We established an improved synthetic route to 4-chlorobenzo[b]thiophene, a key intermediate in brexpiprazole synthesis, via a practical decarboxylation process in three steps. Thermal analysis demonstrated that the coexistence of the decarboxylated product with DBU should be avoided and that removal of the product outside the reactor was vital. Our process yields the target compound by distillation under reduced pressure and is safe, highly batch efficient, cost-effective, and high yielding. Furthermore, manufacturing on a pilot scale was also accomplished through our approach.
4-Chlorobenzo[b]thiophene-2-carboxylic Acid (4)
4 as a white solid
mp 260 °C.
1H NMR (300 MHz, DMSO-d6) δ 7.54 (d, 1H, J = 11.6, 7.7 Hz), 7.56 (dd, 1H, J = 17.8, 7.7 Hz), 8.03 (d, 1H, J = 0.7 Hz), 8.07 (td, 1H, J = 7.6, 0.9 Hz), 13.19 (brs, 1H).
13C NMR (75 MHz, DMSO-d6) δ 122.21, 125.01, 126.84, 127.99, 128.96, 136.50, 136.57, 142.55, 163.10.
Elemental analysis calcd for C: 50.83%, H: 2.37%, found C: 50.84%, H: 2.21%.
2,3,4,6,7,8,9,10-Octahydropyrimido[1,2-a]azepin-1-ium 4-Chlorobenzo[b]thiophene-2-carboxylate 5
5 as a white solid
Mp 182.5 °C.
1H NMR (300 MHz, CDCl3) δ 1.66 (m, 6H), 1.80–1.75 (m, 2H), 2.98–2.94 (m, 2H), 3.45–3.39 (m, 4H), 3.55–3.51 (m, 2H), 7.31–7.20 (m, 2H), 7.69 (dd, 1H, J = 3.9, 0.6 Hz), 7.97 (s, 1H), 13.19 (brs, 1H).
13C NMR (75 MHz, CDCl3) δ 19.51, 24.03, 26.70, 28.88, 31.99, 38.01, 48.36, 53.94, 121.04, 123.00, 125.17, 126.61, 128.98, 138.21, 142.43, 146.85, 165.91, 167.20.
Elemental analysis calcd for C: 59.25%, H: 5.80%, N: 7.68%, found C: 59.10%, H: 5.44%, N: 7.53%.
4-Chlorobenzo[b]thiophene (2)
1H NMR (300 MHz, CDCl3) δ 7.26 (t, 1H, J = 7.8 Hz), 7.36 (dd, 1H, J = 7.8, 0.9 Hz), 7.50 (d, 1H, J = 5.7 Hz), 7.52 (d, 1H, J = 5.7 Hz), 7.76 (d, 1H, J = 7.8 Hz).
13C NMR (75 MHz, CDCl3) δ 121.12, 122.40, 125.02, 127.43, 128.93, 138.06, 141.07.
Elemental analysis calcd for C: 56.98%, H: 2.99%, found C: 56.76%, H: 2.94%.
SEE
http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00340
http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.5b00340/suppl_file/op5b00340_si_001.pdf
Safe and Efficient Decarboxylation Process: A Practical Synthetic Route to 4-Chlorobenzo[b]thiophene
Bulk Pharmaceutical Chemicals Department,
Second Tokushima Factory, Production Headquarters, Otsuka Pharmaceutical
Co., Ltd., 224-18, Hiraishi Ebisuno, Kawauchi-cho, Tokushima 771-0182, Japan
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00340
