B; A mixture of p-chlorobenzoic acid (3.5 g), o-phenylenediamine (2.4 g), boric acid (0.15 g) and dimethylaniline (10 mL) was added to a reaction flask and heated, under a flow of nitrogen, in an oil bath at 195-205 C. for 3 hours. After cooling to room temperature, the resulting mixture was stirred with water (15 mL) and concentrated NH4OH (2 mL) and filtered. The solid product was washed with water and toluene and dried at 60-80 C. An NMR spectrum showed the product to have a structure consistent with 2-(4-chlorophenyl)benzimidazole.
With boric acid; In 2,3-Dimethylaniline; at 195 - 205℃; for 3h; A mixture of p-chlorobenzoic acid (3.5 g) , o- phenylenediamine (2.4 g) , boric acid (0.15 g) and dimethylaniline (10 mL) was added to a reaction flask and heated, under a flow of nitrogen, in an oil bath at 195-205 0C for 3 hours. After cooling to room temperature, the resulting mixture was stirred with water (15 mL) and concentrated NH4OH (2 mL) and filtered. The solid product was washed with water and toluene and dried at 60-80 0C. An NMR spectrum showed the product to have a structure consistent with 2- (4-chlorophenyl)benzimidazole

  • 4
  • [ 50-84-0 ]
  • [ 201230-82-2 ]
  • [ 89-20-3 ]
  • [ 100-21-0 ]
  • [ 528-44-9 ]
  • [ 1967-31-3 ]
  • [ 74-11-3 ]
  • 6
  • [ 7790-94-5 ]
  • [ 7726-95-6 ]
  • [ 74-11-3 ]
  • [ 42860-10-6 ]
  • 7
  • [ 74-11-3 ]
  • sodium bromide [ No CAS ]
  • sulfur [ No CAS ]
  • [ 42860-10-6 ]
  • 9
  • [ 53164-05-9 ]
  • [ 2882-15-7 ]
  • [ 53-86-1 ]
  • 5-methoxy-2-methylindol-3-yl acetic acid carboxymethyl ester [ No CAS ]
  • [ 74-11-3 ]
  • 10
  • (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine [ No CAS ]
  • [ 17794-48-8 ]
  • [ 56602-33-6 ]
  • [ 7087-68-5 ]
  • [ 74-11-3 ]
  • [ 445478-99-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; trifluoroacetic acid; In hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide; (27c) 4-Chlorobenzoic acid (258 mg) was dissolved in DMF (8 mL) prior to the addition of Hunig's base (1.0 mL). After cooling to 0 C., BOP Reagent (729 mg) was added. This was stirred for 15 min before (1S,2R)-1-(N-(t-butoxycarbonyl))-1,2-cyclopentanediamine, (27b), (300 mg) was added as a DMF solution (2 mL). The resulting mixture warmed to rt and was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. The resulting material was dissolved in CH2Cl2 (10 mL) and cooled to 0 C. TFA (1.2 mL) was added and the reaction was stirred for 2 h. This solution was concentrated prior to the addition of DMF (8 mL). After cooling to 0 C., Hunig's base (1 mL) and <strong>[17794-48-8][[3-(trifluoromethyl)benzoyl]amino]acetic acid</strong> (386 mg) were added. BOP Reagent (655 mg) was added next, and the mixture was stirred overnight. EtOAc was added along with 1 N HCl solution. The EtOAc layer was washed with 1 N HCl, NaHCO3 solution, and brine. The EtOAc was dried (MgSO4), filtered, and concentrated. This was stirred in 1:1 EtOAc/hexane and then filtered to give the title benzamide N-[2-[[(1S,2R)-2-[(4-chlorobenzoyl)amino]cyclopentyl]amino]-2-oxoethyl]-3-(trifluoromethyl)benzamide (310 mg) as a solid. MS found: (M+H)+=468.2.
  • 13
  • [ 74-11-3 ]
  • [ 20026-96-4 ]
  • 14
  • [ 2905-56-8 ]
  • [ 762-42-5 ]
  • [ 74-11-3 ]
  • [ 67483-73-2 ]
  • [ 4606-55-7 ]
YieldReaction ConditionsOperation in experiment
93% In dichloromethane; at 20℃; for 14h; General procedure: At room temperature, organic carbonyl acid 3 (R-COOH, 0.5 mmol) was added into a reaction tube equipped with a small magnet. Then a solution of tertiary amine 1 (R1CH2-NR2R3, 0.5 mmol ) in DCM (2.5 mL) was added dropwise in 2 min. After the mixture was stirred at room temperature for a few minutes, 1 equivalents of dimethyl acetylenedicarboxylate (DMAD, 2) was added. The reaction was stirred overnight at room temperature, and then monitored by TLC with silica gel coated plates. After being stirred for 14 h, the solvent was removed and the residue was purified by a flash column chromatography with silica gel with ethyl acetate/hexane (1:25-30) as eluent to give the desired products 4, 5, and 7. Most of compounds are known and confirmed by NMR, ESI-MS, IR.
