57625-74-8|Methyl 2-methyl-2-phenylpropanoate| Ambeed

CAS No. :	57625-74-8
Formula :	C₁₁H₁₄O₂
M.W :	178.23
SMILES Code :	CC(C1=CC=CC=C1)(C)C(OC)=O
MDL No. :	MFCD01846451
InChI Key :	WITYUUTUSPKOAB-UHFFFAOYSA-N
Pubchem ID :	143498

Safety of [ 57625-74-8 ]

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

Computational Chemistry of [ 57625-74-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.36
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	51.8
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.49
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.64
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.14
Log P_o/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.	2.58
Log P_o/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	2.42
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.45

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.75
Solubility	0.316 mg/ml ; 0.00177 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.	-2.84
Solubility	0.256 mg/ml ; 0.00144 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	-3.29
Solubility	0.0906 mg/ml ; 0.000508 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.	-5.51 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	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<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)	1.37

Application In Synthesis of [ 57625-74-8 ]

* 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 [ 57625-74-8 ]

[ 57625-74-8 ] Synthesis Path-Downstream 1~55

1
[ 57625-74-8 ]
[ 75-16-1 ]
[ 2371-91-7 ]

References: [1]Bulletin de la Societe Chimique de France,1969,p. 787 - 790.
[2]Journal of the American Chemical Society,1966,vol. 88,p. 5571 - 5581.

2
[ 31508-44-8 ]
[ 74-88-4 ]
[ 57625-74-8 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; ammonium chloride; diisopropylamine; In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide; hexane; water;	REFERENCE EXAMPLE 78 Methyl 2-methyl-2-phenylpropionate (78) STR97 A solution of n-butyl lithium in hexane (1.44N, 60.0 ml, 86.4 mmol) was added to a solution of diisopropylamine (9.07 g, 89.6 mmol) in anhydrous THF (200 ml) cooled at -30 C. under argon atmosphere, and the mixture was stirred for 20 minutes. To this reaction mixture were added a solution of methyl 2-phenylpropionate (10.5 g, 64.0 mmol) in 10 ml of anhydrous THF and HMPA (16.5 g, 92.0 mmol), and the mixture was stirred at -30 C. for 10 minutes and then at 0 C. for 45 minutes. To this reaction solution was added a solution of methyl iodide (13.6 g, 96.0 mmol) in anhydrous THF (30 ml) at -30 C., and the mixture was stirred at -30 C. for 1 hour. This reaction mixture was added to an aqueous saturated solution of ammonium chloride (400 ml) and water (50 ml) was added. The mixture was extracted with ether (400 ml). The aqueous layer further extracted with ethyl acetate. The combined organic layers were washed with water (300 ml) and brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was distilled (b.p. 99-100 C./6 mmHg) to give an oil of methyl 2-methyl-2-phenylpropionate (7.63 g, 42.9 mmol, 67.0%). This compound was assigned the structure by the following data: IR(Liquid film method): 2970, 1730, 1600, 1500, 1450, 1390, 1370, 1250, 1190, 1150, 1100, 1080, 1030, 1020, 990, 850, 770, 740, 700 cm-1. NMR(90 MHz, CDCl3, delta): 1.58(6H, s), 3.64(3H, s), 7.1-7.4(5H, m).

References: [1]Journal of the Chemical Society. Perkin transactions I,1975,p. 1347 - 1352.
[2]Patent: US4775692,1988,A .
[3]Chemical Communications,2017,vol. 53,p. 8316 - 8319.

