DOI 10.1515/gps-2013-0107 Green Process Synth 2014; 3: 111–116

Review

Rita Kovács, Alajos Grün, Sándor Garadnay, István Greiner and György Keglevich* “Greener” synthesis of bisphosphonic/dronic acid derivatives

Abstract: According to literature, the synthesis of dronic Y Z1 Z2 acid derivatives from the corresponding carboxylic acids Me Na Na Etidronate using and as Ph Na Na Fenidronate OH Pent N(CH) Na H Ibandronate the P-reactants is controversial, due to the wide range of O P OZ1 Me 2 molar ratios and diverse conditions. In this minireview, we Y OH H2N(CH2)3 Na H Alendronate summarize our results on the clarification of these prob- O P OZ2 CH2 N lems. For example, with and risedronic OH H H Zoledronate N acid, we found that, using methanesulfonic acid (MSA) as CH2 the solvent, 3.2 equivalents of phosphorus trichloride was H H Risedronate N enough. Generalizing this optimized method, etidronate, fenidronate, ibandronate and alendronate were obtained Synthetic methods for dronic acids/dronates (1) in yields of 38%–57%, which is reasonable for valuable mainly include the reaction of the corresponding acid dronates, and in most cases, with high purities. Mechanis- with phosphorus trichloride and phosphorous acid tic aspects are also discussed. (Scheme 1) [5]. As can be seen from the short summary of the litera- Keywords: carboxylic acids; dronic acid derivatives; opti- ture methods for the four dronic derivatives in the next mization; phosphorus trichloride; synthesis. part, a great variety of conditions and molar ratios were used and the syntheses were not too efficient. For this reason, the synthesis of dronic derivatives may be consid- *Corresponding author: György Keglevich, Department of Organic Chemistry and Technology, Budapest University of Technology and ered a black-box, which cannot be said to meet the criteria Economics, 1521 Budapest, Hungary, of “green” chemistry. e-mail: [email protected] Etidronic acid, belonging to the first generation of Rita Kovács and Alajos Grün: Department of Organic Chemistry and hydroxymethylenebisphosphonic acids, was described Technology, Budapest University of Technology and Economics, and synthesized in 1897. was reacted with 0.35 1521 Budapest, Hungary equivalent of phosphorus trichloride at room temperature Sándor Garadnay and István Greiner: Gedeon Richter Plc., 1475 Budapest 10, P.O.Box 27, Hungary for 1 day and then at 120°C–130°C for 1 h. After treatment

with Na2CO3, NH4OH and hot water, the mixture was cooled

to 10°C and the product was precipitated with NH4OH. The yield of etidronic acid so obtained was low [6]. The syn- 1 Critical summary of the synthesis thesis was also performed using 3.5 equivalents of phos- of the selected first and second phorus trichloride and the same amount of phosphorous acid in 1,4-dioxane at ~95°C, followed by hydrolysis and generation dronic acids/dronates precipitation of the product by acetonitrile. Etidronic acid (-2011) was obtained in a yield of only 5% [7]. In another varia- tion, pentyl acetate was the starting material and phos- 1-Hydroxy-1,1-bisphosphonic acid derivatives are efficient phorous acid was prepared in situ by the partial hydrolysis drugs against different diseases [1–4]. Classical rep- of phosphorus trichloride. The ester was heated with the resentatives are etidronic acid and fenidronic acid, and mixture of phosphorus trichloride and phosphorous acid more up-to-date variations used in clinics are ibandro- in sulfolane (or in dimethylsulfolane) at approximately nate, alendronate/, and 110°C for about 5 h. The work-up including removal of the zoledronic acid. remaining reactants and suspendation of the final product 112 R. Kovács et al.: “Greener” synthesis of bisphosphonic/dronic acid derivatives

