74733-30-5|Methyl 4-(bromomethyl)-3-chlorobenzoate| Ambeed

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Quality Control of [ 74733-30-5 ] Purity: 95% SDS Specification

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Product Details of [ 74733-30-5 ]

CAS No. :	74733-30-5
Formula :	C₉H₈BrClO₂
M.W :	263.52
SMILES Code :	O=C(OC)C1=CC=C(CBr)C(Cl)=C1
MDL No. :	MFCD10566565
InChI Key :	XTZCVWDSGCVDFI-UHFFFAOYSA-N
Pubchem ID :	22027761

Safety of [ 74733-30-5 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H314
Precautionary Statements:	P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501
Class:	8
UN#:	3261
Packing Group:	Ⅱ

Computational Chemistry of [ 74733-30-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	3
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	55.57
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.	2.58
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	2.96
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.87
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.	3.25
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	3.36
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.0

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.48
Solubility	0.0868 mg/ml ; 0.00033 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.	-3.18
Solubility	0.176 mg/ml ; 0.000668 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	-4.35
Solubility	0.0118 mg/ml ; 0.0000448 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	1.0 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<0.0
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)	1.89

Application In Synthesis of [ 74733-30-5 ]

* 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 [ 74733-30-5 ]

[ 74733-30-5 ] Synthesis Path-Downstream 1~35

1
[ 74733-30-5 ]
[ 104436-05-7 ]
[ 104447-88-3 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2437 - 2451.

2
[ 74733-30-5 ]
[ 148674-44-6 ]
[ 152147-77-8 ]

References: [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 1880 - 1892.

3
[ 56525-63-4 ]
[ 74733-30-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With tert.-butylhydroperoxide; cetyltrimethylammonim bromide; potassium bromide; In water; at 120℃; under 750.075 Torr;Microwave irradiation;	General procedure: The reaction mixture was treated in a controlled microwavesynthesizer (Biotage Initiator+SP Wave model, 0-200 W at2.45 GHz, capped at 60 W during steady state) for severalminutes (the reaction attained 120 C at 1 bar pressure). Thefinal products were isolated by column chromatographyusing an EtOAc-hexane gradient
84%	With 2,2'-azobis(2-methylpropionitrile); N-Bromosuccinimide; In tetrachloromethane; for 18h;Heating / reflux;	To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml) were added N-bromosuccinimide (5.8 g, 32.0 mmol) and 2,2'-azo-bis(2-methylpropionitrile) (0.442 g, 2.70 mmol). The mixture was heated at reflux for 18 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant pet. ether ? 5% ethyl acetate/95% pet. ether) to give an oil identified as methyl 4-bromomethyl-3-chlorobenzoate (5.96 g, 84%).
84%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Heating / reflux;	To a solution of methyl 3-chloro-4-methylbenzoate (5.0g, 27.1mmol) in carbon tetrachloride (50ml) were added NBS (5.8g, 32.0mmol) and AIBN (0.442g, 2.70mmol). The mixture was stirred at reflux for 18h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96g (84%).

