Tài liệu The synthesis of risedronic acid and alendronate applying phosphorus oxychloride and phosphorous acid in methanesulfonic acid

Send Orders for Reprints to [email protected] Letters in Drug Design & Discovery, 2015, 12, 253-258 253 The Synthesis of Risedronic Acid and Alendronate Applying Phosphorus Oxychloride and Phosphorous Acid in Methanesulfonic Acid Alajos Grün1, Rita Kovács1, Sándor Garadnay 2, István Greiner2,# and György Keglevich1,*,# 1 Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary 2 Gedeon Richter Plc., 1475 Budapest, Hungary Abstract: The synthesis of risedronic acid and alendronate from 3-pyridylacetic acid and
aminobutyric acid, respectively, using phosphorus oxychloride and phosphorous acid as the P-reagents and methanesulfonic acid as the solvent was optimized, and the role of phosphorus oxychloride and phosphorous acid in the reaction was clarified. Keywords: Alendronate, mechanism, optimization, phosphorus oxychloride, phosphorous acid, risedronic acid, synthesis. # Author’s Profiles: István Greiner is a chemical engineer, has the MBA degree and was also trained as a patent attorney. He is the Research Director of Gedeon Richter Plc. (Richter Pharmaceuticals) and Adjunct Professor at the Budapest University of Technology and Economics. His interest lies in synthetic and bioorganic chemistry and his special field is microwave chemistry. He is the author or co-author of approximately 75 articles and patents. György Keglevich graduated as a chemical engineer. He has been Professor of Chemistry since 1995, and the Head of the Department of Organic Chemistry and Technology, Budapest Univesity of Technology since 1999. He is engaged with Pheterocyclic and environmentally-friendly chemistry comprising MW chemistry, phase transfer catalysis and the development of new catalysts. He is the author or co-author of 460 papers He holds editorial positions at the journals Curr. Green Chem., Cur. Org. Chem., Lett. Org. Chem., Curr. Org. Synth.. Lett. Drug Des. Disc. and Curr. Catal.. He is the member of the Editorial Board of Heteroatom Chem. and Phosphorus Sulfur Silicon. 1. INTRODUCTION Dronic acid derivates, 1-substituted-1-hydroxy-methylenebisphosphonic acids or their sodium salts, including Csubstituted- (alkyl- or phenyl) derivatives and, especially the representatives of the newer generations, aminoalkyl- and heterocyclic derivatives are used as medicines against osteoporosis, the Paget’s disease and osteolytic tumors [1-4]. The bisphosphonates deposited on the bone surface poison the bone-resorbing osteoclast after being internalized by them. A major issue is the anti-tumor effect of methylenebisphosphonic derivatives with amino-function, especially that of zoledronic acid [5, 6]. The main target of the amino derivatives of methylenebisphosphonic acids is the Farnesyl diphosphate [7] in osteoclasts and in tumor cells. The mode of action of these drugs is associated with the butyrophilin receptor [8, 9]. It is a recent challenge to utilize nanotechnology and encapsulation in the modification of dronic acids/dronates to influence the biodistribution [10, 11]. A major approach for the synthesis of dronic acids/dronates involves the reaction of variety of carboxylic acids and P-reagents, comprising phosphorus trichloride, phosphorous acid or phosphorus oxychloride in different *Address correspondence to this author at the Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary; Tel: 36-1-4631111/5883; Fax: 36-1-463-3648; E-mail: [email protected] 1875-628X/15 $58.00+.00 combinations [12, 13]. We have recently optimized the synthesis of a few dronic acid derivatives starting from the corresponding carboxylic acid and phosphorus trichloride [14, 15]. The application of phosphorus oxychloride, typically together with phosphorous acid, is relatively rare. The examples found in the literature [16-22] were summarized in Table 1. It can be seen that the molar equivalent quantities and the molar ratios of phosphorus oxychloride and phosphorous acid varied on a relatively broad scale. In a few cases, phosphoric acid was also measured in as the third P-reagent [4, 12]. Toluene [16, 17, 19], chlorobenzene [18, 19], silicon oil [19], diethyl carbonate [20] and decaline [22] were used as the solvent. The range of the reaction temperature embraced 60–100°C. The yields of the dronic acid derivates varied between 26 and 83%. In most of the cases, risedronic acid [16-18, 21, 22] and zoledronic acid [16, 17, 19, 21] were the target compounds. It can be seen that the experimental data are rather diverging, moreover, till date, there are no data on the role of phosphorus oxychloride in the synthesis of dronic acid/derivatives. For this, it was a challenge for us to investigate the preparation of dronic acid/derivatives by the reaction of the suitable carboxylic acid with phosphorus oxychloride and phosphorous acid. 2. RESULTS AND DISCUSSION The use of the mixture of phosphorus oxychloride and phosphorous acid in different molar ratios is, for the first ©2015 Bentham Science Publishers 254 Letters in Drug Design & Discovery, 2015, Vol. 12, No. 4 Grün et al. Table 1. Literature Data on the Preparation of Dronic Acid Derivatives Starting from the Corresponding Carboxylic Acid and Using Phosphorus Oxychloride and Phosphorous Acid. Ratio of POCl3 and P(OH)3 (Molar Equivalents) Solvent Temperature (°C) Time (h) Product Yield (%) References 47 45 65 26 16, 17 5:5 PhMe 80 5 alendronic acid pamidronic acid risedronic acid zoledronic acid 2.5 : 2.5 PhCl 90-95 2 risedronic acid no data 18 3.7:3.7 3.7:3.7 3:3 4:4 PhCl PhMe PEG400 silicon oil 100 100 75 80 1 3 2 11 zoledronic acid 83 69 11 74 19 3.3 : 2 silicon oil 80 27 zoledronic acid 58 19 3.7 : 3 silicon oil 80 22 zoledronic acid 50 19 1.4 : 2.4 diethyl carbonate 80 2 ibandronate 74 20 3.2 : 9.7 without solvent 60-70 24 ibandronic acid risedronic acid zoledronic acid 59 60 62 21 MeC6H 11 95 20 risedronic acid 78-81 22 decaline 95 20 risedronic acid 77-81 22 3 : 3.6 + 1 equiv. H3PO4 3 : 3.3 + 3 equiv. H3PO4 PCl323,25-27 or POCl3 (this study) MSA Y CH2 2 CO2H MSCl MSA Y= N PCl3 MSA 1 , O Y CH2COCl PCl3 Y HO P OH H2C C OH P OH HO Y CH2C(O)OSHO2 Me O 3 4 NH2(CH2)2, etc Scheme (1). A general scheme for the formation of dronic acids. sight, surprising. Recalling the speculative mechanism proposed by us [23], neither the phosphorus oxychloride, nor the phosphorous acid is suitable to attack the carbonyl carbon of the corresponding carboxylic acid derivatives (see later). The phosphorus atom of phosphorus oxychloride is not nucleophilic, while phosphorous acid is of low nucleophilicity. However, not only phosphorus trichloride, as described earlier [23], but also phosphorus oxychloride may be suitable to convert the starting carboxylic acid (1) to the corresponding acid chloride (2) that may be a first intermediate on the way for the formation of the dronic acid (4). In our earlier examples, phosphorus trichloride was the reactant converting acid 1 to the chloride 2 (Scheme 1) [23, 24]. Moreover, a part of the methanesulfonic acid (MSA) used as the solvent may also be converted to methanesulfonyl chloride (MSCl) by reaction with phosphorus oxychloride or phosphorus trichloride [25-27], whose reaction with carboxylic acid 1 may lead to mixed anhydride 3. Species 3 may also be obtained from chloride 2 by its reaction with MSA. The dronic acid (4) may be formed from acid chloride 2 or mixed anhydride 3. It was recognized that the interaction of phosphorus oxychloride and phosphorous acid may lead to the formation The Synthesis of Risedronic Acid and Alendronate Letters in Drug Design & Discovery, 2015, Vol. 12, No. 4 O OH N 5 O 1) 75°C/12h POCl3 and/or H3PO3 MSA 2) 105°C/3h H2O 3) pH adjustment 1.8 255 HO P OH OH N HO P OH O 6 Scheme (2). The preparation of risedronic acid. Table 2. Synthesis of Risedronic Acid Applying of Phosphorus Oxychloride and Phosphorous Acid in Methanesulfonic Acid. Reactants Puritya (%) Yielda,b (%) 0 0 0 0 3 0 0 3 3 1 91 10 4 3 2 97 45 5 3 3 97 53 6 2 1 79 32 7 2 2 99 38 8 2 3 98 55 9 1 1 90 12 10 1 2 82 10 11 1 3 90 24 Entry a POCl3 (equiv.) H3PO3 (equiv.) 