111128-12-2

Basic information

• Product Name: 2-(4-Bromomethyl)phenylpropionic acid
• Synonyms: 4-(BROMOMETHYL)HYDRATROPIC ACID;2-[4-(BROMOMETHYL)PHENYL]PROPANOIC ACID;2-[4-(BROMOMETHYL)PHENYL]PROPIONIC ACID;2-[(P-BROMOMETHYL)PHENYL]PROPIONIC ACID;BMPPA;2-[4-(Bromomethyl)phenyl]propinic acid;Loxoprofen Intermediate;2-((4-Bromomethyl)phenyl)propanic acid
• CAS NO: 111128-12-2
• Molecular Formula: C₁₀H₁₁BrO₂
• Molecular Weight: 243.09714
• EINECS: 2017-001-1
• Product Categories: Aromatic Propionic Acids;Organic acids;(intermediate of loxoprofen);C10;Carbonyl Compounds;Carboxylic Acids;Pharmaceutical intermediate
• Mol File: 111128-12-2.mol
• Article Data: 17

Chemical Properties

• Melting Point: 126-130 °C(lit.)
• Boiling Point: 148°C (rough estimate)
• Flash Point: 162 °C
• Appearance: Beige-cream crystalline powder
• Density: 1.4557 (rough estimate)
• Vapor Pressure: 2.54E-05mmHg at 25°C
• Refractive Index: 1.5220 (estimate)
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• PKA: 4.29±0.10(Predicted)
• CAS DataBase Reference: 2-(4-Bromomethyl)phenylpropionic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(4-Bromomethyl)phenylpropionic acid(111128-12-2)
• EPA Substance Registry System: 2-(4-Bromomethyl)phenylpropionic acid(111128-12-2)

Safety Data

• Hazard Codes: C,Xi
• Statements: 34-36/37/38
• Safety Statements: 26-27-36/37/39-45-37/39
• RIDADR: UN 1759 8/PG 2
• WGK Germany: 3
• HazardClass: 8
• PackingGroup: Ⅱ
• Hazardous Substances Data: 111128-12-2(Hazardous Substances Data)

Usage

Chemical Properties

beige-cream crystalline powder

General Description

2-[4-(Bromomethyl)phenyl]propionic acid is a propionic acid derivative. Its enthalpy of vaporization at boiling point (421.15K) is 36.363kjoule/mol and density at 25°C is 1.4212g/ml.

InChI:InChI=1/C10H11BrO2/c1-7(10(12)13)9-4-2-8(6-11)3-5-9/h2-5,7H,6H2,1H3,(H,12,13)/p-1/t7-/m1/s1

Synthetic route

formaldehyd (50-00-0) + hydratropic acid (492-37-5, 2328-24-7) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
With sulfuric acid; hydrogen bromide at 35 - 70℃; for 11h; Temperature;	99%
With sulfuric acid; hydrogen bromide at 35 - 90℃; for 11.5h; Temperature;	96%
Stage #1: formaldehyd; hydratropic acid With hydrogen bromide at 55 - 65℃; Stage #2: With sulfuric acid at 20 - 65℃;	96%

(R,S)-2-(4'-methylphenyl) propionic acid (938-94-3) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
With bromine; dibenzoyl peroxide In dichloromethane Reflux;	92%
With bromine; dibenzoyl peroxide In dichloromethane at 40℃; for 0.0416667h; Temperature;	90%
With hydrogen bromide; bromine In ethyl acetate at 20℃; for 2h;	79%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane Solvent; Reflux;	42.05 g
With hydrogen bromide; dihydrogen peroxide; dibenzoyl peroxide In dichloromethane at 10 - 15℃; Irradiation;

