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“Greener” synthesis of bisphosphonic/dronic acid derivatives

  • Rita Kovács

    Rita Kovács graduated from the Budapest University of Technology and Economics in 2011 as a chemical engineer. From 2011 she has been a PhD student at Budapest University of Technology and Economics/Department of Organic Chemistry and Technology in the subject of synthesis of dronates/dronic acids.

         , Alajos Grün

    Alajos Grün graduated in 1992 as chemical engineer and he obtained his PhD in 2000 from the Budapest University of Technology 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 compounds under microwave conditions and the synthesis of dronates.

         , Sándor Garadnay

    Sándor Garadnay graduated from the University of Debrecen in 1998 as a chemist, where he worked with Professor Sándor Makleit on the synthesis of morphine derivatives. He has been working in Gedeon Richter Ltd. since 2001. His current position is Head of Department of Technology Development Laboratory, which he has had since 2008. He deals with the development of generic active substances.

         , István Greiner

    István Greiner graduated from the Technical University of Budapest in 1984. He became an employee of Richter Pharmaceuticals and obtained his PhD in 1992 in the topic of alkaloids. He also obtained 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 Economics. His interest lies in synthetic and bioorganic chemistry and his special field is microwave chemistry. He holds a few very responsible jobs. Dr Greiner is the author or co-author of approximately 70 articles and patents. He has received a number of decorations.

         and György Keglevich

    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-heterocyclic 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 Editor for Letters in Drug Design and Discovery, Regional Editor for Current Organic Chemistry, co-Editor-in-Chief for Letters in Organic Chemistry, and Editor-in-Chief for Current Green Chemistry. He was given different decorations in respect of his research, educational and science organizing work.

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Green Processing and Synthesis
From the journal Green Processing and Synthesis Volume 3 Issue 2

Abstract

According to literature, the synthesis of dronic acid derivatives from the corresponding carboxylic acids using phosphorus trichloride and phosphorous acid as the P-reactants is controversial, due to the wide range of molar ratios and diverse conditions. In this minireview, we summarize our results on the clarification of these problems. For example, with zoledronic acid and risedronic acid, we found that, using methanesulfonic acid (MSA) as the solvent, 3.2 equivalents of phosphorus trichloride was enough. Generalizing this optimized method, etidronate, fenidronate, ibandronate and alendronate were obtained in yields of 38%–57%, which is reasonable for valuable dronates, and in most cases, with high purities. Mechanistic aspects are also discussed.

Keywords: carboxylic acids; dronic acid derivatives; optimization; phosphorus trichloride; synthesis

1 Critical summary of the synthesis of the selected first and second generation dronic acids/dronates (-2011)

1-Hydroxy-1,1-bisphosphonic acid derivatives are efficient drugs against different bone diseases [1–4]. Classical representatives are etidronic acid and fenidronic acid, and more up-to-date variations used in clinics are ibandronate, alendronate/alendronic acid, risedronic acid and zoledronic acid.

Synthetic methods for dronic acids/dronates (1) mainly include the reaction of the corresponding acid with phosphorus trichloride and phosphorous acid (Scheme 1) [5].

Scheme 1
Scheme 1

As can be seen from the short summary of the literature methods for the four dronic derivatives in the next 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 considered a black-box, which cannot be said to meet the criteria of “green” chemistry.

Etidronic acid, belonging to the first generation of hydroxymethylenebisphosphonic acids, was described and synthesized in 1897. Acetic acid was reacted with 0.35 equivalent of phosphorus trichloride at room temperature 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 synthesis was also performed using 3.5 equivalents of phosphorus trichloride and the same amount of phosphorous acid in 1,4-dioxane at ~95°C, followed by hydrolysis and precipitation of the product by acetonitrile. Etidronic acid was obtained in a yield of only 5% [7]. In another variation, pentyl acetate was the starting material and phosphorous acid was prepared in situ by the partial hydrolysis of phosphorus trichloride. The ester was heated with the mixture of phosphorus trichloride and phosphorous acid in sulfolane (or in dimethylsulfolane) at approximately 110°C for about 5 h. The work-up including removal of the remaining reactants and suspendation of the final product in water, followed by filtration, gave etidronic acid in a yield of 39% [8]. In the very first publication on the preparation of etidronic acid, it was claimed that the reaction of acetyl chloride with phosphorous acid at 20°C for 1 day and then at ~125°C for 1 h led to the desired product [6]. No criterion of purity was reported in the above-mentioned cases. There are other approaches involving the Arbuzov reaction of acetyl chloride and a trialkyl phosphite; addition of a dialkyl phosphite on the carbonyl group of the oxoethylphosphonate so formed followed by hydrolysis (Scheme 2, Y=Me) [9–11].

