Indacrinone synthesis

In the mid-1980s Merck chemists developed a method for asymmetric alkylation of a cyclic ketone in the presence of a simple cinchona alkaloid (see also Section 3.1) [50-52], The resulting product 23, bearing a quaternary stereogenic center, is an intermediate in the synthesis of indacrinone 20 (Scheme 14.9). It should be noted that this impressive contribution from Merck chemists was not only the first exam-... 

In conclusion, this synthesis of the indacrinone intermediate 23 developed by Merck researchers is a highly efficient and technically feasible method for asymmetric alkylation. It not only afforded the desired drug intermediate 23 in quantitative yield and high enantioselectivity but was also found to be suitable for technical applications, as has been demonstrated on a pilot-plant scale. 

Dolling UH, Davis P, Grabowski EJJ (1984) Efficient catalytic asymmetric alkylations, 1. Enantioselective synthesis of (+)-indacrinone via chiral phase-transfer catalysis. J Am Chem Soc 106 446... 

The Nazarov cyclization has also been used industrially. In the Merck synthesis of (+)-indacrinone the indanone unit is formed by an aromatic Nazarov cyclization. ... 

Dolling, U.-H. Davis, P. Grabowski, E. J. J., Efficient Catalytic Asymmetric Alkylations. 1. Enan-tioselective Synthesis of (+)-Indacrinone via Chiral Phase-Transfer Catalysis. / Am. Chem. Soc. 1984, 106, 446. 

Chiral synthesis using cinchinidium derived optically active PT catalyst Synthesis of indacrinone, a diuretic drug candidate... 

This reaction is a step in the synthesis of the diuretic indacrinone (Hughes et al., 1987) and uses a quaternary salt of a cinchona alkaloid (E) as an asymmetric phase-transfer catalyst (Wynberg, 1986). The product enolate (F) formed from the ketone is a precursor of indacrinone... 

Asymmetric phase-transfer catalysis usually stands somewhat separate from the rest of asymmetric organocatalysis and has always been dominated by metal-free catalysts. The earliest report in asymmetric phase-transfer catalysis dates back 30 years to 1984 when Dolling and coworkers first reported the use of a quaternised Cinchona alkaloid (6) as a phase-transfer catalyst for the asymmetric alleviation of ketone 7 during an asymmetric synthesis of (- -)-Indacrinone (Scheme 1.5). Quaternised Cinchona alkaloids dominated the area of asymmetric phase-transfer catalysis for the rest of the 20th century, and were especially used as catalysts for asymmetric amino... 

Scheme 1.5 Asymmetric phase-transfer catalysis during a synthesis of (+)-Indacrinone.

The first asymmetric reaction discussed here, of the fourth-generation type, is based on earlier work by Wynberg and was reported by a group at Merck who were interested in the industrial synthesis of the diuretic indacrinone.f The chiral catalyst is a quaternary salt of a... 

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