3-FLUORO-4-(HYDROXYMETHYL)PYRIDINE

3-FLUORO-4-(HYDROXYMETHYL)PYRIDINE Property

Melting point:

83-84 °C

Boiling point:

221.0±25.0 °C(Predicted)

Density 

1.262±0.06 g/cm3(Predicted)

storage temp. 

Inert atmosphere,Room Temperature

form 

solid

pka

12.71±0.10(Predicted)

Appearance

White to off-white Solid

Safety

HazardClass 

IRRITANT

HS Code 

2933399990

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P301+P312IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

3-FLUORO-4-(HYDROXYMETHYL)PYRIDINE Chemical Properties,Usage,Production

Synthesis

Step 1. Synthesis of (3-fluoropyridin-4-yl)methanol 3-Fluoropyridine (600 g, 6.18 mol) was dissolved in anhydrous THF (6 L) under nitrogen protection, mechanically stirred and cooled to -65 °C. A THF solution of lithium diisopropylamine (3.4 L, 6.5 mol) was slowly added over a period of 2 h. The reaction temperature was kept below -60 °C and stirring was continued for 1 h at this temperature. Subsequently, pure DMF (804 mL, 10.4 mol) was added dropwise over 1 h, the temperature was maintained below -60 °C and the reaction was monitored by TLC until the 3-fluoropyridine was completely consumed. Upon completion of the reaction, the mixture was slowly warmed to -10 °C and water (1.1 Kg, 62 mol) was added. Sodium borohydride (234 g, 6.18 mol) was added in batches at 0 °C and stirred for a few minutes. Next, 6 M HCl (5.6 L) was added slowly over 1 h. The quenching temperature was controlled to be between 0-25°C. The reaction mixture was heated to 40°C and stirred overnight. After cooling to 0-15 °C, the pH was adjusted to 12 by slow addition of 6 M NaOH. the aqueous layer was extracted with isopropyl acetate (500 mL x 1,1L x 3). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Heptane-isopropyl acetate (1.2L, v/v=5/1) was added to the crude product and the product was stirred at 0°C for 30 min to crystallize. Filtered, the filter cake was washed with cooled heptane (250 mL x 1) and dried under vacuum to give the light yellow solid title compound (688 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=4.8 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.49 (t, J=4.8 Hz, 1H), 4.85 (s, 2H), 2.35 (br s, 1H).

References

[1] Patent: WO2016/49048, 2016, A1. Location in patent: Paragraph 0122
[2] Patent: WO2016/100349, 2016, A2. Location in patent: Paragraph 0171