Synthetic processes for the production of 1-((3s,4r)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl)-3-phenylurea
A technology of alkoxy, product, applied in the field of FPR2 agonist
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[0170] The present invention resides in a number of synthetic intermediates and methods of preparing these intermediates and Compound 1. figure 1 The method shown in can minimize or eliminate the number of genotoxic impurities (GTI's) in the synthetic pathway to complete the synthesis in fewer than seven steps compared to the method described in US Patent 9,822,069.
[0171] General aspects of these exemplary methods are described in the Schemes and Examples. Each product of the following process is optionally isolated, isolated, and / or purified before its use in a subsequent process.
[0172] In general, reaction conditions such as temperature, reaction time, solvents, work-up procedures, etc. will be those conventional in the art for the particular reaction being performed. Typically, the temperature will be -100°C to 200°C, the solvent will be aprotic or protic, and the reaction time will be 10 seconds to 10 days. Workup typically consists of quenching any unreacted reage...
Embodiment 1
[0266] Ellman imine formation
[0267]
[0268] Compound 2 (1 kg, 1 equiv) was added to a 20-L reactor. Triisopropyl borate (4 L) was added followed by (R)-(+)-2-methylpropane-2-sulfinamide (810 g, 1.15 equiv). The resulting slurry was heated to 65-70 °C for 18 h, during which time the reaction mixture became homogeneous. The reaction mixture was cooled to 0 °C over 18 h to give a thick slurry. The slurry was kept at 0 °C for 1 h, then the solids were filtered off. The solid was washed with heptane / MTBE (4 L) and the solid was dried at 55 °C to afford compound 3 (1.42 Kg, 89% yield) as an off-white crystalline solid. 1 H NMR (600MHz, C 6 D. 6 ): δ9.08(s, 1H), 6.08(d, J=10.3Hz, 2H), 2.96(s, 3H), 1.14(s, 9H). 13 C NMR (150MHz, C 6 D. 6 ): δ164.4 (t, J = 14.6Hz), 163.8 (dd, J = 257.7, 9.4Hz), 153.0, 106.5 (t, J = 12.6Hz), 99.1 (d, J = 24.8Hz), 57.6, 55.8, 22.8. HRMS(ESI), for [C 12 h 15 f 2 NO 2 S+H] + The calculated value is 276.0864, and the measured value i...
Embodiment 2
[0270] Aziridine formation
[0271]
[0272] In the 20-L reactor, add compound 3 (1Kg, 1 equivalent), Me 3 SBF 4 (715g, 1.2 equiv), and THF (15L, 15V). The resulting slurry was cooled to 15 °C and a solution of Na tert-amyl alcohol (1.4M in THF, 3.1 L, 1.2 equiv) was added over not less than 2 h while maintaining the internal range temperature at 18-22 °C. The reaction mixture was washed with 10% NH 4Aqueous OAc (5 L, 5 ml / g) was quenched. n-Octane (5 L, 5 ml / g) was added to the mixture to aid extraction. The layers were separated and the organic stream was washed with 13% brine (3x5L, 5ml / g). The organic-rich stream was concentrated under reduced pressure to about 3 total volumes, and the solvent was exchanged for n-octane under constant volume conditions (full vacuum, 70°C). The batch was cooled to 30°C and seeds (10 g, 1 wt%) were added. The resulting slurry was aged at 30 °C for 2 h, then cooled to 15 °C over 18 h. The resulting solid was filtered and washed wit...
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