ChemicalBook CAS DataBase List Eszopiclone

Eszopiclone synthesis

5synthesis methods

Product Name:Eszopiclone
CAS Number:138729-47-2
Molecular formula:C17H17ClN6O3
Molecular Weight:388.81

The synthesis of eszopicolone involves enzymatic resolution of a zopicolone derivative to give the chiral compound as depicted in the Scheme 12. Pyrazine-2,3- dicarboxylic acid anhydride was reacted with 2-amino- 5-chloropyridine (61) in refluxing acetonitrile to generate 3- (5-chloro-2-pyridyl)carbamoyl pyrazine-2-carboxylic acid (62) in 95% yield. Compound 62 was cyclized by treating with refluxing SOCl2 to give 6-(5-chloropyrid-2-yl)-5,7- dioxo-5,6-dihydropyrrolo[3,4-b]pyrazine (63) in 79% yield.Compound 63 was subjected to partial reduction with KBH4 in dioxane-water at low temperature to give 6-(5-chloro-2- pyridyl)-7-hydroxy-5,6-dihydropyrrolo[3,4-b]pyrazin-5-one (64) in 64% yield, which was esterified with vinyl chloroformate in pyridine to give corresponding vinyl acetate 65 in 75% yield. The racemic 65 was then subjected to kinetic resolution by a highly enantioselective enzymatic hydrolysis process. Chiral vinyl acetate 67 with desired stereochemistry was obtained when candida antarctica lipase was employed for hydrolysis of 65 in dioxane/water at 60oC for 2 days. Interestingly, the enzymatic hydrolysis stopped at 50% conversion and the hydrolyzed alcohol was recovered as the starting substrate 65 because of spontaneous racemization of the alcohol in the reaction medium. Therefore, although a maximum yield of kinetic resolution is 50%, the overall efficiency of this enzymatic process is 100% because of substrate recycling. Finally, the chiral vinyl acetate 67 was condensed with methyl piperazine in acetone to give eszopicolone (IX).

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Yield:138729-47-2 91.7%

Reaction Conditions:

Stage #1: zopiclonwith D-Malic acid in methanol;acetone at 10 - 56; for 8.5 h;
Stage #2: with potassium carbonate in water; for 1 h;Solvent;Temperature;Reagent/catalyst;

Steps:

3 Preparation of eszopiclone

30 g (57.4 mmo 1) of eszopiclone D-malic acid salt intermediate prepared by the preparation method of Comparative Example 2, In the reaction flask, 40 g of zopiclone, 13.4 g of D-malic acid, 243 g of methanol, 413 g of acetone and the oil bath was heated to reflux (56 ° C) for 30 minutes and then slowly cooled to 10-15 ° C for 8 hours. suction and filtration carried out to obtain crude product. The crude salt, 168 g of methanol and 247 g of acetone were introduced into the reaction flask. The oil bath was heated to reflux (56 ° C) for 30 minutes and then slowly cooled to 10-15 ° C and allowed to stand for 8 hours. Acetone (2 * 20ml, 0-5 ° C) was used to wash filter cake , and dried under reduced pressure to give eszopiclone D-malic acid salt (21.9 g, 40.7%, 99.0% ee). Into the reaction bottle, add water 450g, open the stirring, until the eszopiclone D-malic acid salt dissolved, 15 g of povidone K30 was added and stirring was continued until the solid was dissolved. The stirring speed was adjusted to 80 m / min and poured into a 10 wt% aqueous solution of potassium carbonate95 g (68.8 mmol, 1.20 times of the drug), stirring was continued for 1 hour, filtered, the filter cake was washed three times with 90% of 1% aqueous potassium carbonate solution,The obtained wet crystals were dried at 60 ° C and 150 mmHg under reduced pressure for 8 hours to obtain 20.45 g of a white crystallite solid in a yield of 91.7%. Sampling analysis: the eszopiclonecontent of 99.6%, total impurities 0.04%, no ethyl acetate residue.

References:

CN103980278,2017,B Location in patent:Paragraph 0055-0060; 0063; 0068-0070; 0072; 0075; 0078

109-01-3 Synthesis