80928-23-0

Upstream product

• 288-32-4 1H-imidazole 
• 1871-76-7 diphenylacetic acid chloride 
• 117-34-0 2,2-diphenylacetic acid 
• 530-62-1 1,1'-carbonyldiimidazole 
• 3005-50-3 N,N'-Thionyldiimidazole 

Downstream Products

• 149838-21-1 PD₈₅₆₃₉ 
• 68556-52-5 1-O-(diphenylacetyl)-β-D-glucopyranose 
• 58647-65-7 Diphenyl-acetic acid 2-(2,2-dimethyl-[1,3,6,2]dioxazasilocan-6-yl)-ethyl ester 
• 36147-03-2 N-(tert-butyl)-2,2-diphenylacetamide 
• 55264-81-8 Diphenylessigsaeure--amid 
• 189030-33-9 3-Oxo-4,4-diphenyl-butyric acid tert-butyl ester 
• 1316755-16-4 PD 126055 
• 3066-44-2 diphenylmethyl isocyanate 
• 4099-51-8 N-hydroxy-2,2-diphenylacetamide 
• 22815-70-9 allyl benzhydrylcarbamate 
• 1086277-50-0 N₁-(2,2-diphenylacetyl)-N₂-[3-(1-trityl-1H-imidazol-4-yl)propyl]guanidine 

Relevant academic research and scientific papers

Toward a Scalable Synthesis and Process for EMA401, Part I: Late Stage Process Development, Route Scouting, and ICH M7 Assessment

We present the enantioselective synthesis of sodium (3S)-5-(benzyloxy)-2-(diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (EMA401, olodanrigan), an angiotensin II type 2 antagonist. The manuscript features the process optimizations of the end game used for late phase clinical supplies, an overview of synthetic strategies identified in a route scouting exercise to a key intermediate phenylalanine derivative, and the analytical control strategy of the potentially formed highly toxic impurity bis(chloromethyl) ether (BCME). Starting from the phenylalanine derivative, we describe the optimizations of the end game from early phase to late phase processes with consequent improvements in the PMI factor. This sequence includes a Pictet-Spengler cyclization and an amide coupling as the last bond-forming steps, and the manufacturing process was successfully implemented on a 175 kg scale in a pilot plant setup. The modified process conditions eliminated one step by in situ activation of the carboxylic acid, avoided the REACH listed solvent DMF, and resulted in a PMI improvement by a factor of 3. In the final crystallization, a new, thermodynamically more stable modification of the drug substance was found in the complex solid-state landscape of EMA401 during an extensive polymorph screening. A process suitable for large-scale production was developed to prepare the new polymorph, avoiding the need of any special equipment such as fluidized bed drying required in the early phase process. In the second section, some of the synthetic approaches investigated for the route scouting of the phenylalanine derivative key intermediate are presented. To conclude, we discuss the analytical control strategy for BCME, the formation of which, due to the simultaneous presence of HCl and CH2O in the Pictet-Spengler cyclization, could not be ruled out. The BCME purge factor calculations using the tools of ICH M7 control option 4 are compared to actual results from spiking experiments.

Rational design and synthesis of substrate-product analogue inhibitors of α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis

2,2-Bis(4-isobutylphenyl)propanoyl-CoA and 2,2-bis(4-t-butylphenyl)propanoyl-CoA are rationally designed, gem-disubstituted substrate-product analogues that competitively inhibit α-methylacyl-coenzyme A racemase from Mycobacterium tuberculosis with K

An Environmentally Sustainable Mechanochemical Route to Hydroxamic Acid Derivatives

An operationally simple, and cost efficient conversion of carboxylic acids into hydroxamic acid derivatives via a high-energy mechanochemical activation is presented. This ball milling methodology was applied to a wide variety of carboxylic acids dramatically improving purification issues associated with this class of molecules, which still remain one of the main bottlenecks of classical methodologies. (Figure presented.).