OH 1.) ∆ phosphorous acid were measured in ratios of 1:2.5:1.5 [17] Solvent O P OH (orits mono and 1:2:2 [18, 19] to give alendronic acid and alendronate YC(O)OH+PCl3 /P(OH)3 Y OH 2.)HO or diNa salt) 2 O P OH in yields of 90% and 70%, respectively, after heating 3.)pH Adjustment OH the components in anisole at 105°C, or in acetonitrile at Yisshown above 1 75°C, followed by hydrolysis and pH adjustment (using NaOH in the second case). The purity of the dronic acid/ Scheme 1 dronate was uncertain. Also described was the synthesis of alendronic acid from γ-aminobutyric acid, using phos- in water, followed by filtration, gave etidronic acid in a phorus trichloride and forming the phosphorous acid, by yield of 39% [8]. In the very first publication on the prepa- adding a stoichiometric amount of water to the reaction ration of etidronic acid, it was claimed that the reaction mixture [20]. A recent approach involved the synthesis of acetyl chloride with phosphorous acid at 20°C for 1 day of alendronic acid from aminobutyric acid using three and then at ~125°C for 1 h led to the desired product [6]. No equivalents­ of phosphorus chloride and phosphorous criterion of purity was reported in the above-mentioned acid in sulfolane, under microwave (MW) conditions at cases. There are other approaches involving the Arbuzov 65°C. After hydrolysis, the yield of alendronic acid was reaction of acetyl chloride and a trialkyl phosphite; addi- 41%. The complete procedure required a reaction time of tion of a dialkyl phosphite on the carbonyl group of the 17 min. As a comparison, the thermal accomplishment led oxoethylphosphonate so formed followed by hydrolysis to a yield of 38% after a reaction time of 9.5 h. Hence, the (Scheme 2, Y = Me) [9–11]. yields are quite similar; however, there is a a considerable Interestingly, fenidronic acid was mainly synthesized difference in respect of the reaction times [21]. by the Arbuzov reaction of benzoyl chloride as the first We recently described that heteroaryl-substituted step [10–12]. The following steps were similar to those dronic acids, zoledronic acid (5a) and risedronic acid (5b) described above for a similar preparation of etidronic acid may be best prepared by the reaction of the corresponding (Scheme 2, Y = Ph) [9–11]. heteroaryl-acetic acid with 3.2 equivalents of phosphorus There is a literature procedure for the preparation of trichloride in methanesulfonic acid (MSA), at 75°C for 3 h, fenidronic acid by the reaction of benzoic acid with two followed by hydrolysis and pH adjustment by aqueous equivalents of phosphorus trichloride at 80°C for 4 h sodium hydroxide and, in the case of zoledronic acid (5a), without any solvent, followed by hydrolysis [13], but we by recrystallization from aqueous HCl (Scheme 3) [22, 23]. could not reproduce this procedure. It is noteworthy that unlike in earlier syntheses, there The methods described for the synthesis of ibandro- was no need to use different amounts (1–5 equivalents) of nate used N-methyl-N-pentyl-3-aminopropionic acid, phosphorous acid [7, 24–30], as this reagent does not take phosphorus trichloride and phosphorous acid in ratios part in the reaction under the conditions applied, due to of 1:1.5:1.5 [14], 1:2.9:1.5 [15] and 1:3.7:4.2 [16] in the pres- its low nucleophilicity. It is enough to apply only phos- ence of aromatics as solvents (toluene/chlorobenzene), or phorus trichloride in a quantity of 3.2 equivalents. This in the absence of solvents at 70°C–85°C, to provide iban- observation is of great importance from the point of view dronate in 43%–82% yields after the work-up (including green chemistry, as it makes possible the rational synthe- hydrolysis) and pH adjustment followed by purification. sis of dronic derivatives. No data were provided on the purity of the ibandronate The above mentioned MW-assisted method [21] was obtained. In the preparation of alendronic acid/alendro- also used for the synthesis of zoledronic acid (5a) and nate, γ-aminobutyric acid, phosphorus trichloride and risedronic acid (5b), applying phosphorus trichloride

OH O O O (RO) P(O)H 1.) 75°C 2 O P OH YCCl +(RO)3P YCP(OR)2 MSO3H ArCH2C(O)OH +PCl3 ArCH2 OH 2 2.) 115°C O P OH H O O OH O O OH O 2 H 3.)pH Adjustment OH (RO)2PCP(OR)2 (HO)2PCP(OH)2 4.) Recrystallization H2O 5 Y Y 34 N Ar = (a), (b) Y=Me,PhR=Me, Et N N

