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Structure of 43076-61-5

Chemical Structure| 43076-61-5

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Product Details of [ 43076-61-5 ]

CAS No. :43076-61-5
Formula : C14H19ClO
M.W : 238.75
SMILES Code : O=C(C1=CC=C(C(C)(C)C)C=C1)CCCCl
MDL No. :MFCD00018996
InChI Key :RLKSQLJFGCDUOX-UHFFFAOYSA-N
Pubchem ID :2723694

Safety of [ 43076-61-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319
Precautionary Statements:P264-P280-P302+P352+P332+P313+P362+P364-P305+P351+P338+P337+P313

Computational Chemistry of [ 43076-61-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 6
Fraction Csp3 0.5
Num. rotatable bonds 5
Num. H-bond acceptors 1.0
Num. H-bond donors 0.0
Molar Refractivity 70.32
TPSA ?

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

17.07 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.93
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

4.16
Log Po/w (WLOGP)?

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

4.19
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.

3.76
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

4.68
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

3.94

Water Solubility

Log S (ESOL):?

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

-3.89
Solubility 0.0309 mg/ml ; 0.000129 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.

-4.23
Solubility 0.0142 mg/ml ; 0.0000594 mol/l
Class?

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

Moderately 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

-5.39
Solubility 0.000966 mg/ml ; 0.00000405 mol/l
Class?

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

Moderately 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

Yes
CYP3A4 inhibitor?

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

No
Log Kp (skin permeation)?

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

-4.8 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

1.0 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<2.0
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)

1.66

Application In Synthesis of [ 43076-61-5 ]

* 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.

  • Upstream synthesis route of [ 43076-61-5 ]
  • Downstream synthetic route of [ 43076-61-5 ]

