Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-06-11
2002-11-26
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S178000
Reexamination Certificate
active
06486345
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for preparing 6,6-dialkoxy-5-hydroxy-3-oxohexanoic acid esters of the general formula
in which R
1
and R
2
are identical or different and are C
1-6
-alkyl.
2. Background Art
The abovementioned compounds are important synthesis building blocks for preparing numerous HMG-CoA reductase inhibitors (WO-A 92/10503).
According to WO-A 92/10503, these compounds are obtained by reacting an acetic acid ester with a &ggr;-dialkoxy-&bgr;-hydroxy ester. However, this synthesis has the disadvantage that the latter starting material is difficult to obtain and therefore expensive.
BROAD DESCRIPTION OF THE INVENTION
It was the object of the invention to develop a simpler and more cost-effective route to the abovementioned synthesis building blocks.
This object could be achieved by the process according to the invention.
According to the invention, this involves reacting an alkyl acetoacetate of the general formula
in which R
1
is as defined above in the presence of a base with an aldehyde of the formula
in which R
2
is as defined above.
DETAILED DESCRIPTION OF THE INVENTION
A C
1-6
-alkyl group is hereinbelow understood as a linear or branched alkyl group with 1 to 6 carbon atoms, namely methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert-butyl, pentyl and its isomers and hexyl and its isomers. Preference is given to the C
1-4
-alkyl groups mentioned by name.
The process according to the invention has the advantage that the acetoacetic esters of the general formula II are available industrially.
Acetoacetic esters of the general formula II are obtained by reacting diketenes with the appropriate alcohol. The acetoacetic ester of the formula II may also be provided in situ, starting from diketene. Preferred acetoacetic esters of the general formula II are the methyl ester, the ethyl ester, the n-propyl ester, the isopropyl ester, the n-butyl ester, the isobutyl ester and the tert-butyl ester, particularly preferably the tert-butyl ester.
The aldehydes of the general formula III are generally commercially available. The preferred aldehyde of the formula III is glyoxal 1,1-dimethyl acetal.
The process according to the invention is advantageously carried out in an organic solvent in the substantial absence of water. Suitable solvents are ethers, such as, tetrahydrofuran, dioxane, diethyl ether, tert-butyl methyl ether, etc., aromatic compounds, such as benzene or toluene, or hydrocarbons, such as hexane, and mixtures of the abovementioned solvents.
The reaction temperature is generally chosen in a range from −80° C. to 130° C., preferably in a range from −40° C. to 20° C.
A base is used with the aim of forming the dianion of the alkyl acetoacetate of the general formula II. In principle, this dianion formation can be carried out directly using a strong base, such as, butyllithium, methyllithium, phenyllithium or sodium amide, lithium diisopropylamide or lithium hexamethyldisilazane.
In general, a two-step process is employed, by initially deprotonating the —CH
2
— function using a relatively weak and also cost-effective base, and carrying out the dianion formation only in the second step using the abovementioned strong base. Suitable relatively weak bases are metal hydrides, such as, alkali metal hydrides and alkaline earth metal hydrides, preferably sodium hydride, but also secondary amines (preferably pyrrolidine), which forms an enamine as anion equivalent with the acetoacetic ester. In the latter case, the dianion is understood as the anion of the corresponding enamine.
The desired 6,6-dialkoxy-5-hydroxy-3-oxohexanoic acid ester can be obtained in a manner familiar to the person skilled in the art, for example by neutralization of the reaction mixture and subsequent extraction with a suitable solvent.
REFERENCES:
patent: 5347039 (1994-09-01), Leon et al.
patent: WO 92/10461 (1992-06-01), None
patent: WO 92/10503 (1992-06-01), None
Feryan Ahmed et al, “Convergent Synthesis of the C31-C46 Domain of the Phorboxazole Natural Products”, Tet. Lett., vol. 39 (1998), pp. 183-186.*
Carlo Bonini et al, “Enzyme Catalysed Lactonization of 3,5 Dihydroxy Esters: Enatioselective Synthesis of Naturally Ocurring 3-Hydroxy-5-decanolide, (−)-Massoialactone, and 3-Hydroxy-5-icosanolide”, Tet. Asymm., vol. 3 (1992), pp. 29-32.*
Yoo Tanabe et al, “A Novel and Efficient Synthesis of 2(5H)-Furanone Derivatives”, J. Org. Chem., vol. 53 (1988), pp. 1560-1563.*
K.K. Sharma & K.B.G. Torssell, Synthesis and Cyclopentenones, Nov. 14, 1983, vol. 4, No. 6, pp. 1085 to 1089.
The Chemical Society of Japan, S. Kanemasa, N. Nakagawa, H. Suga & O. Tsuge,, Acid-Catalyzed Formation of &ggr;-Oxo Esters from &agr;-Hydroxy-&ggr;-oxo Acetals, vol. 62, No. 1, pp 180 to 184.
Killos Paul J.
Lonza AG
LandOfFree
Method for producing 6,6-dialkoxy-5-hydroxy-3-oxo-hexanoic... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for producing 6,6-dialkoxy-5-hydroxy-3-oxo-hexanoic..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for producing 6,6-dialkoxy-5-hydroxy-3-oxo-hexanoic... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2991725