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Chemical Structure| 178306-51-9

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Product Details of [ 178306-51-9 ]

CAS No. :178306-51-9
Formula : C16H16O4
M.W : 272.30
SMILES Code : O=C(O)C(O)C(C1=CC=CC=C1)(OC)C2=CC=CC=C2
MDL No. :MFCD13152279
Boiling Point : No data available
InChI Key :RQJWOLFMWKZKCJ-UHFFFAOYSA-N
Pubchem ID :9881947

Safety of [ 178306-51-9 ]

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

Computational Chemistry of [ 178306-51-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 20
Num. arom. heavy atoms 12
Fraction Csp3 0.19
Num. rotatable bonds 5
Num. H-bond acceptors 4.0
Num. H-bond donors 2.0
Molar Refractivity 74.22
TPSA ?

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

66.76 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.0
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

2.04
Log Po/w (WLOGP)?

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

1.91
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.

1.92
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

2.29
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.03

Water Solubility

Log S (ESOL):?

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

-2.93
Solubility 0.322 mg/ml ; 0.00118 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.

-3.07
Solubility 0.232 mg/ml ; 0.000851 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

-3.94
Solubility 0.0314 mg/ml ; 0.000115 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

0.0
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<0.0
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)

2.94

Application In Synthesis of [ 178306-51-9 ]

* 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 [ 178306-51-9 ]

[ 178306-51-9 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 178306-47-3 ]
  • [ 178306-51-9 ]
YieldReaction ConditionsOperation in experiment
91% With water; sodium hydroxide; at 100℃; for 1h; 500 g (1.75 mol) of (RS) 2-hydroxy-3-methoxy-3,3-diphenyl methyl propanoate Suspended and agitated in 1,000 mL of water, 950 mL (1.90 mol) of 2 mol / L sodium hydroxide was added, and the mixture was stirred at 100 C. for 1 hour. The reaction solution was cooled to room temperature, 1500 mL of tert-butyl methyl ether was added, 700 mL of 10% hydrochloric acid was added, and the mixture was stirred for 20 minutes to dissolve the precipitated solid. After liquid-liquid separation, the organic layer was washed with 1000 mL of water. 1200 mL of heptane was added, and the solvent was distilled off under reduced pressure (200 mmHg) at 40 C. to precipitate crystals. 1000 mL of heptane was added, and the mixture was stirred at 0 C. for 1 hour. The crystals were collected by filtration and dried under reduced pressure at 40 C. for 7 hours,(RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid 431 g (yield 91%) was obtained.
90% With water; sodium hydroxide; at 90 - 95℃; for 1.5h; Step-HI : Preparation of 2-hydroxy-3-methoxy-3,3-diphenyl propionic acid of the formula -(IV) :Into a 5L round bottomed flask a mixture water(l.OL) and compound of formula -III (200g) from step-II were charged and stirred for 15 minutes. IN aqueous sodium hydroxide solution was charged and the reaction mass was stirred for 15 minutes.Reaction mass was heated to 90-95C and maintained at the same temperature for one hour. The reaction mass was brought to room temperature adjustment of pH was carried out with IN hydrochloric acid solution(1.6L) to 2-3. The product slurry was cooled to 5- 10C and maintained at the same temperature for 2hours. The product was filtered and dried at 60-65CDry weight : 172g(90%)Purity by HPLC : 99.88%Melting range : 100- 102 C
Example-2: Preparation of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6:Mixture of <strong>[178306-47-3]2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester</strong> (100 grams) and aqueous sodium hydroxide solution (22 grams in 200 ml of water) was heated to 95-1000C and stirred for 120 minutes. The reaction mixture was cooled to 40-450C and quenched with water. The pH of the reaction mixture was adjusted to 1.3 with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent from the ethyl acetate layer was distilled off completely under reduced pressure at 600C. The reaction mixture was cooled to 4O0C and cyclohexane (230 ml) was added and stirred at reflux for 30 minutes. The reaction mixture was cooled to.25-35C and stirred for 40 minutes at 25-35C. The solid formed was filtered off and washed with cyclohexane then dried at 60-70C to get the title compound. Yield: 92 grams; M.R: 108-112C
Preparation of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid compound of formula-6 Mixture of <strong>[178306-47-3]2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester</strong> (100 grams) and aqueous sodium hydroxide solution (22 grams in 200 ml of water) was heated to 95-100 C. and stirred for 120 minutes. The reaction mixture was cooled to 40-45 C. and quenched with water. The pH of the reaction mixture was adjusted to 1.3 with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent from the ethyl acetate layer was distilled off completely under reduced pressure at 60 C. The reaction mixture was cooled to 40 C. and cyclohexane (230 ml) was added and stirred at reflux for 30 minutes. The reaction mixture was cooled to 25-35 C. and stirred for 40 minutes at 25-35 C. The solid formed was filtered off and washed with cyclohexane then dried at 60-70 C. to get the title compound.Yield: 92 grams; M.R: 108-112 C.
123 g With water; sodium hydroxide; In methanol; at 45 - 50℃; for 1h; 140 g of methyl 3,3-diphenyloxirane-2-carboxylate was dissolved in 280 ml of methanol and then cooled to 0C .6.9 ml of BF3OEt2 was added slowly and stirred at 0C for 2 hours. When the methyl 3,3-diphenyloxirane-2-carboxylate disappears completely and <strong>[178306-47-3]methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate</strong> is produced,65.8 g of NaOH was dissolved in 980 ml of water and slowly added dropwise. Methanol (140 ml) was added, the temperature was raised to 45 to 50C, and the mixture was stirred for 1 hour. When the reaction was completed, the methanol was distilled off under reduced pressure, and diluted with 700 ml of dichloromethane. 300 ml of 6N HCl aqueous solution was added to adjust the pH to 2, and the organic layer was separated. The organic layer was washed with 300 ml of brine, dried, filtered and distilled under reduced pressure, and recrystallized from 500 ml of hexane to obtain 123 g of 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (yield: 82%).

