• 10.1002/ejoc.201500356
  • European Journal of Organic Chemistry
  • Volume 2015
  • May 2015
  • pp 4102-4107

A Practical Synthesis of Rosuvastatin and Other Statin Intermediates

Good synthesis method

Details


Summary:

This paper reports an efficient method for aldol condensation between a methyl 3-hydroxy-5-oxohexanoate derivative and a pyrimidine carbaldehyde comprising the core structure of rosuvastatin. The authors have described the method as an alternative approach to the classical methods which employ ylides for synthesizing rosuvastatin. The highlight of this method is the formation of a double bond connecting the aromatic part with the side chain of the statin. This reaction is reported by the authors to be efficiently carried out by using a strong Lewis acid which results in the best result when worked with a tertiary amine. The authors applied this method for the synthesis of pitavastatin as well.

The Reactions of Interest:

The authors have represented the actual process via phosphorus ylide and their new aldol approach for the synthesis of intermediate 11 [for the synthesis of rosuvastatin (7)] in Scheme 1.

Alternative approach for the synthesis of pitavastatin (6) has been reported in Scheme 2.

Practical observations:

  • The scheme 1 does produce the desired product of rosuvastatin. However, the sequential steps yield only 65 % which far less compared to the proposed 87 % yield in literature using new aldol method for the synthesis of intermediate 11, as reproduced under laboratory experiments.
  • The intermediates synthesised with N-methylmorpholine achieved high yields using alternate synthesis route which is much better while comparing to the final product rosuvastatin.
  • The yield of intermediate pitavastatin intermediate 14 is as high of 91% on using Lewis acid (SnCl4) with base of NMMh using THF at 0°C in accordance with the literature the yield (Scheme 4).
  • The use of aldol approach played a vital role in connection of aldehyde 8 with the side chain in the absence of TBDMS protecting group which has never been achieved by using a known procedure in the synthesis of product using sulfur or phosphorous ylides.

Comment:

  • One of the merits of the above-mentioned synthetic route is the novel and simplified route for yielding Rosuvastatin product and its intermediates.


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