Dipolar aprotic and ethereal solvents
comprise just over 40% of
all organic solvents utilized in synthetic organic, medicinal, and
process chemistry. Unfortunately, many of the common “go-to”
solvents are considered to be “less-preferable” for
a number of environmental, health, and safety (EHS) reasons such as
toxicity, mutagenicity, carcinogenicity, or for practical handling
reasons such as flammability and volatility. Recent legislative changes
have initiated the implementation of restrictions on the use of many
of the commonly employed dipolar aprotic solvents such as dimethylformamide
(DMF) and
N
-methyl-2-pyrrolidinone (NMP), and for
ethers such as 1,4-dioxane. Thus, with growing legislative, EHS, and
societal pressures, the need to identify and implement the use of
alternative solvents that are greener, safer, and more sustainable
has never been greater. Within this review, the ubiquitous nature
of dipolar aprotic and ethereal solvents is discussed with respect
to the physicochemical properties that have made them so appealing
to synthetic chemists. An overview of the current legislative restrictions
being imposed on the use of dipolar aprotic and ethereal solvents
is discussed. A variety of alternative, safer, and more sustainable
solvents that have garnered attention over the past decade are then
examined, and case studies and examples where less-preferable solvents
have been successfully replaced with a safer and more sustainable
alternative are highlighted. Finally, a general overview and guidance
for solvent selection and replacement are included in the Supporting
Information of this review.
A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αβ integrin in a radioligand binding assay (p K = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
A diastereoselective synthesis of (S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid (1), a potential therapeutic agent for the treatment of Idiopathic Pulmonary Fibrosis, which is currently undergoing Phase I clinical trials is reported. The key steps in the synthesis involved alkylation of 2-methylnaphthyridine with (R)-N-Boc-3-(iodomethyl)-pyrrolidine, and an asymmetric Rh-catalysed addition of an arylboronic acid to a 4-(N-pyrrolidinyl)crotonate ester. The overall yield of the seven linear step synthesis was 8% and the product was obtained in >99.5% ee proceeding with 80% de. The absolute configuration of 1 was established by an alternative asymmetric synthesis involving alkylation of an arylacetic acid using Evans oxazolidinone chemistry, acylation using the resulting 2-arylsuccinic acid, and reduction. The absolute configuration of the benzylic asymmetric centre was established as (S).
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