Structure of 178306-51-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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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 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 |
66.76 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.04 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.92 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.29 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.03 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.93 |
Solubility | 0.322 mg/ml ; 0.00118 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.07 |
Solubility | 0.232 mg/ml ; 0.000851 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.94 |
Solubility | 0.0314 mg/ml ; 0.000115 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-6.51 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.94 |
* 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.
Yield | Reaction Conditions | Operation 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%). |
Yield | Reaction Conditions | Operation 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 |
Yield | Reaction Conditions | Operation 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 %. |
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