Facile Synthesis of Propranolol and Novel Derivatives

Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam Faculty of Environmental and Chemical Engineering, Duy Tan University, Danang 550000, Vietnam Department of Chemical Engineering, Ho Chi Minh City University of Technology, Ho Chi Minh City, Vietnam NTTHi-Tech Institute, Nguyen Tat)anh University, 300ANguyen Tat)anh,Ward 13, District 4, Ho ChiMinh City, Vietnam Center of Excellence for Green Energy and Environmental Nanomaterials (CE GrEEN), Nguyen Tat )anh University, 300A Nguyen Tat )anh, District 4, Ho Chi Minh City 755414, Vietnam Department of Materials Science, School of Applied Chemistry, Tra Vinh University, Tra Vinh City 87000, Vietnam Biomaterials and Nanotechnology Research Group, Faculty of Applied Sciences, Ton Duc )ang University, Ho Chi Minh City, Vietnam Department of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Go Vap, Ho Chi Minh City, Vietnam Center for Advanced Chemistry, Institute of Research and Development, Duy Tan University, Da Nang 550000, Vietnam


Introduction
Propranolol is one of the original medicines of the betablocker used to treat hypertension, tremors, angina, and cardiovascular disorders [1,2]. Besides, propranolol also is an effective and safe drug for treating migraine headaches, anxiety disorders, and infantile hemangiomas [3,4]. Moreover, several studies have recently reported that patients receiving propranolol reduced the risk of neck and head, colon, stomach, and prostate cancers [5][6][7].
Methods for the synthesis of propranolol were investigated by using enzymes to resolve intermediate compounds [8][9][10]. However, the enzyme strategy did not show effective manufacturing because of several limitations, i.e., multistep, low overall yields (lower than 30%), and use of hazardous and costly reagents [10,11]. Besides, the hydrogenation of the chiral metal of the intermediate by polymer-supported reagent was used [12]. Nevertheless, the methods used to catalyze metal salts are often complex and costly. In addition, the synthesis efficiency and the selectivity of propranolol are not high [10,13].
us, the development of propranolol derivatives to improve biopharmaceutical and therapeutic features, as well as to reduce the first level of metabolism, is absolutely necessary. To minimize the extension of the firstpass conjugation, many prodrugs of propranolol have been synthesized in the investigation of new high-acting lipophilic derivatives. Amongst them, homologous acyl ester prodrugs of propranolol, e.g., O-acetyl and O-propionyl carboxylic acid ester, were discovered with higher bioavailability and lipophilicity than those of propranolol [14][15][16].
In this study, the synthesis of propranolol was conducted between 1-naphthol and isopropylamine under mild, less toxic conditions and fast reaction time. Novel propranolol derivatives were formed by reactions at the C-13 and N-15 position through esterification reactions between propranolol and 2-bromobenzoyl chloride, 2-chlorobenzoyl chloride, and 2-fluorobenzoyl chloride. e oxidation and alkylation reactions between propranolol and pyridinium chlorochromate and n-butyl bromide were also investigated. Novel derivatives were achieved in high yields and significantly enhanced water solubility.
in-layer chromatography (TLC) silica gel 60 F 254 was bought from Merck (Germany, 20.0 × 10.0 cm). Silica gel 230-400 mesh for column chromatography was purchased from HiMedia (India). Water and ethanol (HPLC grade) were used without additional purification. Other chemicals were used as the highest possible quality as received. Glassware was cleaned using an acidic solution of HNO 3 : HCl (1 : 3 v/v) and then washed several times with deionized water.

Methods of Characterization
in-Layer Chromatography (TLC). 5 μL of sample and standard solutions was dropped on a TLC plate, which was immersed in ethyl acetate : hexane system (mobile phase) at different ratios. e moving of the mobile phase was finished until it reached the highest limitation of the TLC plate. e separated TLC plate was dried at room temperature (RT) for 30 min and observed under visible light or UV light.

Column Chromatography (CC).
e CC method was applied for fractionation and purification of the synthesized products by using columns filled with silica gel of 230-400 mesh and glass columns with different diameters of 1.5, 2, and 5 cm and lengths of 30 and 40 cm. e mobile phase of hexane : ethyl acetate at different ratios was used to separate propranolol and its desired derivatives.

Mass Spectrometry (MS).
e determination and detection of fragments and molecular ions from propranolol and its derivatives were carried out by MicroOTOF-Q 10187 mass spectrometer (Bruker, Germany).

