Solvent-free synthesis for imidazole-1-yl-acetic acid hydrochloride: an intermediate for zoledronic acid

ABSTRACT


Introduction
Imidazol-1-yl-acetic acid hydrochloride (4) is a key intermediate for synthesis of (l-hydroxy-2imidazole-l-yl-phosphonoethyl)-bisphosphonic acid (Zoledronic acid) (1, Scheme 1), a third generation and a very popular bisphosphonate derivative. Zoledronic acid is used to treat some diseases including osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, and Paget's disease of bone. Zoledronic acid (1) is used along with cancer chemotherapy; however, it neither suppresses nor stops cancer spreading. Zoledronic acid is used to treat bone related implications in patients who are suffering from cancer. It is widely used as a bone resorption inhibitor.
To minimize the use of environmentally hazardous solvents, we have developed a convenient and practical solvent free protocol for the preparation of imidazol-1-yl-acetic acid hydrochloride (4). Our two step process for the preparation of imidazol-1-yl-acetic acid hydrochloride (4) involves solventfree reaction of imidazole (2) with tert-butyl chloroacetate at the presence of suitable base and isolation of formed imidazol-1-yl-acetic acid tert-butyl ester (3) from water. In the second step, imidazol-1-yl-acetic acid tert-butyl ester (3) was hydrolyzed to imidazol-1-yl-acetic acid followed by a treatment with hydrochloric acid to get imidazol-1-yl-acetic acid hydrochloride (4).

Materials and Methods
Laboratory grade reagents were used without further purification. The progress of the reactions was monitored by TLC (10% methanol in chloroform, iodine visualization) and chromatographic purity of isolated solids was checked by HPLC. The HPLC results were recorded qualitatively, and the details of the chromatographic conditions are summarized in Table 1. All the synthesized compounds were characterized using 1 H NMR, 13 C NMR, IR, and MS spectra. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance 500 spectrometer (500 MHz) at 500 MHz ( 1 H) and 125 MHz ( 13 C). IR spectra were measured on PerkinElmer spectrum 100 FT-IR spectrometer. The mass spectra (ES + mode) were acquired on waters Q-Tof premier micromass. The melting points were recorded using the BUCHI melting point apparatus.

Results and Discussion
Synthesis of imidazol-1-yl-acetic acid hydrochloride (4)  Various solvents have been used for extraction, isolation, and crystallization of the products, which are dangerous to the environment. In this research study, we have developed a very efficient and solvent-free process for the preparation of imidazole-1-yl-acetic acid hydrochloride (4). Our two step process (Scheme 2) involve preparation of imidazol-1-yl-acetic acid tert-butyl ester (3) by reacting imidazole (2) with tert-butyl chloroacetate (TBCA) in the presence of suitable base in solvent-free medium and isolation of imidazol-1-yl-acetic acid tert-butyl ester (3) by adding water to the reaction mixture, in second step imidazol-1-yl-acetic acid tert-butyl ester (3) is hydrolyzed in to imidazol-1-yl-acetic acid followed by treatment with hydrochloric acid to get imidazol-1-yl-acetic acid hydrochloride (4).
The aim of this study was to develop environmentally-friendly synthesis of imidazol-1-yl-acetic acid tert-butyl ester (3) and its conversion to imidazol-1-yl-acetic acid hydrochloride (4) without using any solvent in entire two step process. Imidazol-1-yl-acetic acid tert-butyl ester (3) was synthesized by reacting the imidazole (2) with an equimolar amount of tert-butyl chloroacetate (TBCA) at the presence of the powdered potassium carbonate without using any solvent medium.
The easy workup procedure is another salient feature of our process, after the completion of reaction (2 to 3) reaction mass was cooled down to room temperature and water was added to it, imidazol-1yl-acetic acid tert-butyl ester (3) crystallize out as shiny white crystals, while unreacted imidazole (2), unreacted base and inorganic by products remains with water, thus avoiding extraction, solvent evaporation and solvent crystallization steps of earlier reported methods. Imidazol-1-yl-acetic acid tert-butyl ester (3) was then hydrolysed by heating in water and formed acid was treated with hydrochloric and converted to imidazol-1-yl-acetic acid hydrochloride (4).
Imidazole undergoes di-alkylation reacted with tert-butyl chloroacetate and formed di-acid impurity 4a (Scheme 3). It is reported [10] that, formation of di-acid impurity (4a) resulted from the nature of the condensation of haloester with imidazole. According to reference [10] weak bases such as amines or alkali metal carbonates are less suitable for this reaction and strong bases like potassium tertiary butoxide are preferred. Our study suggested that, the molar equivalent of the haloester is responsible for formation of the di-acid impurity (4a).
Experiments were carried out with different molar equivalent of tert-butyl chloroacetate ( Table   2) keeping same base (KOH), It was observed that one molar equivalent of tert-butyl chloroacetate substantially yield pure imidazol-1-yl-acetic acid hydrochloride (4) with di-acid impurity (4a) less than 0.50%, increasing molar equivalent of tert-butyl chloroacetate to 1.10 results in 4.49% di-acid Scheme 2. Solvent-free synthesis of imidazol-1-yl-acetic acid hydrochloride Scheme 3. Di-acid impurity of imidazol-1-yl-acetic acid respectively. Experiments were also carried out with different bases keeping one molar equivalent of tert-butyl chloroacetate (Table 3), di-acid impurity (4a) was found less than 0.50% in all the cases indicating role of tert-butyl chloroacetate quantity for the formation of di-acid impurity (4a).
Imidazol-1-yl-acetic acid hydrochloride (4) prepared by solvent-free process was converted to zoledronic acid monohydrate (1) by reacting with orthophosphoric acid and phosphorous oxychloride in the media of 1,4-dioxane (Scheme 4). This reaction was tried in numbers of solvents, but 1,4-dioxane was chosen because unlike the other solvents reaction mass the 1,4-dioxane was less sticky and easily stirable, which leads the complete conversion. Unlike chlorobenzene (widely used solvent for this reaction) 1,4-dioxane need not to be separated/decanted after reaction.

Conclusion
An efficient and green, 2-step synthesis of Imidazol-1-yl-acetic acid hydrochloride (an intermediate for Zoledronic acid) was developed by solvent-free N-alkylation of Imidazole using tertbutyl chloroacetate followed by aqueous hydrolysis and hydrochloride salt formation. The method offers several advantages which include less process time, high yield, simple work-up procedure and formation of substantially pure compound.Equimolar ratio of tert-butyl chloroacetate and Imidazole (2) was found optimum for the synthesis of Imidazol-1-yl-acetic acid tert-butyl ester (3), aqueous hydrolysis and hydrochloride salt formation of which afforded Imidazol-1-yl-acetic acid hydrochloride (4) having di-acid impurity (4a) less than 0.50%. Imidazol-1-yl-acetic acid tert-butyl ester (3) can be isolated simply by suspending reaction mass in water followed by filtration which prevents solvent evaporation, recrystallization and drying steps of conventional methods. Imidazol-1-yl-acetic acid hydrochloride (4) produced by the described method was converted into Zoledronic acid monohydrate (1) of 99.70% chromatographic purity

Disclosure Statement
No potential conflict of interest was reported by the authors.