1 3 2 On the basis of potentiometric titration. From at least two parallel experiments. b of phosphorus trichloride [28]. Our independent experiments confirmed that indeed this is the case. We shall return to the possible formation of phosphorus trichloride in our reaction system. In our experiments, the preparation of risedronic and alendronate was aimed at. Both drugs belong to the newer generation of dronic acids/dronates and are used in the treatment of osteoporosis and the Paget’s disease. Quite recently, they revealed potential in the treatment of the Chagas disease [29,30]. The Chagas disease, is among the worlds thirteen most neglected tropical illnesses, and only a few drugs are available for the treatment of this disease. The metal complexes of risedronic and alendronate are good candidates to promote healing from this illness. 2.1. Synthesis of Risedronic Acid (6) In our experiments 3-pyridylacetic acid (5) was reacted with different molar mixtures of phosphorus oxychloride and phosphorous acid in MSA at 75°C for 12 h. Then, the reaction mixture was hydrolyzed, and finally the pH was adjusted. Risedronic acid (6) precipitated on cooling (Scheme 2). Purification involved a recrystallization from water. The purity of the product (6) was analyzed by potentiometric titration, and in certain cases, also by NMR. Experimental data are listed in Table 2. In the cases, when 3-pyridylacetic acid (5) was reacted with phosphorus oxychloride or phosphorous acid as the only reagent, no risedronate (2) was formed (Table 2/Entries 1 and 2). Measuring in 3 equivalents of phosphorus oxychloride together with 1, 2 or 3 equivalents of phosphorous acid, dronic acid 6 was obtained in yields of 10%, 45% and 53%, respectively, in purities of 91%, 97% and 97%, respectively (Table 2/Entries 3-5). In the other series of experiments, when phosphorus oxychloride was applied in a 2 equivalent quantity, while phosphorous acid was used in quantities of 1, 2 and 3 equivalents, risedronic acid (6) was isolated in yields of 32%, 38% and 55%, respectively, while the purities were 79%, 99% and 98%, respectively (Table 2/Entries 6-8). Finally, the combination of 1 equivalent of phosphorus oxychloride with 1, 2 or 3 equivalents of phosphorous acid yielded the dronic acid (6) in 12%, 10% and 24%, respectively, in purities of 90%, 82% and 90%, respectively (Table 2/Entries 9-11). It can be seen that the best yields (~54%) of risedronic acid (6), may be obtained when phosphorus oxychloride is used in a 3 or 2 equivalent quantity, while phosphorous acid is present in a 3 equivalent quantity (Table 2/Entries 5 and 8). How can this experience be explained? As it was mentioned above, the interaction of phosphorus oxychloride with phosphorous acid results in the formation of phosphorus chloride [28]. It means that the combination of 3 equivalents 256 Letters in Drug Design & Discovery, 2015, Vol. 12, No. 4 O H2N OH 7 Grün et al. 1) 75°C/12h POCl3 and/or H3PO3 MSA 2) 105°C/3h H2O 3) pH adjustment HO H2N O P ONa OH HO 1.8 P O OH 8 Scheme (3). The preparation of alendronate. Table 3. Synthesis of Alendronate Acid Applying of Phosphorus Oxychloride and Phosphorous Acid in Methanesulfonic Acid. Reactants Puritya (%) Yield of 1a,b (%) 0 0 0 0 3 0 0 3 3 1 0 0 4 3 2 94 40 5 3 3 97 60 6 2 1 94 15 7 2 2 96 49 8 2 3 97 60 9 1 1 96 8 10 1 2 96 18 11 1 3 94 17 Entry a POCl3 (equiv.) H3PO3 (equiv.) 1 3 2 On the basis of potentiometric titration. From at least two parallel experiments. b of phosphorus oxychloride and the same amount of phosphorous acid is such, as 3 equivalents of phosphorus trichloride were in the mixture. From this point, the further reaction sequence may be substantiated on the basis of our earlier work [23, 25, 26]. This protocol is shown in Scheme (1) (Y = 3-pyridyl). The use of phosphorus oxychloride and phosphorous acid in a molar ratio of 2:3 may be equivalent with the presence of phosphorus trichloride and phosphorous acid in a 2:1 ratio. In the first approach, this could not explain a maximum yield of 55%, as the phosphorous acid was earlier found to be unreactive [23]. However, it may be assumed that under the conditions of the reaction, and in the rather complicated reaction system, one unit of both the phosphorus trichloride and the phosphorous acid may form intermediate Cl2P-O-P(OH)2 that may react efficiently with the P=O-group of the carboxylic acid derivatives (2 and 3) as the precursor of two P(O)(OH)2 functions. This intermediate has