  • 2
  • [ 178306-51-9 ]
  • [ 133773-29-2 ]
  • [ 1260633-70-2 ]
YieldReaction ConditionsOperation in experiment
93.09% In acetonitrile; for 1.75h;Reflux;Product distribution / selectivity; In a 5 liter three necked flask, (302 g) (1.10 mole) 3,3-diphenyl-2-hydroxy-3-methoxy propanoic acid and 3.02 liter acetonitrile was taken. Subsequently, the reaction mixture was stirred and heated at reflux temperature. (105.4 g) (0.55 mole) (R)-2,4-dichloro PEA, in 50 mL acetonitrile was added drop wise in 45 min. time interval Solid material was precipitated during this addition. The reaction mixture was stirred under reflux for 1 hr and cooled to room temperature. The reaction mixture was further stirred at room temperature for 1 hour. Solid material was filtered, washed with acetonitrile and dried. Yield: 219 g, (85.41%), HPLC purity: 99.94%, Chiral purity: 95.01%. Similarly, different diastereomeric salt of (S)-2-hydroxy-3-methoxy 3,3-diphenyl propionate was prepared using different chiral amine in different batches and the results are summarized in Table 2 given below
60% In acetonitrile;Resolution of racemate;Product distribution / selectivity; Similarly, different diastereomeric salt of (S)-2-hydroxy-3 -methoxy 3, 3-diphenyl propionate was prepared using different chiral amine in different batches and the results are summarized in Table 2 given below.Table 2;* Input refers to 3, 3-diphenyl-2-hydroxy-3-methoxy propionic acid
  • 3
  • [ 50919-07-8 ]
  • [ 178306-51-9 ]
  • [ 1260633-84-8 ]
YieldReaction ConditionsOperation in experiment
92.9% In acetonitrile; at 20℃; for 2h;Reflux;Product distribution / selectivity; In 2 liter three necked flask, (90.0 g) (0.33 mole) 3,3-diphenyl-2-hydroxy-3-methoxy propionic acid and 0.9 liter acetonitrile was taken. Subsequently, the reaction mixture was stirred and heated at reflux temperature. (30 g) (0.198 mole) (S)-3-methoxy PEA, in 90 mL acetonitrile was added drop wise in 10 minute time interval. Further, the reaction mixture was stirred under reflux for 0.5 hr. The reaction mixture was cooled at room temperature and was stirred for 1.5 hour. Solid material was filtered, washed with acetonitrile and dried. Yield: 65.0 g, (92.9%), HPLC purity: 99.82%, Chiral purity: 96.57%
85% In ethanol; at 20℃; for 2.16667h;Reflux; Resolution of racemate;Product distribution / selectivity; Example-12: Preparation of (S)-3-methoxyphenylethylammonium (S)-2-hvdroxy-3- methoxy 3, 3-diphenyl propionateIn 100 mL three necked flask, (5g) (0.018 mole) 3, 3-diphenyl-2-hydroxy-3- methoxy propionic acid and 50 mL rectified spirit was taken. Subsequently, the reaction mixture was stirred and heated at reflux temperature. (1.8g) (0.01 1 mole) (S)- 3- methoxy PEA, in 5 mL rectified spirit was added drop wise in 10 min. time intervalThe reaction mixture was stirred under reflux for 0.5 hr and cooled to room temperature and again stirred at room temperature for 1.5 hour. Solid material was filtered, washed with rectified spirit and dried.Yield: 3.3 g, (85.0 %), HPLC purity: 99.91 %, Chiral purity: 99.38 %.
  • 4
  • [ 178306-51-9 ]
  • [ 178306-47-3 ]
 

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