2-Methyl-5-bromobenzoic acid_Kain Industrial Additive

[Background and Overview]^[1][2]

2-Methyl-5-bromobenzoic acid CAS number 79669-49-1, chemical formula C₈H₇BrO₂N , molecular weight 215.04400, Chinese alias 5-bromo-2-methylbenzoic acid; 5-bromo-2-methylbenzoic acid; melting point 170ºC, boiling point 319.4ºC at 760 mmHg, flash point 147ºC, density 1.599 g/cm3, refractive index 1.595. 3-Amino-5-bromotrifluorotoluene provides a good intermediate for the development of new anti-cancer drugs. If 2-methyl-5-bromobenzoic acid is inhaled, move the patient to fresh air; if there is skin contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel unwell; if In case of eye contact, separate eyelids, rinse with running water or saline, and seek medical attention immediately; if ingested, rinse mouth immediately, do not induce vomiting, and seek medical attention immediately. Advice to protect rescuers is as follows: Move the patient to a safe place, consult a doctor, and if conditions permit, please show this chemical safety data sheet to the doctor who comes to the scene. If there is a small leak, collect the leaked liquid in a sealable container as much as possible, absorb it with sand, activated carbon or other inert materials, and transfer it to a safe place. Do not flush it into the sewer; if there is a large leak, build a dike or dig a pit. Contain, seal the drainage pipe, cover it with foam to inhibit evaporation, use an explosion-proof pump to transfer it to a tanker or a special collector, and recycle or transport it to a waste treatment site for disposal.

[Application]

2-Methyl-5-bromobenzoic acid can be used as an intermediate to synthesize the important 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene of canagliflozin. Canagliflozin, also known as Canagliflozin, trade name is Invokana, chemical name is (2S,3R,4R,5S,6R)-2-(3-((5-(4-fluorophenyl)) Thiophen-2-yl)methyl)-4-methyl-phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, can break down glucose and pass it through the kidneys It is excreted from the body to reduce blood sugar levels. Clinical studies have shown that canagliflozin is safe to take, well tolerated, has obvious weight loss effects and good blood sugar control when used alone to treat type II diabetes. 2-(5-Bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene, as an important intermediate in the synthesis of canagliflozin, can be directly used as a raw material for the synthesis of canagliflozin or can be prepared into Another important raw material of canagliflozin is 2-(5-iodo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene. Its preparation method includes the following steps:

1) 2-(4-fluorophenyl)thiophene is obtained through a coupling reaction between 2-bromothiophene and p-bromofluorobenzene; the reaction temperature is 10~70°C; the solvent is selected from tetrahydrofuran, diethyl ether, isopropyl ether, n- One or a combination of two or more of butyl ether, 2-methyltetrahydrofuran, and toluene; the reaction time is 5 to 24 h, and the catalyst is selected from cobalt acetate, cobalt dichloride, di(acetylacetonate) cobalt, tris( Cobalt acetylacetonate, palladium acetate, palladium dichloride, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium, bis(acetylacetonate)palladium , (1,5-cyclooctadiene) palladium dichloride, nickel acetate, nickel chloride, one or a combination of two or more bis(triphenylphosphorus) nickel chloride. The solvent is preferably tetrahydrofuran. The catalyst is preferably bis(acetylacetonate)palladium.

2) 5-bromo-2-methylphenyl-2-(4-fluorophenyl) is obtained through Friedel-Crafts reaction between 2-(4-fluorophenyl)thiophene and 2-methyl-5-bromobenzoic acid. ) thiophene; first prepare 2-methyl-5-bromobenzoyl chloride from 2-methyl-5-bromobenzoic acid, and then combine 2-methyl-5-bromobenzoyl chloride with 2-(4-fluoro Phenyl)thiophene undergoes Friedel-Crafts reaction to obtain compound 5-bromo-2-methylphenyl-2-(4-fluorophenyl)thiophenemethanone.

3) 2-(5-bromo-2-methylbenzyl)-5-( 4-Fluorophenyl)thiophene. The 5-bromo-2-methylphenyl-2-(4-fluorophenyl)thiophenone is subjected to a reduction reaction to obtain the target compound 2-(5-bromo-2-methylbenzyl)-5-( 4-Fluorophenyl)thiophene.

【Synthesis】

Under N2 atmosphere, add 2-methylbenzoic acid (40.0g, 290mmol) to the mixture of Br₂ (160mL) and iron powder (3.20g, 57.0mol) in an ice bath. in suspension. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into water and the reddish solid was collected by filtration. The solid was dried under vacuum at 50°C. The solid was dissolved in 400 mL of methanol, then 640 mL of 0.1 N aqueous HCl solution was added at room temperature. The mixture was stirred to produce a white solid. The solid was recrystallized from ethanol to give 2-methyl-5-bromobenzoic acid (12.0 g, 19%). 1H NMR (300M Hz, CDCl 3) δ8.17 (d, J = 2.1,1H), 7.56 (dd, J = 8.1,2.1,1H), 7.15 (d, J = 8.1,1H), 2.59 (s, 3H)).

[Main reference materials]

[1] Liu Feng; Pan Xianhua; Zhang Xin; Li Xiaojun; Zhao Dongxian. Preparation method of 2-(5-bromo-2-methylbenzyl)-5-(4-fluorophenyl)thiophene. CN201510287802.X , application date 2015-05-29

[2] HADIDA RUAH, SARA S.; Miller, Mark; Zhou, Jinglan; Bear, Brian; Grootenhuis, Peter Patent: US2009/143381 A1, 2009; Location in patent: Page/Page column 55;