A Facile Route of Synthesis for Making Flibanserin
Supporting Information
A Facile Route of Synthesis for Making Flibanserin Feipu Yang,†,⊥,§ Chunhui Wu,‡ Zhiqiang Li,‡ Guanghui Tian,‡ Jianzhong Wu,‡ Yang He,*,† and Jingshan Shen*,† †
CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China ⊥
University of Chinese Academy of Sciences，No.19A Yuquan Road, Beijing 100049, China
‡
Topharman Shanghai Co., Ltd., 1088 Chuansha Road, Shanghai 201209, China
Context P2−P20
Analytical Data of Related Compounds
P1
1．Compound 8 1
H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 7.18–7.12 (m, 1H), 7.12–7.04 (m, 3H), 5.42 (d, J =
1.5 Hz, 1H), 5.26 (s, 1H), 2.25 (s, 3H).
P2
2．Compound 9 1
H NMR (400 MHz, CDCl3) δ 7.15–7.06 (m, 4H), 5.36 (d, J = 1.4 Hz, 1H), 5.21 (s, 1H), 4.28 (t, J
= 7.0 Hz, 2H), 3.66 (t, J = 7.0 Hz, 2H), 2.23 (s, 3H).
P3
3．Compound 11 1
H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 8.0 Hz, 1H), 7.14–7.02 (m, 7H), 5.34 (q, J = 1.4 Hz,
1H), 5.19 (d, J = 0.8 Hz, 1H), 4.06 (t, J = 7.0 Hz, 2H), 3.22 (brt, 4H), 2.77 (t, J = 7.0 Hz, 2H), 2.72 (brt, 4H), 2.22 (s, 3H).
P4
4．Compound 12 1
H NMR (400 MHz, DMSO-d6) δ 11.80 (brs, 1H), 7.29 (m, 2H), 7.03 (m, 2H), 4.48 (q, J = 7.1 Hz,
2H), 1.37 (t, J = 7.1 Hz, 3H).
P5
5．Compound 13 1
H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.17–7.06 (m, 3H), 4.58 (q, J = 7.1 Hz,
2H), 4.17 (t, J = 6.6 Hz, 2H), 3.69 (t, J = 6.6 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 156.9, 140.0, 133.3, 121.6, 120.9, 117.6, 107.9, 66.3, 43.4, 41.2,
14.6.
P6
HRMS (ESI) calcd [M + H]+ for C11H14ClN2O 225.0795, found 225.0798.
P7
HPLC: retention time of 16.0 min, 97.5% pure.
P8
6．Compound 14 1
H NMR (500 MHz, CDCl3) δ 7.56 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.21–7.12 (m, 3H), 7.10 (brt,
J = 1.9 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 8.4, 2.4 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H), 3.19 (brt, J = 5.0 Hz, 4H), 2.75 (t, J = 6.9 Hz, 2H), 2.66 (t, J = 5.0 Hz, 4H), 1.49 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 157.4, 151.3, 140.3, 133.6, 131.4 (q, J = 31.8 Hz), 129.6, 124.4 (q,
J = 272.5 Hz), 121.5, 120.8, 118.7, 117.7, 115.9 (q, J = 3.9 Hz), 112.2 (q, J = 3.8 Hz), 108.1, 66.2, 56.4, 53.1 × 2, 48.6 × 2, 39.7, 14.9.
P9
HRMS (ESI) calcd [M + H]+ for C22H26F3N4O 419.2059, found 419.2071.
P10
HPLC: retention time of 12.4 min, 95% pure.
P11
P12
7．Compound 1 1
H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.4
Hz, 1H), 7.12−7.17 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.94−7.02 (m, 3H), 3.94 (t, J = 6.6 Hz, 2H), 3.17 (brt, 4H), 2.58−2.65 (m, 6H).
P13
HPLC: retention time of 9.06 min, 99.9% pure.
P14
8．Compound 15 1
H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 7.6
Hz, 2H), 6.88 (d, J = 7.8 Hz, 2H), 4.25 (brs, 4H), 4.24 (q, J = 7.1 Hz, 4H), 1.12 (t, J = 7.1 Hz, 6H).
13
C NMR (125 MHz, CDCl3) δ 157.1, 140.3, 133.2, 121.8, 121.1, 117.9, 107.3, 66.2, 40.6, 14.2.
P15
HRMS (ESI) calcd [M + H]+ for C20H23N4O2 351.1821, found 351.1814.
P16
9. Compound 16 1
H NMR (500 MHz, CDCl3) δ 7.56–7.42 (m, 1H), 7.20–7.05 (m, 3H), 4.59 (q, J = 7.1 Hz, 2H),
4.27 (t, J = 7.1 Hz, 2H), 3.54 (t, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 156.9, 140.0, 133.1, 121.7, 121.0, 117.7, 107.9, 66.3, 43.3, 28.3,
14.7
.
P17
HRMS (ESI) calcd [M + H]+ for C11H14BrN2O 269.0289, found 269.0286.
P18
10. Compound 17 1
H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 7.1, 1.8 Hz, 1H), 7.44 (dd, J = 7.1, 1.8 Hz, 1H), 7.24–
7.10 (m, 2H), 7.01 (dd, J = 16.2, 9.5 Hz, 1H), 5.51 (dd, J = 16.2, 0.8 Hz, 1H), 5.05–4.94 (m, 1H), 4.63 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 156.3, 140.4, 132.0, 127.1, 122.5, 121.6, 117.9, 110.1, 101.6, 66.6,
14.6.
P19
HRMS (ESI) calcd [M + H]+ for C11H13N2O 189.1028, found 189.1033.