Proton Nuclear Magnetic Resonance Spectroscopy ( 1 H-NMR).
e structure of propranolol and its derivatives was identified by 1 H-NMR spectra recorded on a Bruker Ultrashield 500 spectrometer (Germany).

Synthesis of Propranolol Derivatives.
To enhance the antioxidation and biological activity, target moieties at C-13 and N-15 of propranolol were investigated for further reactions. New derivatives were produced by reactions from propranolol with benzoyl chloride (esterification), with pyridinium chlorochromate (oxidation-reduction), and with n-butyl bromide (alkylation) (Figure 1).

Synthesis of Propranolol from 1-Naphthol and
Isopropylamine. Propranolol was synthesized from reaction between 1-naphthol and isopropylamine according to reactions described in Figure 2. Typically, 1.25 g of 1-naphthol (8.67 mM) was dissolved in 10 mL of ethanol : water (9 : 1), followed by adding 0.5 g of KOH into the above mixture under stirring for 30 min. Next step, 4 mL of epichlorohydrin (0.05 M) was drop-down until the color of the mixture changed to orange-yellow. After every 30 min of the reaction, the formation of propranolol and its derivatives was determined by TLC. e solvent of the reaction mixture was evaporated and the yellow-brown compound of oil form was obtained. en, 50 mL of diethyl ether was added to the resulting product under shake condition, and the water was removed by Na 2 SO 4 anhydrous. Next, the reaction mixture were isolated by CC using the mobile phase of hexane : ethyl acetate (H : E) 6 : 4, resulting in collecting of 1.05 g (5.25 mM) of 2-((naphthalen-1-yloxy) methyl) oxirane (1a). Besides, two compounds of 1b were also obtained ( Figure 2).
1.05 g of compound 1a dissolved in 10 mL of methanol was added to 15 mL of isopropylamine (12 mM) and stirred at 45°C until obtaining the yellow-brown solution (48 h) and solution was cooled to 5°C. en, 1.5 ml of HCl (2 M) was dropped slowly into the resulting mixture, followed by adding NaOH (2 M) until white precipitate appeared. e precipitate was washed by water, isolated by CC using a mixture of H : E � 5 : 5. Finally, 0.738 g of 1-(isopropylamino)-3-(naphthalen-1-yloxy) propan-2-ol (compound 2) or propranolol was collected ( Figure 2).

Synthesis of Propranolol with 2-Chlorobenzoyl Chloride, 2-Bromobenzoyl Chloride, and 2-Flourobenzoyl Chloride (Compounds 3, 4, and 5).
Briefly, 200 mg of propranolol (0.77 mM) was dissolved in 10 mL CHCl 3 at RT. en, 300 mg of 2-chlorobenzoyl chloride (1.71 mM) or 300 mg (1.37 mM) of 2-bromobenzoyl chloride or 300 mg (1.89 mM) of 2-flourobenzoyl chloride was added to the propranolol mixture. Each reaction mixture was stirred and refluxed at 50 C for 24 h. After every hour, the formation of a new compound from each reaction was identified by TLC. Each reaction mixture was isolated (3 times) by a CC system with the mobile phase of water and ethyl acetate. Next step, 3 mL of saturated NaHCO 3 solution was added to the mixture under stirring condition. e reaction mixture was filtered, solvent was evaporated under vacuum, and the resulting product was purified by CC using a solvent system of H : E 7 : 3. Finally, 136 mg/150 mg/115 mg of compound 3/4/5 were obtained, respectively ( Figure 3). (Compound 6). 100 mg of acetic anhydride (1.11 mM) was added into 200 mg of the propranolol (0.77 mM) in 10 mL CHCl 3 . e reaction mixture was refluxed at 45°C for 24 hours followed by examined TLC every hour. e reaction mixture was isolated by CC three times. en, 5 mL of saturated NaHCO 3 solution was added into the reaction mixture to isolate ethyl acetate and remove water by Na 2 SO 4 anhydrous. e new compound of the reaction was isolated by CC using solvent mixture of H : E 7 : 3. e result obtained 170 mg of compound 6 ( Figure 4). Compound 7). 40 mg of PCC was mixed with 200 mg of propranolol (0.77 mM) in 15 mL of CH 2 Cl 2 . en, reaction mixture was refluxed at 40°C for 20 h. After ending the reaction, the mixture was filtered, solvent was removed, and the resulting product was purified by CC using a mobile system of dichloromethane : methanol (D : M) 8 : 2. Finally, the result of reaction obtained 180 mg of 1-(isopropylamino)-3-(naphthalen-1-yloxy) propan-2-one compound 7 ( Figure 5).    Figure 7(a), (S)-propranolol was prepared by using Zn(NO 3 ) 2 /(+)-tartaric acid for the resolution of the terminal epoxide. is method was conducted at 75°C in enantioselectivity through a kinetic resolution of intermediate α-naphthyl glycidyl ether [10]. However, methods of using metal salts as a catalyst for the synthesis of propranolol are often complicated and costly. Besides, there was low selectivity in isomer separation (S)-propranolol. e nucleophilic ring opening of epoxides was preceded by the perchloric acid supported silica matrix (HClO 4 -SiO 2 ). Besides, microwave-assisted HClO 4 -SiO 2 system was investigated for efficient and cost-effective synthesis processing [18] (Figure 7(b)).

