[ CAS No. 1149388-19-1 ]

Name: 1149388-19-1|Methyl 4-bromo-3-hydroxy-2-methylbenzoate|97%
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Quality Control of [ 1149388-19-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1149388-19-1 ]

SDS Specification

Alternatived Products of [ 1149388-19-1 ]

Product Details of [ 1149388-19-1 ]

CAS No. :	1149388-19-1	MDL No. :	MFCD26389396
Formula :	C₉H₉BrO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KJQPVKLURCKVPY-UHFFFAOYSA-N
M.W :	245.07 g/mol	Pubchem ID :	57700291
Synonyms :

Calculated chemistry of [ 1149388-19-1 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.41
TPSA :	46.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.03 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.34
Log Po/w (XLOGP3) :	2.48
Log Po/w (WLOGP) :	2.25
Log Po/w (MLOGP) :	2.36
Log Po/w (SILICOS-IT) :	2.37
Consensus Log Po/w :	2.36

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.13
Solubility :	0.181 mg/ml ; 0.000739 mol/l
Class :	Soluble
Log S (Ali) :	-3.1
Solubility :	0.194 mg/ml ; 0.000791 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.14
Solubility :	0.176 mg/ml ; 0.000718 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.71

Safety of [ 1149388-19-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1149388-19-1 ]

* 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 [ 1149388-19-1 ]
Downstream synthetic route of [ 1149388-19-1 ]

[ 1149388-19-1 ] Synthesis Path-Upstream 1~2

1
[ 55289-05-9 ]
[ 1149388-19-1 ]

Yield	Reaction Conditions	Operation in experiment
33%	With bromine; <i>tert</i>-butylamine In dichloromethane at -70 - 20℃;	To a solution of iert-butylamine (2.0 g, 27.1 mmol) in DCM (180 mL) at -70 °C was added a solution of Br2 (4.2 g, 27.1 mmol) in DCM (10 mL) dropwise and the mixture was stirred at - 70 °C for 1 hour. A solution of methyl 3-hydroxy-2-methylbenzoate I89 (4.5 g, 27.1 mmol) in DCM (10 mL) was then added dropwise and the resulting mixture allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of water (30 mL) and the aqueous layer extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO.i) and concentrated. The crude residue obtained was purified by silica gel chromatography (2percent EtOAc in petroleum ether) to give the title compound (2.2 g, 33percent) as a white solid. LCMS-C: RT 2.46 min; m/z 245.0, 247.0 [M+H] \ ¹ H NMR (400 MHz, DMSO-cfe) δ 9.38 (s, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 3.80 (s, 3H), 2.38 (s, 3H)
22%	With bromine; <i>tert</i>-butylamine In dichloromethane at -78℃; for 2.5 h;	A 500 ml 3-neck round bottom flask was fitted with two dropping funnels. Towas added a solution of the tert-butyl amine (4.4 g, 60.2 mmol) in CH2C12 (140 ml)the tiask was cooled to -78°C. A solution of bromine (9.6 g, 60.2 mmol) in CH2C12ml) was added drop wise over 30 minutes from the dropping funnel. The mixture was stirred at -78°C for another 1 h. A solution of methyl 3-hydroxy-2-methyl benzoate (10.0 g, 60.2 mrnol) in CH2C12 (25 ml) was added from the second dropping funnel during 1 h. (US 2005110979). The reaction mixture was allowed to warm to room temperature and stir for overnight. LCMS showed 3 peaks. Aqueous work up and extraction with DCM followed by flash column chromatography using an ISCO system (2 X 80 g silica gel column, hexane/EtOAc solvent mixture) gave the product (1st peak, fractions 4-5, 3.3 g, 22percent yield). The side products isolated and characterized as dibromo and 5-bromo derivatives. 1H NMR (CDC13): 7.29-7.21 (dd, 2H), 5.64 (s, 1H), 3.81(s, 3H), 2.45(s, 3H).
20%	With bromine; <i>tert</i>-butylamine In dichloromethane at -78 - 20℃;	A solution of bromine (1.608 mL, 31.29 mmol) in dichloromethane (20 mL) was added was added dropwise over 30 min to a solution of 2-methylpropan-2-amine (3.30 mL, 31.29 mmol) in dichloromethane (100 mL) at -78° C. The solution was stirred for 30 min at -78° C. A solution of methyl 3-hydroxy-2-methylbenzoate (5.2 g, 31.29 mmol) in dichloromethane (30 mL) was added over 30 min. The reaction was allowed to reach room temperature, stirred over night and water was added. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, dried over magnesium sulphate and concentrated in vacuo. Purification by column chromatography, using a gradient of 0 to 10percent ethyl acetate in heptane as the eluent, gave 1.51 g (20percent yield) of the title compound:MS (ESI) m/z 245, 243 [M-1]^-