P20
A Facile Route of Synthesis for Making Flibanserin Feipu Yang,†,⊥,§ Chunhui Wu,‡ Zhiqiang Li,‡ Guanghui Tian,‡ Jianzhong Wu,‡ Yang He,*,† and Jingshan Shen*,† †
CAS Key Laboratory for Receptor Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China ⊥
University of Chinese Academy of Sciences，No.19A Yuquan Road, Beijing 100049, China
‡
Topharman Shanghai Co., Ltd., 1088 Chuansha Road, Shanghai 201209, China
Context P2−P20
Analytical Data of Related Compounds
P1
1．Compound 8 1
H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 7.18–7.12 (m, 1H), 7.12–7.04 (m, 3H), 5.42 (d, J =
1.5 Hz, 1H), 5.26 (s, 1H), 2.25 (s, 3H).
P2
2．Compound 9 1
H NMR (400 MHz, CDCl3) δ 7.15–7.06 (m, 4H), 5.36 (d, J = 1.4 Hz, 1H), 5.21 (s, 1H), 4.28 (t, J
= 7.0 Hz, 2H), 3.66 (t, J = 7.0 Hz, 2H), 2.23 (s, 3H).
P3
3．Compound 11 1
H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 8.0 Hz, 1H), 7.14–7.02 (m, 7H), 5.34 (q, J = 1.4 Hz,
1H), 5.19 (d, J = 0.8 Hz, 1H), 4.06 (t, J = 7.0 Hz, 2H), 3.22 (brt, 4H), 2.77 (t, J = 7.0 Hz, 2H), 2.72 (brt, 4H), 2.22 (s, 3H).
P4
4．Compound 12 1
H NMR (400 MHz, DMSO-d6) δ 11.80 (brs, 1H), 7.29 (m, 2H), 7.03 (m, 2H), 4.48 (q, J = 7.1 Hz,
2H), 1.37 (t, J = 7.1 Hz, 3H).
P5
5．Compound 13 1
H NMR (500 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.17–7.06 (m, 3H), 4.58 (q, J = 7.1 Hz,
2H), 4.17 (t, J = 6.6 Hz, 2H), 3.69 (t, J = 6.6 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 156.9, 140.0, 133.3, 121.6, 120.9, 117.6, 107.9, 66.3, 43.4, 41.2,
14.6.
P6
HRMS (ESI) calcd [M + H]+ for C11H14ClN2O 225.0795, found 225.0798.
P7
HPLC: retention time of 16.0 min, 97.5% pure.
P8
6．Compound 14 1
H NMR (500 MHz, CDCl3) δ 7.56 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.21–7.12 (m, 3H), 7.10 (brt,
J = 1.9 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 8.4, 2.4 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H), 3.19 (brt, J = 5.0 Hz, 4H), 2.75 (t, J = 6.9 Hz, 2H), 2.66 (t, J = 5.0 Hz, 4H), 1.49 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 157.4, 151.3, 140.3, 133.6, 131.4 (q, J = 31.8 Hz), 129.6, 124.4 (q,
J = 272.5 Hz), 121.5, 120.8, 118.7, 117.7, 115.9 (q, J = 3.9 Hz), 112.2 (q, J = 3.8 Hz), 108.1, 66.2, 56.4, 53.1 × 2, 48.6 × 2, 39.7, 14.9.
P9
HRMS (ESI) calcd [M + H]+ for C22H26F3N4O 419.2059, found 419.2071.
P10
HPLC: retention time of 12.4 min, 95% pure.
P11
P12
7．Compound 1 1
H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.20 (dd, J = 8.4 Hz, 2.4
Hz, 1H), 7.12−7.17 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.94−7.02 (m, 3H), 3.94 (t, J = 6.6 Hz, 2H), 3.17 (brt, 4H), 2.58−2.65 (m, 6H).
P13
HPLC: retention time of 9.06 min, 99.9% pure.
P14
8．Compound 15 1
H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 2H), 7.06 (t, J = 7.6
Hz, 2H), 6.88 (d, J = 7.8 Hz, 2H), 4.25 (brs, 4H), 4.24 (q, J = 7.1 Hz, 4H), 1.12 (t, J = 7.1 Hz, 6H).
13
C NMR (125 MHz, CDCl3) δ 157.1, 140.3, 133.2, 121.8, 121.1, 117.9, 107.3, 66.2, 40.6, 14.2.
P15
HRMS (ESI) calcd [M + H]+ for C20H23N4O2 351.1821, found 351.1814.
P16
9. Compound 16 1
H NMR (500 MHz, CDCl3) δ 7.56–7.42 (m, 1H), 7.20–7.05 (m, 3H), 4.59 (q, J = 7.1 Hz, 2H),
4.27 (t, J = 7.1 Hz, 2H), 3.54 (t, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 156.9, 140.0, 133.1, 121.7, 121.0, 117.7, 107.9, 66.3, 43.3, 28.3,
14.7
.
P17
HRMS (ESI) calcd [M + H]+ for C11H14BrN2O 269.0289, found 269.0286.
P18
10. Compound 17 1
H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 7.1, 1.8 Hz, 1H), 7.44 (dd, J = 7.1, 1.8 Hz, 1H), 7.24–
7.10 (m, 2H), 7.01 (dd, J = 16.2, 9.5 Hz, 1H), 5.51 (dd, J = 16.2, 0.8 Hz, 1H), 5.05–4.94 (m, 1H), 4.63 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H).
13
C NMR (125 MHz, CDCl3) δ 156.3, 140.4, 132.0, 127.1, 122.5, 121.6, 117.9, 110.1, 101.6, 66.6,
14.6.
P19
HRMS (ESI) calcd [M + H]+ for C11H13N2O 189.1028, found 189.1033.
P20
