Article pubs.acs.org/OPRD
A Facile Route of Synthesis for Making Flibanserin Feipu Yang,†,‡ Chunhui Wu,§ Zhiqiang Li,§ Guanghui Tian,§ Jianzhong Wu,§ Fuqiang Zhu,§ Jian Zhang,§ 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 S Supporting Information *
ABSTRACT: 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.
■
to the method described by Khodarahmi.10 Condensation of 8 with 1,2-dibromoethane in the presence of potassium carbonate, followed by purification with n-heptane 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 five steps with purity at 99.5%, which did not meet our expectations. As reported,11,12 the benzimidazole scaffold could be constructed by condensation of benzene-1,2-diamine (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, 2-ethoxy-1Hbenzo[d]imidazole (12) was proposed as key intermediate in our new synthetic route (Scheme 3). In the condensation step, 1.05 equiv of tetraethyl orthocarbonate was found to give the best result. Monosubstitution of compound 12 with 1-bromo-2chloroethane in acetone at reflux in the presence of potassium carbonate gave 13 in 75% yield. Replacement of 1-bromo-2chloroethane with 1,2-dichloroethane gave lower conversion of compound 12, whereas 1,2-dibromoethane led to larger amount of bis-substituted impurity 15 (Figure 2). The optimum equivalent of 1-bromo-2-chloroethane was found to be 2.5 equiv as lower equivalent led to incomplete conversion of compound 12. The K2CO3/ acetone system was selected as the reaction condition for the scale-up. 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 the K2CO3/DMF or Cs2CO3/ CH 3 CN 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,
INTRODUCTION Flibanserin (1) (Figure 1), a 5-HT1A serotonin receptor agonist and 5-HT2A serotonin receptor antagonist, is a nonhormonal
Figure 1. Chemical structure of flibanserin.
compound launched in 2015 for the oral treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.1,2 It is the first and only FDA-approved treatment for HSDD. The original preparation of flibanserin (1) (Scheme 1) used benzene-1,2-diamine (2) and ethyl benzoylacetate to prepare 3 at 200 °C.3−5 The harsh conditions involved in the thermal rearrangement required special equipment and tedious operations and led to an inferior product profile because of the formation of impurity 6.6,7 In addition, O-substituted byproduct (7), a potential genotoxic impurity, was generated inevitably owing to the amide-imidic acid tautomerization in the step of synthesizing 4.8,9 The O-substituted 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.
■
RESULTS 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 benzene-1,2-diamine, compound 8 was prepared in mediocre yield at high temperature according © 2016 American Chemical Society
Received: March 30, 2016 Published: July 26, 2016 1576
DOI: 10.1021/acs.oprd.6b00108 Org. Process Res. Dev. 2016, 20, 1576−1580
Organic Process Research & Development
Article
Scheme 1. Original Route of Synthesis for Making Flibanserina
a Reagents and conditions: (a) ethyl benzoylacetate, 200 °C; (b) dichloroethane, NaH, DMF; (c) conc HCl (aq); (d) 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride, Na2CO3, KI, EtOH; (e) NaOH (aq), EtOH.
Scheme 2. Modified Original Route of Flibanserina
Reagents and conditions: (a) ethyl acetoacetate, KOH, EtOH, xylene, reflux, 56%; (b) 1,2-dibromoethane, 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.
a
Scheme 3. New Synthetic Route of Flibanserina
Reagents and conditions: (a) tetraethyl orthocarbonate, AcOH, 70 °C, 94%; (b) 1-bromo-2-chloroethane, K2CO3, acetone, reflux, 75%; (c) K2CO3, NaI, H2O, reflux, 92%; (d) conc. HCl (aq), isopropanol, 70 °C; (e) NaOH (aq), 68% over two steps.
a
1577
DOI: 10.1021/acs.oprd.6b00108 Org. Process Res. Dev. 2016, 20, 1576−1580
Organic Process Research & Development
Article
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 O-substituted impurities. Third, water was used as solvent in nucleophilic substitution reaction of 13 and 10, which was environment-friendly and costeffective. The last but not the least, the 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 has been filed in China (CN201610527244.4).
Figure 2. Impurities 15−17.
were identified in the reaction mixture by LC-MS. Among them, impurities 15 and 17 could be removed completely by recrystallization in n-heptane. Impurity 16 could react with 10 to give desired intermediate 14 in the next step. After recrystallization in n-heptane, compound 13 was obtained with excellent purity (97.5%). 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 acid-binding 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 the 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.
■
CONCLUSION An improved process for making flibanserin via 2-ethoxy-1Hbenzo[d]imidazole as the key intermediate had been provided in five steps. This novel route fully satisfied our aim of developing a safe, convenient, cost-effective, high-yielding, and environment-friendly process. We are confident that it should be valuable in the industrial manufacturing of flibanserin.
■
EXPERIMENTAL SECTION General Procedures. All commercially available materials and solvents were used directly without further purification. 1H NMR spectra and 13C NMR spectra were recorded on a Bruker AM-500 spectrometer with TMS as an internal standard. The mass spectra (LRMS and HRMS) were recorded on a Finnigan MAT-95/711 spectrometer. HPLC method: Waters XTerra Phenyl column (5 μm, 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 Dean−Stark trap. It was refluxed for another 5
Table 1. Exploration of Nucleophilic Substitution Reaction Conditions of 13 and 10
a
entry
solvents
base (1.1 equiv)
NaI
temperature
reaction time
yielda
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
acetone THF EtOH i-PrOH n-BuOH 1,4-dioxane DMF DMF NMP CH3CN CH3CN:H2O = 2:1 H2O H2O H2O H2O H2O
K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Cs2CO3
1 eq 1 eq 1 eq 1 eq 1 eq 1 eq 0 eq 1 eq 1 eq 1 eq 1 eq 0.2 eq 1 eq 1 eq 1 eq 1 eq
reflux reflux reflux reflux reflux 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 24 h 24 h 24 h 24 h 24 h 12 h 6h 6h