so far been substantiated only in the synthesis of pamidronic acid in sulfolane [31]. In the third place, the reaction of 3-pyridylacetic acid (5) with 3 equivalents of phosphorus oxychloride and 2 equivalents of phosphorous acid should be interpreted (Table 1/Entry 4). The given ratio of these P-reagents corresponds to the presence of 1 equivalent of phosphorus oxychloride and 2 equivalents of phosphorus trichloride. If the phosphorus oxychloride converted carboxylic acid 5 to the corresponding chloride (2), or if the corresponding anhydride (3, Y = 3-pyridyl) was formed with the participation of phosphorus oxychloride, the presence of 2 equivalents of phosphorus trichloride would basically justify a higher yield than 45%. However, in the first stage of reaction, phosphorus trichloride may also compete to convert carboxylic acid 5 to the chloride (2, Y = 3-pyridyl), and to establish the anhydride (3, Y = 3-pyridyl), for this, there will not remain enough phosphorus trichloride to react with the 3-pyridylacetic acid derivatives (2 and 3). In the other cases (Table 2/Entries 3, 6, 7, 9-11), the quantity of the P-reagents simply is not enough to allow an efficient reaction sequence. 2.2. The Synthesis of Alendronate The preparation of alendronate (8) was studied from
aminobutyric acid (7) using again the phosphorus oxychloride/phosphorous acid reactant pair in MSA. The reaction temperature was 75°C. The work-up included hydrolysis, and pH adjustment (Scheme 3). The crude product precipitated on cooling was purified by recrystallization from water including also a pH adjustment to 4.5. The product was actually obtained as alendronate (8) trihydrate. The purity of the dronate (8) was established by potentiometric titration and in certain cases also by NMR. Experimental data are listed in Table 3. The Synthesis of Risedronic Acid and Alendronate The conclusion may be drawn that the experiences are quite similar to those observed for risedronic acid (6). The best yields (60%) of alendronate (8) were obtained when 3 or 2 equivalents of phosphorus oxychloride were applied together with 3 equivalents of phosphorous acid. In these cases, the purity was 97% (Table 3/Entries 5 and 8). The results of the experiments marked by entries 4 and 7 of Table 3 are also considerable. In these cases, yields of 49% and 40%, respectively, were recorded with a purity of ca. 95%. All other combinations (Table 3/Entries 1-3, 6, 9-11) were inefficient. Assuming that the POCl3/H3PO3 system generates phosphorus trichloride, Scheme 1 is recalled to understand the formation of alendronate, or primarily alendronic acid. This is the first case that the reaction sequence starting from the corresponding substituted acetic acids and phosphorus oxychloride along with phosphorous acid as the P-reagents was interpreted. The yields of risedronic acid (6) and alendronate (8) were somewhat different or almost comparable with those obtained with phosphorus trichloride (6: 55% vs. 74% [23]; 8: 60% vs. 57% [27]). Interestingly, the “POCl3 – H3PO3” method did not work well for the synthesis of other dronates, such as zoledronic acid, ibandronate and pamidronate. In summary, the 3:3 or 2:3 mixture of phosphorus oxychloride and phosphorous acid were found to be efficient reagents in the synthesis of risedronic acid and alendronate. According to our explanation, the real reagent may be phosphorus trichloride formed “in situ” from the other two P-reagents. Letters in Drug Design & Discovery, 2015, Vol. 12, No. 4 257 off to give 3.9 g (53%) of risedronic acid (6) in a purity of 97%. 31P NMR (D2O)
17.0
[32] 18.2; 13C NMR (D2O)
145.9 (s, C2), 145.2 (s, C6), 141.2 (s, C3), 136.8 (t, J = 8.6, C4), 125.1 (s, C5), 73.7 (t, J = 131.1, PCP), 36.2 (s, CH2),
[12] (D2O) 144.5, 133.5 (d, J = 4.3), 130.5 (t, J = 6.5), 129.8, 116.6, 76.3 (t, J = 133.8), 39.5. 3.3. Preparation of Sodium Alendronate Trihydrate from
