5-(CHLOROMETHYL)-2-METHOXYPYRIDINE

5-(CHLOROMETHYL)-2-METHOXYPYRIDINE Property

Boiling point:

236.1±25.0℃ (760 Torr)

Density 

1.173±0.06 g/cm3 (20 ºC 760 Torr)

Flash point:

96.6±23.2℃

storage temp. 

Inert atmosphere,Store in freezer, under -20°C

pka

2.62±0.10(Predicted)

Appearance

Colorless to light yellow Liquid

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Danger

Hazard statements

H302Harmful if swallowed

H314Causes severe skin burns and eye damage

H335May cause respiratory irritation

Precautionary statements

P260Do not breathe dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P280Wear protective gloves/protective clothing/eye protection/face protection.

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

P301+P330+P331IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.

P303+P361+P353IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.

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.

P310Immediately call a POISON CENTER or doctor/physician.

P321Specific treatment (see … on this label).

P330Rinse mouth.

P363Wash contaminated clothing before reuse.

P405Store locked up.

P501Dispose of contents/container to..…

5-(CHLOROMETHYL)-2-METHOXYPYRIDINE Chemical Properties,Usage,Production

Uses

5-(Chloromethyl)-2-methoxypyridine is used in preparation of pyrazolopyridine compounds as RET kinase inhibitor for treatment of RET-related diseases.

Synthesis

(6-Methoxypyridin-3-yl)methanol (2) (537.8 g, 3.86 mol) obtained in Preparation Example 1 was dissolved in dimethylformamide (1.6 L), cooled in an ice bath under nitrogen protection, and thionyl chloride (310 mL, 4.25 mol) was added slowly and dropwise over a period of 1.3 hours. After the dropwise addition, the reaction mixture was continued to be stirred in an ice bath for 1 hour. Subsequently, toluene (5.4 L) and 2N aqueous sodium hydroxide solution (5.4 L) were sequentially added to the reaction mixture at a temperature not exceeding 23 °C. After stirring for about 10 minutes, the aqueous layer was separated and the organic layer was washed with water (2.7 L). The organic layer was concentrated to dryness under reduced pressure, and toluene (1.0 L) was added to the residue for azeotropic distillation, resulting in 618.8 g of the target product, 5-chloromethyl-2-methoxypyridine (3), as a light yellow oil (556.3 g, 91.4% yield). The structure of the product was confirmed by 1H-NMR (CDCl3): δ (ppm) 8.15 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=2.4 Hz, 8.4 Hz), 6.75 (1H, d, J=8.4 Hz), 4.55 (2H, s), 3.94 (3H, s).

References

[1] Patent: WO2016/33445, 2016, A1. Location in patent: Paragraph 0259
[2] Tetrahedron, 2014, vol. 70, # 40, p. 7207 - 7220
[3] Patent: US2006/235225, 2006, A1. Location in patent: Page/Page column 4
[4] Patent: US2007/49632, 2007, A1. Location in patent: Page/Page column 38
[5] Patent: US2011/224225, 2011, A1. Location in patent: Page/Page column 23