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Chemical Structure| 4457-32-3 Chemical Structure| 4457-32-3

Structure of 4457-32-3

Chemical Structure| 4457-32-3

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Product Details of [ 4457-32-3 ]

CAS No. :4457-32-3
Formula : C8H6ClNO4
M.W : 215.59
SMILES Code : O=C(Cl)OCC1=CC=C([N+]([O-])=O)C=C1
MDL No. :MFCD00007375
InChI Key :MHSGOABISYIYKP-UHFFFAOYSA-N
Pubchem ID :78205

Safety of [ 4457-32-3 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H314
Precautionary Statements:P280-P305+P351+P338-P310
Class:8
UN#:3261
Packing Group:

Computational Chemistry of [ 4457-32-3 ] Show Less

Physicochemical Properties

Num. heavy atoms 14
Num. arom. heavy atoms 6
Fraction Csp3 0.12
Num. rotatable bonds 4
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 51.51
TPSA ?

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

72.12 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.8
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

2.79
Log Po/w (WLOGP)?

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

2.32
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.89
Log Po/w (SILICOS-IT)?

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

0.09
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.58

Water Solubility

Log S (ESOL):?

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

-2.99
Solubility 0.222 mg/ml ; 0.00103 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.

-3.96
Solubility 0.0236 mg/ml ; 0.000109 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

-2.5
Solubility 0.69 mg/ml ; 0.0032 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

Yes
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.

-5.63 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

3.0 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)

1.71

Application In Synthesis of [ 4457-32-3 ]

* 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 [ 4457-32-3 ]

