Asian Journal of Chemistry V ol. 21, No. 6 (2009), 4909-4913
A Convenient Method for the Preparation of
Losartan Active Metabolite (EXP-3174)
M ORTEZA P IRALI-H AMEDANI†, A LIREZA A LIABADI, M. S HEKARCHI†, M. A MINI,
M OHAMMAD R EZA R OUINI‡, A BBAS S HAFIEE and A LIREZA F OROUMADI*§永远英语
一路芬芳Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Rearch Center, Tehran University of Medical Sciences, Tehran 14174, Iran
破碎的近义词
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Losartan is an angiotensin antagonist with a 5-carboxylate active
metabolite (EXP-3174). This active metabolite is the result of the oxida-
tion of 5-hydroxymethyl group to the corresponding 5-carboxyl group
in liver. The active metabolite (EXP-3174) is important in pharmaco-
logical and biopharmaceutical studies of parent drug. Therefore, a con-
venient two steps procedure has been developed bad on the oxidation
of hydroxymethyl group of losartan to aldehyde and subquent oxidation
to carboxylate using different oxidizing reagents. H2O2-KOH reagent
was found the most convenient and efficient method.
Key Words: Synthesis, Losartan active metabolite, EXP-3174,
Oxidation.
INTRODUCTION
Losartan is an angiotensin II type 1 receptor antagonist that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system. The renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure and hyper-tension. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers) are highly effective in reducing blood pressure, exhibit renoprotective properties and have placebo-like tolerability1.新年好英文怎么写
正宗糖醋排骨After oral administration, losartan is mainly converted to an active metabolite EXP-3174 (Scheme-I). This active metabolite is the conquences of the oxidation of 5-hydroxymethyl group to the corresponding 5-carboxaldehyde (EXP-3179) and finally 5-carboxylic acid group. The isoenzymes of cytochrome P450 in liver are responsible for metabolism and conversion of losartan to its major active metabolite. The EXP-3174 metabolite of losartan is 10 to 40 times more potent than its parent compound and the most of the pharmacological activity of losartan relates to this metabolite2. On the other hand, 5-carboxaldehyde metabolite (EXP-3179) is respon-sible for antiinflammatory and antiaggregatory activities of losartan3.
†Food & Drug Control Laboratories Rearch Center, Emam Khomeini Ave., Tehran, Iran.
长沙黄兴路步行街
‡Biopharmaceutics and Pharmacokinetics Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14155-6451, Iran.
§Kerman Neuroscience Rearch Center, Kerman University of Medical Sciences, Kerman, Iran.
H
Losartan EXP-3174
Scheme-I: Metabolism of losartan in liver and conversion to its active metabolite EXP-3174Since the EXP-3174 is important in pharmacological and biopharmaceutical studies of losartan 4 and there are veral reports on determination of losartan and its metabolites 5,6. We have developed a convenient two steps procedure for preparation of EXP-3174 through its carboxaldehyde intermediate (EXP-3179), using MnO 2and subquent oxidation to carboxylate using different oxidizing reagents. The aldehyde intermediate is also a uful reagent for preparation of the biologically active compounds 7,8.
EXPERIMENTAL
Losartan was ud as starting material for all experiments and the target compound EXP-3174 was synthesized through the 5-carboxaldehyde intermediate. The 5-carbox-aldehyde intermediate was prepared using the mild oxidizing agent, MnO 29-11. Sub-quent oxidation of aldehyde to the corresponding 5-carboxylate was performed by oxidation of the aldehyde with other reagents such as silver nitrate 12, hydrogen peroxide 13, oxone
14-16 and Pd/C 17 (Scheme-II ).
N
N NH N
N N C H 2OH
Cl
Losartan Losartan 5-carboxaldehyde (EXP-3179)Losartan 5-carboxylic acid (EXP-3174)
Procedure Reagents Time (h) Solvent Yield (%)
A AgNO 3 1.0 H 2O 51
B H 2O 2, KOH 0.5 MeOH 71
C Oxone 5.0 DMF 65
D Pd/C, NaBH 4, KOH, air Overnight MeOH/H 2O 57
Scheme-II: Synthesis of active metabolite of losartan using different oxidizing reagents 4910 Pirali-Hamedani et al.
Asian J. Chem.
V ol. 21, No. 6 (2009)Preparation of Losartan Active Metabolite (EXP-3174) 4911 The purity of the synthesized compounds was confirmed by thin layer chromato-graphy using various solvents of diffe
rent polarities. Merck silica gel 60 F254 plates were applied for analytical TLC. Column chromatography was performed on Merck silica gel (70-230 mesh). 1H NMR spectra were measured using a Bruker 500 spectro-meter and chemical shifts are expresd as δ (ppm) with tetramethylsilane as internal standard. Melting points were determined on a Kofler hot stage apparatus and are uncorrected. The mass spectra were run on a Finigan TSQ-70 spectrometer (Finigan, USA) at 70 eV. Elemental analys were carried out on a CHN-O-rapid elemental analyzer (GmbH-Germany) for C, H and N and the results are within ± 0.4 % of the theoretical values.
Synthesis of 2-n-butyl-4-chloro-5-formyl-1-[{2´-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]imidazole: A mixture of losartan (10 g, 0.024 mol) and excess of MnO2 (50 g) in 200 mL CHCl3 was stirred at room temperature for 10 h. The reaction monitored by thin layer chromatography. After the completion of reaction, the mixture was pasd through a short pad of diatomatous earth and washed with chloroform. Chloroform was evaporated and the residue was purified by column chromatography using chloroform as mobile pha.
