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CAS No.: 152628-03-0

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Quality Control of [ 152628-03-0 ] Purity: 98% SDS Specification

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Product Details of [ 152628-03-0 ]

CAS No. :	152628-03-0
Formula :	C₁₂H₁₄N₂O₂
M.W :	218.25
SMILES Code :	O=C(C1=CC(C)=C2C(NC(CCC)=N2)=C1)O
MDL No. :	MFCD06656215
InChI Key :	XWAJTVCEILFDGU-UHFFFAOYSA-N
Pubchem ID :	10262831

Safety of [ 152628-03-0 ]

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

Computational Chemistry of [ 152628-03-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	9
Fraction Csp3	0.33
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	2.0
Molar Refractivity	62.6
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	65.98 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.6
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	2.57
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.52
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.	1.78
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	3.0
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.29

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.03
Solubility	0.203 mg/ml ; 0.000932 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.	-3.6
Solubility	0.0544 mg/ml ; 0.000249 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	-3.88
Solubility	0.029 mg/ml ; 0.000133 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	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.	-5.81 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	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)	1.95

Application In Synthesis of [ 152628-03-0 ]

* 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 [ 152628-03-0 ]

[ 152628-03-0 ] Synthesis Path-Downstream 1~32

1
[ 25148-68-9 ]
[ 152628-03-0 ]
[ 152628-02-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With methanesulfonic acid; In i-Amyl alcohol; at 130 - 135℃; for 18h;	1.2 kg of isoamyl alcohol was added to the reaction flask.Add <strong>[152628-03-0]2-n-propyl-4-methyl-6-carboxybenzimidazole</strong> (400 g, 1.83 mol) and stir.Methanesulfonic acid (176 g, 1.83 mol, 1.0 eq) was added and N-methyl-phenylenediamine hydrochloride (360 g, 1.85 mol) was added.The temperature was raised to 130-135 C to reflux and the reaction was carried out for at least 18 hours until no significant moisture was separated. After the reaction is completed, cool to about 70 C,Add 2000 ml of water, stir, adjust the pH to 6~7 with 30% NaOH solution, stir and cool to 20~25 C after completion, and filter to obtain the product, the yield is 93.0%, and the HPLC purity is 99.6%.
77.4%		4-Methyl-2-n-propyl-lH-benzimidazole-6-carboxylic acid (50 gms) is suspended in Poly phosphoric acid (300 gms), temperature is raised and maintained for 30 min at 70 - 750C, N-Methyl-o-phenylenediamine dihydrochloride. (45 gms) is added lot wise over 2 hrs and maintained at temperature of 70 - 750C for lhr. The temperature of the reaction mass is raised and maintained for 10 hrs at 130 - 1350C. Mass temperature is cooled to 7O0C, water (600 ml) is added slowly at temperature of 60 - 9O0C. Temperature of the reaction mass is cooled to 3O0C, pH is adjusted to 8.0 - 8.5 with aqueous ammonia solution. EPO <DP n="12"/>Temperature of the reaction mass is raised, maintained at 50- 550C for 1 hr, filter the solid, wet cake is washed with hot water (200 ml) and unload the wet cake. The above wet cake suspended in water (900 ml), temperature is raised and mixed for 1 hr at 50 - 550C. Filtered the solid, washed with hot water (100 ml) and dried the wet cake at temperature of 70 - 750C till constant weight. The above dry material is suspended in methanol (260 ml), and temperature is raised to 45 - 5O0C, charcoal (6.5 gms) is added and mixed for about 30 min. Insolubles are filtered through hyflow bed, washed the bed with hot methanol (60 ml), collect and cooled the filtrate to 250C. Water (160 ml) is added slowly to the filtrate at temperature of 25 - 350C, Mass temperature is raised, maintained for 1 hr at reflux temperature. Reaction mass temperature is cooled, maintained for 2 hrs at 0 - 50C. The solid obtained is filtered, wet cake is washed with methanol (60 ml), the wet cake is dried at temperature of 70 - 750C till becomes constant weight. The dry weight of 4-Methyl-6(l -methyl benzimidazol-2-yl)-2-n-propyl IH- benzimidazole is 54 gms (Yield 77.4%). Water content by KF is 5.85%.
	With polyphosphoric acid; at 150℃; for 14h;	General procedure: A solution of an appropriate ester (25.01mmol) in methanol (25mL) was added to a solution of NaOH (2.0g) in water (25mL), and the mixture was heated under reflux for 2h. After evaporation of methanol, the pH was adjusted to 4-5 by addition of aqueous citric acid. The precipitated solid was filtered, washed with ethanol and dried to yield carboxylic acid. The resulting compound was dissolved in polyphosphoric acid (10mL) at 150C. N-Methyl-o-phenylenediamine dihydrochloride (3.65g, 18.8mmol) was added to the mixture for 4 times in 4h. After stirring at 150C for 10h, the mixture was cooled and then poured into ice water (30mL). The pH was adjusted to 10 by addition of concentrated ammonia (ice cooling). The precipitated solid was filtered off, dried, and boiled in ethyl acetate (300mL). After cooling, the precipitated solid was filtered off, washed with diethyl ether, and dried to give the product as white solid.4.1.2.3 2-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole (8c) [14] 8c was prepared by following the above general procedure. Yield: 60.1%. MP: 193-195 C. 1H NMR (400 MHz, CDCl3) delta: 7.82 (d, 2H), 7.30-7.53 (m, 4H), 3.95 (s, 3H), 2.89 (t, 2H), 2.61 (s, 3H), 1.79 (m, 2H), 0.91 (t, 3H). MS (ESI): [M + H]+ calcd 305.2; found 305.1.

