How to make 5-Hydroxymethylthiazole

5-Hydroxymethylthiazole is a kind of slightly yellow oil liquids, the Molecular Formula is C4H5NOS, Molecular weight is 115.15, and the CAS NO. is 38585-74-9. It is an important intermediate for Ritonavir, and a kind of anti-AIDS pharmaceuticals.

Since the discovery of 5-Hydroxymethylthiazole can be used for synthesis of second-generation anti-AIDS drugs ritonavir (Ritonavir), scientists have done many studies on the synthesis method of 5-Hydroxymethylthiazole. But how to prepare it, in this Article, I will introduce 3 new approaches：

Approach one

In a reaction flask IOOml 250ml of ethanol, 15g (0. Imol) 2_ chloro-5 - (hydroxymethyl) thiazole and 13. 5g (0. 20mol) zinc powder, the above mixture was heated to 50 C , then slowly add 150ml hydrochloric acid (2N), at a temperature of 70 C for 2 hours detected by TLC or HPLC, until the starting material disappeared, the reaction was stopped and the reaction solution was filtered, concentrated and neutralized with sodium hydroxide to PH of 10, and then extracted with ethyl acetate to give crude product, the final crude solvent was removed by distillation under reduced pressure, collecting 115 ~ 122 C (24mmHg) the distillate, 8. 5g 5 - (hydroxymethyl) thiazole. The determination of the purity% 99. 3% (HPLC), the yield was 74%.

Approach two

In a reaction flask IOOml 250ml of ethanol, 45g (0. 3mol) 2_ chloro-5 - (hydroxymethyl) thiazole and 33g (0. 5mol) zinc powder, and then added slowly 75ml hydrochloric acid (6N), the temperature of 60 C for 2 hours, by TLC or HPLC detection, until the starting material disappeared, the reaction was stopped and the reaction solution was filtered, concentrated and neutralized with sodium hydroxide to a PH of 10, and then extracted with ethyl acetate and to give the crude product, the final crude solvent was removed by distillation under reduced pressure, collecting 115 ~ 1220C (24mmHg) the distillate, 25g 5 - (hydroxymethyl) thiazole. The purity was determined 99. 5% (HPLC), the yield was 72%.

Approach three

2–Chloro-5-hydroxymethylthiazole hydrochloride(3.72 g 0.02 mole) was dissolved in methanol (30 mL) and charged into a Parr shaker. To this solution was charged sodium carbonate( 2.12 g 0.02 mole) and 10 palladium on carbon (0.9 g). The system was heated (60 C) under 50 psi (3.40 atm) of hydrogen gas and agitated for 18 hours. The reaction was monitored by TLC or GC and allowed to proceed for an additional 5 hours after completion. The reaction mixture was cooled and the contents filtered through a bed of diatomaceous earth. The filtrate was then concentrated under reduced pressure (38 C) and the residue was taken up in methyl t butyl ether (100 mL) and dried over sodium sulfate (10 g). The dried solution was filtered and concentrated under reduced pressure (38 C) to provide 5-hydroxymethylthiazole as a slightly colored oil Yield 

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