Preparation of dihydroxycarboxylic esters in the absence of...

Details Preparation of dihydroxycarboxylic esters in the absence of... Preparation of dihydroxycarboxylic esters in the absence of...

2002-12-02

2003-09-16

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Carboxylic acid esters

C560S145000, C560S180000, C549S039000

Reexamination Certificate

active

06620964

ABSTRACT:

The present invention relates to a process for preparing dihydroxycarboxylic esters and an overall process for preparing R-(+)-&agr;-lipoic acid.
Dihydroxycarboxylic esters are valuable intermediates and synthesis building blocks in organic chemistry. In particular, (6S)-6,8-dihydroxyoctanoic esters serve as intermediates for the synthesis of enantiomerically pure R-(+)-&agr;-lipoic acid.
EP 487 986 discloses preparing (6S)-6,8-dihydroxyoctanoic esters by reducing the corresponding (3S)-3-hydroxyoctanedioic diesters with complex hydrides in the presence of aprotic solvents.
Using this process, the yields which are good but are still in need of improvement are achieved. In addition, the process has the disadvantages that solvents and relatively large amounts of complex hydrides must be used.
It is an object of the present invention, therefore, to provide a process for preparing dihydroxycarboxylic esters which does not have the disadvantages of the prior art and provides the dihydroxycarboxylic esters without solvent and in improved yields.
We have found that this object is achieved by a process for preparing dihydroxycarboxylic esters of the formula I,
where
n is 1, 2, 3, 4, 5, 6 or 7 and
R
1
is an unsubstituted or substituted C
1
-C
20
-alkyl, C
2
-C
20
-alkenyl, C
2
-C
20
-alkynyl, C
3
-C
8
-cycloalkyl, aralkyl, aryl, hetarylalkyl or hetaryl radical,
which comprises reacting hydroxycarboxylic diesters of the formula II,
 where
R
2
is a radical R
1
independent of R
1
,
with complex hydrides in the absence of a solvent.
The index n which is the number of —CH
2
— radicals is 1, 2, 3, 4, 5, 6 or 7, preferably 3. In a preferred embodiment of the process, therefore dihydroxyoctanoic esters are prepared according to the invention.
The radicals R
1
and R
2
can be different or identical. The radicals R
1
and R
2
are therefore independently of one another an unsubstituted or substituted C
1
-C
20
-alkyl, preferably C
1
-C
12
-alkyl, particularly preferably C
1
-C
4
-alkyl, an unsubstituted or substituted C
2
-C
20
-alkenyl, preferably C
2
-C
12
-alkenyl, particularly preferably C
1
-C
4
-alkenyl, an unsubstituted or substituted C
2
-C
20
-alkynyl, preferably C
2
-C
12
-alkynyl, particularly preferably C
1
-C
4
-alkynyl, an unsubstituted or substituted C
3
-C
8
-cycloalkyl, an unsubstituted or substituted aralkyl, an unsubstituted or substituted aryl, an unsubstituted or substituted hydroxyalkyl or an unsubstituted or substituted hetaryl.
For all substituted radicals of the present invention, if the substituents are not specified in more detail, independently of one another there may be up to five substituents, for example selected from the following group:
halogen, in particular F or Cl, unsubstituted or substituted C
1
-C
12
-alkyl, in particular C
1
-C
4
-alkyl, for example methyl, CF
3
, C
2
F
5
or CH
2
F or C
1
-C
12
-alkoxy, in particular C
1
-C
4
-alkoxy.
C
1
-C
12
-Alkyl radicals for R
1
and R
2
are independently of one another, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-2-methylpropyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl, preferably branched or unbranched C
1
-C
4
-alkyl radicals, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularly preferably methyl.
A C
2
-C
12
-alkenyl radical for R
1
and R
2
is, independently of one another, for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 15 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-ethyl-l-methyl-2-propenyl, 1-ethyl-2-methyl-2-propenyl and the corresponding heptenyls, octenyls, nonenyls, decenyls, undecenyls and dodecenyls.
A C
2
-C
12
-alkynyl radical for R
1
and R
2
is, independently of one another, for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl and 1-ethyl-l-methyl-2-propynyl, preferably ethynyl, 2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl, and the corresponding heptynyls, octynyls, nonynyls, decynyls, undecynyls and dodecynyls.
A C
3
-C
8
-cycloalkyl radical for R
1
and R
2
is, independently of one another, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Preferred unsubstituted or substituted aryl radicals for R
1
and R
2
are, independently of one another, unsubstituted or substituted phenyl, 1-naphthyl or 2-naphthyl.
Preferred unsubstituted or substituted arylalkyl radicals for R
1
and R
2
are, independently of one another, unsubstituted or substituted benzyl or ethylenephenyl (homobenzyl).
Hetaryl radicals for R
1
and R
2
are, independently of one another, for example radicals such as 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, thiadiazolyl, oxadiazolyl or triazinyl.
Substituted hetaryl radicals R
1
and R
2
are, independently of one another, also anellated derivatives of the abovementioned hetaryl radicals, for example indazole, indole, benzothiophene, benzofuran, indoline, benzimidazole, benzthiazole, benzoxazole, quinoline, 2,3-dihydro-1-benzofuran, furo[2,3]pyridine, furo[3,2]pyridine or isoquinoline.
Hetarylalkyl radicals for R
1
and R
2
are, independently of one another, radicals which are composed, for example, of C
1
-C
6
-alkylene radicals and of the above-described hetaryl radicals, for example the radicals —CH
2
-2-pyridyl, —CH
2
-3-pyridyl, —CH
2
-4-pyridyl, —CH
2
-2-thienyl, —CH
2
-3-thienyl, —CH
2
-2-thiazolyl, —CH
2
-4-thiazolyl, CH
2
-5-thiazolyl, —CH
2
—CH
2
-2-pyridyl, —CH
2
—CH
2
-3-pyridyl, —CH
2
—CH
2
-4-pyridyl, —CH
2
—CH
2
-2-thienyl, —CH
2
—CH
2
-3-thienyl, —CH
2
—CH
2
-2-thiazolyl, —CH
2
—CH
2
-4-thiazolyl, or —CH
2
—CH
2
-5-thiazolyl.
Preferred radicals for R
1
and R
2
are, independently of one another, unsubstituted radicals. Particularly preferred radicals for R
1
and R
2
are, independently of one another, the above-described C
1
-C
12
-alkyl radicals, in particular C
1
-C
4
-alkyl, in particular methyl.
In a particularly preferred embodiment, the radicals R
1
and R
2
are identical.
Th

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