Aminolysis of Esters or Lactones Promoted by NaHMDS - A General and Efficient Method for the Preparation of N-Aryl Amides

The development of an efficient manufacturing route to 3-acetyl-N-(5,8-dichloro-1,2,3,4-tetrahydro-7-isoquinolinyl)-4-(1-methylethoxy)-benzamide hydrochloride SB-406725A (1) is described. The synthesis begins with dichlorination of isoquinoline, followed by nitration using nitronium tetrafluoroborate in sulpholane. Nitroisoquinoline (12) was hydrogenated under pressure using Pt/ C. The resultant tetrahydroisoquinoline (13) was selectively coupled with benzoate side chain (15) under base-promoted conditions using sodium hexamethyldisilazane to yield the parent molecule SB-406725 (16). SB-406725 was then converted to the HCl salt SB-406725A (1). This process has been successfully demonstrated on a pilot-plant scale to prepare ∼30 kg of SB-406725A (1).

Section: Resultsmentioning

confidence: 99%

The Development of a New Manufacturing Route to the Novel Anticonvulsant, SB-406725A

Walker

Andrews

Burton

et al. 2009

“…Formation of the 3,3-Dimethoxy-N-arylpropanamides. An efficient method for the preparation of N-aryl amides was described by Wang et al 16 They treated aniline derivatives with an ester in the presence of sodium bis(trimethylsilyl) amide (NaHMDS) in THF at room temperature and isolated the desired products in yields from 26 to 99%. To our delight, this protocol was successful with methyl 3,3-dimethoxypropionate and 2-iodoaniline (1a) to give 2a in quantitative yield with a purity of 88% (LC-MS) (Scheme 1).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Scalable and Practical Synthesis of Halo Quinolin-2(1H)-ones and Quinolines

Zaugg

Schmidt

Abele

2017

A practical and scalable synthesis of halo quinolin-2(1H)-ones is presented. The heterocycles are easily accessed from inexpensive halo anilines in a two-step sequence. The anilines are acylated with methyl 3,3-dimethoxypropionate under basic conditions in quantitative yields. The crude amides undergo cyclization in sulfuric acid to the desired halo quinolin-2(1H)ones in 28−93% yield (2 steps). The synthetic sequence was successfully applied on 800 g scale. Anilines with strong electron withdrawing or electron donating groups were poor substrates for this procedure. 6-Iodoquinolin-2(1H)-one and 6-bromo-8iodoquinolin-2(1H)-one were further functionalized to obtain quinolines substituted with various functional groups.

“…Because the desymmetrization of homopiperazine is not a trivial problem, we were especially pleased with this second generation synthesis. , Also, direct ester to amide transformation is arguably underutilized. − Another advantage of this route is the introduction of the most expensive piece on a molar basis, cyclobutanone, in the final chemical transformation.…”

Section: Resultsmentioning

confidence: 99%

First, Second, and Third Generation Scalable Syntheses of Two Potent H₃ Antagonists

Pippel

Mills

Pandit

et al. 2011

Our teams have recently completed scale-up campaigns for two structurally similar H3 receptor antagonists. The first and second generation processes were developed for the synthesis of 107 and 125 g batches of (4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone·HCl (1·HCl). A third generation process was utilized for production of 104 g of 3-((5-(4-cyclobutyl-1,4-diazepane-1-carbonyl)pyridin-2-yl)oxy)benzonitrile·HCl (2·HCl). The evolution from first to second generation process was driven by a desire to minimize cost of goods through employment of symmetrical homopiperazine rather than a more expensive monoprotected variant. Project demands for a late stage intermediate that could provide 1 or 2 led to additional route scouting and the ultimate determination of a third scalable synthesis for these types of molecules. The use of a lithium alkoxide for Lewis base catalysis of an ester to amide transformation represents a key improvement for the third generation synthesis.