A Facile Route of Synthesis for Making Flibanserin

Article abstract of DOI:10.1021/acs.oprd.6b00108

A novel and efficient route of synthesis for making flibanserin via 2-ethoxy-1H-benzo[d]imidazole (12) was described with excellent yield. This protocol provided a more facile approach to flibanserin.

Full text of DOI:10.1021/acs.oprd.6b00108

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Full Paper
A Facile Route of Synthesis for Making Flibanserin
Feipu Yang, Chunhui Wu, Zhiqiang Li, Guanghui Tian, Jianzhong Wu, Yang He, and Jingshan Shen
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00108 • Publication Date (Web): 26 Jul 2016
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A Facile Route of Synthesis for Making Flibanserin
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Feipu Yang,†,⊥,§ Chunhui Wu,‡ Zhiqiang Li,‡ Guanghui Tian,‡ Jianzhong Wu,‡ Yang
He,*,† and Jingshan Shen*,†
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†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
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ABSTRACT
novel and efficient route of synthesis for making flibanserin via
A
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2ꢀethoxyꢀ1Hꢀbenzo[d]imidazole (12) was described with excellent yield. This protocol
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provided a more facile approach to flibanserin.
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INTRODUCTION
Flibanserin (1) (Figure 1), a 5ꢀHT1A serotonin receptor agonist and 5ꢀHT2A serotonin
receptor antagonist, is a nonꢀhormonal compound launched in 2015 for the oral treatment
of acquired, generalized hypoactive sexual desire disorder (HSDD) in preꢀmenopausal
women.1,2 It is the first and only FDAꢀapproved treatment for HSDD.
Figure 1. Chemical structure of flibanserin
The original preparation of flibanserin (1) (Scheme 1) used benzeneꢀ1,2ꢀdiamine (2)
and ethyl benzoylacetate to prepare 3 at 200 °C.3ꢀ5 The harsh condition involved in the
thermal rearrangement required special equipment and tedious operations and led to
inferior product profile because of the formation of impurity 6.6,7 In addition,
Oꢀsubstituted byproduct (7), a potential genotoxic impurity, was generated inevitably
owing to the amideꢀimidic acid tautomerization in the step of synthesizing 4.8,9 The
Oꢀsubstituted impurity (7) would participate in the following transformation, thus
affecting the quality of the final API. The route not only provided low yield but also
presented tremendous challenges to operability and quality control. Herein we report a
novel and efficient route of synthesis for making flibanserin to address the issues
mentioned above.
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Scheme 1. Original Route of Synthesis for Making Flibanserina
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aReagents and conditions: (a) ethyl benzoylacetate, 200 °C; (b) dichloroethane, NaH,
DMF; (c) conc HCl (aq); (d) 1ꢀ(3ꢀ(trifluoromethyl)phenyl)piperazine hydrochloride,
Na2CO3, KI, EtOH; (e) NaOH (aq), EtOH.
RESULT AND DISCUSSION
Our development initiated from improving the original process by introducing some
modifications, exemplified in Scheme 2. Cheaper and atom economic ethyl acetoacetate
was used instead of ethyl benzoylacetate. The deprotection reaction was performed in the
last step to mitigate the formation of related impurities. Starting from
benzeneꢀ1,2ꢀdiamine, compound 8 was prepared in mediocre yield at high temperature
according to the method described by Khodarahmi10. Condensation of 8 with
1,2ꢀdibromoethane in the presence of potassium carbonate, followed by purification with
nꢀheptane afforded 9 in 50% yield. Flibanserin hydrochloride was obtained by coupling 9
with commercially available 10 in acetonitrile and subjecting the resultant intermediate
with concentrated hydrochloride. Basification of Flibanserin hydrochloride with aqueous
sodium hydroxide furnished Flibanserin (1). However, the overall yield was only 16%
over 5 steps with purity at 99.5%, which didn’t meet our expectation.