3
[ 67-56-1 ]
[ 826-55-1 ]
[ 57625-74-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 20℃; for 12h;Heating / reflux;	Methanol (2.5 LTR), 2,2-dimethyl-2-phenyl-acetic acid (Intermediate 1) (0.5 kg), and conc. sulphuric acid (50 ml) were charged to a reactor at room temperature. The temperature was raised to reflux and maintained for 12 hours. The pH was adjusted to 7-8 using aqueous ammonia and the methanol concentrated completely. The reaction mass was quenched in water (1 LTR) and extracted with MDC (750 ml). The MDC layer was dried over sodium sulphate and concentrated to obtain 500 gms of the title compound as an oil having 98% purity
	With sulfuric acid; at 25 - 45℃; for 4h;Heating / reflux;	(a) Reaction of alpha,alpha-Dimethyl phenyl acetic acid and methanol alpha,alpha-Dimethylphenyl acetic acid was reacted with methanol in presence of cone, sulfuric acid between about 25 to 45C. Reaction mixture was refluxed for about 4 hours. Methanol was distilled off after the said time to give thick oily slurry of Methyl-alpha,alpha-dimethylphenyl acetic acid. Water was added to the pre-cooled reaction mixture and extracted with chloroform EPO <DP n="8"/>followed by washing with aqueous sodium bicarbonate solution and finally with potable water. Removal of chloroform under reduced pressure yielded title compound as oily mass in about 98 % HPLC purity.EXAMPLE 1Methyl- a, a-Dimethyl phenyl acetate (ester)51 Kg (0.3109 Kmole) of alpha,alpha-Dimethyl acetic acid was dissolved in 100 to 150 Ltr methanol and to it was added concentrated sulfuric acid, 6 to 9 Kg maintaining temperature 25 to 450C. After complete addition of sulfuric acid reaction mixture was refluxed for 4 hours. After completion of the reaction methanol was distilled off under vacuum to obtain thick slurry which was cooled to room temperature and to it was added water. Reaction mixture was then extracted with chloroform and washed with 10% w/v sodium bicarbonate aqueous solution. Finally, chloroform layer was washed with potable water. On removal of chloroform under vacuum, Methyl-alpha,alpha-Dimethyl phenyl acetate as oily mass was obtained. HPLC Purity = 98%. Yield = 40 to 50 Kg
1 g	With methanesulfonic acid; for 2h;Sealed tube; Reflux;	A 100 mL sealed tube was charged with intermediate 39b (1.6 g, 9.7 mmol) and methanol (10 mL). To the above stirred solution CH3SO3H (1 .6 mL) was added drop wise and refluxed for 2 h. The reaction mixture concentrated and was diluted with ice- water and neutralized with NaHCO3, extracted with ethyl acetate, washed with water and dried. The product was obtained by concentrating under vacuo, which was further purified by combiflash to yield the title compound (1 .0 g) as a colourless liquid.H NMR: (ODd3, 300MHz) 6 7.25-7.27(d, 4H) 7.17-7.20 (m, 1H), 3.58 (5, 3H),1 .51 (5, 6H).

2 g

With sulfuric acid; at 0℃;Reflux;

To a stirred solution of 2-methyi-2-phenyipropanoic acid (2 g, 12.18 mmol) in methanol (30m1) at 0 was added drop wise solution of H2S04 (2 ml, 37.5 mmol), The reaction mixture was heated torefiux for overnight. After completion of reaction, methanol was evaporated under reduced pressure and the residue was diluted with dichioromethane. The organic portion was washed with saturatedsodium bicarbonate solution, brine and evaporated under reduced pressure to give methyl 2-methyl-2-phenyipropanoate (2 g) as oil.

References: [1]Journal of labelled compounds and radiopharmaceuticals,2011,vol. 54,p. 352 - 356.
[2]Journal of Organic Chemistry,1994,vol. 59,p. 2792 - 2798.
[3]Patent: WO2005/19175,2005,A1 .Location in patent: Page/Page column 23.
[4]Patent: WO2007/7347,2007,A1 .Location in patent: Page/Page column 4; 6-7; 10.
[5]Patent: WO2014/202528,2014,A1 .Location in patent: Page/Page column 107; 108.
[6]Patent: WO2018/116072,2018,A1 .Location in patent: Page/Page column 75; 76; 79.

4
[ 67-56-1 ]
[ 10409-54-8 ]
[ 59671-36-2 ]
[ 57625-74-8 ]

References: [1]Synthesis,1985,p. 436 - 437.

5
[ 67-56-1 ]
[ 36293-05-7 ]
[ 57625-74-8 ]

References: [1]Journal of the American Chemical Society,1986,vol. 108,p. 4119 - 4125.

6
[ 57625-74-8 ]
[ 826-55-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With water; sodium hydroxide; In 1,4-dioxane; for 24h;	Methyl 2-methyl-2-phenylpropanoate (0.840 g, 4.71 mmol) was dissolved in 5 mL of l,4-dioxane and 10 mL of 1.0 M NaOH (10.0 mmol, 2.1 equiv) was added. The mixture was heated at 95 C for 24 h. 20 mL of 1.0 M HC1 was added and the mixture was extracted with dichloromethane (3 x 20 mL). Combined organic fractions were washed with brine (30 mL), filtered through cotton and concentrated under reduced pressure to yield a crude mixture which was purified by flash chromatography (hexanes/ethyl acetate), 0.758 g of 2-methyl-2-phenylpropanoic acid (4.62 mmol, 98%).
89 g	With water; sodium hydroxide; In methanol; at 10℃; for 3h;Reflux;	Example-l: Preparation of 2-methyl-2-phenylpropanoic acid (FormuIa-3) Methyl 2-methyl-2-phenylpropanoate compound of formula-2 (100 gm) and methanol (500 ml) were added to a pre-cooled mixture of sodium hydroxide (45 gm) and water (500 ml) at 10-15C. Heated the reaction mixture to reflux temperature and stirred for 3 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and cooled the reaction mixture to 25-30C. Water was added to the reaction mixture and cooled to 5-10C. Acidified the reaction mixture using dil.HCl solution at 5-10C. Raised the temperature of the reaction mixture to 25-30C and stirred for 30 rhin at the same temperature. Filtered the solid, washed with water and dried the material to get the title compound. Yield: 89.0 gm.
	With water; sodium hydroxide; In methanol; at 65℃;	General procedure: The ester II was added to a mixture of NaOH (2.0 M, 8 mL) and methanol (10 mL)and stirred overnight at 65 C. After removal of methanol in vacuo, the residue wasdiluted with water and extracted with EtOAc (10 mL × 3). Then the pH value of thewater layer was adjusted to 2.0 with HCl (2.0 M) and extracted with EtOAc (30 mL ×3). The combined organic phases were evaporated in vacuo to give the crudecarboxylic acid III, which was used directly for the next step without furtherpurification.