Scheme 2 Scheme 3 R. Kovács et al.: “Greener” synthesis of bisphosphonic/dronic acid derivatives 113 and phosphorous acid in quantities of two equivalents in Table 1 Synthesis of etidronate and fenidronate using the sulfolane at 65°C; the yields of the corresponding prod- P-reactants in different ratios. ucts were 70% and 74%, respectively, after hydrolysis. Entry Reactants Puritya (%) Yield (%) The thermal variation provided zoledronic acid (5a) in a similar yield (67%). However, the reaction times were dif- PCl3 H3PO3 6a 6b 6a 6b ferent (approximately 14 min for the MW version vs. 9.5 h (equiv.) (equiv.) for the thermal variation). 1 0 3.2 – – 0 0 2 1.1 2.2 – 74 < 5 13 3 2.2 1.1 85 94 36 36 2 Extension of our method to 4 3.2 0 90b 100b 38 46 aOn the basis of potentiometric titration. the synthesis of etidronate, bThe purity was also confirmed by 31P and 13C NMR. ­fenidronate, ibandronate and Using a reversed molar ratio, both dronates (6a and 6b) alendronic acid/alendronate were formed in yields of 36%, in purities of 85% and 94%, respectively. The application of 3.2 equivalents of phos- 2.1 The synthesis of etidronate and phorus trichloride alone led to the best results. Etidronate fenidronate (6a) was obtained in a yield of 38%, in a purity of 90%, and fenidronate (6b) was obtained in a yield of 46%, in a In this part, the optimization for the synthesis of etidronic pure form. acid, fenidronic acid, ibandronate and alendronic acid/ As we substantiated the intermediacy of the corre- alendronate is summarized [31–33]. sponding acid chlorides [34], we performed the synthe- The synthesis of etidronate (6a) and fenidronate (6b) ses in a two-step manner, forming first acetyl chloride or from acetic acid or benzoic acid, respectively (Scheme 4) benzoyl chloride by reaction with 1.1 equivalents of phos- was performed using phosphorus trichloride and phos- phorus trichloride or thionyl chloride, and then adding phorous acid in different ratios in MSA as the solvent, at the P-reactant; 2.2 equivalents of phosphorus trichloride 75°C for 1 day. After the hydrolysis, the pH was adjusted to or phosphorous acid (Scheme 5, Table 2). In MSA it is also 1.8, followed by precipitation of the disodium salt (6a or possible that a mixed anhydride formulated by RC(O)-

6b) by the addition of methanol. Purification involved two O(O)2SMe (7) is formed from the acid chloride and MSA. other precipitations by the addition of methanol and three It can be seen that the application of phosphorus more digestions in methanol. trichloride in a two-step procedure gave rise to an outcome The experimental data are summarized in Table 1. which was almost equal to that of the one-step procedure. One may see that using 3.2 equivalents of phosphorous Product 6a was obtained in a yield of 32% and with a acid alone, there was no reaction. Decreasing the quan- purity of 88%. The corresponding values for product 6b tity of phosphorous acid and at the same time, increasing were 43% and 98%, respectively. Using thionyl chloride, that of phosphorus trichloride, produced better and better the results were somewhat more modest. The last com- results. When 1.1 equivalents of phosphorus trichloride bination (1., PCl3 2., H3PO3) led to insufficient yields and and 2.2 equivalents of phosphorous acid were applied, impure products (6a and 6b). products 6a and 6b were formed in approximately 5% Then, choosing the model of fenidronate 6b, we wished and 13% yields, respectively, in unpure ( ≤ 74%) forms. to prove the reaction sequence by starting from benzoyl chloride [Scheme 6/(1)]. This reaction resulted in fenidronate OH (6b) in a yield of 35% and with a purity of 100%. Moreover, 1.)75°C/1 day O P ONa ethyl benzoate could also be used as the starting material R O MSA + PCl3 R OH [Scheme 6/(2)]. The yield and the purity were comparable 2.) 105°C/4 h OH 3.2equiv. O P ONa H2O with the previous case (36% and 94%, respectively). 3.)NaOH/H2O OH 4.)MeOH 6