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Scheme 2. Modified Original Route of Flibanserina
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CF3
7
8
HN
N
H
N
9
HCl
NH2
NH2
N
N
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a
b
10
O
O
c
N
Br
8
9
2
O
O
CF3
CF3
d,e
N
HN
N
N
N
N
N
N
1
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aReagents and conditions: (a) ethyl acetoacetate, KOH, EtOH, xylene, reflux, 56%; (b)
1,2ꢀdibromoethane, K2CO3, DMF, 50 °C, 50%; (c) K2CO3, CH3CN, 70 °C, 80%; (d) conc
HCl (aq), isopropanol, 70 °C; (e) NaOH (aq), rt, 72 % over two steps.
Scheme 3. New Synthetic Route of Flibanserina
CF3
HN
N
N
N
HCl
O
NH2
NH2
N
10
b
a
O
c
N
H
Cl
2
12
13
O
O
N
CF3
CF3
HN
d,e
N
N
N
N
N
N
1
14
aReagents and conditions: (a) tetraethyl orthocarbonate, AcOH, 70 °C, 94%; (b)
1ꢀbromoꢀ2ꢀchloroethane, K2CO3, acetone, reflux, 75%; (c) K2CO3, NaI, H2O, reflux, 92%;
(d) conc HCl (aq), isopropanol, 70 °C; (e) NaOH (aq), 68% over two steps.
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As reported,11,12 the benzimidazole scaffold could be constructed by condensation of
benzeneꢀ1,2ꢀdiamine (2) with orthoester in excellent yield under mild conditions. The
symmetrical characteristic and masked oxygen atom of the benzimidazole moiety
eliminated the possibility of forming related impurities. Because tetramethyl
orthocarbonate is much more expensive than tetraethyl orthocarbonate,
2ꢀethoxyꢀ1Hꢀbenzo[d]imidazole (12) was proposed as key intermediate in our new
synthetic route (Scheme 3). In the condensation step, 1.05 equivalent of tetraethyl
orthocarbonate was found to give the best result. Monoꢀsubstitution of compound 12 with
1ꢀbromoꢀ2ꢀchloroethane in acetone at reflux in the presence of potassium carbonate gave
13 in 75% yield. Replacement of 1ꢀbromoꢀ2ꢀchloroethane with 1,2ꢀdichloroethane gave
lower conversion of compound 12, whereas 1,2ꢀdibromoethane led to larger amount of
bisꢀsubstituted impurity 15. The optimum equivalent of 1ꢀbromoꢀ2ꢀchloroethane was
found to be 2.5 equivalent as lower equivalent led to incomplete conversion of compound
12. The K2CO3/ acetone system was selected as the reaction condition for the scaleꢀup.
Other conditions such as TEA/toluene, Na2CO3/DMF, K2CO3/MeOH or K2CO3/THF
system resulted in either poor conversion or formation of more impurities. Although
K2CO3/DMF or Cs2CO3/CH3CN system condition provided good results, the consequent
environmental issues or cost considerations limited their applications in manufacturing
production. Three impurities 15−17, 1.8%, 1.5% and 0.4% AUC respectively, were
identified in the reaction mixture by LCꢀMS. Among them, impurity 15 and 17 could be
removed completely by recrystallization in nꢀheptane. Impurity 16 could react with 10 to
give desired intermediate 14 in the next step. After recrystallization in nꢀheptane,
compound 13 was obtained with excellent purity (97.5%).
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Figure 2. Impurities 15−17
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With intermediates 13 and 10 in hand, a host of nucleophilic substitution reaction
conditions (Table 1) were explored. In polar solvents with moderate dielectric constants,
the reaction proceeded very slowly and a large amount of 13 and 10 remained intact,
probably attributing to poor solubility of the acidꢀbinding reagent potassium carbonate.
Polar aprotic solvents with high dielectric constants such as acetonitrile, DMF and NMP
would facilitate the replacement. In acetonitrile, however, low conversion of the raw
materials was recorded even prolonging reaction time to 2 days. Reaction of 13 and 10
proceeded well and completely in DMF, but DMF was a real issue in EHS consideration.
Elimination impurity 17 was observed in NMP, thus resulting in low yield of 14. Using
mixed solvents of acetonitrile and water could result in higher yield than using
acetonitrile only probably due to better solubility of potassium carbonate and sodium
iodide which could accelerate reaction remarkably. Later, we found the reaction
proceeded quite well in water and the yield was over 90%. Therefore, we selected
H2O/K2CO3/NaI as the optimum condition in nucleophilic substitution of 13 with 10.
