121936-68-3|2-Bromo-5-hydroxy-4-methoxybenzoic acid| Ambeed

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Quality Control of [ 121936-68-3 ] Purity: 98% SDS Specification

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Product Details of [ 121936-68-3 ]

CAS No. :	121936-68-3
Formula :	C₈H₇BrO₄
M.W :	247.04
SMILES Code :	COC1=CC(Br)=C(C=C1O)C(O)=O
MDL No. :	MFCD16659606
Boiling Point :	No data available
InChI Key :	QOHWIPQTBHQOQW-UHFFFAOYSA-N
Pubchem ID :	44139642

Safety of [ 121936-68-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302+H312+H332-H315-H319-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 121936-68-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	2.0
Molar Refractivity	49.62
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	66.76 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.6
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	1.76
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.86
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.	1.48
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	1.43
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.63

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.69
Solubility	0.504 mg/ml ; 0.00204 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.	-2.78
Solubility	0.41 mg/ml ; 0.00166 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	-2.18
Solubility	1.62 mg/ml ; 0.00658 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.	-6.56 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)	1.65

Application In Synthesis of [ 121936-68-3 ]

* 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.

Upstream synthesis route of [ 121936-68-3 ]
Downstream synthetic route of [ 121936-68-3 ]

[ 121936-68-3 ] Synthesis Path-Upstream 1~8

1
[ 2973-59-3 ]
[ 121936-68-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: With aminosulfonic acid In water; ethyl acetate Stage #2: With sodium chlorite In water; ethyl acetate at -10 - 20℃; for 1 h;	Example 3; 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13); 1 Kg of 2-bromo-5-hydroxy-4-methoxy benzaldehyde (B2) and 1.255 Kg of sulfamic acid were added with stirring into a mixture of 4.473 Kg of EtOAc and 8 L of water. The reaction mixture was stirred until all of the solid had dissolved. The reaction mixture was cooled to between -10 and 0° C. An aqueous solution of sodium chlorite was prepared by dissolving 505 g of sodium chlorite in 3 L of water. The sodium chlorite solution was added to the pre-cooled B2 solution at a rate that maintained the reaction temperature under 5° C. After the complete addition of sodium chlorite solution, the reaction mixture was stirred for another hour at 0° C. and was then allowed to warm up to room temperature. The reaction was monitored by TLC. After the TLC analysis showed completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with EtOAc (1.789 Kg) and the combined organic layer was transferred to another flask and EtOAc was removed by vacuum distillation at 40° C. 6.92 Kg of toluene was added at between 30 to 40° C., the slurry was cooled to between -10 to 0° C. and the precipitate was collected by filtration to give about 950 g (89percent (wt?)yield) of 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13). ¹H NMR (CDCl₃) δ 3.95 (3H, s, CH₃), 7.22 (1H, s, CH), 7.46 (1H, s, CH).

References: [1] Patent: US2008/255347, 2008, A1, . Location in patent: Page/Page column 5.

2
[ 850856-55-2 ]
[ 121936-68-3 ]

References: [1] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208.

3
[ 621-59-0 ]
[ 121936-68-3 ]

References: [1] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208.

4
[ 52805-46-6 ]
[ 121936-68-3 ]

References: [1] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208.

5
[ 51673-94-0 ]
[ 121936-68-3 ]

References: [1] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208.

6
[ 859767-02-5 ]
[ 121936-68-3 ]

References: [1] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208.

7
[ 6286-46-0 ]
[ 121936-68-3 ]

References: [1] Yakugaku Zasshi, 1956, vol. 76, p. 1122,1125[2] Chem.Abstr., 1957, p. 3505.

8
[ 645-08-9 ]
[ 121936-68-3 ]

References: [1] Journal of Organic Chemistry, 1940, vol. 5, p. 204,208.

[ 121936-68-3 ] Synthesis Path-Downstream 1~23

1
[ 6286-46-0 ]
[ 121936-68-3 ]

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1956,vol. 76,p. 1122,1125.
Chem.Abstr.,1957,p. 3505.

2
[ 645-08-9 ]
[ 121936-68-3 ]

References: [1]Journal of Organic Chemistry,1940,vol. 5,p. 204,208.

3
[ 850856-55-2 ]
[ 121936-68-3 ]

References: [1]Journal of Organic Chemistry,1940,vol. 5,p. 204,208.

4
[ 621-59-0 ]
[ 121936-68-3 ]

References: [1]Journal of Organic Chemistry,1940,vol. 5,p. 204,208.

5
[ 52805-46-6 ]
[ 121936-68-3 ]

References: [1]Journal of Organic Chemistry,1940,vol. 5,p. 204,208.

6
[ 51673-94-0 ]
[ 121936-68-3 ]

References: [1]Journal of Organic Chemistry,1940,vol. 5,p. 204,208.

7
[ 859767-02-5 ]
[ 121936-68-3 ]

References: [1]Journal of Organic Chemistry,1940,vol. 5,p. 204,208.