[ 4457-32-3 ] Synthesis Path-Downstream   1~13

  • 1
  • [ 51-35-4 ]
  • [ 4457-32-3 ]
  • [ 96034-57-0 ]
YieldReaction ConditionsOperation in experiment
93% Example 4: Synthesis of (4R,5S,6S)- 3-[[(3S,5S)-5-[(dimethylamino)carbonyl]-3-ρyrrolidinyl]thio]-6-[(lR)-l-hydroxyethyl]-4-methyl- 7-oxo-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid (I)Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-thio-l-PNZ-pyrrolindine (XX)L-hydoxyproline (XXVI) (26.2 g, 0.20 mol) was added to a solution of sodium hydroxide (220 ml, 2N) and cooled to O0C to 50C. The solution of p-nitrobenzyl chloroformate dissolved in <n="17"/>methylene chloride (40 ml) was added dropwise. After stirred at the same temperature for 1 h, the phase of methylene chloride was separated. The aqueous phase was washed with methylene chloride (70 ml) and acidified with concentrated sulfuric acid (36.6 g) at a temperature of O0C to 5 C . Substantive crystals were precipitated, collected by filtration under vacuum, washed with water, dried, and afford trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XXV) (57.8 g, yield 93%), m.p.: 134~135.5C.
93% Example 6] Synthesis of (2S,4S)-2-dimethylaminocarbonyl -4-acetylthio-l-PNZ-pyrrolidine (XIX)1. Synthesis of trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XV) L-hydoxyproline (XXVI) (26.2 g, 0.20 mol) was added to a solution of sodium hydroxide(220 ml, 2N) and cooled to 0C to 5C. The solution, of p-nitrobenzyl chloroformate dissolved in methylene chloride (40 ml) was added dropwise. After stirred at the same temperature for 1 h, the phase of methylene chloride was separated. The aqueous phase was washed with methylene chloride (70 ml) and acidified with concentrated sulfuric acid (36.6 g) at a temperature of 0C to 5 C . Substantive crystals were precipitated, collected by filtration under vacuum, washed with water, dried, and afford trans- l-(p-nitrobenzyloxycarbonyl) -4-hydroxyl-L-proline (XXV) (57.8 g, yield 93%), m.p.: 134~135.5C.
92.6% With sodium hydroxide; In dichloromethane; water monomer; at 0 - 5℃; for 3h; Add sodium hydroxide (66.9g, 1.68mol) and 600g of water to the reaction flask, after stirring and dissolving, add trans-L-hydroxyproline (100g, 0.76mol), stir and dissolve completely and then cool down to 0C, Add dropwise a solution of 50% p-nitrobenzyl chloroformate in dichloromethane (370 g, 0.86 mol), the temperature does not exceed 5 C; after the dropping is completed, the reaction is carried out at 0 to 5 C for 3 hours. The phases were extracted with 100 mL of dichloromethane; the aqueous phase was separated, and the pH was adjusted to 2-3 with 10% hydrochloric acid, then extracted three times with ethyl acetate (200 mL×3), and the organic phases were combined, washed with saturated brine, and washed with anhydrous sodium sulfate. It was dried, filtered, concentrated to dryness, and recrystallized with ethanol to obtain 219.2 g of white solid (intermediate 7) with a yield of 92.6%.
80% With sodium hydroxide; In water monomer; toluene; at 0 - 20℃; for 2h;Inert atmosphere; Schlenk technique; trans-4-Hydroxy-L-proline (SI, 1.0 g, 7.6 mmol, 1.0 eq.) was dissolved in aqueous NaOH (0.5 M, 34 mL) and cooled in an ice bath. At 0 - 5 C, 4-nitrobenzoylchloroformate (1.9 g, 8.6 mmol, 1.1 eq.) in toluene (25 mL) was added dropwise. The bi-phasic mixture was stirred for two hours, after which the toluene (30 mL) was added and the phases separated. The aqueous phase was extracted with toluene and the combined organic phases extracted with aqueous NaOH (0.5 M). The aqueous phases were combined, adjusted to pH = 1 by adding cone. HCI and extracted with ethyl acetate (3 times). The extract was dried over sodium sulfate, filtered and concentrated in vacuo. Thus, compound 1 (1.89 g, 6.1 mmol, 80%) was obtained as off-white solid. ESI-LRMS for Ci3Hi5N207+[MH+]: calcd. 311.1 found 311.2
Trans-4-hydroxy-L-proline (II) was added to a solution of sodium hydroxide in water at 0-5 C, and stirred to get a clear solution, followed by p- nitrobenzyloxycarbonyl chloride in dichloromethane (MDC) was added and stirred till completion of reaction. at 0-5 C. To this reaction mass sodium hydroxide solution was added and the layers were separated. To the aqueous layer methanol was added and pH was adjusted to acidic using sulphuric acid at 0-5 C. The solid obtained was filtered, washed with water and dried in vacuum at 50C to afford the title compound (III) as colorless crystals.
31.95 kg With sodium hydroxide; In dichloromethane; water monomer; at 0 - 5℃; for 5h;Large scale; 20L reactor water 12kg,1kg sodium hydroxide, stirred and dissolved, cooled to 25 ~ 30 ,Add L-hydroxyproline 15kg, stirring to dissolve,Cool to 0 ~ 5 ,The temperature was controlled at 0 ~ 5 2.7kg of p-nitrobenzyl chloroformate and 3kg of dichloromethane were added dropwise.Dropping about 2 hours, dropping is completed,Keep stirring 0 ~ 5 for about 3 hours. Detection reaction is complete.The dichloromethane phase was separated, the aqueous phase was washed with 3 kg of dichloromethane, the aqueous phase was separated,Control temperature but 15 degrees,Concentrated sulfuric acid adjusted to pH 2, cooled to 0 filtration,Washed, dried in the product(5) To a solution of (2S, 4R) -4- hydroxy- 1 - (((4-nitrobenzoyl) oxy) carbonyl) pyrrolidine-31.95kg
With sodium hydroxide; In water monomer; toluene; at -5 - 0℃; for 1.25h;pH 9.0; In a 500mL three-neck bottle added purified water 192g, add 15.3g of sodium hydroxide, stir and dissolve, and cool at 0 C; add 3g of 3-hydroxyproline, stir and dissolve; cool down at -5 C, added the drops of about 180g of p-nitrobenzyl chloroformate toluene solution, after about 1 hour, the drop is completed and pΗ=9; continue to stir for 15 minutes, and then let stand for 20 min, dispense, and obtained lower aqueous phase; in the lower aqueous phase added toluene 63mL X 3 and wash three times, stand still; control the internal temperature at 10 C, and add 6N hydrochloric acid to the aqueous phase, add dropwise until the water phase becomes turbid and stop adding, pH=4, add a small amount of seed crystals and stir until more crystals are precipitated, continue to add hydrochloric acid at pΗ = 2 (a total of about 5g of 6N dilute hydrochloric acid is required), cool down at 0 C, heat 1h suction filtration, wash with pure water to pΗ = 3, obtained compound I hydrate product.