20%	With bromine; <i>tert</i>-butylamine In dichloromethane at -78 - 20℃;	A solution of bromine (1.608 mL, 31.29 mmol) in dichloromethane (20 mL) was added was added dropwise over 30 min to a solution of 2-methylpropan-2-amine (3.30 mL, 31.29 mmol) in dichloromethane (100 mL) at -78⁰C. The solution was stirred for 30 min at - 78⁰C. A solution of methyl 3-hydroxy-2-methylbenzoate (5.2 g, 31.29 mmol) in dichloromethane (30 mL) was added over 30 min. The reaction was allowed to reach room temperature, stirred over night and water was added. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, dried over magnesium sulphate and concentrated in vacuo. Purification by column chromatography, using a gradient of 0 to 10percent ethyl acetate in heptane as the eluent, gave 1.51 g (20percent yield) of the title compound: MS (ESI) m/z 245, 243 [M-I]^"
17%	With bromine; <i>tert</i>-butylamine In dichloromethane at -78 - 20℃; for 15.5 h;	STEP 2: To a solution of tert-butylamine (1.6 mL, 15 mmol) in dichloromethane (100 mL) at -78⁰C was added drop-wise over 30 minutes a solution of bromine (773 μl, 15 mmol in 15 mL of dichloromethane). The solution was stirred at -78⁰C for 30 minutes. While maintaining the temperature at -78⁰C, a solution of methyl 3-hydroxy-2-methylbenzoate (2.5 g, 15 mmol in 15 mL of dichloromethane) was added to the reaction mixture drop-wise over 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The mixture was washed with 20percent aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was purified by silica gel column chromatography. Eluting with 10percent diethyl ether in hexane, purified fractions were pooled and concentrated to afford 612 mg, 2.5 mmol (17percent) of methyl 4-bromo-3-hydroxy-2-methylbenzoate as a colorless oil. ¹H NMR (400 MHz, CDCl₃): 7.37-7.29 (m, 2H), 5.71 (s, IH), 3.81 (s, 3H), 2.53 (s, 3H). MS (EI) for C₉H₉BrO₃: 245 (MH⁺).

Reference： [1] Patent: WO2016/34673, 2016, A1, . Location in patent: Page/Page column 108
[2] Patent: WO2014/144380, 2014, A1, . Location in patent: Paragraph 0482
[3] Patent: US2009/131468, 2009, A1, . Location in patent: Page/Page column 40-41
[4] Patent: WO2009/64251, 2009, A1, . Location in patent: Page/Page column 78
[5] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 401

2
[ 603-80-5 ]
[ 1149388-19-1 ]

Reference： [1] Patent: WO2014/144380, 2014, A1,
[2] Patent: WO2016/34673, 2016, A1,

