Preparation method of 2,3-pyridine dimethanol hydrochloride_Industrial additives

Background and Overview

2,3-Pyridine dimethanol hydrochloride is an organic chemical that can be used as an organic intermediate.

Preparation^[1]

1: Preparation of methyl 2,3-pyridinedicarboxylate

In a 1000mL three-necked round-bottomed flask, add 34.08g (0.2mol) 2,3-pyridinedicarboxylic acid and 600mL (14.8mol) methanol. Under an ice-water bath, slowly add 47.59g (0.4mol) of thionyl chloride dropwise. After the dropwise addition is completed, continue stirring for 10 minutes. Then change the cooling device to a heating device and heat to reflux until the reaction is completed (use thin layer chromatography (TLC) to follow the reaction). After the reaction is completed, the solvent in the reaction mixture is rotary evaporated. An appropriate amount of methylene chloride was added to the residue, and the pH of the reaction mixture was adjusted to between 8 and 9 with 20% sodium hydroxide solution under stirring. Separate the liquids, and extract the aqueous phase with dichloromethane 2-3 times. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was spun dry to obtain 31.60 g of light yellow solid with a yield of 81%.

2: Preparation of 2,3-dihydroxymethylpyridine hydrochloride

Add 4.45g (0.023mol) of methyl 2,3-pyridinedicarboxylate and 40mL of absolute ethanol into a 100mL three-necked round-bottomed flask. Add 1.8g (0.048mol) of sodium borohydride while cooling with ice water. The addition is complete. After that, stir for 20 minutes. Keep cooling, and slowly add 2.77g (0.025mol) anhydrous calcium chloride in 20mL of absolute ethanol solution dropwise. After the dropwise addition is completed, slowly raise the reaction mixture to room temperature. The reaction was followed by TLC. After the reaction was completed, the reaction was quenched with a mixture of 15 mL of water and 15 mL of ethanol. The reaction mixture was then evaporated to dryness to obtain a crude product of 2,3-dihydroxymethylpyridine as a pale yellow solid.

The solid was dried overnight at room temperature and under reduced pressure. Grind the dried solid into another three-necked flask, add 120 mL of absolute ethanol, and heat to reflux for 1.5 hours with vigorous stirring. Stop stirring and cool to room temperature. Prepare a hydrogen chloride gas generator, and pass hydrogen chloride gas into the cooled reaction liquid while stirring until the reaction mixture is saturated with hydrogen chloride gas to obtain a turbid reaction mixture. Filter the reaction mixture and use a small amount of anhydrous water to filter the filter cake. Wash with ethanol and then with 20 mL of methyl tert-butyl ether. The filter cake was dried overnight at room temperature and under reduced pressure to obtain 5.0 g (0.028 mol) of crude 2,3-dihydroxymethylpyridine hydrochloride. After the filtrate is concentrated to a certain amount (about one-fifth of the total amount), hydrogen chloride gas can be continued to be introduced, and the above operation can be repeated, and some 2,3-dihydroxymethylpyridine hydrochloride can also be recovered.

Main reference materials

[1] Preparation method of CN200910130327.X (4,7-cis)-octahydro-pyrrolo[3,4-b]pyridine and moxifloxacin