Flibanserin hydrochloride could be expediently achieved with 99.8% purity just by
filtration without further purification after deethylation with concentrated hydrochloride
in isopropanol. The impurities could be well controlled in this step and no impurity
would be generated in the next basification step.
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Table 1. Exploration of Nucleophilic Substitution Reaction conditions of 13 and 10
entry
solvents
base (1.1 eq)
NaI
temperature
reaction time
yielda
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2
3
4
5
acetone
THF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1 eq
1 eq
1 eq
1 eq
1 eq
reflux
reflux
reflux
reflux
reflux
24 h
24 h
24 h
24 h
24 h
< 10%
< 10%
22%
EtOH
iꢀPrOH
nꢀBuOH
24%
23%
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1,4ꢀdioxane
DMF
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
1 eq
0 eq
1 eq
1 eq
1 eq
1 eq
0.2 eq
1 eq
1 eq
1 eq
1 eq
reflux
70 °C
70 °C
70 °C
reflux
reflux
reflux
reflux
reflux
reflux
reflux
24 h
24 h
24 h
24 h
24 h
24 h
24 h
24 h
12 h
6 h
20%
25%
85%
40%
50%
75%
42%
87%
88%
75%
62%
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DMF
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NMP
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CH3CN
CH3CN:H2O=2:1
H2O
H2O
H2O
H2O
H2O
6 h
aIsolated yield after purification by column chromatography.
There were several advantages in the new approach. First, the cyclization was carried
out under mild conditions with excellent yield, which gave pure product and simplified
workup operations. Second, 12 was involved as key intermediate, which could avoid
generating Oꢀsubstituted impurities. Third, water was used as solvent in nucleophilic
substitution reaction of 13 and 10, which was environmentꢀfriendly and cost effective.
The last but not the least, purity of flibanserin could be controlled as hydrochloride salt,
which ensured the quality of the final API. The overall yield obtained following this route
was around 45% with purity at 99.9% and all three identified impurities were below
0.05% indicated by HPLC. A patent application for the new synthetic route had been filed
in China (CN201610527244.4).
CONCLUSION
An improved process for making flibanserin via 2ꢀethoxyꢀ1Hꢀbenzo[d]imidazole as the
key intermediate had been provided in 5 steps. This novel route fully satisfied our aim of
developing a safe, convenient, costꢀeffective, highꢀyielding, and environmentꢀfriendly
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process. We are confident that it should be valuable in the industrial manufacturing of
flibanserin.
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EXPERIMENTAL SECTION
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General Procedures. All commercially available materials and solvents were used
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directly without further purification. H NMR spectra and 13C NMR spectra were
recorded on a Bruker AMꢀ500 spectrometer with TMS as internal standard. The mass
spectra (LRMS and HRMS) were recorded on a finnigan MATꢀ95/711 spectrometer.
HPLC method: Waters XTerra Phenyl column (5 ꢀm，4.6 mm × 250 mm); flow rate = 1.0
mL/min; 30 °C; gradient elution from 95:5 A/B to 20:80 A/B over 30 min, where A =
0.1% H3PO4 in water and B = acetonitrile; UV detection at 210 nm.
1-(Prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one (8). Potassium hydroxide
solution in ethanol (1.8 g, 9.2 mL) and subsequently ethyl acetoacetate (132.3 g, 1.017
mol) in xylene (50 mL) was added dropwise within 2.5 h to a refluxing solution of 2 (100
g, 0.924 mol) in xylene (400 mL) under nitrogen, while the water produced during the
reflux was removed using a DeanꢀStark trap. It was refluxed for another 5 h and then
cooled to 40 °C. An aqueous solution of potassium hydroxide (71.8 g, 250 mL) was
added and the mixture was stirred at 40 °C for 0.5 h. The organic layer was separated and
acetic acid (111 mL) was added slowly. The resulting slurry was filtered and washed with
nꢀheptane, and dried under vacuum to give compound 8 (89.7 g) as pale brown solid with
yield of 56%. 1H 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). ESIꢀMS (m/z): 175.4 [M +
H]+, 173.3 [M − H]−; HPLC: retention time of 12.5 min, 99.5% purity.