References: [1]Patent: CN104974096,2019,B .Location in patent: Paragraph 0028-0035.
[2]Patent: WO2007/10558,2007,A1 .Location in patent: Page/Page column 5; 10-11.
[3]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051.
[4]European Journal of Medicinal Chemistry,2016,vol. 115,p. 161 - 178.

2
[ 152628-00-7 ]
[ 152628-03-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With water; sodium hydroxide; In methanol; at 80℃;Product distribution / selectivity;	Example 1:Methyl-4-methyl-2-propyl-lH-benzimidazole-6-carboxylate (40 gms, 0.172 moles) was suspended in methanol (200 ml) and stirred for few minutes. Sodium hydroxide (13.76 gms, 0.344 moles) dissolved in water (50 ml) was added to the reaction mass and the temperature is maintained at 80C. After completion of the reaction, methanol was evaporated under reduced pressure and water (100 ml) was added to the crude mass at 5-10 C. Then adjusted the pH of the crude mass to 6- 6.5 and the obtained solid was filtered. The solid was washed with water and dried at temperature of 45-50 C under vacuum (700 mm) to yield 2-n-propyl-4-methyl- 6-carboxy benzimidazole (30gms, Yield: 80 %).
		Reference Example A3: 4-Methyl-6-(2-oxazolyl)-2-propylbenzimidazole [step 1] 6-Methoxycarbonyl-4-methyl-2-propylbenzimidazole (EP502314; 500 mg, 2.29 mmol) was suspended in ethanol (15 mL), 4 mol/L aqueous sodium hydroxide solution (3.1 mL) was added, and the mixture was stirred under reflux for 7 hr. The mixture was concentrated under reduced pressure, and water (20 mL) was added. Under ice-cooling, the mixture was adjusted to pH 1 with 2 mol/L hydrochloric acid, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, aminoacetaldehyde dimethylacetal (0.50 mL, 4.58 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (527 mg, 2.75 mmol) and 1-hydroxybenzotriazole (421 mg, 2.75 mmol) were added, and the mixture was stirred at room temperature for 6 hr. To the mixture were added saturated aqueous sodium hydrogen carbonate solution (100 mL) and chloroform (100 mL), and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 6-(2,2-dimethoxyethylcarbamoyl)-4-methyl-2-propylbenzimidazole. ESI-MS m/z; 306 (M + H)+; 1H-NMR (CDCl3, delta): 1.02 (t, J = 7.3 Hz, 3H), 1.82-1.97 (m, 2H), 2.65 (s, 3H), 2.92 (t, J= 7.3 Hz, 2H), 3.45 (s, 6H), 3.64 (t, J = 5.3 Hz, 2H), 4.52 (t, J = 5.3 Hz, 1H), 6.42 (s, 1H), 7.89 (s, 1H).
	With sodium hydroxide; In methanol; water; for 2h;Reflux;	General procedure: A solution of an appropriate ester (25.01mmol) in methanol (25mL) was added to a solution of NaOH (2.0g) in water (25mL), and the mixture was heated under reflux for 2h. After evaporation of methanol, the pH was adjusted to 4-5 by addition of aqueous citric acid. The precipitated solid was filtered, washed with ethanol and dried to yield carboxylic acid. The resulting compound was dissolved in polyphosphoric acid (10mL) at 150C. N-Methyl-o-phenylenediamine dihydrochloride (3.65g, 18.8mmol) was added to the mixture for 4 times in 4h. After stirring at 150C for 10h, the mixture was cooled and then poured into ice water (30mL). The pH was adjusted to 10 by addition of concentrated ammonia (ice cooling). The precipitated solid was filtered off, dried, and boiled in ethyl acetate (300mL). After cooling, the precipitated solid was filtered off, washed with diethyl ether, and dried to give the product as white solid.

References: [1]Journal of Heterocyclic Chemistry,2003,vol. 40,p. 1107 - 1112.
[2]Patent: WO2012/28925,2012,A2 .Location in patent: Page/Page column 17.
[3]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051.
[4]Patent: EP2327690,2011,A1 .Location in patent: Page/Page column 83-84.
[5]European Journal of Medicinal Chemistry,2016,vol. 115,p. 161 - 178.
[6]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 40 - 43.
[7]European Journal of Medicinal Chemistry,2019,vol. 181.

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[ 152628-03-0 ]
[ 675882-72-1 ]