HETEROCYCLIC COMPOUNDS AND METHODS FOR THEIR USE

The present invention relates to heterocyclic compounds useful for antagonising angiotensin II Type 2 (AT2) receptor. More particularly the invention relates to pyrrolidine and azetidine compounds, compositions containing them and their use in methods of treating or preventing disorders or diseases associated with AT2 receptor function including neuropathic pain, inflammatory pain, conditions associated with neuronal hypersensitivity, impaired nerve conduction velocity, cell proliferation disorders, disorders associated with an imbalance between bone resorption and bone formation and disorders associated with aberrant nerve regeneration.

N-methylimidazole-catalyzed synthesis of carbamates from hydroxamic acids via the lossen rearrangement

An efficient, one-pot, N-methylimidazole (NMI) accelerated synthesis of aromatic and aliphatic carbamates via the Lossen rearrangement is reported. NMI is a catalyst for the conversion of isocyanate intermediates to the carbamates. Moreover, the utility of arylsulfonyl chloride in combination with NMI minimizes the formation of often-observed hydroxamate-isocyanate dimers during the sequence. Under the present conditions, lowering of temperatures is also possible, enabling a mild protocol.

Acylguanidines as bioisosteres of guanidines: NG-acylated imidazolylpropylguanidines, a new class of histamine h2 receptor agonists

N1-Aryl(heteroaryl)alkyl-N2-[3-(1H-imidazol-4-yl) propyl]guanidines are potent histamine H2-receptor (H2R) agonists, but their applicability is compromised by the lack of oral bioavailability and CNS penetration. To improve pharmacokinetics, we introduced carbonyl instead of methylene adjacent to the guanidine moiety, decreasing the basicity of the novel H2R agonists by 4-5 orders of magnitude. Some acylguanidines with one phenyl ring were even more potent than their diaryl analogues. As demonstrated by HPLC-MS, the acylguanidines (bioisosteres of the alkylguanidines) were absorbed from the gut of mice and detected in brain. In GTPase assays using recombinant receptors, acylguanidines were more potent at the guinea pig than at the human H2R. At the hH1R and hH3R, the compounds were weak to moderate antagonists or partial agonists. Moreover, potent partial hH4R agonists were identified. Receptor subtype selectivity depends on the imidazolylpropylguanidine moiety (privileged structure), opening an avenue to distinct pharmacological tools including potent H4R agonists.

Activation of imidazolides using methyl trifluoromethanesulfonate: A convenient method for the preparation of hindered esters and amides

Treatment of imidazolides with methyl trifluoromethanesulfonate followed by reaction with alcohols or amines provides a convenient one-pot procedure for the preparation of esters and amides. The method is applicable to imidazolides of low reactivity as well as to hindered nucleophiles.

Xanthene derived potent nonpeptidic inhibitors of recombinant human calpain I

Novel and potent, xanthene derived reversible aldehyde (7c) and α- ketocarboxamide (10a), and irreversible fluoromethyl ketone (10b) inhibitors of recombinant human calpain I are described.

Synthesis and pharmacological evaluation of phenylacetamides as sodium- channel blockers

The synthesis and structure-activity relationships of a series of phenylacetamides related to N-[3-(2,6-dimethyl-1-piperidinyl)propyl]-α- phenylbenzeneacetamide (1) (PD85639) acting at the voltage-dependent Na+ channel are described. All struct

Acylimidazolides as Versatile Synthetic Intermediates for the Preparation of Sterically Congested Amides and Ketones: A Practical Synthesis of Proscar

Acylimidazolides react with magnesium amides to produce carboxamides in excellent yields, whereas Fe(III) catalyzed cross coupling between acylimidazolide and Grignard reagents produce ketones in high yields.These methods were utilized to prepare the α-reductase inhibitor Proscar as well as various 17β-amide and ketone analogs of Δ1-4-aza-5α-androsten-3-one.