Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Patent
1997-05-08
1998-01-20
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
568426, C07C 37055
Patent
active
057103437
DESCRIPTION:
BRIEF SUMMARY
This is the US National Stage Application of PCT/FI95/00513 filed Sep. 20, 1995 now WO96/09274 Published Mar. 28, 1996.
The invention relates to a new method for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde, which is an important intermediate in the synthesis of several pharmaceutically important compounds having 5-substituted 3-nitrocatechol structure, e.g. entacapone.
All known methods for the preparation of 3,4-dihydroxy-5-nitrobenzaldehyde are based on demethylation of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde. The oldest method (Hayduck, F. Chem. Ber. 36 (1903), p. 2930) uses hydrochloric acid as the reagent. The method is inapplicable because the starting material and/or the product decomposes during the process, which decreases the yield. The process also produces an impure product (mp: 106.degree. C.) and the reaction must be performed under pressure.
An improved method is described in EP 237929 and GB 2200109. This method uses hydrobromic acid in stead of hydrochloric acid. A specific problem with this method is the formation of a ring brominated impurity (probably 2-bromo-3,4-dihydroxy-5-nitrobenzaldehyde) and of an unspecified brownish black impurity. Further, this method and the above mentioned hydrochloric acid based method share the common problem that pushing the reaction to completion highly increases the amount of impurities. If the demethylation is not performed to completion the 3,4-dihydroxy-5-nitrobenzaldehyde produced contains some 4-hydroxy-3-methoxy-5-nitrobenzaldehyde. This impurity is very difficult to remove and therefore makes the 3,4-dihydroxy-5-nitrobenzaldehyde poorly suitable for further processing.
The third method has been described in the PCT patent application WO 93/00323. It is based on dealkylation using the combination of lithium hydroxide and thiophenol or 2-mercaptobenzothiazole in a polar aprotic solvent. This procedure does not have the problems associated with the decomposition of the product in the reaction medium, so the reaction can be pushed to completion. The method makes it possible to prepare pure 3,4-dihydroxy-5-nitrobenzaldehyde, but it still has many problems which make its large scale industrial utilisation difficult. First, the organic reagent and the expansive lithium hydroxide are consumed during the reaction, so they are not recyclable. Secondly, the process necessitates the use of a polar aprotic solvent together with an another organic solvent and water. During the recycling of the solvents a method is needed to separate the two organic solvents from each other and also to get the polar aprotic solvent dry enough for further use.
This invention is based on the surprising observation, that 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde may be cleaved by a reagent containing zinc chloride, water and hydrogen chloride to form 3,4-dihydroxy-5-nitrobenzaldehyde. It is surprising to be able to use zinc chloride as the Lewis acid to facilitate dealkylation reaction even though it is known that alkyl aryl ethers can be cleaved using a Lewis acid (Bhatt, M. V. and Kulkami, S. U., Synthesis (1983), p. 249; Burwell, R. L. Chem. Rev. 54 (1954), p. 615; K. F. Wedemeyer in Methoden der Organischen Chemie (Houben-Weyl), Vol 6/1c, pp. 340-358, Georg Thieme Verlag, Stuttgart 1976).
It is also exceptional, that the reaction may be carried under aqueous conditions. The method described here is specific for 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde and it is not applicable to 4-hydroxy-3-methoxy-5-nitrobenzaldehyde, which is practically inert under the conditions used. This finding is surprising, because an ethoxy group is reported to have low reactivity compared to a methoxy group in common acid catalyzed dealkylation (K. F. Wedemeyer in Methoden der Organischen Chemie (Houben-Weyl, Vol 6/1c, p. 314, Georg Thieme Verlag, Stuttgart 1976).
The present process is simple and the reagents are cheap and easily recyclable. Further, a high purity product is obtained because the residual starting material, 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde, is easily removed by one crystall
REFERENCES:
patent: 3256336 (1966-06-01), Lange
patent: 5455238 (1995-10-01), Aszodi et al.
F. Hayduck, Versuche zur Darstellung eines Tetraoxyindigos, F. Chem. Ber. 36, Aug. 7, 1903, 2930-2936.
R. L. Burwell, Jr., The Cleavage of Ethers, Chem. Rev. 54, 1954, 615-685.
K.-F. Wedemeyer, II. Phenole durch Umwandlung funktioneller Phenol-Derivate, Methoden der Organischen Chemie (Houben-Weyl), vol 6/1c, 1976, 313-339, 340-358.
M. V. Bhatt et al., Cleavage of Ethers, Synthesis, 1983, 249-282.
Geist Gary
Orion-yhtyma Oy
Padmanabhan Sreeni
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