Synthesis
1. 4.5 kg (26.1 mol) of 4-cyclopentanone-1,2-dicarboxylic acid (Compound IV) was added to a solvent mixture of 20 L of methanol and 30 L of toluene.
2. 0.831 kg (13.7 mol) of concentrated sulfuric acid was added slowly dropwise, with the rate of dropwise acceleration controlled to maintain the reaction temperature below 30 °C.
3. the reaction mixture was heated to 70 °C with continuous stirring until dimethyl 4-oxocyclopentane-1,2-dicarboxylate (Compound JY) was completely converted (about 1-3 hours).
4. Upon completion of the reaction, the reaction solution was concentrated to half of the original volume (approximately 24 L of solvent was distilled).
5. The reaction mixture was cooled to 30 °C, 25 L of water and 6 L of methyl tert-butyl ether (MeTHF) were added sequentially and stirred for 1 h. Phase separation was carried out.
6. Discard the aqueous layer, the organic layer was washed sequentially with 10L of water, 10L of saturated sodium bicarbonate solution and 5L of brine.
7. The washed organic layer was concentrated to a final volume of about 9L.
8. The yield of dimethyl 4-oxocyclopentane-1,2-dicarboxylate in the resulting solution was determined by quantitative analysis to be 4.5 kg (86% yield), and the solution was used directly in the next step of the reaction.
References
[1] Patent: WO2016/157058, 2016, A1. Location in patent: Page/Page column 22; 32
[2] Synlett, 1997, vol. 1997, # 2, p. 193 - 194