8
[ 2973-59-3 ]
[ 121936-68-3 ]

Yield	Reaction Conditions	Operation in experiment
89%		Example 3; 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13); 1 Kg of 2-bromo-5-hydroxy-4-methoxy benzaldehyde (B2) and 1.255 Kg of sulfamic acid were added with stirring into a mixture of 4.473 Kg of EtOAc and 8 L of water. The reaction mixture was stirred until all of the solid had dissolved. The reaction mixture was cooled to between -10 and 0 C. An aqueous solution of sodium chlorite was prepared by dissolving 505 g of sodium chlorite in 3 L of water. The sodium chlorite solution was added to the pre-cooled B2 solution at a rate that maintained the reaction temperature under 5 C. After the complete addition of sodium chlorite solution, the reaction mixture was stirred for another hour at 0 C. and was then allowed to warm up to room temperature. The reaction was monitored by TLC. After the TLC analysis showed completion of the reaction, the aqueous layer was separated. The aqueous layer was extracted with EtOAc (1.789 Kg) and the combined organic layer was transferred to another flask and EtOAc was removed by vacuum distillation at 40 C. 6.92 Kg of toluene was added at between 30 to 40 C., the slurry was cooled to between -10 to 0 C. and the precipitate was collected by filtration to give about 950 g (89% (wt?)yield) of 2-bromo-5-hydroxy-4-methoxy benzoic acid (B13). 1H NMR (CDCl3) delta 3.95 (3H, s, CH3), 7.22 (1H, s, CH), 7.46 (1H, s, CH).

References: [1]Patent: US2008/255347,2008,A1 .Location in patent: Page/Page column 5.

9
[ 121936-68-3 ]
2-bromo-5-hydroxy-4-methoxybenzoyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;N,N-dimethyl-formamide; In ethyl acetate; at 45 - 50℃; for 1h;Product distribution / selectivity;	Example 4; N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2); Method 1; A mixture of <strong>[121936-68-3]2-bromo-5-hydroxy-4-methoxy benzoic acid</strong> (B13) (1.49 kg by purity), DMF (0.071 kg) and EtOAc (6.712 kg) was stirred and heated to about 45 to 50 C. under an atmosphere of nitrogen. To this was slowly added thionyl chloride (1.29 Kg) whilst maintaining the temperature at between 45 to 50 C. This was then stirred for about 1 hour. Thus formed 2-bromo-5-hydroxy-4-methoxy benzoyl chloride solution was concentrated under vacuum, cooled to about 30 C. and was then diluted with dichloromethane (9.95 kg) under an atmosphere of nitrogen.; Method 3; To a solution of 138 g <strong>[121936-68-3]2-bromo-5-hydroxy-4-methoxy benzoic acid</strong> (B13) in EA (690 mL) was added DMF (6.9 mL) and the reaction mixture was heated to 45-50 C. Thionyl chloride (120 g) was added to the solution and stirred at this temperature until TLC analysis indicated the complete disappearance of B13. The excess thionyl chloride and EA was removed by distillation at atmosphere pressure to give a liquid residue. The residue was cooled to 30 C. and was diluted with methylene chloride (690 mL) to give a B-13-Cl solution.
	With thionyl chloride;N,N-dimethyl-formamide; In 4-methyl-2-pentanone; at 80℃;Product distribution / selectivity;	Method 2; To a solution of 138 g <strong>[121936-68-3]2-bromo-5-hydroxy-4-methoxy benzoic acid</strong> (B13) in MIBK (690 mL) was added thionyl chloride (106 g) and DMF (13 mL) and the reaction mixture was heated to 80 C. and stirred at this temperature until TLC analysis indicated the complete disappearance of B13. The resulting mixture was subjected to distillation to remove the excess thionyl chloride. After distillation of thionyl chloride, the resulting acid chloride solution was cooled to room temperature and was added to a solution of 100 g of N-methyl-N-(2-[4-hydroxyphenyl]ethyl) amine HBr (A12 HBr) and 94 g Na2CO3 in 1000 mL of MIBK and 600 mL H2O pre-cooled to 0 C. A solution of NaOH (82.5 g) in 165 mL H2O was added slowly to maintain the temperature under 5 C. The reaction mixture was stirred at this temperature until TLC analysis showed the complete disappearance of B13 acid chloride. The pH of the reaction mixture was brought to 10-11 by adding more NaOH and the resulting mixture was heated to 50 C. and stirred at this temperature for another 1 h. The reaction mixture was cooled to room temperature and the aqueous layer was separated. The organic layer was concentrated to th of its volume. 500 mL of heptane was added. The precipitate was collected by filtration to give 163 g (65% yield) of N-methyl-N-(2-[4-hydroxyphenyl]ethyl)-2-bromo-5-hydroxy-4-methoxy benzene carboxamide (C2).
	With thionyl chloride; In dichloromethane; at 76℃; for 7h;	General procedure: To the respective 2-bromobenzoic acid (2-bromo-4,5- dimethoxybenzoic acid, <strong>[121936-68-3]2-bromo-5-hydroxy-4-methoxybenzoic acid</strong> or 2-bromo-3,4,5-trimethoxybenzoic acid) (1 eq) was added thionyl chloride (1 M in CH2Cl2, 2 mL per mmol carboxylic acid) and the reaction mixture was stirred at 76 C for 7 h. After cooling to room temperature, the volatiles were removed in vacuo and the amine (44 eq of conc. aqueous NH3 solution or methyl amine, respectively) was added at 0 C. The reaction mixture was stirred at 0 C for 1 h and allowed to warm up to room temperature while stirring overnight. The mixture was acidified with conc. HCl and extracted with EtOAc (3 20 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4 and the solvents were removed in vacuo.

References: [1]Patent: US2008/255347,2008,A1 .Location in patent: Page/Page column 6.
[2]Patent: US2008/255347,2008,A1 .Location in patent: Page/Page column 6.
[3]Tetrahedron,2020.

10
[ 121936-68-3 ]
[ 108-46-3 ]
[ 1006683-96-0 ]