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Structure of 145742-50-3

Chemical Structure| 145742-50-3

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Product Details of [ 145742-50-3 ]

CAS No. :145742-50-3
Formula : C8H8ClNO2
M.W : 185.61
SMILES Code : O=CC1=CC(Cl)=C(N)C=C1OC
MDL No. :MFCD24645097
InChI Key :FRPLOCDKNDMVOD-UHFFFAOYSA-N
Pubchem ID :53646819

Safety of [ 145742-50-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 145742-50-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 47.74
TPSA ?

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

52.32 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.63
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

1.3
Log Po/w (WLOGP)?

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

1.75
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.

1.09
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

1.9
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.54

Water Solubility

Log S (ESOL):?

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

-2.05
Solubility 1.66 mg/ml ; 0.00896 mol/l
Class?

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

Soluble
Log S (Ali)?

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

-2.0
Solubility 1.86 mg/ml ; 0.01 mol/l
Class?

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

Very soluble
Log S (SILICOS-IT)?

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

-2.73
Solubility 0.344 mg/ml ; 0.00185 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.

-6.51 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.

0.55

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

2.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<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 [ 145742-50-3 ]

* 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 [ 145742-50-3 ]

[ 145742-50-3 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 2401-24-3 ]
  • [ 145742-50-3 ]
  • 2
  • 4-bromo-2-chloro-5-methoxyphenylamine [ No CAS ]
  • [ 68-12-2 ]
  • [ 145742-50-3 ]
YieldReaction ConditionsOperation in experiment
80% Step B: Preparation of 4-Amino-5-chloro-2-methoxybenzaldehydeIsopropylmagnesium chloride (2M in tetrahydrofuran, 23 ml, 46 mmol) (commercially available, for example, from Aldrich) was added over 5 minutes to a stirred solution of 4-bromo-2-chloro-5-methoxyaniline (Step A) (10 g, 42 mmol) in tetrahydrofuran (70 ml) at -10 C. The resulting solution was allowed to warm to 0 C. over 50 minutes to give a thick slurry, then cooled to -25 C. and n-butyllithium (1.6M in hexanes, 90 ml, 144 mmol) was added over 20 minutes followed by tetrahydrofuran (20 ml). The solution was warmed to -10 C. over 30 minutes and then N,N-dimethylformamide (16 ml, 207 mmol) was added over 5 minutes and the resulting thick slurry was warmed to 0 C. over 20 minutes. A solution of citric acid (22 g, 105 mmol) in water (50 ml) was added cautiously over 15 minutes keeping reaction at <10 C. The slurry was aged at 20 C. for 30 minutes then filtered under vacuum. The cake was washed with water (100 ml) and then dried under vacuum at 40 C. for 16 hours to give 4-amino-5-chloro-2-methoxybenzaldehyde (6.1 g, 80% th) as a pale yellow solid.1H NMR (400 MHz, DMSO-d6) deltaH (ppm) 9.95 (1H, s), 7.49 (1H, s), 6.50-6.57 (2H, br s), 6.44 (1H, s), 3.81 (3H, s)m/z (ES+) 186 (M+H)
  • 3
  • [ 145742-50-3 ]
  • [ 625-36-5 ]
  • [ 1251456-89-9 ]
YieldReaction ConditionsOperation in experiment
at 20℃; for 2.5h; Preparation 23-Chloropropionyl chloride (98.4 ml, 1.0 mol) was added over 30 minutes to a stirred suspension of <strong>[145742-50-3]4-amino-5-chloro-2-methoxybenzaldehyde</strong> (47.4 g, 0.26 mol) ensuring the reaction temperature did not exceed 20 C. After the addition was complete the reaction was stirred at 20 C. for a further 2 hours and then filtered. The filtrate was concentrated to 150 ml under reduced pressure and then diluted with ethyl acetate (100 ml) and water (400 ml). The mixture was stirred at 20 C. for 1 hour and then filtered to give 3-chloro-N-[2-chloro-4-formyl-5-(methyloxy)phenyl]propanamide as an off-white solid which was not isolated but suspended in tetrahydrofuran (730 ml) and treated with diisopropylethylamine (154 ml, 0.88 mol). The resulting mixture was stirred at 45 C. for 46 hours and then concentrated under reduced pressure to leave a residue which was diluted with ethyl acetate (300 ml), washed with 2M hydrochloric acid (4×100 ml) and concentrated under reduced pressure to give N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (37.8 g, 62%).1H NMR (400 MHz, CDCl3) deltaH (ppm) 10.31 (1H, s), 8.43 (1H, s), 8.02 (1H, br s), 7.82 (1H, s), 6.47-6.53 (1H, dd), 6.28-6.38 (1H, dd), 5.88-5.93 (1H, dd), 3.96 (3H, s)m/z (ES+) 240 (M+H)
  • 4
  • [ 145742-50-3 ]
  • [ 79-10-7 ]
  • [ 1251456-87-7 ]
YieldReaction ConditionsOperation in experiment
71% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 25 - 40℃; for 1.5h; Step C: Preparation of N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamidePreparation 1Acrylic acid (commercially available, for example, from Aldrich) (46 ml, 0.67 mol) was added slowly to a stirred suspension of <strong>[145742-50-3]4-amino-5-chloro-2-methoxybenzaldehyde</strong> (Step B) (50.0 g, 0.27 mol) and triethylamine (204 g, 2.02 mol) in ethyl acetate (0.85 L) at 25 C. Propanephosphonic anhydride (50% in ethyl acetate; 429 g, 0.67 mol) was added over 30 minutes keeping reaction temperature at 30-40 C. The mixture was stirred at 30-40 C. for a further 1 hour and then cooled to 25 C. and diluted with water (0.26 L) and acidified with 32% hydrochloric acid (108 g) to pH 2-3. The organic layer was separated and washed with a mixture of water (0.23 L) and 32% sodium hydroxide (14 g)-aqueous layer ca. pH 7. The organic phase was washed with water (0.23 L) and then concentrated under reduced pressure (ca. 300 mbar) to remove 0.56 kg of distillate. Methylcyclohexane (335 g) was added and then a further 286 g of distillate was removed under reduced pressure. Methylcyclohexane (111 g) was added and then the resulting suspension was cooled to 20 C., filtered and washed with methylcyclohexane. The cake was dried at 40 C. under reduced pressure for 12 hours to give N-[2-chloro-4-formyl-5-(methyloxy)phenyl]-2-propenamide (46 g, 71%)
