A large scale synthesis of 3-chloro-5-methoxypyridazine

A large scale synthesis of 3-chloro-5-methoxypyridazine was developed (18 moles) that relies on the protection of the pyridazinone nitrogen of 4,5-dichloro-3(2H)-pyridazinone as the tetrahydropyranyl derivative 2 . The 5-chloro position of the protected pyridazinone was selectively displaced with methoxide to give 3 followed by catalytic hydrogenation of the 4-chloro group to give 4. Removal of the protecting group with acid followed by phosphorous oxychloride treatment gave the target compound 6 in good yield. This route is superior to the previously described synthesis of this compound.     

A practical high through-put continuous process for the synthesis of chiral cyanohydrins

A practical high through-put continuous process for the synthesis of chiral cyanohydrins is reported. Pretreated almond meal (or other solid raw enzyme sources) was loaded in a column to form a reactor, to which were attached a supplying system to deliver a solution of substrate and HCN in solvent on one end and a collecting-separating system on the other end. By controlling the flowing rate, optimal conditions were achieved for the hydrocyanation of various aromatic carboxaldehydes in a "micro-aqueous" medium to produce chiral cyanohydrins in high yields and high enantiomeric excess (ee) with high substrate/catalyst ratio.     

Pursuing practical elegance in chemical synthesis

In the 21st century, the field of chemistry will face more than just academic challenges. Indeed, our ability to devise straightforward and practical chemical syntheses is indispensable to the survival of our species.     

A practical synthesis of a [2.2.1] bicyclic chiral sulfide for asymmetric transformations

A substantially improved synthesis of synthetically useful chiral sulfide 1 is described. Starting from (+)-10-camphorsulfonic acid, the chiral sulfide was synthesised on large scale in five steps and 56% overall yield. Significant improvements include the use of Bu₃P in place of Ph₃P for the reduction of the chlorosulfonyl group to the thiol, allowing removal of phosphine oxide by aqueous extraction and improvements in the photochemistry using either a modified batch reactor or a single pass continuous flow reactor.     

Highly efficient lipase-catalyzed asymmetric synthesis of chiral glycerol derivatives leading to practical synthesis of s-propranolol

Efficient asymmetric synthesis of chiral glycerol derivatives was realized by lipase-catalyzed reaction in organic medium and its application for synthesis of (S)-propranolol was demonstrated.     

Design of chiral organocatalysts for practical asymmetric synthesis of amino acid derivatives

A series of structurally rigid, chiral quaternary ammonium salts and several chiral sec-amine catalysts derived from commercially available (R)- or (S)-binaphthol have been designed as new C(2)-symmetric chiral phase-transfer catalysts and chiral bifunctional amino-catalysts. These chiral organocatalysts have been successfully applied to the highly practical asymmetric synthesis of various amino acid derivatives.     

Serine as chiral educt for the practical synthesis of enantiopure N-protected beta-hydroxyvaline

N-tert-Butyloxycarbonyl- and N-benzenesulfonyl-beta-hydroxyvalines 1a and 1b were, respectively, synthesized in enantiomerically pure form by a two-step protocol from their enantiomeric N-protected serine methyl esters 2a and 2b. The addition of CH(3)MgBr to 2a and 2b provided diols 3a and 3b, respectively as major products in 83% and 81% yields. Selective oxidation of diols 3a and 3b was performed using a TEMPO, NaClO(2), NaOCl cocktail in 96% and 93% respective yields. This two-step process effectively furnished multigram amounts of enantiopure N-Boc-beta-hydroxyvaline 1a.     

A practical synthesis of nitrocefin

Nitrocefin is a key reagent for high and low throughput assays of the activities of penicillin-binding proteins (PBPs) and beta-lactamases, the former used for discovery of antibiotics and the latter for inhibitors of resistance determinants for beta-lactam antibiotics. This compound is commercially available but is prohibitively expensive because of the circuitous routes to its synthesis. We describe herein a three-step synthesis of nitrocefin that gives an overall yield of 44%. This is a practical route to the synthesis of this key reagent for drug discovery.     

