3-Fluoropyridine-2-methanol_Industrial additive

[Background and Overview]^[1]

The English name of 3-Fluoropyridin-2-methanol is (3-Fluoropyridin-2-yl)methanol, CAS number is 31181-79-0, and the molecular formula is C₆H₆ FNOS, molecular weight: 127.04300; PSA: 33.12000; LogP: 0.71300. Density 1.263g/cm3, boiling point 194.287ºC at 760 mmHg, flash point 71.303ºC, refractive index 1.524. If inhaled, move the patient to fresh air; in case of skin contact, take off contaminated clothing, rinse the skin thoroughly with soap and water, and seek medical attention if you feel uncomfortable; if eye contact occurs, separate the eyelids and rinse with fluid Rinse with 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.

【Synthesis】 ^[2]

Method 1: Reduce 3-fluoropyridine-2-aldehyde to formula 3-fluoropyridine-2-methanol by using sodium borohydride in ethanol or methanol at room temperature to 60°C for about 30 minutes to 24 hours, the specific reaction equation is as follows:

Method 2: Dissolve (6-bromo-3-fluoro-pyridin-2-yl)-methanol (850 mg, 4.13 mmol) in methanol (40 mL), then purge the solution with nitrogen. Palladium on carbon (200 mg 5% wet) was added and the mixture was stirred under a hydrogen atmosphere (2 balloons) for 20 hours. The mixture was filtered through CELITE and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure and the resulting residue was dissolved in chloroform (150 mL). The organic phase was washed with saturated aqueous sodium bicarbonate solution (75 mL), dried over magnesium sulfate, filtered and concentrated to give 433 mg (82%) of 3-fluoropyridine-2-methanol, which was used without further purification. The specific reaction equation is as follows:

[Application]^[2]

3-Fluoropyridine-2-methanol is a pharmaceutical intermediate used to synthesize compounds with other uses. For example, 3-fluoropyridine-2-methanol can be used as a raw material to synthesize a compound that can be used as an androgen receptor. Tetrahydrocarbazole derivatives of body regulators, the structure is as follows:

Dissolve 3-fluoropyridine-2-methanol (215 mg, 1.69 mmol) in dichloromethane (10 mL) and cool to 0°C. Thionyl chloride (160 μL, 2.20 mmol) was added and the reaction was stirred for 1 hour. Dichloromethane (50 mL) was added and the reaction was stirred with saturated aqueous sodium bicarbonate solution (2 x 40 mL) and brine (2 x 40 mL). The organic portion was separated and dried over magnesium sulfate, filtered and concentrated under pressure to give 2-chloromethyl-3-fluoro-pyridine. Sodium hydride (60% in oil, 80 mg, 1.99 mmol) was then suspended in DMF (2 mL) and cooled to 0°C. A solution of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (253 mg, 0.90 mmol) in DMF (2 mL) was added slowly via syringe , and stir for 30 minutes, then warm to ambient temperature for 60 minutes. 2-Chloromethyl-5-fluoro-pyridine hydrochloride (180 mg, 0.99 mmol) was added and the reaction was stirred for approximately 12 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (5 mL). Ethyl acetate (50 mL) was added and the solution was washed with water (50 mL), then brine (2 x 50 mL). The organic phase was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The resulting residue was triturated with diethyl ether (10 mL) for 5 minutes and then filtered to afford 187 mg (53%) of the above compound as a pale yellow solid.

[References]

[1] https://baike.molbase.cn/cidian/834540

[2] ELI LILLY AND COMPANY Patent: WO2007/2181 A2, 2007; Location in patent: Page/Page column 165; WO 2007/002181 A2