84%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Heating / reflux;	To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol).. The mixture was stirred at reflux for 18 h.. The mixture was allowed to cool to room temperature and then concentrated in vacuo.. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%).
75%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 4h;Heating / reflux;	step 1-A mixture of 184a (2 mmol), NBS (2.2 mmol) and AIBN (100 mg) in CCl4 (20 mL) was heated at reflux for 4 h. The mixture was cooled, filtered and the filtrate was concentrated in vacuo. The residue was purified by SiO2 chromatography to afford 0.395 g (75%) of 184b.
5.96 g (84%)	With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane;	A1. Methyl 4bromomethyl-3-chlorobenzoate To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%).
	With N-Bromosuccinimide;benzoic peroxyanhydride; In tetrachloromethane;	(2) Preparation of methyl 4-bromomethyl-3-chlorobenzoate Methyl 4-methyl-3-chlorobenzoate (4.5 g, 0.024 mol) was dissolved in carbon tetrachloride (100 ml), and thereto were added N-bromosuccinimide (4.8 g, 0.026 mol) and a catalytic amount of perbenzoic anhydride. The mixture was heated and refluxed under nitrogen atmosphere for 2 hours, allowed to cool, and the precipitate was separated by filtration. The filtrate was concentrated, and separated and purified by using a silica-gel column chromatography (ethyl acetate:n-hexane=1:20) to give the title compound (4.7 g, 0.018 mol) (yield 75%). NMR (CDCl3) delta: 8.04 (s, 1H), 7.91 (bd, J=8.13Hz, 1H), 7.50 (d, J=7.92Hz, 1H), 4.58 (s, 2H), 3.92 (s, 3H)
5.96 g (84%)	With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane;	A1. Methyl 4-bromomethyl-3-chlorobenzoate To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%).
	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux;	(2-Chloro-4-(methoxycarbonyl)benzyl)triphenylphosphonium bromideMethyl 3-chloro-4-methylbenzoate (2.20 g, 11.96 mmol) was dissolved in carbon tetrachloride (30 mL) and N-bromosuccinimide (2.10 g, 11.80 mmol) was added followed by a catalytic amount of benzoyl peroxide (25 mg). The reaction mixture was refluxed for 6h. (ca. 90% conversion). After cooling to room temperature, a precipitate was filtered. The filtrate was concentrated to give crude brominated intermediate (3.20 g), which was used for the next step without further purification.
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 6h;Reflux;	Methyl 3-chloro-4-methylbenzoate (2.20 g, 11.96 mmol) was dissolved in carbon tetrachloride (30 mL) and N-bromosuccinimide (2.10 g, 11.80 mmol) was added followed by a catalytic amount of benzoyl peroxide (25 mg). The reaction mixture was refluxed for 6 h. (ca. 90% conversion). After cooling to room temperature, a precipitate was filtered. The filtrate was concentrated to give crude brominated intermediate (3.20 g), which was used for the next step without further purification.
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃;	Methyl 3-chloro-4-methylbenzoate (0.30 mL, 2.0 mmol) was dissolved in carbon tetrachloride (5 mL), N-bromosuccinimide (0.39 g, 2.2 mmol) and benzoyl peroxide (48 mg, 0.20 mmol) were added, and the mixture was stirred at 80 C. overnight. The reaction mixture was filtered and concentrated under reduced pressure, 8 mol/L ammonia-methanol solution was added to the obtained residue, and the mixture was stirred at room temperature for 90 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (5 mL). A-1 (0.36 g, 1.2 mmol), WSC hydrochloride (0.29 g, 1.5 mmol) and HOAt (0.16 g, 1.2 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reversed-phase high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (0.40 g, 0.84 mmol, 42%).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 100℃; for 15h;	To a solution of methyl 3-chloro-4-methyl-benzoate (22.5 g, 121 mmol) and 2,2- azobisisobutyronitrile (2.00 g, 12.2 mmol) in carbon tetrachloride (300 mL) was added 1- bromopyrrolidine-2,5-dione (23.8 g, 134 mmol) portion wise. The mixture was heated to 100 C and stirred at 100 C for 15 hours. On completion, the mixture was concentrated in vacuo to give a solid. The solid was washed with water (200 mL) and extracted with DCM (2 X 150 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified with silica gel chromatograph (petroleum ether: ethyl acetate = 100: 1) to give the title compound. NMR (400MHz, CDCh) delta = 7.99 (d, J = 1.5 Hz, 1H), 7.84 (dd, 7= 1.6, 8.0 Hz, 1H), 7.45 (d, J= 8.0 Hz, 1H), 4.53 (s, 2H), 3.86 (s, 3H).

