Synthesis of Bisphosphonic/Dronic Acid Derivatives

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 phosphorus trichloride and phosphorous acid 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 zoledronic acid 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. Acetic acid 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 variation, 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 bone 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/alendronic acid, risedronic acid 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.

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