Novel Syntheses of 2-Butyl-5-chloro-3<i>H</i>-imidazole-4-carbaldehyde:  A Key Intermediate for the Synthesis of the Angiotensin II Antagonist Losartan

Griffiths, Gareth; Hauck, Michael; Imwinkelried, René; Kohr, Jörg; Roten, Conrad A.; Stucky, Gerhard C.; Gosteli, J.

doi:10.1021/jo9824910

Cited by 45 publications

(23 citation statements)

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“…2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde (4) (Griffiths et al, 1999) Glycine 3 (16.4 g, 0.21 mol) in methanol (65 mL) and water (4 mL) was cooled to 0-5°C. pH was adjusted to 9-9.5 by using 30% NaOH solution.…”

Section: Methodsmentioning

confidence: 99%

“…Losartan potassium, a well-known pharmaceutically active compound used as a nonpeptide angiotensin II antagonist, is an orally active antihypertensive agent (Carini et al, 1991). 2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde is the main active metabolite and is one of the key intermediates in the synthesis of Losartan (Griffiths et al, 1999). This broad spectrum of biological activity of imidazole derivatives prompted us to synthesize and evaluate the anti-inflammatory activity of a series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives.…”

Section: Introductionmentioning

confidence: 99%

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Microwave-assisted synthesis and evaluation of anti-inflammatory activity of new series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives

2008

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A series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives bearing potentially bioactive substituents were synthesized by microwave irradiation method in good yield compared with conventional method. The synthesized compounds were screened for their anti-inflammatory activity and were compared with a standard drug. The compounds demonstrated potent to weak anti-inflammatory activity. Of the compounds studied, compounds 6i and 6d showed potent activity comparable to the standard drug ibuprofen at the same dose in carrageenan-induced paw edema in rat model.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microwave-assisted synthesis and evaluation of anti-inflammatory activity of new series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives

2008

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“…170 The synthetic step involving a Suzuki coupling in the synthesis of losartan developed by Merck research chemists is outlined in the following (Scheme 48). 171,172 First, the trityl-protected phenyltetrazole was ortholithiated by means of butyllithium and then quenched with triisopropyl borate, giving the boronic acid derivative after treatment with aqueous ammonium chloride. The resulting boronic acid participated in a Suzuki cross-coupling reaction with the other key intermediate, an imidazole alcohol.…”

Section: Genotoxic Compounds Used As Reactantsmentioning

confidence: 99%

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

et al. 2015

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alkylation of the second nitrogen of the piperazine ring with the genotoxic reagent 4-chloro-1-bromobutane (Scheme 10). 64 APIs streams may contain genotoxic alkyl halides impurities when a reaction takes place in alcoholic solvent at reflux temperature in the presence of hydrogen halides or alkali halides and strong acids. These reaction conditions may be applied in cyclization, decarboxylation, sulfonyl cleavage, Narylation and API salt formation. Note that this list is not exhaustive. For instance, capecitabine is a chemotherapeutic agent used in the treatment of metastatic breast and colorectal cancers. 65 During its synthesis, D-ribose is heated under reflux in methanol in the presence of concentrated HCI and acetone Scheme 2. O-Alkylation of Isovanillin during the Synthesis of Aliskiren Using Genotoxic 1,3-Dibromopropane Scheme 3. Use of Methyl Iodide in the Preparation of Cerivastatin Scheme 4. S-Alkylation with Methyl Iodide during the Last Synthetic Step of Lamifiban Scheme 5. S-Alkylation with Methyl Iodide during the Synthesis of Eldacimibe Scheme 6. N-Methylation with Genotoxic Methyl Iodide during the Preparation of Efegatran Scheme 7. Quaternization by Means of Methyl Iodide during Milameline Synthesis Scheme 8. Direct Use of Genotoxic 2-Iodopropane in the Synthesis of Latanoprost Scheme 9. Use of Genotoxic 2-Bromopropane and Nitrogen Mustard during the Synthesis of Mazapertine

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“…Cyclisation, followed by a Vilsmeier-type reaction then furnishes the key chloroimidazolyl building block 172 in good yield (Scheme 34) [51]. …”

Section: Reviewmentioning

confidence: 99%

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Baumann¹,

Baxendale²,

Ley³

et al. 2011

Beilstein J. Org. Chem.

496

269

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SummaryThis review presents a comprehensive overview on selected synthetic routes towards commercial drug compounds as published in both journal and patent literature. Owing to the vast number of potential structures, we have concentrated only on those drugs containing five-membered heterocycles and focused principally on the assembly of the heterocyclic core. In order to target the most representative chemical entities the examples discussed have been selected from the top 200 best selling drugs of recent years.

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Novel Syntheses of 2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde: A Key Intermediate for the Synthesis of the Angiotensin II Antagonist Losartan

Cited by 45 publications

References 7 publications

Microwave-assisted synthesis and evaluation of anti-inflammatory activity of new series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives

Microwave-assisted synthesis and evaluation of anti-inflammatory activity of new series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives

Genotoxic Impurities in Pharmaceutical Manufacturing: Sources, Regulations, and Mitigation

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

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