Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagents

Taghizadeh, Mohammad Javad; Malakpouri, Gholam Reza; Javidan, Abdollah

doi:10.1007/s13738-018-1555-0

Cited by 10 publications

(7 citation statements)

References 31 publications

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“…Very recently, Taghizadeh et al reported a one-pot condensation of benzodiazepines with the monoanion of tosylmethyl isocyanide or ethyl isocyanoacetate under mild conditions, which provides rapid synthetic access to 67 (Scheme ). At present, midazolam is used for the treatment of seizures, irregular sleeping patterns, severe agitation, procedural sedation, and anesthesia…”

Section: Five-membered Ring Heterocycles As Amide Bioisosteresmentioning

confidence: 99%

“…tosylmethyl isocyanide or ethyl isocyanoacetate under mild conditions, which provides rapid synthetic access to 67 (Scheme 7). 120 At present, midazolam is used for the treatment of seizures, 121 irregular sleeping patterns, 122 severe agitation, procedural sedation, and anesthesia. 123 Several preclinical and clinical studies have shown that blocking the calcitonin gene related peptide (CGRP) receptor could be beneficial to discover therapeutic agents for preventive treatment of migraine.…”

Section: ■ Introductionmentioning

confidence: 99%

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Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

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Section: Five-membered Ring Heterocycles As Amide Bioisosteresmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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“…The In a different strategy, the methyl group can be inserted in position 2 of the imidazole via a lithiation, as outlined in Scheme 24. This method allows the insertion of different residues on the imidazole ring independently of the cyclization step [115]. In a different strategy, the methyl group can be inserted in position 2 of the imidazole via a lithiation, as outlined in Scheme 24.…”

Section: Diazolobenzodiazepinesmentioning

confidence: 99%

Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

et al. 2020

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GABAA receptor modulators are structurally almost as diverse as their target protein. A plethora of heterocyclic scaffolds has been described as modulating this extremely important receptor family. Some made it into clinical trials and, even on the market, some were dismissed. This review focuses on the synthetic accessibility and potential for library synthesis of GABAA receptor modulators containing at least one heterocyclic scaffold, which were disclosed within the last 10 years.

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“…A combined yield of 87% was reported for ethyl 8-chloro-6-(2-phenyl)-4 H -benzo[ f ]imidazo[1,5- a ][1,4]diazepine-3-carboxylate when precipitated in diethyl ether and the remainder isolated from the mother liquor using column chromatography. Several subsequent publications have used these conditions, but the necessity for column chromatography to achieve moderate to good yields precluded multigram scale production. − Herein, we describe an improved four-step synthesis of ( R )-8-bromo-6-(2-fluorophenyl)-4-methyl-4 H -benzo[ f ]imidazo[1,5- a ][1,4]diazepine-3-carboxylic acid (MIDD0301) that enabled us to manufacture 88 g of this chiral compound without racemization. MIDD0301 is a clinical drug candidate for asthma that binds allosterically to the γ amino butyric acid type A receptor (GABA A R) .…”

Section: Introductionmentioning

confidence: 99%

Improved Scale-up Synthesis and Purification of Clinical Asthma Candidate MIDD0301

Knutson

Roni

Mian

et al. 2020

Org. Process Res. Dev.

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We report an improved and scalable synthesis of MIDD0301, a positive GABAA receptor modulator that is under development as oral and inhaled treatments for asthma. In contrast to other benzodiazepines in clinical use, MIDD0301 is a chiral compound that has limited brain absorption. The starting material to generate MIDD0301 is 2-amino-5-bromo-2′-fluorobenzophenone, which has a nonbasic nitrogen due to electron-withdrawing substituents in the ortho and para positions, reducing its reactivity toward activated carboxylic acids. Investigations of peptide coupling reagents on a multigram scale resulted in moderate yields due to incomplete conversions. Second, the basic conditions used for the formation of the seven-membered 1,4-diazepine ring resulted in racemization of the chiral center. We found that neutral conditions comparable to the pK a of the primary amine were sufficient to support the formation of the intramolecular imine but did not enable the simultaneous removal of the protecting group. Both difficulties were overcome with the application of the N-carboxyanhydride of d-alanine. Activated in the presence of an acid, this compound reacted with nonbasic 2-amino-5-bromo-2′-fluorobenzophenone and formed the 1,4-diazepine upon neutralization with triethylamine. Carefully designed workup procedures and divergent solubility of the synthesic intermediates in solvents and solvent combinations were utilized to eliminate the need for column chromatography. To improve compatibility with large-scale reactors, temperature-controlled slow addition of reagents generated the imidazodiazepine at −20 °C. All intermediates were isolated with a purity of >97% and impurities were identified and quantified. After the final hydrolysis step, MIDD0301 was isolated in a 44% overall yield and a purity of 98.9% after recrystallization. The enantiomeric excess was greater than 99.0%.

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Improved and scalable methods for the synthesis of midazolam drug and its analogues using isocyanide reagents

Cited by 10 publications

References 31 publications

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Allosteric GABAA Receptor Modulators—A Review on the Most Recent Heterocyclic Chemotypes and Their Synthetic Accessibility

Improved Scale-up Synthesis and Purification of Clinical Asthma Candidate MIDD0301

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