  • 5
  • [ 145742-50-3 ]
  • [ 743461-63-4 ]
  • 6
  • [ 145742-50-3 ]
  • [ 1251456-87-7 ]
  • 7
  • [ 32315-10-9 ]
  • [ 145742-50-3 ]
  • [ 138108-72-2 ]
  • tert-butyl (3R)-3-[(2-chloro-4-formyl-5-methoxyphenyl)carbamoyloxymethyl]pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
<strong>[145742-50-3]4-amino-5-chloro-2-methoxybenzaldehyde</strong> (3a) (462 mg, 2.49 mmol) was dissolved in 49 toluene (15 ml), 50 triethylamine (630 mg, 6.22 mmol) was added thereto, and then 51 triphosgene (554 mg, 1.87 mmol) was added under N2 protection, followed by a reaction at 120C for 1 hour. After cooling to room temperature, Reaction Solution 1 was obtained. 44 Tert-butyl (3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (4B) (500 mg, 2.49 mmol) was dissolved in 13 tetrahydrofuran (15 ml), to which triethylamine (630 mg, 6.22 mmol) and then Reaction Solution 1 were added, followed by a reaction at 85C for 3 hours. The reaction solution was cooled to room temperature, and water (50 ml) was added thereto, which was extracted with ethyl acetate (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to obtain 46 tert-butyl (3R)-3-[(2-chloro-4-formyl-5-methoxy-phenyl)carbamoyloxymethyl] pyrrolidine-1-carboxylate (4C) as a brown liquid, which was directly used in the next step without purification. LCMS m/z =451.4[M+39].
  • 8
  • [ 32315-10-9 ]
  • [ 145742-50-3 ]
  • [ 123855-51-6 ]
  • tert-butyl 4-[(2-chloro-4-formyl-5-methoxyphenyl)carbamoyloxymethyl]piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
74% <strong>[145742-50-3]4-amino-5-chloro-2-methoxybenzaldehyde</strong> (3a) (6.9 g, 37.2 mmol) was dissolved in toluene (100 ml), to which triphosgene (5.51 g, 18.6 mmol) was added, followed by a reaction at 120C for 2 hours, and the resultant was concentrated to obtain Reaction solution 1. Tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2a) (2.00 g, 9.29 mmol) was dissolved in tetrahydrofuran (50 ml), to which Reaction solution 1 and then triethylamine (3.76 g, 37.2 mmol) were added, followed by a reaction at 70C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v) = 1:9 to 3:7) to give yellow oily tert-butyl 4-[(2-chloro-4-formyl-5-methoxy-phenyl)carbamoyloxymethyl]piperidine-1-carboxyl ate (3b) (2.2 g, yield: 74%). 1H NMR (400 MHz, CDCl3) delta 10.29 (s, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 7.41 (s, 1H), 4.16 (d, 2H), 4.09 (d, 2H), 3.95 (s, 3H), 2.73 (m, 2H), 1.96 - 1.83 (m, 1H), 1.75 (d, 2H), 1.46 (s, 9H), 1.32 - 1.18 (m, 2H). LCMS m/z =449.3 [M+23].
  • 9
  • [ 145742-50-3 ]
  • 4-piperidylmethyl N-(2-chloro-4-formyl-5-methoxyphenyl)carbamate [ No CAS ]
  • 10
  • [ 145742-50-3 ]
  • [1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-(2-chloro-4-formyl-5-methoxyphenyl)carbamate [ No CAS ]
  • 11
  • [ 145742-50-3 ]
  • [1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[4-[[[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)et hyl]amino]methyl]-2-chloro-5-methoxyphenyl]carbamate [ No CAS ]
  • 12
  • [ 145742-50-3 ]
  • [1-[3-[4-[(2-phenylphenyl)carbamoyloxy]-1-piperidyl]propanoyl]-4-piperidyl]methyl N-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino] methyl]-5-methoxyphenyl]carbamate bis(trifluoroacetate) [ No CAS ]
  • 13
  • [ 32315-10-9 ]
  • [ 145742-50-3 ]
  • [ 199174-24-8 ]
  • tert-butyl (3S)-3-[(2-chloro-4-formyl-5-methoxyphenyl)carbamoyloxymethyl]pyrrolidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
4-amino-5-chloro-2-methoxybenzaldehyde (3a) (1.38 g, 7.45 mmol) was dissolved in 49 toluene (15 ml), 50 triethylamine (0.75 g, 7.45 mmol) was added thereto, and then 51 bis(trichloromethyl)carbonate (1.1 mg, 3.72 mmol) was added under N2 protection, followed by a reaction at 120C for 1 hour. A reaction solution was obtained after cooling to room temperature. 69 Tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (5B) (0.6 g, 2.98 mmol) was dissolved in 13 tetrahydrofuran (15 ml), to which triethylamine (0.75 g, 7.45 mmol) and the reaction solution were added, followed by a reaction at 85C for 3 hours. The reaction solution was cooled to room temperature, and water (50 ml) was added thereto, which was extracted with ethyl acetate (100 mL×2).The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, to obtain 74 tert-butyl (3S)-3-[(2-chloro-4-formyl-5-methoxy-phenyl)carbamoyloxymethyl]pyrrolidine-1-car boxylate (5C) as a brown liquid, which was directly used in the next step.
  • 14
  • [ 32315-10-9 ]
  • [ 145742-50-3 ]
  • [(3aR,5s,6aS)-2-(2-hydroxyethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]-2-hydroxy-2,2-diphenylacetate [ No CAS ]
  • [(3aR,5s,6aS)-2-[2-[(2-chloro-4-formyl-5-methoxyphenyl)carbamoyloxy]ethyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-yl]-2-hydroxy-2,2-diphenylacetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
84.3% 4-Amino-5-chloro-2-methoxy-benzaldehyde (0.464 g, 2.50 mmol) and bis(trichloromethyl)carbonate (0.475 g, 1.60 mmol) were added to 1,4-dioxane. (20mL),The reaction was refluxed at 100 C for 3 hours.The solvent was removed under reduced pressure.The residue and 14A (0.381 g, 1.00 mmol) were added to THF (15 mL).Add triethylamine (0.253 g, 2.50 mmol),The reaction was refluxed for 2 hours.Cool to room temperature,The solvent was removed under reduced pressure.The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 30:1).14B (0.500 g, yield 84.3%) was obtained as a yellow liquid.
 