-Aminobutyric Acid Using Phosphoryl Chloride and Phosphorous Acid as Reagents (Table 3/Entry 5) 2.6 g (0.025 mol) of -aminobutyric acid and 6.2 g (0.075 mol) of phosphorous acid was added into 6.8 mL of MSA on stirring. Then 7.0 mL (0.075 mol) of phosphoryl chloride was added dropwise in ca. 15 min, and the contents of the flask were stirred at 75°C for 12 h. After cooling the mixture to 26°C, 19 mL (1.1 mol) of water was added and the mixture was stirred further at 105°C for 4 h. The pH was adjusted to 1.8 by adding ~12 mL of 50% aqueous sodium hydroxide to the mixture. Then, the mixture was stirred at room temperature for 2 h and the precipitate was removed by filtration. The crude product was suspended in 50 mL of water and the mixture was stirred at 100°C for 1 h, then the pH was adjusted to 4,5. After cooling the mixture to 26°C, the solid product was filtered off to give 5.0 g (60%) of sodium alendronate trihydrate (8) in a purity of 97%. 31P NMR (D2O)
18.6
[33] 18.7; 13C NMR (D2O)
73.9 (t, J = 127.6, PCP), 40.4 (s, NCH2), 31,1 (s, PCCH2), 22.8 (t, J = 6.9, NCH2CH2)
[34] (D2O) 73.3 (t, J = 132.0), 39.5, 31.1, 22.0. CONFLICT OF INTEREST 3. EXPERIMENTAL The authors confirm that this article content has no conflict of interest. 3.1. General The 31P NMR spectra were obtained on a Bruker AV-300 spectrometer operating at 121.50 MHz, while the 13C NMR spectra were recorded on a Bruker DRX-500 instrument at 125.7 MHz. Chemical shifts are downfield relative to 85% H3PO4. The dronic acid/dronate content of the samples was determined by potentiometric acid-base titrations on a Mettler DL77 potentiometric titrator. ACKNOWLEDGEMENTS 3.2. Preparation of Risedronic Acid from 3-Pyridylacetic Acid Using Phosphoryl Chloride and Phosphorous Acid as the Reagents (Table 2/Entry 5) [2] 3.4 g (0.025 mol) of 3-pyridylacetic acid and 6.2 g (0.075 mol) of phosphorous acid were added into 6.8 mL of MSA on stirring. Then 7.0 mL (0.075 mol) of phosphoryl chloride was added dropwise in ca. 15 min, and the contents of the flask were stirred at 75°C for 12 h. After cooling the mixture to 26°C, 19 mL (1.1 mol) of water was added and the mixture was stirred further at 105°C for 4 h. The pH was adjusted to 1.8 by adding ~12 mL of 50% aqueous sodium hydroxide to the mixture. Then, the mixture was stirred at room temperature for 2 h and the precipitate was removed by filtration. The crude product was suspended in 50 mL of water and the mixture was stirred at 100°C for 1 h. After cooling the mixture to 26°C, the solid product was filtered The partial support from Hungarian Scientific Research Found (OTKA No K83118) is thanked. REFERENCES [1] [3] [4] [5] [6] Russell, R.G.G. Bisphosphonates: The first 40 years. Bone, 2011, 49, 2-19. Russell, R. G. G. Bisphosphonates: Mode of action and pharmacology. Pediatrics, 2007, 119, S150-S162. Breuer, E. The development of bisphosphonates as drugs, In Analogue-based drug discovery; Fischer, J.; Ganelli, C.R. (Eds.), Wiley-VCH, Weinheim, 2006; Ch. 15. Widler, L.; Jaeggi, K.A.; Glatt, M.; Müller, K.; Bahmann, R.; Bisping, M.; Born, A.-R.; Cortesi, R.; Guiglia, G.; Jeker, H.; Klein, R.; Ramseier, U.; Schmid, J.; Schreiber, G.; Seltenmeyer, Y.; Green, J.R. Highly potent geminal bisphosphonates. From pamidronate disodium (Aredia) to zoledronic acid (Zometa). J. Med. Chem., 2002, 45, 3721-3738. Marra, M.; Abbruzzese Saccardi, A.; Addeo, R.; Del Prete, S.; Tassone, P.; Tonini, G.; Tagliaferri, P.; Santini, D.; M. Caraglia, M. Cutting the limits of aminobisphosphonates: new strategies for the potentiation of their anti-tumour effects. Curr. Cancer Drug Targets, 2009, 9, 791-800. Caraglia, M.; Marra, M.; Naviglio, S.; Botti, G.; Addeo, R.; Abbruzzese Saccardi, A. Zoledronic acid: an unending tale for an antiresorptive agent. Expert Opin. Pharmacother., 2010, 11, 141154. 258 [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] Letters in Drug Design & Discovery, 2015, Vol. 12, No. 4 Grün et al. Kavanagh, K.L.; Guo, K.D.; Dunford, J.E.; Wu, X.Q.; Knapp, S.; Ebetino, F.H.; Rogers, M.J.; Russell, R.G.G.; Oppermann, U. The molecular mechanism of nitrogen-containing bisphosphonates as anti osteoporosis drugs. Proc. Natl. Acad. Sci. USA, 2006, 103, 7829-7834. Sandstrom, A.; Peigné, C.-M.; Léger, A.; Crooks, J.E.; Konczak, F.; Gesnel, M.-C.; Breathnach, R.; Bonneville, M.; Scotet, E.; Adams, E.J. The intracellular B30.2 domain of butyrophilin 3A1 binds phosphoantigens to mediate activation of human V
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