R= CH3 (a), (b) 2.2 The synthesis of ibandronate

Etidronate Fenidronate Ibandronate (9) was synthesized from N-methyl-N- Scheme 4 pentyl-β-amino-propionic acid hydrochloride using 114 R. Kovács et al.: “Greener” synthesis of bisphosphonic/dronic acid derivatives

26°C PCl3 or SOCl2 (1.1 equiv.) R O 1.)110/75°C P-reactant (2.2 equiv.) OH MSA Cl 2.) 105°C O P ONa R O H2O MSA R OH OH 3.)NaOH/H2O O P ONa 4.)MeOH MSACl R O OH MSA OSO2Me 6 R=as in Scheme 3 7

Scheme 5

Table 2 Synthesis of etidronate and fenidronate in two steps. OH ⋅ HCl 1.) 75°C/1 day PCl /H PO O P ONa N O 3 3 3 N a MSA Entry Inorg. halide P-reactant Purity (%) Yield (%) OH (1.1 equiv.) (2.2 equiv.) OH 2.) 105°C/4 h 6a 6b 6a 6b O P OH H2O 1 PCl PCl 88 98b 32 43 3.)NaOH/H2O OH 3 3 4.)MeOH 8 9 2 SOCl2 PCl3 99 97 25 26

3 PCl3 H3PO3 < 50 76 < 5 ~10 Scheme 7 aOn the basis of potentiometric titration. bThe purity was also confirmed by 31P and 13C NMR. one-step procedure (41% vs. 46%). Applying thionyl chlo- ride in the first step, the yield was lower (30%) (Table 4). different ratios of the P-reactants in MSA at 75°C for 1 day The mechanism for the formation of ibandronate (9) (Scheme 7). The work-up was similar as that for the pre- is similar to that shown for etidronate/fenidronate in vious cases. Hydrolysis was followed by pH adjustment Scheme 5. and precipitation by the addition of methanol. Purifica- tion involved two other precipitations by the addition of methanol. Table 3 Synthesis of ibandronate using the P-reactants in different ratios. The effect of the different molar ratios of phospho- rus trichloride and phosphorous acid was similar to that Entry Reactants Purified ibandronate (9) observed for the previous cases. Applying ratios of 0–3, PCl H PO Purity (%)a Yield (%) 1–2, 2–1 and 3.2–0, the yields of ibandronate 9 were 0%, 3 3 3 (equiv.) (equiv.) 6%, 18% and 46%, respectively, while the purity was quite good (approximately 98%) in the last two cases (Table 3). 1 0 3 0 2 1 2 24b 6b Experiences with the preparation in two steps were 3 2 1 97 18 similar. Using phosphorus trichloride in two stages, the 4 3.2 0 98c 46 yield of ibandronate (9) was almost the same as that in the aOn the basis of potentiometric titration. bFor crude ibandronate. 1.)75°C/1 day cThe purity was also confirmed by 31P and 13C NMR. PCl3 MSA 2.) 105°C/4 h O H2O 6b (1) ° 3.)NaOH/H O Table 4 Synthesis of ibandronate in two steps (1., 26 C/6 h, 2., Cl 2 4.)MeOH 75°C/12 h).

1.) 75°C/1 day Entry Inorg. halide PCl Purified ibandronate (9) PCl 3 3 (1.1 equiv.) (2.2 equiv.) MSA Purity (%)a Yield (%) 2.) 105°C/4 h O H2O b 6b (2) 1 PCl3 PCl3 94 41 3.)NaOH/H2O OEt 2 SOCl2 PCl3 95 30 4.)MeOH aOn the basis of potentiometric titration. Scheme 6 bThe purity was also confirmed by 31P and 13C NMR. R. Kovács et al.: “Greener” synthesis of bisphosphonic/dronic acid derivatives 115