[ 1149388-19-1 ] Synthesis Path-Downstream 1~53

1
[ 1149388-19-1 ]
[ 74-88-4 ]
[ 1149388-20-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In acetonitrile; at 50℃; for 5h;	G1. 4-Bromo-3-methoxy-2-methyl-benzoic acid methyl ester A solution of <strong>[1149388-19-1]methyl 4-bromo-3-hydroxy-2-methylbenzoate</strong> (1.0 g, 4.08 mmoi) in dry MeCN (7 mL) was treated with potassium carbonate (0.677 g, 4.90 mmol), then iodomethane (0.762 mL, 12.24 mmoi) and the mixture heated at 50 C for 5 hrs. Solvents were removed in vacuo and the residue partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with further EtOAc (2 x 20 mL) and the combined organics washed with brine (20 mL), dried (MgSO4), filtered and concentrated to give 4-bromo-3-methoxy-2-methyl-benzoic acid methyl ester (974 mg, 91 % yleld). [MH]+ = 259.0//261.0
81%	With potassium carbonate; In N,N-dimethyl-formamide; acetone; at 20℃;	<strong>[1149388-19-1]Methyl 4-bromo-3-hydroxy-2-methylbenzoate</strong> (1.51 g, 6.16 mmol), iodomethane (1.161 mL, 18.48 mmol) and potassium carbonate (2.55 g, 18.48 mmol) were dissolved in N,N-dimethylformamide (10 mL) and acetone (10 mL) and stirred at room temperature over night. Water was added and the aqueous phase was extracted with ethyl acetate and dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo to gave 1.3 g (81% yield) of the title compound.1H NMR (CDCl3) delta ppm 7.56-7.49 (m, 1H) 7.47-7.38 (m, 1H) 3.90 (s, 3H) 3.81 (s, 3H) 2.57 (s, 3H)
81%	With potassium carbonate; In N,N-dimethyl-formamide; acetone; at 20℃;	<strong>[1149388-19-1]Methyl 4-bromo-3-hydroxy-2-methylbenzoate</strong> (1.51 g, 6.16 mmol), iodomethane (1.161 mL, 18.48 mmol) and potassium carbonate (2.55 g, 18.48 mmol) were dissolved in N,N- dimethylformamide (10 mL ) and acetone (10 mL) and stirred at room temperature over night. Water was added and the aqueous phase was extracted with ethyl acetate and dichloromethane. The combined organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo to gave 1.3 g (81% yield) of the title compound. 1H NMR (CDCl3) delta ppm 7.56 - 7.49 (m, 1 H) 7.47 - 7.38 (m, 1 H) 3.90 (s, 3 H) 3.81 (s, 3 H) 2.57 (s, 3 H)

71%

With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 15h;

STEP 3 : A solution of methyl 4-bromo-3 -hydroxy-2-methylbenzoate (610 mg, 2.5 mmol), cesium carbonate (1.22 g, 3.7 mmol) and iodomethane (162 mul, 2.6 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 15 hours. The mixture was diluted with ethyl acetate, then washed with 5% aqueous lithium chloride then brine and dried over anhydrous sodium sulfate. Filtration and <n="404"/>concentration affored an orange residue, which was purified by silica gel column chromatography. Eluting with 15% diethyl ether in hexane, purified fractions were pooled and concentrated to afford 455 mg, 1.76 mmol (71%) of methyl 4-bromo-2- methyl-3-(methyloxy)benzoate as a colorless residue. 1H NMR (400 MHz, CDCl3): 7.52 (d, IH), 7.43 (d, IH), 3.88 (s, 3H), 3.80 (s, 3H), 2.55 (s, 3H). MS (EI) for Ci0HnBrO3: 260 (MH+).

Reference： [1]Patent: WO2016/83816,2016,A1 .Location in patent: Page/Page column 41-42
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 14625 - 14628
Angew. Chem.,2019,vol. 131,p. 14767 - 14770,4
[3]Patent: US2009/131468,2009,A1 .Location in patent: Page/Page column 41
[4]Patent: WO2009/64251,2009,A1 .Location in patent: Page/Page column 77
[5]Patent: WO2009/55077,2009,A1 .Location in patent: Page/Page column 401-402

2
[ 55289-05-9 ]
[ 1149388-19-1 ]