Scheme 2
Scheme 2

Interestingly, fenidronic acid was mainly synthesized by the Arbuzov reaction of benzoyl chloride as the first step [10–12]. The following steps were similar to those described above for a similar preparation of etidronic acid (Scheme 2, Y=Ph) [9–11].

There is a literature procedure for the preparation of fenidronic acid by the reaction of benzoic acid with two equivalents of phosphorus trichloride at 80°C for 4 h without any solvent, followed by hydrolysis [13], but we could not reproduce this procedure.

The methods described for the synthesis of ibandronate used N-methyl-N-pentyl-3-aminopropionic acid, phosphorus trichloride and phosphorous acid in ratios of 1:1.5:1.5 [14], 1:2.9:1.5 [15] and 1:3.7:4.2 [16] in the presence of aromatics as solvents (toluene/chlorobenzene), or in the absence of solvents at 70°C–85°C, to provide ibandronate in 43%–82% yields after the work-up (including hydrolysis) and pH adjustment followed by purification. No data were provided on the purity of the ibandronate obtained. In the preparation of alendronic acid/alendronate, γ-aminobutyric acid, phosphorus trichloride and phosphorous acid were measured in ratios of 1:2.5:1.5 [17] and 1:2:2 [18, 19] to give alendronic acid and alendronate in yields of 90% and 70%, respectively, after heating the components in anisole at 105°C, or in acetonitrile at 75°C, followed by hydrolysis and pH adjustment (using NaOH in the second case). The purity of the dronic acid/dronate was uncertain. Also described was the synthesis of alendronic acid from γ-aminobutyric acid, using phosphorus trichloride and forming the phosphorous acid, by adding a stoichiometric amount of water to the reaction mixture [20]. A recent approach involved the synthesis of alendronic acid from aminobutyric acid using three equivalents of phosphorus chloride and phosphorous acid in sulfolane, under microwave (MW) conditions at 65°C. After hydrolysis, the yield of alendronic acid was 41%. The complete procedure required a reaction time of 17 min. As a comparison, the thermal accomplishment led to a yield of 38% after a reaction time of 9.5 h. Hence, the yields are quite similar; however, there is a a considerable difference in respect of the reaction times [21].

We recently described that heteroaryl-substituted dronic acids, zoledronic acid (5a) and risedronic acid (5b) may be best prepared by the reaction of the corresponding heteroaryl-acetic acid with 3.2 equivalents of phosphorus trichloride in methanesulfonic acid (MSA), at 75°C for 3 h, followed by hydrolysis and pH adjustment by aqueous sodium hydroxide and, in the case of zoledronic acid (5a), by recrystallization from aqueous HCl (Scheme 3) [22, 23]. It is noteworthy that unlike in earlier syntheses, there was no need to use different amounts (1–5 equivalents) of phosphorous acid [7, 24–30], as this reagent does not take part in the reaction under the conditions applied, due to its low nucleophilicity. It is enough to apply only phosphorus trichloride in a quantity of 3.2 equivalents. This observation is of great importance from the point of view green chemistry, as it makes possible the rational synthesis of dronic derivatives.

Scheme 3
Scheme 3

The above mentioned MW-assisted method [21] was also used for the synthesis of zoledronic acid (5a) and risedronic acid (5b), applying phosphorus trichloride and phosphorous acid in quantities of two equivalents in sulfolane at 65°C; the yields of the corresponding products were 70% and 74%, respectively, after hydrolysis. The thermal variation provided zoledronic acid (5a) in a similar yield (67%). However, the reaction times were different (approximately 14 min for the MW version vs. 9.5 h for the thermal variation).

2 Extension of our method to the synthesis of etidronate, fenidronate, ibandronate and alendronic acid/alendronate

2.1 The synthesis of etidronate and fenidronate

In this part, the optimization for the synthesis of etidronic acid, fenidronic acid, ibandronate and alendronic acid/alendronate is summarized [31–33].