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7774 - 7789.
[2]Synlett,2014,vol. 25,p. 2485 - 2487.
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4585 - 4589.
[4]Patent: EP1449844,2004,A1 .Location in patent: Page 20.
[5]Patent: WO2006/18443,2006,A1 .Location in patent: Page/Page column 19.
[6]Patent: US6664249,2003,B1 .Location in patent: Page column 10.
[7]Journal of Medicinal Chemistry,2017,vol. 60,p. 7703 - 7724.
[8]Patent: US2008/146595,2008,A1 .Location in patent: Page/Page column 39; 40.
[9]Journal of Medicinal Chemistry,2003,vol. 46,p. 345 - 348.
[10]Patent: US2003/87892,2003,A1 .
[11]Patent: US5409928,1995,A .
[12]Patent: US2004/38962,2004,A1 .
[13]Journal of Medicinal Chemistry,2009,vol. 52,p. 4481 - 4487.
[14]Patent: WO2012/118782,2012,A1 .Location in patent: Page/Page column 97-98.
[15]Patent: US2013/317003,2013,A1 .Location in patent: Paragraph 0468.
[16]Patent: US2015/284375,2015,A1 .Location in patent: Paragraph 0309.
[17]Patent: WO2017/156165,2017,A1 .Location in patent: Paragraph 00525; 00528; 00529.

4
[ 10442-39-4 ]
[ 74733-30-5 ]
[ 467442-06-4 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 345 - 348.

5
[ 74733-30-5 ]
[ 940062-11-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In ethanol; at 20℃; for 1h;	To a saturated solution of ammonia in ethanol (170ml) was added <strong>[74733-30-5]methyl 4-bromomethyl-3-chlorobenzoate</strong> from Example Al (5.5g, 20.9mmol). The mixture was stirred at room temperature for lhr and then concentrated in vacuo. The residue was triturated with diethyl ether and the resultant white crystals were filtered off and washed with more diethyl ether. To a solution of this solid in water (100ml) were added solutions of (BOC)20 (5.0g, 23.0mmol) in dioxan (100ml) and sodium hydroxide (1.86g, 46.0mmol) in water (100ml).The mixture was stirred at room temperature for 18h and then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with chloroform/IP A. The organic layer was washed with water, dried over MgS04, and concentrated in vacuo to give a white solid; yield 2.8g (67%).
	With ammonia; In methanol; at 20℃; for 1.5h;	Methyl 3-chloro-4-methylbenzoate (0.30 mL, 2.0 mmol) was dissolved in carbon tetrachloride (5 mL), N-bromosuccinimide (0.39 g, 2.2 mmol) and benzoyl peroxide (48 mg, 0.20 mmol) were added, and the mixture was stirred at 80 C. overnight. The reaction mixture was filtered and concentrated under reduced pressure, 8 mol/L ammonia-methanol solution was added to the obtained residue, and the mixture was stirred at room temperature for 90 min. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in dichloromethane (5 mL). A-1 (0.36 g, 1.2 mmol), WSC hydrochloride (0.29 g, 1.5 mmol) and HOAt (0.16 g, 1.2 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by reversed-phase high performance liquid chromatography (water-acetonitrile, each containing 0.1% trifluoroacetic acid) to give the title compound (0.40 g, 0.84 mmol, 42%).

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 4585 - 4589.
[2]Patent: WO2006/18443,2006,A1 .Location in patent: Page/Page column 19-20.
[3]Patent: US2015/284375,2015,A1 .Location in patent: Paragraph 0309.

6
[ 913078-78-1 ]
[ 74733-30-5 ]
[ 916913-67-2 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7774 - 7789.

7
3-chloro-4-methylphenyl trifluoromethanesulfonate [ No CAS ]
[ 74733-30-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7774 - 7789.

8
[ 615-62-3 ]
[ 74733-30-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7774 - 7789.

9
[ 74733-30-5 ]
3-chloro-4-{2-[isobutyl-(5-methyl-furan-2-sulfonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-benzoic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7774 - 7789.

10
[ 74733-30-5 ]
[ 165528-69-8 ]