Yield	Reaction Conditions	Operation in experiment
33%	With bromine; tert-butylamine; In dichloromethane; at -70 - 20℃;	To a solution of iert-butylamine (2.0 g, 27.1 mmol) in DCM (180 mL) at -70 C was added a solution of Br2 (4.2 g, 27.1 mmol) in DCM (10 mL) dropwise and the mixture was stirred at - 70 C for 1 hour. A solution of methyl 3-hydroxy-2-methylbenzoate I89 (4.5 g, 27.1 mmol) in DCM (10 mL) was then added dropwise and the resulting mixture allowed to warm to room temperature and stirred overnight. The reaction was quenched by addition of water (30 mL) and the aqueous layer extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine, dried (Na2SO.i) and concentrated. The crude residue obtained was purified by silica gel chromatography (2% EtOAc in petroleum ether) to give the title compound (2.2 g, 33%) as a white solid. LCMS-C: RT 2.46 min; m/z 245.0, 247.0 [M+H] 1 H NMR (400 MHz, DMSO-cfe) delta 9.38 (s, 1 H), 7.46 (d, J = 8.4 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 1 H), 3.80 (s, 3H), 2.38 (s, 3H)
22%	With bromine; tert-butylamine; In dichloromethane; at -78℃; for 2.5h;	A 500 ml 3-neck round bottom flask was fitted with two dropping funnels. Towas added a solution of the tert-butyl amine (4.4 g, 60.2 mmol) in CH2C12 (140 ml)the tiask was cooled to -78C. A solution of bromine (9.6 g, 60.2 mmol) in CH2C12ml) was added drop wise over 30 minutes from the dropping funnel. The mixture was stirred at -78C for another 1 h. A solution of methyl 3-hydroxy-2-methyl benzoate (10.0 g, 60.2 mrnol) in CH2C12 (25 ml) was added from the second dropping funnel during 1 h. (US 2005110979). The reaction mixture was allowed to warm to room temperature and stir for overnight. LCMS showed 3 peaks. Aqueous work up and extraction with DCM followed by flash column chromatography using an ISCO system (2 X 80 g silica gel column, hexane/EtOAc solvent mixture) gave the product (1st peak, fractions 4-5, 3.3 g, 22% yield). The side products isolated and characterized as dibromo and 5-bromo derivatives. 1H NMR (CDC13): 7.29-7.21 (dd, 2H), 5.64 (s, 1H), 3.81(s, 3H), 2.45(s, 3H).
21%	With N-Bromosuccinimide; In dichloromethane; at -78℃; for 1h;	[0280] NBS (53.6 g, 301.2 mmol) was added to a solution of methyl 3-hydroxy- 2-methylbenzoate (50.0 g, 301.2 mmol) in DCM (800 mL) at -78 oC. The mixture was stirred at -78 oC for 1 hour then concentrated. The crude product was purified by silica gel chromatography eluting with EtOAc in petroleum ether (from 0% to 8%) to give methyl 4- bromo-3-hydroxy-2-methylbenzoate (15.0 g, 21% yield) as a colorless solid.

