Method of producing 2-hydroxycarboxylic acid esters

Details Method of producing 2-hydroxycarboxylic acid esters Method of producing 2-hydroxycarboxylic acid esters

2002-03-12

2003-11-11

Shippen, Michael L. (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S126000, C560S145000, C560S179000

Reexamination Certificate

active

06646152

ABSTRACT:

The present invention relates to a process for preparing 2-hydroxycarboxylic esters having a quaternary &bgr;-carbon atom.
Endothelin receptor antagonists are novel active compounds for the treatment of various cardiovascular disorders. WO 97/38981 describes various endothelin receptor antagonists, for example (S)-3,3-diphenyl-2-(4,6-dimethylpyrimid-2-yloxy)butyric acid. According to the description in WO 97/38981, this compound is obtained from (S)-2-hydroxy-3,3-diphenylbutyric acid by reaction with 4,6-dimethylpyrimidin-3-yl sulfone. 2-Hydroxy-3,3-diphenyl-butyric acid for its part is obtained by reducing 2,2-diphenylpropionitrile to the aidehyde, which is converted into the cyanohydrin which is then subjected to acid hydrolysis. However, this process has a number of disadvantages. The cyanohydrin synthesis involves the handling of hydrogen cyanide, which is objectionable for safety and health reasons. Furthermore, 2,2-diphenylpropionitrile is a comparatively expensive starting material, and the overall yield obtained by this route is unsatisfactory.
It is an object of the present invention to provide an alternative process for preparing 2-hydroxycarboxylic acids having a quaternary &bgr;-carbon atom, and/or esters thereof.
Fukumasa et al., THL 32 (1991), 1059-1062, describe the reaction of monosubstituted epoxides with trimethylaluminum.
Danishewsky, S. et al., J. Org. Chem. 41 (1976), 1669-1671, describe the use of functionalized alanes for converting epoxides into trans-fused &ggr;-lactones.
Kuran, W. et al., J. Organomet. Chem 73 (1974), 187-193, describe the reaction of methylaluminum compounds with propylene oxide.
Visnick, M. et al. Synthesis 1983, 284-287, describe the addition of t-butoxycarbonylmethyldiethylalane to 1-alkylidene-2,3-epoxy-3-methylcyclohexanes.
Pfaltz, A. et al., Angew. Chem. Int. Ed. Engl. 21 (1982), 71, report the regioselective ring-opening of &agr;- and &bgr;-alkoxyepoxides with trimethylaluminum in the presence of catalytic amounts of butyllithium or lithium methoxide.
Alexakis, A. et al., Tetrahedron 45 (1989), 6197-6202, describe the boron-trifluoride-supported ring-opening of epoxides by lithium alkenyl aluminate reagents. The epoxides used were cyclohexene oxide and n-butyl epoxide.
In a general manner, Gorzynski-Smith, J., Synthesis 1984, 634, refers to the possibility of reacting epoxides with organoaluminum compounds. Simple trialkyl alanes are said to be of limited utility, since the reaction is accompanied by undesirable side-reactions, such as the reduction of the epoxide.
Miyashita, M. et al., J. Org. Chem. 56 (1991), 6483-6485, describe the stereospecific methylation of &ggr;,&dgr;-epoxy acrylates by trimethylaluminum in the presence of water. Miyashita, M. et al., Tetrahedron Asym. 4 (1993), 157.3-1578, describe the use of the epoxide ring-opening with trimethylaluminum in the presence of water in the synthesis of (−)-serricornin. Miyashita, M. et al., Chem. Soc., Chem. Commun. 9 (1996), 1027-1028, describe the use of the epoxide ring-opening with trimethylaluminum in the presence of water in the synthesis of the ansa chain segment of streptovaricin U.
Poon, T. et al., Synthesis 1998, 832, disclose the following reaction:
The above literature references do not disclose any reactions in which the epoxide ring carries an ester group.
Neukom, C. et al., J. Am. Chem. Soc. 108 (1986), 5559-5568, describe the reaction of ethyl trans-2,3-epoxybutyrate with diethylpropynylalane. Bartlett, A. et al., J. Org. Chem. 47 (1982), 3941-3945, describe the reaction of ethyl trans-2,3-epoxybutanoate with diethyltrimethylsilylethylalane. The conversion into the &agr;-hydroxy esters with a tertiary &bgr;-carbon atom succeeds with only moderate yields.
We have found that the object of the invention is achieved by a process for preparing 2-hydroxycarboxylic esters of the formula I
in which
R
1
and R
2
independently of one another are C
1
-C
20
-alkyl, C
3
-C
8
-cycloalkyl, C
2
-C
20
-alkenyl, C
2
-C
20
-alkynyl,C
6
-C
10
-aryl, C
7
