4-Chlorobenzo[b]thiophene a key intermediate in brexpiprazole synthesis

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

Masahiro Miyake^*, Masamichi Shimizu, Koichi Tsuji, and Keiichi Ikeda

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