20%	With bromine; tert-butylamine; In dichloromethane; at -78 - 20℃;	A solution of bromine (1.608 mL, 31.29 mmol) in dichloromethane (20 mL) was added was added dropwise over 30 min to a solution of 2-methylpropan-2-amine (3.30 mL, 31.29 mmol) in dichloromethane (100 mL) at -78 C. The solution was stirred for 30 min at -78 C. A solution of methyl 3-hydroxy-2-methylbenzoate (5.2 g, 31.29 mmol) in dichloromethane (30 mL) was added over 30 min. The reaction was allowed to reach room temperature, stirred over night and water was added. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, dried over magnesium sulphate and concentrated in vacuo. Purification by column chromatography, using a gradient of 0 to 10% ethyl acetate in heptane as the eluent, gave 1.51 g (20% yield) of the title compound:MS (ESI) m/z 245, 243 [M-1]-
20%	With bromine; tert-butylamine; In dichloromethane; at -78 - 20℃;	A solution of bromine (1.608 mL, 31.29 mmol) in dichloromethane (20 mL) was added was added dropwise over 30 min to a solution of 2-methylpropan-2-amine (3.30 mL, 31.29 mmol) in dichloromethane (100 mL) at -780C. The solution was stirred for 30 min at - 780C. A solution of methyl 3-hydroxy-2-methylbenzoate (5.2 g, 31.29 mmol) in dichloromethane (30 mL) was added over 30 min. The reaction was allowed to reach room temperature, stirred over night and water was added. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with water, dried over magnesium sulphate and concentrated in vacuo. Purification by column chromatography, using a gradient of 0 to 10% ethyl acetate in heptane as the eluent, gave 1.51 g (20% yield) of the title compound: MS (ESI) m/z 245, 243 [M-I]"
17%	With bromine; tert-butylamine; In dichloromethane; at -78 - 20℃; for 15.5h;	STEP 2: To a solution of tert-butylamine (1.6 mL, 15 mmol) in dichloromethane (100 mL) at -780C was added drop-wise over 30 minutes a solution of bromine (773 mul, 15 mmol in 15 mL of dichloromethane). The solution was stirred at -780C for 30 minutes. While maintaining the temperature at -780C, a solution of methyl 3-hydroxy-2-methylbenzoate (2.5 g, 15 mmol in 15 mL of dichloromethane) was added to the reaction mixture drop-wise over 30 minutes. The mixture was allowed to warm to room temperature and was stirred for 15 hours. The mixture was washed with 20% aqueous citric acid then brine and dried over anhydrous sodium sulfate. Filtration and concentration afforded a brown residue that was purified by silica gel column chromatography. Eluting with 10% diethyl ether in hexane, purified fractions were pooled and concentrated to afford 612 mg, 2.5 mmol (17%) of methyl 4-bromo-3-hydroxy-2-methylbenzoate as a colorless oil. 1H NMR (400 MHz, CDCl3): 7.37-7.29 (m, 2H), 5.71 (s, IH), 3.81 (s, 3H), 2.53 (s, 3H). MS (EI) for C9H9BrO3: 245 (MH+).

Reference： [1]Patent: WO2016/34673,2016,A1 .Location in patent: Page/Page column 108
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 14625 - 14628
Angew. Chem.,2019,vol. 131,p. 14767 - 14770,4
[3]Patent: WO2014/144380,2014,A1 .Location in patent: Paragraph 0482
[4]Patent: WO2019/40274,2019,A1 .Location in patent: Paragraph 0280
[5]Patent: US2009/131468,2009,A1 .Location in patent: Page/Page column 40-41
[6]Patent: WO2009/64251,2009,A1 .Location in patent: Page/Page column 78
[7]Patent: WO2009/55077,2009,A1 .Location in patent: Page/Page column 401

3
[ 1149388-19-1 ]
[ 6482-24-2 ]
methyl 4-bromo-3-(2-methoxyethoxy)-2-methlbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		2-Methyl-3-hydroxyl-4-Bromo methyl ester (2.0 g, 8.16 mmol) was dissolved in anhydrous DMF (20 ml) in a 100 ml round bottom flask fitted with a reflux condenser, and anhydrous potassium carbonate (2.26 g, 16.32 mmol) was added to it. The reaction mixture was stirred at room temperature under argon for 15 nin. To this, 1-bromo-2- methoxyethane (1.70 g, 12.24 mmol) was added and the reaction mixture was heated to 90C and stirred overnight under argon. LCMS showed single peak. The reaction mixture was cooled. After aqueous work up and extraction with EtOAc, the organic fractions were collected, dried over anhydrous MgSO4, filtered, and concentrated. It was used in the next step without further purification.

Reference： [1]Patent: WO2014/144380,2014,A1 .Location in patent: Paragraph 0498

4
[ 603-80-5 ]
[ 1149388-19-1 ]

Reference： [1]Patent: WO2014/144380,2014,A1
[2]Patent: WO2016/34673,2016,A1
[3]Patent: WO2019/40274,2019,A1

5
[ 1149388-19-1 ]
4-bromo-N'-(tert-butyl)-2-methyl-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzohydrazide [ No CAS ]