  • 15
  • [ 1428774-23-5 ]
  • [ 2882-15-7 ]
  • C12H19O5P [ No CAS ]
  • [ 2504-32-7 ]
  • [ 53-86-1 ]
  • [ 74-11-3 ]
YieldReaction ConditionsOperation in experiment
With glucose-6-phosphate dehydrogenase; beta-D-glucopyranose-6-phosphate; NADP; magnesium chloride; In aq. phosphate buffer; at 37℃; for 3h;pH 7.4;Enzymatic reaction; PTI was preincubated at 37 C for 5 min with NADPH-regenerating solution (1.3 mM NADP, 3.3 mM d-glucose 6-phosphate, 3.3 mM MgCl2, and 0.4 U/ml glucose-6-phosphate dehydrogenase) in 0.1 M potassium phosphate buffer (pH 7.4). The reaction was initiated by the addition of mouse, rat and human liver microsomes (protein concentration 0.5 mg/ml) or human intestine, kidney, and lung microsomes (protein concentration 0.25 mg/ml) and samples were maintained at 37 C for various time periods. At each of the designated time-points, 0.1-ml aliquots were mixed with 0.2 ml of CH3CN, vortexed, and then centrifuged for 10 min at 13,000 × g. The supernatants were subjected to HPLC analyses. The HPLC peaks corresponding to each metabolite of PTI were collected and subjected to mass spectrometry analys
  • 16
  • [ 1428774-23-5 ]
  • [ 2882-15-7 ]
  • C12H19O5P [ No CAS ]
  • [ 1428774-26-8 ]
  • [ 1428774-24-6 ]
  • [ 2504-32-7 ]
  • [ 74-11-3 ]
YieldReaction ConditionsOperation in experiment
With glucose-6-phosphate dehydrogenase; beta-D-glucopyranose-6-phosphate; NADP; magnesium chloride; In aq. phosphate buffer; at 37℃; for 0.333333h;pH 7.4;Enzymatic reaction; PTI was preincubated at 37 C for 5 min with NADPH-regenerating solution (1.3 mM NADP, 3.3 mM d-glucose 6-phosphate, 3.3 mM MgCl2, and 0.4 U/ml glucose-6-phosphate dehydrogenase) in 0.1 M potassium phosphate buffer (pH 7.4). The reaction was initiated by the addition of mouse, rat and human liver microsomes (protein concentration 0.5 mg/ml) or human intestine, kidney, and lung microsomes (protein concentration 0.25 mg/ml) and samples were maintained at 37 C for various time periods. At each of the designated time-points, 0.1-ml aliquots were mixed with 0.2 ml of CH3CN, vortexed, and then centrifuged for 10 min at 13,000 × g. The supernatants were subjected to HPLC analyses. The HPLC peaks corresponding to each metabolite of PTI were collected and subjected to mass spectrometry analys
  • 17
  • [ 1428774-23-5 ]
  • [ 2882-15-7 ]
  • C12H19O5P [ No CAS ]
  • [ 74-11-3 ]
YieldReaction ConditionsOperation in experiment
With mouse microsomes; In aq. phosphate buffer; at 37℃; for 20h;pH 7.4;Enzymatic reaction; PTI was preincubated at 37 C for 5 min with NADPH-regenerating solution (1.3 mM NADP, 3.3 mM d-glucose 6-phosphate, 3.3 mM MgCl2, and 0.4 U/ml glucose-6-phosphate dehydrogenase) in 0.1 M potassium phosphate buffer (pH 7.4). The reaction was initiated by the addition of mouse, rat and human liver microsomes (protein concentration 0.5 mg/ml) or human intestine, kidney, and lung microsomes (protein concentration 0.25 mg/ml) and samples were maintained at 37 C for various time periods. At each of the designated time-points, 0.1-ml aliquots were mixed with 0.2 ml of CH3CN, vortexed, and then centrifuged for 10 min at 13,000 × g. The supernatants were subjected to HPLC analyses. The HPLC peaks corresponding to each metabolite of PTI were collected and subjected to mass spectrometry analys
  • 19
  • [ 621-38-5 ]
  • [ 74-11-3 ]
  • [ 1462270-89-8 ]
  • 20
  • [ 3537-14-2 ]
  • [ 74-11-3 ]
  • [ 1186224-02-1 ]
  • 21
  • [ 13139-86-1 ]
  • [ 74-11-3 ]
  • [ 725-14-4 ]
  • 22
  • [ 57297-29-7 ]
  • [ 74-11-3 ]
  • C11H11ClN2O [ No CAS ]
  • 23
  • [ 138588-22-4 ]
  • [ 74-11-3 ]
  • 4-chloro-N-[3-(2-pyridyl)-1,2,4-thiadiazol-5-yl]benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
60% With N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere; 3-Pyridm-2-yl-[l,2,4]thiadiazol-5-yIamine (50 mg, 0.28 mmol) and p-chlorobenzoic acid (44 mg, 0.28 mmol) were mixed in 1 mL of anhydrous dimethvlformamide, to which solution was added N,N-diisopropylethylamine (0.1 mL, 0.58 mmol) followed by addition of 1 - [his(dimethylammo)methylene]~ 1H- 1 ,2,3-triazolo[4,5-b]pyridinium 3 -oxide hexafluorophosphate (1 14 mg, 0.30 mmol). The mixture was stirred under nitrogen at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography to obtain Compound 7 as a white solid (53.5 mg, 60%). NMR (400 MHz, DMSO-rfe) delta ppm 7.36 - 7.64 (m, 1 H) 7.69 (d, J=8.69 Hz, 2 H) 7.91 - 8.10 (m, 1 H) 8.12 - 8.34 (m, 3 H) 8.72 (d, J=4.00 Hz, 1 H); LCMS (M/Z): M+HT' 317.