C10H10Br2O2 → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; phosphonic acid diethyl ester In water; toluene at 5 - 85℃; for 6h; Reagent/catalyst; Inert atmosphere;	85.3%

trioxane (188680-60-6) + hydratropic acid (492-37-5, 2328-24-7) + cetyltrimethylammonim bromide (57-09-0) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
With hydrogen bromide; acetic acid
With hydrogen bromide; acetic acid

sodium 2-phenyl-2-cyanopropionate → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene / 3 h / 35 - 75 °C 2.1: sodium hydroxide / 1 h / 80 °C 3.1: sodium hydroxide / 12.5 h / 105 °C / Reflux 3.2: 0.58 h / pH 3 4.1: sulfuric acid; hydrogen bromide / 11.5 h / 35 - 90 °C View Scheme

phenylacetonitrile (140-29-4) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium methylate / methanol; toluene / 10 h / 20 °C 2.1: toluene / 3 h / 35 - 75 °C 3.1: sodium hydroxide / 1 h / 80 °C 4.1: sodium hydroxide / 12.5 h / 105 °C / Reflux 4.2: 0.58 h / pH 3 5.1: sulfuric acid; hydrogen bromide / 11.5 h / 35 - 90 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / 15 h / 250 °C / 30003 Torr / Autoclave 2: sodium hydroxide; water / 8 h / 40 °C 3: sulfuric acid; hydrogen bromide / 11 h / 35 - 70 °C View Scheme

2-methoxycarbonyl-2-phenylpropionitrile (79341-72-3) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium hydroxide / 1 h / 80 °C 2.1: sodium hydroxide / 12.5 h / 105 °C / Reflux 2.2: 0.58 h / pH 3 3.1: sulfuric acid; hydrogen bromide / 11.5 h / 35 - 90 °C View Scheme

CH3C6H4CH(CH3)OH (536-50-5) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; calcium chloride / dichloromethane / 40 h 2: dimethyl sulfoxide / 18 h / 90 °C / Reflux 3: hydrogenchloride / 1 h / Reflux 4: hydrogen bromide; bromine / ethyl acetate / 2 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: thionyl chloride / toluene / Reflux 2: tetrabutylammomium bromide / toluene; water / 8 h / 60 - 70 °C 3: sodium hydroxide / 100 - 105 °C 4: dibenzoyl peroxide; bromine / dichloromethane / Reflux View Scheme

1-(4-methylphenyl)ethyl 4-methylbenzenesulfonate (82925-34-6) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: dimethyl sulfoxide / 18 h / 90 °C / Reflux 2: hydrogenchloride / 1 h / Reflux 3: hydrogen bromide; bromine / ethyl acetate / 2 h / 20 °C View Scheme

para-methylacetophenone (122-00-9) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / methanol 2: triethylamine; calcium chloride / dichloromethane / 40 h 3: dimethyl sulfoxide / 18 h / 90 °C / Reflux 4: hydrogenchloride / 1 h / Reflux 5: hydrogen bromide; bromine / ethyl acetate / 2 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: sodium tetrahydroborate / methanol / 15 - 35 °C 2: thionyl chloride / toluene / Reflux 3: tetrabutylammomium bromide / toluene; water / 8 h / 60 - 70 °C 4: sodium hydroxide / 100 - 105 °C 5: dibenzoyl peroxide; bromine / dichloromethane / Reflux View Scheme

(+/-)-2-(4'-methylphenyl)-propionitrile (75920-45-5) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride / 1 h / Reflux 2: hydrogen bromide; bromine / ethyl acetate / 2 h / 20 °C View Scheme

1-(1-chloroethyl)-4-methylbenzene (2362-36-9) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium / tetrahydrofuran / 1.5 h / 20 - 30 °C / Inert atmosphere 2: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / dichloromethane / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: magnesium / tetrahydrofuran; ethylene dibromide / 13 h / 60 - 65 °C / Inert atmosphere 1.2: 20 - 25 °C 2.1: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: magnesium / tetrahydrofuran; ethylene dibromide / 13 h / 60 - 65 °C / Inert atmosphere 1.2: 20 - 25 °C 2.1: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere 3.1: tetra-(n-butyl)ammonium iodide; phosphonic acid diethyl ester / water; toluene / 6 h / 5 - 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: tetrabutylammomium bromide / toluene; water / 8 h / 60 - 70 °C 2: sodium hydroxide / 100 - 105 °C 3: dibenzoyl peroxide; bromine / dichloromethane / Reflux View Scheme