Reaction Mechanisms.
Propranolol has been synthesized according to the drug manufacturing process from 1naphthol and isopropylamine. Besides the formation of propranolol, two intermediate compounds 1a and 1b also were found. From the pristine propranolol, seven new derivatives have been synthesized from the compound (2) to (8), in which every compound of 3, 4, 5, and 6 produced only two isomers, different from the theory of 3 isomers (as shown in Table 1).
e new compounds structures were confirmed by MS and 1 H-NMR spectra, indicating that these compounds were entirely suitable. e propranolol derivatives were obtained in high yields from 57.4% to 90.2%. e mechanism of the esterification reactions for formation compounds 3, 4, and 5 is very close. e OH group of propranolol is reacted with the activating group (Cl/Br/F) replaced by the alcohol moiety. e reaction continues by either an addition-elimination through attack of the incoming nucleophile at the sp 2 carbon atom or an elimination-addition chain. Cl/Br/F is a good leaving group to maximize the efficiency of the esterification protocol by minimizing electron donation to the carbonyl functional group. Besides, when anhydrides are employed in the esterification reaction, 50% of the acid component is lost because only one of the acid moieties is transformed to the desired ester. erefore, this approach was used for simple, inexpensive carboxylic acids with a low degree of functionalization, including acetic anhydride (compound 6) [19,20].
In the oxidation reaction of propranolol using pyridinium chlorochromate, the first step is the attack of oxygen on the chromium to form the Cr-O bond. Secondly, a proton on the OH is transferred to one of the oxygen atoms of the chromium, possibly through the intermediacy of the       pyridinium salt. A chloride ion is then displaced to form what is known as a chromate ester. e C-O double bond is formed when a base removes the proton on the carbon adjacent to the oxygen. It is also necessary for pyridine to be used as the base here, but only very small amounts of the deprotonated component would be found under such acidic conditions. e electrons from the C-H bond move to form the C=O bond of compound 7, and in the process, the Cr-O bond is broken, and Cr(VI) becomes Cr(IV) as shown in Figure 8(a) [21]. N of propranolol functions as the nucleophile and attacks the electrophilic C of n-butyl bromide, displacing the bromide and creating the new C-N bond. en the base (excess amine) deprotonates the positive N (ammonium) center, creating the alkylation product [22], so-called compound 8 (Figure 8(b)).

Solubility of Propranolol Derivatives.
e water solubility of these propranolol derivatives was investigated (as shown in Table 2). e water solubility of propranolol was 61.7 μg/mL. In contrast, new derivatives from acetone and n-butyl groups were slightly less soluble due to the involvement of hydrophilic functional supplement groups. Propranolol derivatives from 2-chlorobenzoyl chloride (3), 2-fluorobenzoyl chloride (5), and especially acetic anhydride (6) showed a significant increase toward water solubility compared to propranolol. e water solubility of other compounds was not much changed compared to that of propranolol.

Conclusions
Polypharmacology remains one of the significant difficulties in drug improvement, and it initiates novel avenues to create the next generation of drugs. A route for the synthesis of propranolol has been developed under simple, inexpensive, and mild reaction conditions. Remarkably, we successfully synthesized seven novel propranolol derivatives at the C-13 and N-15 of propranolol, obtained in high yields. e water solubility of compounds 3, 5, and 6, corresponding to products of propranolol with 2-chlorobenzoyl chloride, 2fluorobenzoyl chloride, and acetic anhydride, was improved significantly. e present study shows that the synthesized propranolol derivatives represent promising new compounds to enhance antioxidative, biological activities and the need for investigation in the near future.

Data Availability
e data used to support the findings of this study are included in the article.  Figure 8: (a) Oxidation reaction mechanism of propranolol using pyridinium chlorochromate; (b) amine alkylation reaction mechanism between propranolol and n-butyl bromide. Journal of Chemistry 9