  • 24
  • [ 392331-66-7 ]
  • [ 74-11-3 ]
  • tert-butyl 4-((4-chlorobenzamido)methyl)-4-hydroxypiperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
90% With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; for 2h; A solution of tert-butyl 4-(aminomethyl)-4-hydroxypiperidine- 1 -carboxylate (0.25 g, 1.086 mmol) and 4-chlorobenzoic acid (0.204 g, 1.303 mmol) in DMF (2 mL)was treated with triethylamine (0.454 mL, 3.26 mmol) followed by BOP (0.576 g, 1.303 mmol). The reaction was stirred for 2h then quenched with dil. aq. HOAc. This resulted in the formation of a precipitate, so the mixture was filtered and rinsed with water. It was then suspended in dil. aq. sodium bicarbonate, sonicated, then filtered, rinsed with water, and air-dried to afford tert-butyl 4-((4-chlorobenzamido)methyl)-4-hydroxypiperidine- 1-carboxylate (0.38 g, 90% yield) as a colorless solid, mp 172-173 C. MS(ES): m/z = 369 [M+H]. tR = 0.93 mm (Method A).
  • 25
  • [ 124-38-9 ]
  • [ 14752-66-0 ]
  • [ 74-11-3 ]
YieldReaction ConditionsOperation in experiment
93% With copper(l) iodide; 1,10-Phenanthroline; potassium tert-butylate; In dimethyl sulfoxide; at 140℃; under 750.075 Torr; for 3h;Schlenk technique; Sealed tube; In 20 mL of dehydrated deoxygenated Schlenk tubes, <strong>[14752-66-0]sodium p-chlorobenzenesulfinate</strong> (0.2 mmol,(0.60 mmol, 3.81 mg), 1, 10-o-phenanthroline (0. 06 mmol, 10.8 mg), potassium t-butoxide (0.6 mmol) , 67.3 mg), 2.5 mL of dimethyl sulfoxide (DMS0), and finally into the reaction tube into 0.1 MPa of C02.The sealed reaction tube was placed in a 140 C oil bath and heated and stirred for about 3 hours. Use 2 mL of 1 M hydrochloric acid to dissolveThe reaction solution was acidified and the system was extracted with ethyl acetate (4 mL x 5). The organic phase was collected and finally passed through a columnThe product was purified by chromatography and then dried to give a white solid powder 29.1 mg in 93% yield.
  • 26
  • [ 35418-07-6 ]
  • [ 74-11-3 ]
  • C17H16ClNO3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
General procedure: To a solution of 3a (1 g) in ethanol was added Pd/C (5%, 0.1 g) and the mixture was stirred for 24 hrs at room temperature in a hydrogen atmosphere under atmospheric pressure. Insoluble matters were removed using Celite, and the filtrate was concentrated in vacuo to give the desired product 4a (0.76 g) as a yellow solid. To a solution of carboxylic acid (1 equiv) in CH2Cl2 (15 mL) at 0 C was added DMAP (1 equiv) and EDCI (1 equiv). The reaction mixture was stirred at 0 C for 45 minutes. At this time 4a (1 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo, partitioned between 1.0 M HCl (20 ml) and ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 × 15 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 5, v/v) as eluent to afford the product as a white solid. To a solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 2-17 as white solid.
  • 28
  • [ 3325-11-9 ]
  • [ 74-11-3 ]
  • 1-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(4-chlorophenyl)urea [ No CAS ]
  • 29
  • [ 180683-64-1 ]
  • [ 74-11-3 ]
  • C18H25ClN2O3 [ No CAS ]
 

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