1-ethenyl-4-methylbenzene (622-97-9) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / water / 6 h / 65 - 70 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran; ethylene dibromide / 13 h / 60 - 65 °C / Inert atmosphere 2.2: 20 - 25 °C 3.1: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: hydrogen bromide / 5 h / 60 - 65 °C / Inert atmosphere 2: magnesium / tetrahydrofuran; ethylene dibromide / 55 - 65 °C 3: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: hydrogenchloride / water / 6 h / 65 - 70 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran; ethylene dibromide / 13 h / 60 - 65 °C / Inert atmosphere 2.2: 20 - 25 °C 3.1: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere 4.1: tetra-(n-butyl)ammonium iodide; phosphonic acid diethyl ester / water; toluene / 6 h / 5 - 85 °C / Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1: hydrogen bromide / 5 h / 60 - 65 °C / Inert atmosphere 2: magnesium / tetrahydrofuran; ethylene dibromide / 55 - 65 °C 3: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere 4: tetra-(n-butyl)ammonium iodide; phosphonic acid diethyl ester / water; toluene / 6 h / 5 - 85 °C / Inert atmosphere View Scheme

1-(1-bromoethyl)-4-methylbenzene (159755-12-1) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: magnesium / tetrahydrofuran; ethylene dibromide / 55 - 65 °C 2: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: magnesium / tetrahydrofuran; ethylene dibromide / 55 - 65 °C 2: bromine; 2,2'-azobis(isobutyronitrile) / dichloromethane / 40 - 55 °C / Inert atmosphere 3: tetra-(n-butyl)ammonium iodide; phosphonic acid diethyl ester / water; toluene / 6 h / 5 - 85 °C / Inert atmosphere View Scheme

(R,S)-2-(4'-methylphenyl) propionic acid (938-94-3) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + C10H10Br2O2

Conditions	Yield
With 2,2'-azobis(isobutyronitrile); bromine In dichloromethane at 40 - 55℃; Solvent; Reagent/catalyst; Temperature; Inert atmosphere;

styrene (292638-84-7) → 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / dichloromethane / 5 h / 10 - 20 °C 2.1: magnesium / 2-methyltetrahydrofuran / 5 h / 20 - 30 °C 2.2: 5 h / 20 - 30 °C 3.1: sulfuric acid; hydrogen bromide / 3 h / 50 - 120 °C View Scheme

methanol (67-56-1) + 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) → 2-(4-bromomethylphenyl)propionic acid methyl ester (99807-54-2)

Conditions	Yield
In 2,2,4-trimethylpentane at 65℃; for 0.5h; Solvent; Temperature;	99.7%
Stage #1: methanol With sulfuric acid In toluene at 35℃; Stage #2: 2-[4-(bromomethyl)phenyl]propanoic acid In toluene at 281℃; for 5h;	98.7%
With sulfuric acid at 0 - 5℃; for 6h;	98%

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + ethanol (64-17-5) → ethyl 2-(4-bromomethylphenyl)propanoate

Conditions	Yield
In toluene at 79℃; for 0.333333h; Time;	97.8%

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) → 2-(4-(azidomethyl)phenyl)propanoic acid

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide at 20℃; Inert atmosphere;	96%
With sodium azide; 15-crown-5 In 1,4-dioxane at 80℃; for 16h;
With sodium azide In N,N-dimethyl-formamide at 100℃; for 12h; Temperature; Inert atmosphere;
With sodium azide In N,N-dimethyl-formamide at 100℃; for 12h; Inert atmosphere;

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + 1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + triphenylphosphine (603-35-0) → [4-(methyl)phenyl-2-propionyl-N-succinimido]-triphenylphosphonium bromide

Conditions	Yield
With dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 16h;	94.9%

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + 2-ethoxycarbonyl-1-cyclopentanone (611-10-9) → sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate (80382-23-6)

Conditions	Yield
Stage #1: 2-[4-(bromomethyl)phenyl]propanoic acid; 2-ethoxycarbonyl-1-cyclopentanone With sodium hydroxide In N,N-dimethyl-formamide under 760.051 Torr; for 8h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide pH=5 - 6; Further stages;	92%

2-methyl-1-buten-4-ol (763-32-6) + 2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) → C15H19BrO2