The synthesis of etidronate (6a) and fenidronate (6b) from acetic acid or benzoic acid, respectively (Scheme 4) was performed using phosphorus trichloride and phosphorous acid in different ratios in MSA as the solvent, at 75°C for 1 day. After the hydrolysis, the pH was adjusted to 1.8, followed by precipitation of the disodium salt (6a or 6b) by the addition of methanol. Purification involved two other precipitations by the addition of methanol and three more digestions in methanol.

Scheme 4
Scheme 4

The experimental data are summarized in Table 1. One may see that using 3.2 equivalents of phosphorous acid alone, there was no reaction. Decreasing the quantity of phosphorous acid and at the same time, increasing that of phosphorus trichloride, produced better and better results. When 1.1 equivalents of phosphorus trichloride and 2.2 equivalents of phosphorous acid were applied, products 6a and 6b were formed in approximately 5% and 13% yields, respectively, in unpure (≤74%) forms. Using a reversed molar ratio, both dronates (6a and 6b) were formed in yields of 36%, in purities of 85% and 94%, respectively. The application of 3.2 equivalents of phosphorus trichloride alone led to the best results. Etidronate (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 pure form.

Table 1

Synthesis of etidronate and fenidronate using the P-reactants in different ratios.

EntryReactantsPuritya (%)Yield (%)
PCl3 (equiv.)H3PO3 (equiv.)6a6b6a6b
103.2––00
21.12.2–74<513
32.21.185943636
43.2090b100b3846

aOn the basis of potentiometric titration.

bThe purity was also confirmed by 31P and 13C NMR.

As we substantiated the intermediacy of the corresponding acid chlorides [34], we performed the syntheses in a two-step manner, forming first acetyl chloride or benzoyl chloride by reaction with 1.1 equivalents of phosphorus trichloride or thionyl chloride, and then adding the P-reactant; 2.2 equivalents of phosphorus trichloride or phosphorous acid (Scheme 5, Table 2). In MSA it is also possible that a mixed anhydride formulated by RC(O)-O(O)2SMe (7) is formed from the acid chloride and MSA.

Scheme 5
Scheme 5
Table 2

Synthesis of etidronate and fenidronate in two steps.

EntryInorg. halide (1.1 equiv.)P-reactant (2.2 equiv.)Puritya (%)Yield (%)
6a6b6a6b
1PCl3PCl38898b3243
2SOCl2PCl399972526
3PCl3H3PO3<5076<5~10

aOn the basis of potentiometric titration.

bThe purity was also confirmed by 31P and 13C NMR.

It can be seen that the application of phosphorus trichloride in a two-step procedure gave rise to an outcome which was almost equal to that of the one-step procedure. Product 6a was obtained in a yield of 32% and with a purity of 88%. The corresponding values for product 6b were 43% and 98%, respectively. Using thionyl chloride, the results were somewhat more modest. The last combination (1., PCl3 2., H3PO3) led to insufficient yields and impure products (6a and 6b).

Then, choosing the model of fenidronate 6b, we wished to prove the reaction sequence by starting from benzoyl chloride [Scheme 6/(1)]. This reaction resulted in fenidronate (6b) in a yield of 35% and with a purity of 100%. Moreover, ethyl benzoate could also be used as the starting material [Scheme 6/(2)]. The yield and the purity were comparable with the previous case (36% and 94%, respectively).

Scheme 6
Scheme 6

2.2 The synthesis of ibandronate

Ibandronate (9) was synthesized from N-methyl-N-pentyl-β-amino-propionic acid hydrochloride using different ratios of the P-reactants in MSA at 75°C for 1 day (Scheme 7). The work-up was similar as that for the previous cases. Hydrolysis was followed by pH adjustment and precipitation by the addition of methanol. Purification involved two other precipitations by the addition of methanol.

Scheme 7
Scheme 7

The effect of the different molar ratios of phosphorus trichloride and phosphorous acid was similar to that observed for the previous cases. Applying ratios of 0–3, 1–2, 2–1 and 3.2–0, the yields of ibandronate 9 were 0%, 6%, 18% and 46%, respectively, while the purity was quite good (approximately 98%) in the last two cases (Table 3).

Table 3

Synthesis of ibandronate using the P-reactants in different ratios.

