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Quality Control of [ 431888-57-2 ] Purity: 95% SDS Specification

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Product Details of [ 431888-57-2 ]

CAS No. :	431888-57-2
Formula :	C₉H₇ClO₄
M.W :	214.60
SMILES Code :	COC(=O)C1=CC(Cl)=C(C=C1)C(O)=O
MDL No. :	MFCD21603679
InChI Key :	ICUITMASTQNLIL-UHFFFAOYSA-N
Pubchem ID :	14372237

Safety of [ 431888-57-2 ]

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

Calculated chemistry of [ 431888-57-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.11
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	49.69
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	63.6 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.51
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	2.04
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.82
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.	2.08
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	1.76
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.84

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.57
Solubility	0.571 mg/ml ; 0.00266 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.	-3.0
Solubility	0.213 mg/ml ; 0.000991 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	-2.47
Solubility	0.725 mg/ml ; 0.00338 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.	-6.16 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<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)	1.66

Application In Synthesis of [ 431888-57-2 ]

* 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 [ 431888-57-2 ]

[ 431888-57-2 ] Synthesis Path-Downstream 1~14

1
[ 431888-57-2 ]
[ 115-11-7 ]
[ 232275-84-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In dichloromethane; at -78 - 20℃;	To 24.9 g of <strong>[431888-57-2]2-chloro-4-(methoxycarbonyl)benzoic acid</strong> and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at -78 C. until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to -78 C. before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate. 3.35 g of 1-tert-butyl 4-methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3-chlorobenzoic acid was was cooled to 0 C. in 25 mL of THF before a solution of 19.5 mL of 1M BH3-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at -50% complete by TLC. The reaction is re-cooled to 0 C. and another 19.5 mL of BH3-THF is added dropwise before the ice bath is removed. Upon completion, the reaction is re-cooled to 0 C. and quenched with 3N HCl dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 564 mg of tert-butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to 0 C. in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Combi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 mg of tert-butyl 4-(bromomethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of tert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was treated with 4N HCl in Dioxane at 45 C. and concentrated to give 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2-trifluoroethylamino)methyl)benzamide. MS (Q1) 454.6 (M)+.

References: [1]Patent: US2006/63779,2006,A1 .Location in patent: Page/Page column 119.

2
[ 18643-84-0 ]
[ 431888-57-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With boron tribromide; In dichloromethane; at -5 - 20℃; for 18.5h;	A solution of dimethyl 2-chloroterephthalate (2.5 g, 1 1 mmol) in DCM (20 mL) was cooled to -5C and treated with BBr3 (1 M in DCM) (1 1 mL, 1 1 mmol) dropwise over 30 min. The mixture was then warmed to RT and stirred for 18 h. The mixture was poured into ice, warmed to RT and the pH was adjusted to 8 by the addition of solid NaHC03. The aq. solution was washed with EtOAc (50 mL), acidified by the addition of 1 M HCI and extracted with EtOAc (160 mL). The organic solution was washed with brine (80 mL), dried over MgS04, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (120 g, 0-10% [MeOH 5% AcOH] in DCM) to afford the title compound (2) (1.5 g, 62%) as white solid: m/z 215 [M+H]+ (ES+), 213 [M-H]- (ES-); NMR (400 MHz, DMSO-de) delta: 13.79 (1 H, br. s), 8.00 - 7.95 (2H, m), 7.90 - 7.88 (1 H, m), 3.89 (3H, s)
	With boron tribromide; In dichloromethane; at 0 - 20℃;	20 g of dimethyl 2-chloroterephthalate was cooled to 0C in DCM and 87 mL of a IM in DCM solution Of BBr3 was added dropwise over several hours. The reaction mixture was subsequently warmed to room temperature and stirred until complete. Following basic workup, 2-chloro-4-(methoxycarbonyl)benzoic acid was purified by ISCO Combi-Flash.
	With boron tribromide; In dichloromethane; at 0 - 20℃;	67 mL of 2-chloro-1,4-dimethylbenzene and 356 g of Potassium Permanganate were refluxed in 1.5 L of H2O for several hours and monitored for disappearance of starting material by TLC. The Potassium Permanganate was filtered and the reaction mixture was acidified and filtered to yield 2-chloroterephthalic acid. 46.8 g of 2-chloroterephthalic acid was treated with a saturated HCl gas solution in MeOH overnight at room temperature. The reaction mixture was concentrated, subjected to basic workup and dried to yield the dimethyl 2-chloroterephthalate. 20 g of dimethyl 2-chloroterephthalate was cooled to 0 C. in DCM and 87 mL of a 1 M in DCM solution of BBr3 was added dropwise over several hours. The reaction mixture was subsequently warmed to room temperature and stirred until complete. Following basic workup, 2-chloro-4-(methoxycarbonyl)benzoic acid was purified by ISCO Combi-Flash. 959 mg of 2-chloro-4-(methoxycarbonyl)benzoic acid was coupled to 750 mg of 4-chloro-3-(pyridin-2-yl)aniline via procedure G. 1 g of methyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was hydrolyzed via Procedure M to give 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to tert-butylamine via Procedure G. The product was purified on reverse phase HPLC to yield N4-tert-butyl-2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (Q1) 443.2 (M)+.

References: [1]Patent: WO2016/97004,2016,A1 .Location in patent: Page/Page column 112.
[2]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6748 - 6753.
[3]Patent: WO2009/126863,2009,A2 .Location in patent: Page/Page column 119-120.
[4]Patent: US2006/63779,2006,A1 .Location in patent: Page/Page column 88-89.

Yield	Reaction Conditions	Operation in experiment
		4-methyl 2-chloro-1,4-benzenedicarboxylate (B) STR11 Acidification of product from Example 4 with 10% hydrochloric acid gives the titled acids.

4
[ 431888-57-2 ]
[ 115-11-7 ]
[ 431888-58-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; In dichloromethane; at -78 - 20℃;	To 24.9 g of <strong>[431888-57-2]2-chloro-4-(methoxycarbonyl)benzoic acid</strong> and 2 mL of Sulfuric Acid in 350 mL of DCM was added isobutylene gas at -78C until the solvent was saturated and capped off securely. Let go several days at room temperature and re -cool to -78C before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and concentrate to give 31.4 g of 1-tert-butyl 4-methyl 2-chloroterephthalate.

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 6748 - 6753.
[2]Patent: WO2009/126863,2009,A2 .Location in patent: Page/Page column 180.

5
[ 879088-41-2 ]
[ 431888-57-2 ]
methyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate [ No CAS ]