  • 3
  • [ 301225-58-1 ]
  • [ 4457-32-3 ]
  • 4-[(4-nitro-benzyloxycarbonyl)-propyl-amino]-piperidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]
  • 4
  • [ 4457-32-3 ]
  • [ 274692-08-9 ]
  • (S)-1-tert-butoxycarbonyl-3-(4-nitrobenzyloxycarbonylaminoethyl)pyrrolidine [ No CAS ]
  • 5
  • [ 91183-71-0 ]
  • [ 4457-32-3 ]
  • N-methyl-L-phenylalanine allyl ester hydrochloride [ No CAS ]
  • N,O-dimethyl-L-tyrosine allyl ester hydrochloride [ No CAS ]
  • Fmoc-D-Tyr(O-Wang resin)-OAll [ No CAS ]
  • (S)-2-[(S)-2-[(R)-3-(4-Hydroxy-phenyl)-2-(4-nitro-benzyloxycarbonylamino)-propionyl]-methyl-amino}-3-(4-methoxy-phenyl)-propionyl]-methyl-amino}-3-phenyl-propionic acid [ No CAS ]
  • N-4-nitrobenzyloxycarbonyl-D-tyrosyl-N,O-dimethyl-L-tyrosyl-N-methyl-L-phenylalanyl-L-methionine [ No CAS ]
  • N-4-nitrobenzyloxycarbonyl-D-tyrosyl-N,O-dimethyl-L-tyrosyl-N-methyl-L-phenylalanyl-L-methionine sulfoxide [ No CAS ]
  • 6
  • [ 113283-93-5 ]
  • [ 4457-32-3 ]
  • N-(tert-butoxycarbonyl)-2-[ethyl(4-nitrobenzyloxycarbonyl)amino]ethylamine [ No CAS ]
  • 7
  • [ 301225-58-1 ]
  • [ 4457-32-3 ]
  • [ 301232-39-3 ]
YieldReaction ConditionsOperation in experiment
With trifluoroacetic acid; In dichloromethane; Step A 4-(N-((4-Nitrobenzyl)oxycarbonyl)-N-(prop-1-yl)amino)-piperidine trifluoroacetate The title compound was prepared by the reaction of <strong>[301225-58-1]4-(N-(prop-1-yl)amino)-1-tert-butoxycarbonylpiperidine</strong> (from Example 17, Step A) with (4-nitrobenzyl)chloroformate, followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 322.2 (M+H).
  • 8
  • [ 5382-17-2 ]
  • [ 4457-32-3 ]
  • [ 86207-61-6 ]
YieldReaction ConditionsOperation in experiment
48% With pyridine; triethylamine; In dichloromethane; (1) 4-Hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine To a solution of <strong>[5382-17-2]4-hydroxypiperidine hydrochloride</strong> (3.0 g, 21.8 mmol) in a mixture of methylene chloride (90 ml) and pyridine (15 ml) were added chloroformic acid p-nitrobenzyl ester (15.4 g, 72.0 mmol) and triethylamine (13.1 ml, 93.8 mmol) in an ice bath. The mixture was stirred at room temperature for 3 days. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The obtained organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane: ethyl acetate (1: 1) --> ethyl acetate as the eluant to afford 4-hydroxy-1-(p-nitrobenzyloxycarbonyl)piperidine (2.96 g, yield 48percent) as pale yellow crystals. 1H-NMR (400 MHz, CDCl3): delta (ppm) 8.23 (2H, d, J=8.1Hz), 8.51 (2H, d, J=8.1Hz), 5.23 (2H, s), 3.98 - 3.87 (3H, m), 3.30 - 3.15 (2H, m), 1.96 - 1.85 (2H, m), 1.59 - 1.48 (2H, m).
  • 9
  • [ 22600-30-2 ]
  • C24H31N4O6PolS [ No CAS ]
  • [ 4457-32-3 ]
  • C31H36N5O10PolS [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a mixture of 56.4 mg (0.4 mmol) ethyl methyl 5-amino-2- furancarboxylate in 5mL of anhydrous dichloromethane was added 84.5 mg (0.42 mmol) 4-nitrobezenechloroformate. The reaction mixture was stirred at room temperature for half an hour and concentrated. Diisopropylethylamine (0.14 mL, 0.8 mmol), DMHB resin bound 0-(1, 1-dimethylethyl)-N-{(3S)-1-[(2- nitrophenyl) sulfonyll-3-pyrrolidinyl}-L-tyrosinamide 4 (200 mg, 0.16 mmol) and dimethyl formamide (5 mL) were added to reaction mixture and shaked overnight.. The resin was washed with CH2CI2 (3 x 1 mL), CH2CI2/MeOH (1: 1, 3 x 1 mL), MeOH (3 x 1 mL) and CH2CI2 (3 x 10mL).
  • 10
  • [ 2914-69-4 ]
  • [ 4457-32-3 ]
  • [ 1186603-82-6 ]
  • 11
  • [ 4457-32-3 ]
  • [ 96034-64-9 ]
  • 12
  • [ 2799-07-7 ]
  • [ 4457-32-3 ]
  • [ 1431430-16-8 ]
  • 13
  • [ 2799-07-7 ]
  • [ 4457-32-3 ]
  • pNz-Cys(Trt)-OH [ No CAS ]
 

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[ 4457-32-3 ]

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