A practical synthesis of pyoluteorin

A convenient, large-scale synthesis of the antibiotic pyoluteorin, 2,3-dichloro-5-(2′,6′-dihydroxybenzoyl)-pyrrole ( 1 ), is described. A key step in the synthesis involved a Friedel-Crafts aroylation of pyrrole with 2,6-dimethoxybenzoyl chloride ( 3 ) in methylene chloride. The desired intermediate, 2-(2′,6′-dimethoxybenzoyl)pyrrole ( 4 ), was obtained as the major product, along with a product of beta substitution ( 6 ). Compound 4 was converted to pyoluteroin ( 1 ) in four steps in an overall yield of 51%.     

A practical synthesis of cabergoline

Cabergoline is an N-acylurea derived from 9,10-dihydrolysergic acid, which is a potent prolactin inhibitor. It is marketed by Pharmacia as Dostinex for the treatment of hyperprolactinemia and is currently under active development for the treatment of a variety of CNS disorders. In the existing process, the N-acylurea is formed by the reaction of an amide with a large excess of ethyl isocyanate at elevated temperatures. An improved process was developed that eliminates this hazardous reaction. The amide is reacted with phenyl chloroformate and then with ethylamine, which provides a mild and efficient means of forming the unsymmetrical N-acylurea.     

A practical synthesis of L-ribose

L-Ribose was synthesized by a simple four-step method with overall yield of 76.3% from a protected L-arabinose derivative, which is a compatible intermediate for the synthesis of L-deoxyribose. The key step of this strategy is the Swern oxidation and subsequent stereoselective reduction accompanied by inversion of the 2-hydroxy group of protected L-arabinose.     

A short large scale synthesis of (±) sarkomycin esters

(±) Sarkomycin ethyl ester has been prepared in four steps from ethyl acrylate.     

A convenient large scale synthesis of 2,6-dimethyl-4-(trimethylstannyl)pyridine

Reaction of phosphorus oxychloride with 2,6-dimethylpyridine N-oxide hydrochloride ( 1 ) gave a mixture of 2-(chloromethyl)-6-methylpyridine ( 2 ) and 4-chloro-2,6-dimethylpyridine ( 3 ). Treatment of this mixture with triethylamine converted 2 to the quaternary salt 4 which was separated by water extraction leaving 3 which was subsequently reacted with trimethylstannyl sodium to yield 2,6-dimethyl-4-(trimethylstannyl)pyridine ( 6 ).     

A practical synthesis of bridged diarylacetylenes

An efficient and practical synthesis of bridged diarylacetylenes in multigram quantities has been successfully carried out using high-yielding (classical) synthetic methods and readily available starting materials. The structural analysis of the representative bridged diarylacetylenes by X-ray crystallography strongly suggests that conformations, bending of the linear triple bond, and the angle between the mean planes of aromatic rings in various bridged diarylacetylenes are governed by the p-pi conjugation among the aromatic rings and the ethereal groups. Furthermore, the synthetic scheme also allows the preparation of (appropriately) bromo-substituted bridged diarylacetylenes which hold potential for their future usage for the preparation of polymeric analogues as well as the hexaarylbenzene derivatives for potential applications in the emerging area of molecular electronics and nanotechnology.     

A practical synthesis of fluoromethyltriphenylphosphonium salts

A practical synthesis of [Ph₃$\text{P}\text{+}$CH₂F]BF₄^? is reported $\text{via}$ two routes, $\text{via}$ fluorination of [Ph₃$\text{P}\text{+}$CH₂OH]BF₄^? with DAST or $\text{via}$ hydrolysis of the phosphoranium salt, [Ph₃$\text{P}\text{+}$$\text{C}$F$\text{P}\text{+}$Ph₃]Br^?.     

A practical synthesis of betulinic acid

A new synthetic route for the synthesis of betulinic acid from betulin has been developed. The main step of this procedure is the selective oxidation of the primary alcohol function of betulin without affecting the secondary hydroxyl group. Applying shorter reaction times and lower temperatures results in the exclusive formation of the corresponding aldehyde, betulinal.