1-(2-Bromoethyl)-3-(prop-1-en-2-yl)-1H-benzo[d]imidazol-2(3H)-one
(9).
A
mixture of 8 (10 g, 0.154 mol), 1,2ꢀdibromoethane (43 g, 0.229 mol), potassium
carbonate (15.9 g, 0.115 mol) and DMF (60 mL) was heated at 50 °C overnight. The
reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 × 2 mL)
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and water (120 mL). The organic layer was dried and evaporated under reduced pressure
to obtain crude 9, which was further purified by recrystallization in nꢀheptane (60 mL),
and dried to give compound 9 (8 g) as white solid with yield of 50%. 1H 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). ESIꢀMS (m/z): 283.4 [M + H]+, 585.3 [2 M +
Na]+. HPLC: retention time of 18.6 min, 96.5% purity.
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1-(Prop-1-en-2-yl)-3-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-be
nzo[d]imidazol-2(3H)-one(11). A reactor was charged with compound 9 (5 g, 0.018 mol),
compound 10 (6.2 g, 0.023 mol), potassium carbonate (7.4 g, 0.053 mol) and acetonitrile
(30 mL). Then the mixture was stirred at 70 °C overnight. Then the solution was cooled
to room temperature and filtered. The filtrate was concentrated, extracted with ethyl
acetate (30 mL) and water (10 mL). The organic layer was dried, evaporated under
reduced pressure and recrystallization in isopropanol (30 mL) to give 11 as white solid
with yield of 80%. 1H 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). ESIꢀMS (m/z): 431.5 [M + H]+.
HPLC: retention time of 23.7 min, 97.6% purity.
1-(2-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzo[d]imidazol-2(3
H)-one (1). Compound 11 (9.5 g, 0.022 mol) was dissolved in isopropanol (40 mL) and
concentrated hydrochloric acid (7.4 mL, 0.088 mol) was added. The reaction mixture was
stirred at 70 °C for 2 hours. After condensation of the solution, ethyl acetate (30 mL) and
aqueous sodium hydroxide solution was added and stirred for 30 min. The organic layer
was dried and evaporated under reduced pressure. Pure compound 1 as white solid (6.2 g,
72%) was produced via recrystallization in isopropanol (30 mL). HPLC: retention time of
9.0 min, 99.5% purity.
2-Ethoxy-1H-benzo[d]imidazole (12). A mixture of 2 (0.8 kg, 7.39 mol), tetraethyl
orthocarbonate (1.49 kg, 7.76 mol), and acetic acid (444 g) was heated at 70 °C for 2
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hours. Then the solution was cooled to room temperature and 5% aqueous potassium
hydroxide solution (6.4 L) was added slowly. The reaction mixture was stirred for 1 hour.
The precipitation was collected by filtration, washed with water, dried to give compound
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12 (1.13 kg) as white solid with yield of 94%. H NMR (400 MHz, DMSOꢀd6) δ 11.80
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(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).
ESIꢀMS (m/z): 163.5 [M + H]+, 161.2 [M − H]−; HPLC: retention time of 12.2 min,
96.3% purity.
1-(2-Chloroethyl)-2-ethoxy-1H-benzo[d]imidazole (13). A mixture of 12 (1 kg, 6.16
mol), 1ꢀbromoꢀ2ꢀchloroethane (2.21 kg, 15.41 mol), potassium carbonate (5.11 kg, 36.99
mol) and acetone (10 L) was heated at reflux for 10 h. Then the solution was cooled to
room temperature and filtered. The filtrate was concentrated to obtain crude 13, which
was further purified by recrystallization in nꢀheptane (4 L), and dried to give compound
13 (1.04 kg) as white solid with yield of 75%. 1H 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,
13
J = 6.6 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). 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. ESIꢀMS (m/z): 225.3 [M + H]+;
HRMS (ESI) calcd [M + H]+ for C11H14ClN2O 225.0795, found 225.0798. HPLC:
retention time of 16.0 min, 97.5% purity.
