A reinvestigation and improvement in the synthesis of meso-2,5-dibromoadipates by application of Le Chatelier's principle

Streamlined Synthesis of a Bicyclic Amine Moiety Using an Enzymatic Amidation and Identification of a Novel Solid Form

“…It has been previously demonstrated that the dibromide stereoisomers can be epimerized via S N 2 displacement by bromide anions (Br − ), which can allow for recycling of the more soluble racemic isomers to increase the recovery of the more highly crystalline meso-diastereomer (Figure 2). 13 We have also observed that the same epimerization as described above occurs during the reaction of dibromide 1 with benzylamine. By monitoring the diastereomeric purity of the unreacted dibromide 1 (>95% meso at t = 0) as well as the pyrrolidine diester 9 being formed during the reaction, we found that stereochemical purity continually decreases throughout the reaction.…”

“…To the reaction was added additional water (1.0 kg, 0.48 kg, 0.17 kg, and 0.284 equiv total) after 24.5, 43.5, and 64 h, and additional HMDS (25.00 kg, 154.9 mol, and 0.47920 equiv) was added after 25 h. After 86 h, the reaction was filtered to remove the immobilized enzyme, which was washed with MTBE (130 kg) to give 1267 kg of an MTBE solution containing amide 10. HPLC purity: 89−93% (a/a); 1 H NMR (400 MHz, CDCl 3 ): δ 7.87 (s, 1H), 7.22−7.06 (m, 5H), 5.83 (s, 1H), 3.87 (q, J = 7.0 Hz, 2H), 3.77 (d, J = 13.2 Hz, 1H), 3.67 (d,J = 13.2 Hz,1H),2H),2H),1H),1H), 1.02 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 178. 3, 175.3, 137.39, 129.4, 128.5, 127.6, 67.9, 66.4, 61.0, 59.1, 30.7, 30.5, 14. The MTBE solution containing 10 was concentrated at 55− 60 °C to remove ∼1000 kg of the solvent.…”

“…Two batches were performed using the above procedure to produce a total of 110.2 kg of cocrystal 21 (79.4% yield from imide 7). HPLC purity: >99.9% (a/a); 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.40−7.33 (m, 8H), 7.29 (t, J = 7.3 Hz, 4H), 7.21 (t, J = 7.3 Hz, 2H), 6.80 (d, J = 8.4 Hz, 4H), 3.39 (s, 4H), 2.90 (s, 4H), 2.75 (d, J = 12.0 Hz, 4H), 2.43 (dd, J = 12.0, 1.7 Hz, 4H), 1.92−1.84 (m, 4H), 1.71−1.64 (m, 4H); 13 To a solution of KOH in water (45%, 6.0 mL, and 8.2 equiv) were added additional water (15 mL, 3 mL/g), an organic solvent (25 mL, 5 mL/g), and cocrystal 21 (5.0 g, 8.5 mmol, and 1.0 equiv). The mixture was stirred until all solids were dissolved, and the solution was transferred to a separatory funnel.…”

“…An analytical sample was obtained by concentrating the organic layer to give 11 as an oil. 1 H NMR (400 MHz, CD 3 CN): δ 7.41 (d, J = 6.9 Hz, 2H), 7.34 (t, J = 7.4 Hz, 2H), 7.26 (t, J = 7.2 Hz, 1H), 3.47 (s, 2H), 2.99 (s, 2H), 2.86 (d, J = 12.0 Hz, 2H), 2.62 (s, 1H), 2.55 (dd, J = 12.1, 1.8 Hz, 2H), 2.05−1.96 (m, 2H), 1.78−1.71 (m, 2H); 13 C NMR (100 MHz, CD 3 CN): δ 141. 3, 129.6, 129.1, 127.6, 61.3, 58.5, 52.9, 25.8; HRMS (ESI/Orbitrap) m/z: [M + H] + calcd for C 13 H 19 N 2 , 203.1543; found, 203.1543.…”

Asymmetric Trans-esterification ofmeso-2,5-Dibromoadipate and Synthesis of Optically Activecis-2,5-Disubstituted Pyrrolidines

“…Starting from cis- 4,6) an equivalent asymmetric transformation was also performed by a chemical method (Scheme 2). Selective hydrolysis of cis-4 with sodium methoxide and water in methanol afforded mono-sodium salt 5, which was converted to diester 3 having 66% de in an overall yield of 30% from cis-4.…”