86477-09-0

A reaction was carried out with 3a,4,5,6-tetrahydro-3-oxo-3H-pyrrolo[1,2-c][1,2,3]oxadiazol-7-ium innerium salt (13.5 g, 0.107 mol, crude from Example 4) and ethyl propargylate (15.8 g, 16.3 ml, 0.16 mol) in anhydrous N,N-dimethylformamide (50 ml) under nitrogen The reaction was stirred under protection and heated to 120-122 °C for 12 hours. The course of the reaction was monitored by HPLC (using a Prodigy ODS3 4.6×150 mm column with 90:10 to 10:90 water/acetonitrile containing 0.02% trifluoroacetic acid as the mobile phase in a gradient elution for 10 min). Under these conditions, the retention time of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (the more polar target isomer) was 2.6-2.7 min, whereas the retention time of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate (the less polar non-target isomer) was 2.8-2.9 min. The UV detector was set at 215 nm because the absorption difference between the two isomers is significant at 254 nm and the non-target isomer is almost undetectable. After completion of the reaction, the mixture was concentrated to a dark syrupy consistency using an oil pump vacuum at a bath temperature not exceeding 50 °C. The ratio of the two esters in the dark syrup was 2.13:1 in favor of the target product ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate as determined by NMR. The dark syrup was diluted with toluene and up-sampled by washing with hexane to a silica gel column (500 mL) preloaded in hexane. The column was eluted first with hexane-ethyl acetate (4:1) followed by hexane-ethyl acetate (1:1). The elution process was monitored by HPLC (conditions as above). Fractions containing both esters were collected and separated again by column chromatography. Fractions containing only ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate were combined and concentrated to give 11 g (57%) of the pure product in white crystalline form with a melting point of 35-37 °C. Similarly, 6.5 g (33.7%) of ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-3-carboxylate was obtained as white crystals with a melting point of 205 °C.

[1] Patent: US2004/242874, 2004, A1. Location in patent: Page 13-14
[2] Indian Journal of Chemistry - Section B Organic Chemistry Including Medicinal Chemistry, 1991, vol. 30, # 2, p. 169 - 175
[3] Patent: US2004/242874, 2004, A1. Location in patent: Page 12-13
[4] Patent: US2004/242874, 2004, A1. Location in patent: Page 13
[5] Organic Process Research and Development, 2006, vol. 10, # 4, p. 712 - 716