-C
14
-aralkyl or C
7
-C
20
-alkylaryl, or R
1
and R
2
together with the carbon atom to which they are attached form a 5- to 8-membered ring;
R
3
is C
1
-C
20
-alkyl, C
2
-C
20
-alkenyl or C
2
-C
20
-alkynyl;
R
4
is C
1
-C
20
-alkyl, C
3
-C
8
-cycloalkyl, C
2
-C
20
-alkenyl, C
2
-C
20
-alkynyl, C
6
-C
10
-aryl, C
7
-C
14
-aralkyl or C
7
-C
20
-alkylaryl;
which comprises reacting a glycidyl ester of the formula II
in which R
1
, R
2
and R
4
are as defined above with an organoaluminum reagent of the formula III
in which R
3
is as defined above, X in each case independently have the meanings given for R
3
or are halogen or C
1
-C
4
-alkoxy and n is from 0 to 10.
Suitable C
1
-C
20
-alkyl groups are straight-chain and branched alkyl groups, for example C
1
-C
8
-alkyl, such as methyl, ethyl, propyl, n-butyl, isobutyl, t-butyl, pentyl.
Suitable C
3
-C
8
-cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Suitable C
2
-C
20
-alkenyl groups are, preferably, C
1
-C
8
-alkenyl, such as vinyl, allyl, 1-hexenyl.
Suitable C
2
-C
20
-alkynyl groups are, preferably, C
1
-C
8
-alkynyl, for example ethynyl or propynyl.
Suitable C
6
-C
10
-aryl groups are, in particular, phenyl or naphthyl.
Suitable C
7
-C
14
-aralkyl groups are, for example, benzyl or phenethyl.
Suitable C
7
-C
20
-alkylaryl groups are, for example, 2-, 3-, 4-methylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-dimethylphenyl or 2,4,6-trimethylphenyl.
Preferably, at least one of the radicals R
1
and R
2
is aryl, aralkyl or alkylaryl, cycloalkyl or branched alkyl, in particular alkyl having a branch in the 1- or 2-position, such as isopropyl, t-butyl, isobutyl.
Particularly preferably, R
1
and R
2
are both phenyl.
R
1
, R
2
and R
3
may carry 1, 2, 3, 4 or 5 substituents which do not negatively affect the reaction according to the invention, such as, for example, C
1
-C
6
-alkyl, C
1
-C
6
-alkoxy, di(C
1
-C
6
-alkyl)amino, nitro, ester (for example CO
2
R
5
, where R
5
may have the meanings given for R
4
), amide, sulfonamide, silyl or nitrile groups.
The glycidyl esters of the formula II can be obtained, for example, by Darzens glycidyl ester synthesis from corresponding ketones, by reaction with chloroacetic esters and base. Furthermore, they can be obtained, for example, by epoxidation of suitably substituted cinnamic esters. They may have the (S) or (R) configuration at the &agr;-carbon and may be present as pure or enriched enantiomers or as racemate. If R
1
≠R
2
, it is also possible for both configurations to be present at the &bgr;-carbon.
R
3
is preferably methyl, ethyl, n-butyl, particularly preferably methyl. R
3
may furthermore be, for example, AlkOCO—CH
2
—, AlkO—C≡C—, Alk-C≡C—, Alk-CH═CH—, Alk-CH═CH—CH
2
—, in which Alk is C
1
-C
4
-alkyl.
In the formula III, X has the meanings given for R
3
, in particular C
1
-C
4
-alkyl; halogen, such as fluorine, chlorine or bromine; or C
1
-C
4
-alkoxy.
The index n is preferably 0. Particularly preferred organoaluminum reagents are trimethylaluminum, triethylaluminum and tributylaluminum, trimethylaluminum being most preferred. Other suitable reagents are, for example, AlkOCOCH
2
Al(C
2
H
5
)
2
, Alk-CH═CH—Al(C
2
H
5
)
2
.
Organoaluminum reagents in which n≠0 are known under the term alumoxanes, and they can be obtained by controlled reaction of aluminum organyls with water (cf., for example, DE-A-37 31 665).
The reaction according to the invention of the glycidyl ester of the formula II with the organoaluminum reagent of the formula III is preferably carried out at a temperature of less than 20° C., in particular at from −10 to +10° C.
The reaction according to the invention is advantageously carried out in a nonpolar solvent, preferably an aliphatic or aromatic hydrocarbon or a mixture of aliphatic and/or aromatic hydrocarbons, such as hexane, heptane, cyclohexane, benzene, toluene or xylene.
The reaction time is generally from 0.5 to 2 h. After the reaction has ended, the reaction mixture is generally worked up acidic-aqueous; the

Affiliated with

Also associated with

Rating

Method of producing 2-hydroxycarboxylic acid esters 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 of producing 2-hydroxycarboxylic acid esters, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method of producing 2-hydroxycarboxylic acid esters will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3156753