2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzo[d]imi
dazole (14). A reactor was charged with compound 13 (500 g, 2.23 mol), compound 10
(595 g, 2.23 mol), sodium iodide (334 g, 2.23 mol), potassium carbonate (338 g, 2.45 mol)
and water (3 L). Then the mixture was heated at reflux for 12 hours. The reaction mixture
was cooled to room temperature, extracted with ethyl acetate (2 L). The organic layer was
washed with water (700 mL) and brine (500 mL), dried and evaporated under reduced
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pressure to provide 14 which was used directly in the next step (857 g, 92%). 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
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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). 13C 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. ESIꢀMS (m/z): 419.6 [M + H]+; HRMS (ESI) calcd [M + H]+ for C22H26F3N4O
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419.2059, found 419.2071. HPLC: retention time of 12.4 min, 95% purity.
1-(2-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzo[d]imidazol-2(3
H)-one (1). Compound 14 (857 g, 2.05 mol) was dissolved in isopropanol (3 L) and
concentrated hydrochloric acid (0.68 L, 8.2 mol) was added. The reaction mixture was
stirred at 70 °C for 2 hours. Upon completion of reaction indicated by TLC, the reaction
mixture was cooled down gradually and a mass of white solid was separated out.
Flibanserin hydrochloride was obtained as white solid ( 845 g, 96.5%) after washed by
1
isopropanol (150 mL × 3) and dried in vacuo at 45 °C overnight. H NMR (400 MHz,
DMSOꢀd6) δ 11.27 (s, 1H), 11.08 (s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.40-7.34 (m, 1H),
7.31 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.09-7.01 (m, 3H), 4.32 (t, J = 6.6 Hz,
2H), 4.01 (d, J = 9.9 Hz, 2H), 3.75 (d, J = 8.6 Hz, 2H), 3.48 (d, J = 4.0 Hz, 2H),
3.33-3.15 (m, 4H). ESIꢀMS (m/z): 391.1 [M + H]+. HPLC: retention time of 9.1 min,
99.8% purity.
Then ethyl acetate (3 L) and aqueous sodium hydroxide solution (100 g sodium
hydroxide was dissolved in 1.5 L water) was added and stirred for 30 min. The organic
layer was dried and evaporated under reduced pressure. Pure compound 1 as white solid
1
(540 g, 70%) was produced via recrystallization in isopropanol (1.2 L). H NMR (400
MHz, DMSOꢀd6) 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); ESIꢀMS (m/z): 391.6 [M + H]+; HPLC: retention
time of 9.1 min, 99.9% purity.
1,2-Bis(2-ethoxy-1H-benzo[d]imidazol-1-yl)ethane (15)
1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 2H), 7.06 (t,
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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). 13C 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. HRMS (ESI) calcd [M + H]+ for C20H23N4O2 351.1821, found
351.1814.
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1-(2-Bromoethyl)-2-ethoxy-1H-benzo[d]imidazole (16)
1H NMR (500 MHz, CDCl3) δ 7.56–7.42 (m, 1H), 7.20–7.05 (m, 3H), 4.59 (q, J = 7.1
13
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). 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. HRMS (ESI) calcd [M + H]+ for C11H14BrN2O 269.0289, found 269.0286.
2-Ethoxy-1-vinyl-1H-benzo[d]imidazole (17)
1H 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),
13
5.05–4.94 (m, 1H), 4.63 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H). 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.
HRMS (ESI) calcd [M + H]+ for C11H13N2O 189.1028, found 189.1033.
ASSOCIATED CONTENT
NMR spectra, HRMS and HPLC data for compounds 1, 8, 9, 11-17.
AUTHOR INFORMATION
Corresponding Author
*For Y.H.: phone, +86 21 20231000-2409; Eꢀmail: heyang@simm.ac.cn.
*For J.S.: phone, +86 21 20231962; Eꢀmail: jsshen@mail.shcnc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors gratefully acknowledge Topharman Shanghai Co., Ltd for providing
intermediates.
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Funding
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This work was supported by Chinese Ministry of National Science and Technology create
significant new drugs, special major science and technology (2013ZX09507001).
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Table of Contents Graphic
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A facile route of synthesis for making flibanserin with 45%
overall yield
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