Synthesis of related substances of olmesartan medoxomil, anti-hypertensive drug#

Olmesartan medoxomil 1 is the latest angiotensin receptor antagonist approved by the FDA for the treatment of hypertension. During the process development of olmesartan medoxomil, four related substances (impurities) were observed along with the final API. Those impurities were identified as olmesartan acid, 4-acetyl olmesartan, 5-acetyl olmesartan


Introduction
The presence of impurities, also called as, related substances in an active pharmaceutical ingredient (API) can have a significant impact on the quality and safety of the drug products.Therefore, it is necessary to study the impurity profile of any API and control it during the manufacturing of a drug product.As per the ICH guidelines any impurities, which are forming at a level of ≥ 0.10% with respect to the API should be identified, synthesized and characterized thoroughly. 1 Olmesartan medoxomil 1 [Benicar®, Sankyo pharma] is the latest angiotensin receptor antagonist 2,3 approved by the FDA for the treatment of hypertension (Figure 1). 4 The drug works by inhibiting the effects of angiotensin II, a potent vasoconstrictor and one of the key contributors to cardiovascular and renal disease. 5During the process for the synthesis of 1, four unknown impurities were observed.However, as far as we are aware, the syntheses of these four Very recently, we have described an efficient, industrial scale synthesis of olmesartan medoxomil 1. 6 During the synthesis of 1, we came across many process related impurities and some of them were captured in our prior report. 7To comprehend the complete impurity profile of olmesartan medoxomil 1 and to compare the extent of contamination of the impurities in 1, we have decided to synthesize all the possible impurities.The HPLC chromatogram, Figure 2, shows the impurity profile of 1.Initially, 1 was subjected to LCMS to learn about the number of contaminants associated with it.Apart from the molecular ion peak of 1, four more peaks with distinct molecular ions were observed in LCMS (Figure 3).Based on the molecular ion peaks, the following four structures 2 -5 were proposed (Figure 4).Although, the structure of impurity 2 has been already reported in the literature, surprisingly its synthesis was not accounted. 8Other impurities 3, 4 and 5 are process related new impurities and were not reported elsewhere.In this report, syntheses and characterization of all the four impurities of 1 will be discussed in detail.

Results and Discussion
The synthesis of impurity 2, also known as olmesartan acid impurity, is described in Scheme 1. Olmesartan medoxomil 1 was subjected to basic hydrolysis using sodium hydroxide in methanol at ambient reaction conditions afforded the impurity 2 in good yield and 99% HPLC purity.The structure of 2 was confirmed by spectral analysis.imidazole derivative 9 was then condensed with biphenyl derivative 13 in presence of potassium carbonate in refluxing acetone to provide the N-alkylated acetyl imidazole derivative 10, which on further hydrolysis using aqueous NaOH in acetone gave the sodium salt 11.Alkylation of 11 with 4-chloromethyl-5-methyl-1,3-dioxolen-2-one 9 14 provided the medoxomil ester 12. Finally, deprotection of trityl group in 12 with acetic acid afforded 4-acetyl impurity of olmesartan medoxomil 3.
The synthesis of 5-acetyl impurity 4 commenced from the N-alkylated imidazole derivative 15, which is one of the intermediates in the synthesis of 1 (Scheme 3).The Grignard reaction of 15 with excess moles of methyl magnesium chloride in anhydrous toluene afforded 5-acetyl derivative of N-alkylated imidazole 16, which on deprotection using acetic acid provided 5acetyl impurity 4 in good yield and purity.The structure of 4 was confirmed by standard spectral analysis.Preparation of dehydro olmesartan impurity 5, originated from the medoxomil ester derivative of N-alkylated imidazole 17.Dehydration of 17 with p-toluenesulphonic acid in toluene under reflux conditions provided the corresponding dehydro derivative 18, which on deprotection with acetic acid provided dehydro olmesartan impurity 5 in good purity.Finally, all the impurities 2 -5 were individually co-injected with the API 1 in the HPLC and the HPLC data was compared with that of the API 1.As expected, all the impurities were matching with the impurity profile of 1.

Conclusions
We have demonstrated the synthesis and complete characterization of some of the critical impurities of olmesartan medoxomil 1.This investigation helped us to establish the impurity profile of 1.

Experimental Section
General. 1 H NMR spectra were recorded at 400 MHz Varian FT NMR Spectrometer.The chemical shifts are reported in δ ppm relative to TMS.The IR spectra were obtained using Perkin Elmer, Spectrum One FT IR spectrophotometer, with substances being pressed in a KBr pellet.The mass analyses have been performed on AB-4000 Q-trap LC-MS/MS mass spectrometer (MDS SCIEX, Applied Bio systems, California, USA).All the solvents and reagents were used without further purification.

Synthesis of olmesartan acid impurity 2
To a solution of olmesartan medoxomil 1 [10.0 g, 0.0179 mol] in 200.0 mL of methanol was added a solution of sodium hydroxide (1.5 g, 0.0075 mol) in water (25.0mL) and the reaction mixture was stirred at 25-30 °C for 15-20 h.After completion of the reaction, methanol was distilled off completely at 45-50 °C and diluted with water.It was then washed with ethyl acetate (100.0 mL x 1).The aqueous layer was separated and the pH was adjusted to 8.0-8.

Synthesis of 5-acetyl impurity 4
Compound 16.To a solution of 15 (35.0 g, 0.05 mol) in toluene (105.0 mL) was added a solution of methyl magnesium chloride in tetrahydrofuran (24.5 %, 228.0 mL, 0.45 mol) at room temperature and maintained for 6-7 h.After completion of the reaction, the reaction mass was quenched with 10% acetic acid (460.0 mL) and extracted with toluene (35.0 mL).The organic layer was washed with saturated brine solution (105.0 mL).Solvent was distilled off under reduced pressure to obtain the title compound 16 as a residue.The residue was further purified by column chromatography in 10% ethyl acetate in hexane to provide pure compound 16 as a white solid (12.0 g, yield 34%; purity by HPLC 99%); IR (KBr) 3337, 3059-3034, 1624 cm -1 ;

Synthesis of impurity 4
A solution of 16 (10.0g, 0.013 mol) in 40% aqueous acetic acid (300.0 mL) was heated at 55-60 °C for 1-2 h.The reaction mass was cooled to room temperature and diluted with water (100.0mL).The precipitated solids were filtered and washed with 40% aqueous acetic acid (10.0 mL), and the filtrate was extracted with dichloromethane (550.0 mL).The organic layer was washed with a mixture of 5% aqueous sodium bicarbonate solution (100.0 mL) and 5% sodium chloride solution (450.0 mL).Removal of the solvent followed by isolation in cyclohexane (30.0 mL)