OH 1.) 75°C/12 h 3 Summary PCl3 O P ONa O MSA H2N H2N OH 2.) 105°C In conclusion, it can be said that a rational and a relatively OH ⋅ 3H O O P OH 2 10 H2O green approach to dronic derivatives comprises the reac- 3.)NaOH/H2O OH tion of the corresponding carboxylic acid with 3.2 equiv- 11 ° Yield: 57%(Purity:98%) alents of phosphorus trichloride in MSA at 75 C. After hydrolysis with aqueous NaOH, pH adjustment and puri- Scheme 8 fications, the dronic derivatives under discussion were obtained in yields of 38%–57%, in most cases, with high purities. These moderate yields should be appreciated as relate to pure dronic acids/dronates. In most cases, the 2.3 The synthesis of alendronate higher yields provided mostly in the patent literature are unreliable due to the lack of the criterion for purity. Our Finally, alendronate (11) was synthesized from method and results are helpful in respect of the critical γ-aminobutiric acid (10) applying the best set of experi- overview of the earlier literature data. ments (3.2 equivalents of phosphorus trichloride in MSA at 75°C for 12 h) followed by hydrolysis and pH adjustment Acknowledgments: This project was supported by Gedeon to 1.8. The crude product consisted of 9% of alendronic Richter Plc. and, partially, by the Hungarian Scientific and acid and 34% alendronate. After dissolving the crude Research Fund (OTKA No K83118). product in water and adjusting the pH to 4.5, alendronate- trihydrate 11 was obtained in a yield of 57%, and with a Received November 22, 2013; accepted January 30, 2014; previously purity of 98% (Scheme 8). published online February 22, 2014

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Rita Kovács graduated from the Budapest University of Technol- ogy and Economics in 2011 as a chemical engineer. From 2011 she István Greiner graduated from the Technical University of Budapest has been a PhD student at Budapest University of Technology and in 1984. He became an employee of Richter Pharmaceuticals and Economics/Department of Organic Chemistry and Technology in the obtained his PhD in 1992 in the topic of alkaloids. He also obtained subject of synthesis of dronates/dronic acids. an MBA degree in the English Open University in 1997 and he is also a patent attorney. Dr Greiner has been Deputy Research Director of Richter Pharmaceuticals for more than 15 years and was promoted to Adjunct Professor at the Budapest University of Technology and Eco- nomics. His interest lies in synthetic and bioorganic chemistry and his special field is microwave chemistry. He holds a few very respon- sible jobs. Dr Greiner is the author or co-author of approximately 70 articles and patents. He has received a number of decorations.

Alajos Grün graduated in 1992 as chemical engineer and he obtained his PhD in 2000 from the Budapest University of Technol- ogy and Economics, where he worked with Professor István Bitter on the synthesis of calixarene derivatives. He is an Associate Professor. Since 2008 he has been working in the research group of Professor György Keglevich at the same university. His main research interests include the reactions of organophosphorus com- pounds under microwave conditions and the synthesis of dronates. György Keglevich graduated from the Technical University of Budapest in 1981 as a chemical engineer. He got his Doctor of Chemical Science degree in 1994 and was appointed to full Professor in 1996. He has been the Head of the Department of Organic Chemistry and Technology since 1999. He is a P-hetero­ cyclic chemist and also deals with environmentally friendly chemistry: microwave chemistry, phase transfer catalysis and the development of new catalysts. He is the author or co-author of approximately 400 papers (the majority of which have appeared in international journals). He is a member of the Editorial Board of Heteroatom Chemistry, Phosphorus, Sulfur and Silicon, and the Related Elements, and Current Organic Synthesis. He is Associate Sándor Garadnay graduated from the University of Debrecen in Editor for Letters in Drug Design and Discovery, Regional Editor 1998 as a chemist, where he worked with Professor Sándor Makleit for Current Organic Chemistry, co-Editor-in-Chief for Letters in on the synthesis of morphine derivatives. He has been working Organic Chemistry, and Editor-in-Chief for Current Green Chemis- in Gedeon Richter Ltd. since 2001. His current position is Head of try. He was given different decorations in respect of his research, Department of Technology Development Laboratory, which he has educational and science organizing work. had since 2008. He deals with the development of generic active substances.