References: [1]Patent: WO2019/99760,2019,A1 .Location in patent: Paragraph 0055; 0058.
[2]Synthesis,1985,p. 436 - 437.
[3]Il Farmaco,1999,vol. 54,p. 600 - 610.
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3887 - 3890.
[5]Patent: WO2014/188453,2014,A2 .Location in patent: Page/Page column 22.
[6]Chemical Communications,2017,vol. 53,p. 8316 - 8319.
[7]Chinese Chemical Letters,2018,vol. 29,p. 191 - 193.

7
[ 71254-82-5 ]
[ 3461-39-0 ]
[ 2438-04-2 ]
[ 57625-74-8 ]
[ 71302-96-0 ]
[ 66164-33-8 ]
[ 129976-23-4 ]

References: [1]Canadian Journal of Chemistry,1990,vol. 68,p. 1106 - 1115.

8
[ 140-29-4 ]
[ 616-38-6 ]
[ 57625-74-8 ]
[ 1823-91-2 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1994,p. 1323 - 1328.

9
[ 84782-16-1 ]
[ 3461-39-0 ]
[ 57625-74-8 ]

References: [1]Journal of Organic Chemistry,1990,vol. 55,p. 5037 - 5041.

10
[ 84782-16-1 ]
[ 29393-16-6 ]
[ 57625-74-8 ]

References: [1]Bulletin of the Chemical Society of Japan,1982,vol. 55,p. 3939 - 3940.
[2]Journal of the American Chemical Society,1988,vol. 110,p. 3112 - 3120.
[3]Journal of the American Chemical Society,1988,vol. 110,p. 3112 - 3120.

11
[ 67-56-1 ]
[ 201230-82-2 ]
[ 98-83-9 ]
[ 3461-39-0 ]
[ 57625-74-8 ]

References: [1]Organic Letters,2006,vol. 8,p. 6143 - 6145.
[2]Applied Organometallic Chemistry,2014,vol. 28,p. 364 - 371.

12
[ 50407-04-0 ]
[ 57625-74-8 ]

References: [1]Journal of Organic Chemistry USSR (English Translation),1992,vol. 28,p. 1229 - 1230.
Zhurnal Organicheskoi Khimii,1992,vol. 28,p. 1546 - 1548.

13
[ 57625-74-8 ]
2-[5-amino-2-(4-fluoro-phenyl)-6-oxo-6H-pyrimidin-1-yl]-N-{2-methyl-1-[5-(1-methyl-1-phenyl-ethyl)-[1,3,4]oxadiazole-2-carbonyl]-propyl}-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

14
[ 57625-74-8 ]
[ 252253-32-0 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

15
[ 57625-74-8 ]
[ 337969-19-4 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

16
[ 57625-74-8 ]
(2S)-2-amino-3-methyl-1-[5-(1-methyl-1-phenylethyl)-1,3,4-oxadiazol-2-yl]butan-1-ol hydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

17
[ 57625-74-8 ]
2-[6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrimidinyl]-N-[(1S)-1-[[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazole-2-yl]carbonyl]-2-methylpropyl]acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

18
[ 57625-74-8 ]
[ 251958-58-4 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

19
[ 57625-74-8 ]
2-[5-amino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl]-N-[(1S)-1-[[5-(α,α-dimethylbenzyl)-1,3,4-oxadiazole-2-yl]carbonyl]-2-methylpropyl]acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

20
[ 57625-74-8 ]
[ 1026751-56-3 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

21
[ 57625-74-8 ]
[ 1027923-09-6 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

22
[ 57625-74-8 ]
[ 337969-30-9 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

23
[ 57625-74-8 ]
[ 208840-36-2 ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1268 - 1285.

24
[ 57625-74-8 ]
[ 18755-52-7 ]

References: [1]Il Farmaco,1999,vol. 54,p. 600 - 610.
[2]Journal of labelled compounds and radiopharmaceuticals,2011,vol. 54,p. 352 - 356.

25
[ 57625-74-8 ]
[ 83799-24-0 ]