EntryReactantsPurified ibandronate (9)
PCl3 (equiv.)H3PO3 (equiv.)Purity (%)aYield (%)
1030
21224b6b
3219718
43.2098c46

aOn the basis of potentiometric titration.

bFor crude ibandronate.

cThe purity was also confirmed by 31P and 13C NMR.

Experiences with the preparation in two steps were similar. Using phosphorus trichloride in two stages, the yield of ibandronate (9) was almost the same as that in the one-step procedure (41% vs. 46%). Applying thionyl chloride in the first step, the yield was lower (30%) (Table 4). The mechanism for the formation of ibandronate (9) is similar to that shown for etidronate/fenidronate in Scheme 5.

Table 4

Synthesis of ibandronate in two steps (1., 26°C/6 h, 2., 75°C/12 h).

EntryInorg. halide (1.1 equiv.)PCl3 (2.2 equiv.)Purified ibandronate (9)
Purity (%)aYield (%)
1PCl3PCl394b41
2SOCl2PCl39530

aOn the basis of potentiometric titration.

bThe purity was also confirmed by 31P and 13C NMR.

2.3 The synthesis of alendronate

Finally, alendronate (11) was synthesized from γ-aminobutiric acid (10) applying the best set of experiments (3.2 equivalents of phosphorus trichloride in MSA at 75°C for 12 h) followed by hydrolysis and pH adjustment to 1.8. The crude product consisted of 9% of alendronic acid and 34% alendronate. After dissolving the crude product in water and adjusting the pH to 4.5, alendronate-trihydrate 11 was obtained in a yield of 57%, and with a purity of 98% (Scheme 8).

Scheme 8
Scheme 8

3 Summary

In conclusion, it can be said that a rational and a relatively green approach to dronic derivatives comprises the reaction of the corresponding carboxylic acid with 3.2 equivalents of phosphorus trichloride in MSA at 75°C. After hydrolysis with aqueous NaOH, pH adjustment and purifications, 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 higher yields provided mostly in the patent literature are unreliable due to the lack of the criterion for purity. Our method and results are helpful in respect of the critical overview of the earlier literature data.

Corresponding author: György Keglevich, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, 1521 Budapest, Hungary, e-mail:

About the authors

Rita Kovács

Rita Kovács graduated from the Budapest University of Technology and Economics in 2011 as a chemical engineer. From 2011 she has been a PhD student at Budapest University of Technology and Economics/Department of Organic Chemistry and Technology in the subject of synthesis of dronates/dronic acids.

Alajos Grün

Alajos Grün graduated in 1992 as chemical engineer and he obtained his PhD in 2000 from the Budapest University of Technology 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 compounds under microwave conditions and the synthesis of dronates.

Sándor Garadnay

Sándor Garadnay graduated from the University of Debrecen in 1998 as a chemist, where he worked with Professor Sándor Makleit on the synthesis of morphine derivatives. He has been working in Gedeon Richter Ltd. since 2001. His current position is Head of Department of Technology Development Laboratory, which he has had since 2008. He deals with the development of generic active substances.

István Greiner

István Greiner graduated from the Technical University of Budapest in 1984. He became an employee of Richter Pharmaceuticals and obtained his PhD in 1992 in the topic of alkaloids. He also obtained 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 Economics. His interest lies in synthetic and bioorganic chemistry and his special field is microwave chemistry. He holds a few very responsible jobs. Dr Greiner is the author or co-author of approximately 70 articles and patents. He has received a number of decorations.

György Keglevich

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-heterocyclic 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 Editor for Letters in Drug Design and Discovery, Regional Editor for Current Organic Chemistry, co-Editor-in-Chief for Letters in Organic Chemistry, and Editor-in-Chief for Current Green Chemistry. He was given different decorations in respect of his research, educational and science organizing work.

Acknowledgments

This project was supported by Gedeon Richter Plc. and, partially, by the Hungarian Scientific and Research Fund (OTKA No K83118).

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Received: 2013-11-22
Accepted: 2014-1-30
Published Online: 2014-2-22
Published in Print: 2014-4-1

©2014 by Walter de Gruyter Berlin/Boston

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/gps-2013-0107
Keywords for this article
carboxylic acids; dronic acid derivatives; optimization; phosphorus trichloride; synthesis
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Articles in the same Issue

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  2. In this issue
  3. Editorial
  4. Megatrends – megascience?
  5. 1st EuGSC 2013
  6. First EuCheMS Congress on Green and Sustainable Chemistry
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