[ 43076-61-5 ] Synthesis Path-Upstream   1~6

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  • [ 43076-61-5 ]
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YieldReaction ConditionsOperation in experiment
55.27% With potassium carbonate In 4-methyl-2-pentanone at 105 - 116℃; for 2.25 h; Inert atmosphere 2.2 Synthesis of I" from Benzyhydryloxypiperidine toluenesulfonate Benzhydryloxypiperidine toluenesulfonate (1 1.44 g, 0.025 mol), 4'-tert-butyl-4- chlorobutyrophenone (10.15 g, 170 mol percent), potassium carbonate (8.47 g, 245 mol percent) and methyl isobutyl ketone (18.3 g) were placed in a round bottom flask and a further 20 mL of methyl isobutyl ketone were added and the reaction mixture was placed under a nitrogen atmosphere. The mixture was heated to between 1 15-116°C and vigorous evolution of gas was noted. The reaction mixture was heated at reflux temperature (105-1 15 °C) for 2 h and 15 minutes and then cooled to 30 °C internal temperature. Water (50 mL) was added and the phases were separated. The organic phase was washed with water (3x 50 mL) and then concentrated under reduced pressure (45 °C, 8 mbar) to give the crude product. The crude material was suspended in ethanol (30 mL, 96percent denatured with toluene) and the mixture was heated to reflux (82°C). The resulting solution was stirred at reflux temperature for 15 minutes and then cooled to 30 °C (the solution was seeded with a small quantity of I") and stirred at 30 °C for 30 minutes. The resulting suspension was then cooled to 2-3 °C and stirred at this temperature for 1 h. The product was isolated by filtration and washed with ethanol (3 x 5 niL). The moist product was dried in a vacuum oven (45°C) to give pure I" (6.49 g, 55.27percent). HPLC purity (areapercent): 99.27percent RRT 0.62 0.38percent.
55.27% With potassium carbonate In 4-methyl-2-pentanone at 105 - 116℃; Inert atmosphere 2.2
Synthesis of I' from Benzyhydryloxypiperidine toluenesulfonate
Benzhydryloxypiperidine toluenesulfonate (11.44 g, 0.025 mol), 4'-tert-butyl-4-chlorobutyrophenone (10.15 g, 170 mol percent), potassium carbonate (8.47 g, 245 mol percent) and methyl isobutyl ketone (18.3 g) were placed in a round bottom flask and a further 20 mL of methyl isobutyl ketone were added and the reaction mixture was placed under a nitrogen atmosphere.
The mixture was heated to between 115-116°C and vigorous evolution of gas was noted.
The reaction mixture was heated at reflux temperature (105-115 °C) for 2 h and 15 minutes and then cooled to 30 °C internal temperature.
Water (50 mL) was added and the phases were separated.
The organic phase was washed with water (3x 50 mL) and then concentrated under reduced pressure (45 °C, 8 mbar) to give the crude product.
The crude material was suspended in ethanol (30 mL, 96percent denatured with toluene) and the mixture was heated to reflux (82°C).
The resulting solution was stirred at reflux temperature for 15 minutes and then cooled to 30 °C (the solution was seeded with a small quantity of I') and stirred at 30 °C for 30 minutes.
The resulting suspension was then cooled to 2-3°C and stirred at this temperature for 1 h.
The product was isolated by filtration and washed with ethanol (3 x 5 mL).
The moist product was dried in a vacuum oven (45°C) to give pure I' (6.49 g, 55.27percent). HPLC purity (areapercent): 99.27percent RRT 0.62 0.38percent.
References: [1] Patent: WO2011/121099, 2011, A2, . Location in patent: Page/Page column 39-40.
[2] Patent: EP2371817, 2011, A1, . Location in patent: Page/Page column 27.
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References: [1] Patent: WO2011/121099, 2011, A2, . Location in patent: Page/Page column 42.
  • 3
  • [ 43076-61-5 ]
  • [ 90729-43-4 ]
References: [1] Patent: EP2371817, 2011, A1, . Location in patent: Page/Page column 29.
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  • [ 5382-16-1 ]
  • [ 119-61-9 ]
  • [ 43076-61-5 ]
  • [ 90729-43-4 ]
YieldReaction ConditionsOperation in experiment
31 g
Stage #1: With aluminum (III) chloride; trifluorormethanesulfonic acid In toluene at 50℃; for 0.333333 h;
Stage #2: With toluene-4-sulfonic acid In water; toluene for 5 h; Reflux
Stage #3: With sodium hydrogencarbonate In water; toluene for 12 h; Reflux
The preparation method of ebastine provided in this embodiment specifically includes the following steps: (1) Add benzophenone (30 g, 0.165 mol) to 300 mL of toluene solution, stir and dissolve, aluminum trichloride (2.2 g, 0.017 mol) was added in sequence,trifluoromethanesulfonic acid (2.5 g, 0.018 mol),the mixture was heated to 50 ° C for 20 min, cooled to room temperature, p-toluenesulfonic acid (31.2 g, 0.18 mol) was added, 4-hydroxypiperidine (17.2 g, 0.17 mol) was added, and the mixture was heated to reflux, and refluxed with water for 5 h. After the reaction was completed, the reaction solution was cooled to room temperature, and 230 mL of 1N NaOH solution was slowly added thereto under ice cooling, and the mixture was stirred for 30 minutes, left to stand for 30 minutes, and the aqueous layer was separated. The organic layer was further added with sodium hydrogencarbonate (35 g, 0.41 mol). ,4-chloro-1-(4-tert-butylphenyl)-1-butanone (37.5 g, 0.157 mol), warmed to reflux, and refluxed with water for 12 h. After the reaction was completed, the temperature was lowered to room temperature and washed three times. , 200mL each time, wash to neutral.(2) The obtained organic solution was evaporated to the remaining 10percent volume, 100 mL of 95percent ethanol was added, the temperature was dissolved, the temperature was lowered to -10 ° C, and the crystal was frozen for 12 hours. The next day, the crystal was filtered off and dried to obtain ebastine (31g) 0.067mol), mp 84.2-86.3°C, total yield 40percent
References: [1] Patent: CN109593058, 2019, A, . Location in patent: Paragraph 0052-0064.
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  • [ 90729-43-4 ]
YieldReaction ConditionsOperation in experiment
66.43% With sodium hydrogencarbonate In toluene for 12 h; Reflux Example 3. Preparation of discoloured l-[4-(l,l-dimethyIethyl)phenyI]-4-[4- (diphenylmethoxy)-l-piperidinyl]-l-butanone I"A toluene solution of 4-benzhydryloxypiperidine (73.27 g of the toluene solution contained 26.74 g of 4-benzhydryloxypiperidine), sodium hydrogen carbonate (14.28 g), DMF (5.3 mL) and 4'-tert-butyl-4-chloro-butyrophenone (28.65 g) were heated to reflux temperature. The reaction mixture was heated at reflux temperature for 12 h, to produce a solution of I" of 84.3percent) purity on the basis of HPLC area-percent and then cooled to room temperature. The orange reaction mixture was washed with water (3 x 100 mL) and the organic phase wasconcentrated under reduced pressure. Ethanol (110 mL) was added to the residue and the mixture was heated to reflux. The hot solution was filtered and the filtrate was cooled to 2 °C. The product was isolated by filtration and washed with ethanol (5 x 20 mL). The product was dried in a vacuum oven for several hours to afford the title compound (31.2 g, 66.43 percent) as a beige solid (commercial I" is white and specifications (such as those found in the European Pharmacopoeia) require a white to almost white crystalline substance). HPLC purity 99.77 percent, significant impurities at relative retention times 0.05 and 0.19 were observed and had HPLC area-percent of 0.04 and 0.06percent>. Discolouration was also sometimes observed when other solvents, including methyl isobutyl ketone were used, but was able to be efficiently suppressed when air was excluded from the reaction mixture, or was able to be efficiently suppressed when an adequate purification procedure by salt formation/neutralization, alternatively or optionally in combination with recrystallization, was used.
References: [1] Patent: WO2011/121099, 2011, A2, . Location in patent: Page/Page column 40-41.
[2] Patent: EP2371817, 2011, A1, . Location in patent: Page/Page column 28.
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References: [1] Patent: WO2012/76919, 2012, A1, .
 

Historical Records

Technical Information

• Alkyl Halide Occurrence • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Benzylic Oxidation • Birch Reduction • Blanc Chloromethylation • Bucherer-Bergs Reaction • Clemmensen Reduction • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Fischer Indole Synthesis • Friedel-Crafts Reaction • General Reactivity • Grignard Reaction • Henry Nitroaldol Reaction • Hiyama Cross-Coupling Reaction • Horner-Wadsworth-Emmons Reaction • Hydride Reductions • Hydrogenolysis of Benzyl Ether • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Lawesson's Reagent • Leuckart-Wallach Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Preparation of Amines • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reformatsky Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Stille Coupling • Stobbe Condensation • Substitution and Elimination Reactions of Alkyl Halides • Suzuki Coupling • Tebbe Olefination • Ugi Reaction • Vilsmeier-Haack Reaction • Wittig Reaction • Wolff-Kishner Reduction

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