4442-53-9|2,3-Dihydrobenzo[b][1,4]dioxine-5-carboxylic acid| Ambeed

Structure of 4442-53-9

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Quality Control of [ 4442-53-9 ] Purity: 97% SDS Specification

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Product Details of [ 4442-53-9 ]

CAS No. :	4442-53-9
Formula :	C₉H₈O₄
M.W :	180.16
SMILES Code :	O=C(C1=C2C(OCCO2)=CC=C1)O
MDL No. :	MFCD00239415
InChI Key :	VCLSWKVAHAJSFL-UHFFFAOYSA-N
Pubchem ID :	78184

Safety of [ 4442-53-9 ]

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

Computational Chemistry of [ 4442-53-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	44.27
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	55.76 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.44
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	1.16
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.16
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.	0.66
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	1.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.18

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.96
Solubility	1.96 mg/ml ; 0.0109 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.93
Solubility	2.14 mg/ml ; 0.0119 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-1.8
Solubility	2.84 mg/ml ; 0.0158 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.	-6.58 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.	0.56

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)	2.23

Application In Synthesis of [ 4442-53-9 ]

* 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 [ 4442-53-9 ]

[ 4442-53-9 ] Synthesis Path-Downstream 1~35

1
[ 4442-53-9 ]
[ 38871-41-9 ]

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 14: 2,3-ETHYLENEDIOXYBENZOYL CHLORIDE By carrying out the procedure as in Preparation 2--Stage B, but replacing 4,5-methylenedioxy-2-nitrobenzoic acid by 2,3-ethylenedioxybenzoic acid, the title product is obtained.
	With thionyl chloride; at 70 - 80℃; for 4h;	General procedure: The starting two acids (<strong>[4442-53-9]2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylic acid</strong> and 2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid) shoud be activated by firstly SOCl2: acid (100 mg) and (6-10 mL) was mixed and stirred at reflux 80 ? for 4 hours. The reaction mixture was cooled and evaporated to give reactive acyl chloride obtained as an oil, which would be dissolved in ethyl acetate (5-6 mL) in the next step.
	With thionyl chloride; In N,N-dimethyl-formamide; for 4h;	General procedure: Method B: SOCl2 (10mL) was added to a stirred solution of compound 3 (20mmol) in anhydrous DMF (50mL). The reaction solution was allowed to stir at room temperature for approximately 4h. Then, active compound 4 (15mmol) and metronidazole (15mmol) were dissolved in CH2Cl2 followed by drop wise addition triethylamine and compound 5 was obtained with yield of 85percent. Compound 5 (10mmol), different substituted benzaldehydes (12mmol) and NaOH (15mmol) were dissolved in DMSO (30mL) at room temperature. The appropriate amount of water was then added in the residue and filtered. The resulting solid was collected and washed with cold water, dried and crystallized from anhydrous ethanol to get the desired compounds. All of the synthetic compounds gave satisfactory analytical and spectroscopic data, which were in full accordance with their depicted structures.

With thionyl chloride; at 85℃; for 1h;

Intermediate 35: 2-diazo-1-(2,3-dihvdro-1 ,4-benzodioxin-5-yl)ethanone; A solution of 1 g of 2,3-dihydro-1 ,4-benzodioxin-5-carboxylic acid (5.55 mmole, Aldrich) in 30.7 mL of SOCI2 was stirred at 850C for 1 h in a dry flask under nitrogen atmosphere. The excess of SOCI2 was removed under reduced pressure, the resulting crude oil was <n="76"/>dissolved in 20.3 ml. of MeCN and to this solution, a solution of TMSCHN2 2M in hexane (11.1 mmole, Aldrich) was added dropwise at O0C. The reaction mixture was warmed to RT and stirred for 2 h. A 1 M solution of citric acid was added and then extracted with AcOEt. The organic layer was washed with a saturated solution of NaHCC>3, dried over Na2SO4 and concentrated under reduced pressure. The crude oil was purified by flash chromatography (from CH to CH/AcOEt 80/20) to give the title compound as a yellow oil (489 mg, 42percent). 1H-NMR (500 MHz, CDCI3): delta 4.29-4.34 (2H, m), 4.35-4.40 (2H, m), 6.25 (1 H, s), 6.92 (1 H, t), 7.02 (1 H, dd), 7.46 (1 H, s); m/z (ES): 205 [M+H]+.

References: [1]Journal of Organic Chemistry,1948,vol. 13,p. 489,493.
[2]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1609 - 1616.
[3]Patent: US5332735,1994,A .
[4]Journal of Agricultural and Food Chemistry,2011,vol. 59,p. 635 - 644.
[5]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5870 - 5875.
[6]Journal of Medicinal Chemistry,2013,vol. 56,p. 220 - 240.
[7]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 2947 - 2954.
[8]Chemistry - A European Journal,2016,vol. 22,p. 12286 - 12289.
[9]Journal of Medicinal Chemistry,2017,vol. 60,p. 180 - 201.
[10]Journal of Medicinal Chemistry,2018,vol. 61,p. 918 - 933.
[11]Patent: WO2008/148853,2008,A1 .Location in patent: Page/Page column 73-74.
[12]Organic Letters,2019,vol. 21,p. 2645 - 2649.

2
[ 303-38-8 ]
[ 106-93-4 ]
[ 4442-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	Step A 5-Carboxy-2,3-dihydro-1,4-benzodioxin A mixture of 10.8 g (70 mmol) of 2,3-dihydroxybenzoic acid, 38.6 g (280 mmol) of dry potassium carbonate and 24 ml (278 mmol) of 1,2-dibromoethane in 40 ml of N,N-dimethylformamide is heated at 65° C. for 24 hours under an inert atmosphere. After cooling, the reaction mixture is diluted with water and then extracted with ether. The aqueous phase is then acidified with a 3N hydrochloric acid solution and subsequently extracted with dichloromethane. After removal of the solvent by evaporation in vacuo, the residue obtained is recrystallized from toluene to yield the title acid in the form of a white solid. Melting point 193-194° C.

References: [1]Journal of Organic Chemistry,1948,vol. 13,p. 489,493.
[2]Patent: US5919814,1999,A .

3
[ 4442-53-9 ]
[ 148703-15-5 ]
2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid 1-butyl-piperidin-4-ylmethyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 4121 - 4123.

5
[ 953772-17-3 ]
[ 4442-53-9 ]
4-{2-[(2,3-Dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 40℃;	Example 8 Synthesis of 4-{2-[(2,3-Dihydro-benzo[1,4]dioxine-5-carbonyl)-amino]-benzooxazol-6-yloxy}-pyridine-2-carboxylic acid methylamide (Table 2, Compound 110) 4-(2-Amino-benzooxazol-6-yloxy)-pyridine-2-carboxylic acid methylamide (1 eq) and <strong>[4442-53-9]2,3-dihydro-1,4-benzodioxane-5-carboxylic acid</strong> (1 eq) were dissolved in DMF. To this solution were added DIPEA (3 eq) and [dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammonium hexafluoro phosphate (1 eq). The mixture was stirred at 40° C. overnight, then diluted with ethyl acetate and washed once each with 1N HCl, saturated aqueous sodium bicarbonate, and brine, and finally dried with anhydrous sodium sulfate, filtered, and concentrated. This was purified by preparatory reverse phase HPLC. MH+=447.0.

References: [1]Patent: US2008/45528,2008,A1 .Location in patent: Page/Page column 42.

6
[ 4442-53-9 ]
[ 364765-74-2 ]