Spectral data and physicochemical properties: White solid, m.p. 153-155ºC, 1H NMR (DMSO-d6): 9.67 (s, 1H), 7.69 (d, 1H, J = 8 Hz), 7.65 (t, 1H, J = 8 Hz),
7.56 (t, 1H, J = 8 Hz), 7.52 (d, 1H, J = 8 Hz), 7.11 (d, 2H, J = 8.5), 7.04 (d, 2H, J =
8.5 Hz), 5.55 (s, 2H), 2.62 (t, 2H, J = 7Hz), 1.8-1.1 (m, 4H), 0.85 (t, 3H, J = 7Hz). MS (m/z): 419 (M+, 5%).
Synthesis of 2-n-butyl-4-chloro-5-carboxy-1-[{2´-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]imidazole
Procedure A: A mixture of 4.5 g (0.011 mol) of losartan 5-carboxaldehyde and 2.25 g (0.056 mol) of NaOH in 100 mL of water was stirred for 15 min. Then 0.1 g of AgNO3 was dissolved in warm water and was added to the reaction mixture and the resulting mixture was refluxed overnight. The mixture was filtered and acidified by HCl. The obtained yellowish precipitate was filtered and was crystal-lized from ethanol.
Procedure B: Hydrogen peroxide (30 %, 5.7 mL, 56.8 mmol) was added dropwi to a stirring solution of aqueous KOH 50 % (3.2 mL, 28.4 mmol) and losartan 5-carboxaldehyde (3 g, 7.1 mmol) in methanol (25 mL) at 65 ºC and the mixture was stirred for 20 min. After the completion of reaction, the reaction was cooled and was acidified with concentrated HCl to obtain 2.9 g of 5-carboxylate derivative.
Procedure C: A mixture of 1.5 g (3.6 mmol) of losartan 5-carboxaldehyde and 0.55 g (3.6 mmol) of oxone (potassium peroxymonosulfate) was dissolved in 10 mL of DMF and the reaction mixture was
stirred for 5 h. The reaction was monitored by thin layer chromatography. After the completion of reaction, the solvent was evaporated and the residue was purified by acid ba workup and was crystallized from ethanol.
4912 Pirali-Hamedani et al.Asian J. Chem.
Procedure D: A catalytic amount of Pd/C was added to 10 mL of H2O and 0.6 mmol of NaBH4 was slowly added to this suspension followed by 1 g (18 mmol) of KOH. Then, 2.5 g (5.9 mmol) losartan 5-carboxaldehyde was added to the suspension and reaction mixture was stirred overnight under the air at room temperature for 10 h. The completion of the reaction was controlled by thin layer chromatography. After the completion, the reaction mixture was neutralized with 0.1 M HCl solution. The obtained mixture was extracted with 10 mL of ethyl acetate 3 times and the organic layers were combined and evaporated. The residue was purified by acid ba workup and was crystallized from ethanol.
Spectral data and physico-chemical properties: White solid, m.p. 175-177ºC, 1H NMR (DMSO-d6): 7.71(d, 1H, J = 8 Hz), 7.68 (t, 1H, J = 8 Hz), 7.57 (t, 1H, J = 8Hz), 7.54 (d, 1H, J = 8 Hz), 7.10 (d, 2H, J = 8.5), 7.01 (d, 2H, J = 8.5 Hz), 5.57 (s, 2H), 2.59 (t, 2H, J = 7 Hz), 2.1-1.3 (m, 4H), 1.1 (t, 3H, J = 7Hz). MS (m/z ): 435 (M+, 6 %).
RESULTS AND DISCUSSION
A microwave-assisted synthesis of an active metabolite of losartan (EXP-3174) using excess of MnO2 is reported by Santagada et al.18; however, the purification procedure was performed using preparative RP-HPLC. Recent report by Schmidt and Schieffer19 indicated a procedure for synthesis of EXP-3179 in the prence of RuCl3 and H2O2 with 16 % yield.
In all procedures reported in this study, the aldehyde intermediate was ud for the preparation of EXP-3174. In the first procedure, A, the 5-carboxylate derivative was synthesized using a lective reagent for the oxidation of aldehydes to related carboxylic acids. Silver nitrate as oxidizing agent was ud concurrently with NaOH in water for this conversion10. This procedure had the lowest yield in comparison with other methods. Procedure B (H2O2, KOH) is an efficient and rapid method for oxidation of aldehydes to carboxylic acids13. The reagents of this procedure are convenient and inexpensive and the time of 0.5 h is a positive point and an advantage of this procedure. Procedure C (oxone)14-16 was also found as an efficient method for obtaining active metabolite of losartan from its aldehyde intermediate. In the prence of oxone as an oxidizing agent in dimethyl formamide the reaction was completed after 5 h. Procedure D (Pd/C, NaBH4 and KOH)17 is a good method for the oxidation of losartan 5-carboxaldehyde to EXP-3174. Stirring overnight is necessary f
or the completion of the reaction.
In summary, we have developed four methods for the synthesis of losartan active metabolite (EXP-3174) from its aldehyde intermediate (EXP-3179).
ACKNOWLEDGEMENTS
This work was financially supported by grants from Pharmaceutical Sciences Rearch Center, Tehran University of Medical Sciences and INSF (Iran National Science Foundation).
V ol. 21, No. 6 (2009)Preparation of Losartan Active Metabolite (EXP-3174) 4913
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(Received: 1 December 2008; Accepted: 11 April 2009)AJC-7409