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 23℃; Inert atmosphere;	87%

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + dimethylmonochlorosilane (1066-35-9) + diethyl ether (60-29-7) + hexane I ethyl acetate → 2-[(4-dimethylsilylmethyl)phenyl]propionic acid (1096356-08-9)

Conditions	Yield
With triethylamine In (2S)-N-methyl-1-phenylpropan-2-amine hydrate	85%

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + 1H-[1,2,4]triazole-3-thiol (3179-31-5) → 2-(4-(((1H-1,2,4-triazol-3-yl)thio)methyl)phenyl)propanoic acid

Conditions	Yield
In acetone at 40℃; for 12h; Reflux;	85%

2-(4-(bromomethyl)phenyl)propanoic acid (111128-12-2) + 5-chloro-2-mercaptobenzothiazole (5331-91-9) → 2-(4-(((5-chlorobenzo[d]thiazol-2-yl)thio)methyl)phenyl)propanoic acid

Conditions	Yield
In acetone at 40℃; for 12h; Reflux;	85%

Upstream product

• 43153-04-4 ethyl 2-(4-formylphenyl)propionate 
• 2510-99-8 ethyl 2-phenylpropanoate 
• 492-37-5 hydratropic acid 
• 100-42-5 styrene 
• 938-94-3 (R,S)-2-(4'-methylphenyl) propionic acid 
• 159755-12-1 1-(1-bromoethyl)-4-methylbenzene 
• 622-97-9 1-ethenyl-4-methylbenzene 
• 2362-36-9 1-(1-chloroethyl)-4-methylbenzene 
• 188680-60-6 trioxane 
• 57-09-0 cetyltrimethylammonim bromide 
• 75920-45-5 (+/-)-2-(4'-methylphenyl)-propionitrile 
• 122-00-9 para-methylacetophenone 
• 82925-34-6 1-(4-methylphenyl)ethyl 4-methylbenzenesulfonate 
• 536-50-5 CH₃C₆H₄CH(CH₃)OH 

Downstream Products

• 63476-54-0 2-(4-formylphenyl)propionic acid methyl ester 
• 81762-92-7 loxoprofen methyl ester 
• 80382-23-6 sodium 2-<4-<(2-oxocyclopentyl)methyl>phenyl>propionate 
• 68767-14-6 loxoprofen 

Relevant articles and documents

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Preparation method of p-bromomethyl isophenylpropionic acid

The invention belongs to the field of synthesis of drug intermediates, and particularly relates to a preparation method of p-bromomethyl isophenylpropionic acid, which comprises the following steps: A, synthesis of alpha-methyl benzyl chloride: carrying out addition reaction on styrene serving as a raw material and hydrogen chloride gas in an organic solvent to generate alpha-methyl benzyl chloride, B, synthesis of 2-phenylpropionic acid: preparing alpha-methyl benzyl chloride into a Grignard solution through a Grignard reaction, the Grignard solution and carbon dioxide gas are subjected to acarboxylation reaction to generate a carboxylation solution, and the carboxylation solution is hydrolyzed to obtain 2-phenylpropionic acid, and C, synthesis of p-bromomethyl isophenylpropionic acid: carrying out bromomethylation reaction of 2-phenylpropionic acid, hydrobromic acid and polyformaldehyde so that p-bromomethyl isophenylpropionic acid is generated. The preparation method of p-bromomethyl isophenylpropionic acid provided by the invention has the advantages of cheap and accessible raw materials and simple technique, and is suitable for industrial production.

Novel synthesizing method of 2-(4-bromomethyl)phenylpropionic acid

The invention belongs to the field of preparation of intermediates in chemical engineering, and particularly relates to a novel synthesizing method of 2-(4-bromomethyl)phenylpropionic acid. The novelsynthesizing method comprises the following steps of using 4-methyl acetophenone as the raw material; performing reduction, chlorinating and cyaniding, so as to obtain 2-(4-methyl)phenylpropionitrile;hydrolyzing, and brominating, so as to obtain the 2-(4-bromomethyl)phenylpropionic acid. The novel synthesizing method has the advantages that the yield rate is increased, and the cost of raw material is low; the novel synthesizing method is suitable for industrialized production.