Historical Records

Technical Information

• Alkyl Halide Occurrence • Barbier Coupling Reaction • Baylis-Hillman Reaction • Bucherer-Bergs Reaction • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Chan-Lam Coupling Reaction • Clemmensen Reduction • Complex Metal Hydride Reductions • Corey-Chaykovsky Reaction • Corey-Fuchs Reaction • Fischer Indole Synthesis • General Reactivity • Grignard Reaction • Hantzsch Dihydropyridine Synthesis • Henry Nitroaldol Reaction • Hiyama Cross-Coupling Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Julia-Kocienski Olefination • Kinetics of Alkyl Halides • Knoevenagel Condensation • Kumada Cross-Coupling Reaction • Leuckart-Wallach Reaction • Mannich Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Mukaiyama Aldol Reaction • Nomenclature of Ethers • Nozaki-Hiyama-Kishi Reaction • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Amines • Preparation of Ethers • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Ethers • Reformatsky Reaction • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Vilsmeier Reagent • Stetter Reaction • Stille Coupling • Stobbe Condensation • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling • Tebbe Olefination • Ugi Reaction • Wittig Reaction • Wolff-Kishner Reduction

Categories

Related Functional Groups of
[ 145742-50-3 ]

Aryls

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Chlorides

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Aldehydes

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Ethers

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