Process for the preparation of enantiomerically pure...

Details Process for the preparation of enantiomerically pure... Process for the preparation of enantiomerically pure...

1999-11-18

2001-05-08

Killos, Paul J. (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S145000

Reexamination Certificate

active

06229042

ABSTRACT:

The present invention relates to a novel process for the preparation of enantiomerically pure 3-hydroxyoctanedioic acid diesters of the general formula I, where R
1
and R
2
are identical or different and are a C
1
-C
20
-alkyl group, C
3
-C
12
-cycloalkyl group, C
7
-C
12
-aralkyl group or a mono- or binuclear aryl group.
The compounds (R)-I are novel, whereas the compounds (S)-I are known. Both are used mainly as intermediates for the synthesis of enantiomerically pure &agr;-lipoic acid of the formula II and its derivatives. &agr;-Lipoic acid is 1,2-dithiolane-3-pentanoic acid (thioctic acid).
The (R)-enantiomer of &agr;-lipoic acid (R)-(+)-II is a natural substance which occurs in low concentrations in virtually all animal and plant cells. As a coenzyme in the oxidative decarboxylation of &agr;-ketocarboxylic acids (e.g. pyruvic acid), &agr;-lipoic acid is of essential importance. &agr;-Lipoic acid is pharmacologically active and has anti-inflammatory and antinociceptive (analgesic) and cytoprotective properties. An important medical indication is the treatment of diabetic polyneuropathy. According to recent results (A. Baur et al., Klin. Wochenschr. 1991, 69, 722; J. P. Merin et al., FEBS Lett. 1996, 394, 9), &agr;-lipoic acid may possibly gain importance in the control of diseases caused by HIV-1 and HTLV IIIB viruses.
In the case of the pure optical isomers of &agr;-lipoic acid (R- and S-form, i.e. (R)-&agr;-lipoic acid and (S)-&agr;-lipoic acid), unlike the racemate, the (R)-enantiomer mainly has anti-inflammatory activity and the (S)-enantiomer mainly antinociceptive activity (EP 0427247, 08.11.90). Different pharmacokinetic properties of the two enantiomers have likewise been found (R. Hermann et al., Eur. J. Pharmaceut. Sci. 1996, 4, 167). The synthesis of the pure enantiomers is therefore of great importance.
Known preparation processes for the enantiomerically pure &agr;-lipoic acids include the resolution of the racemates of &agr;-lipoic acid or its precursors, asymmetric syntheses using chiral auxiliaries, “chiral pool” syntheses using naturally occurring optically active starting compounds and microbial syntheses (review article: J. S. Yadav et al., J. Sci. Ind. Res. 1990, 49, 400; and also: E. Walton et al., J. Am. Chem. Soc. 1955, 77, 5144; D. S. Acker and W. J. Wayne, J. Am. Chem. Soc. 1957, 79, 6483; L. G. Chebotareva and A. M. Yurkevich, Khim.-Farm. Zh. 1980, 14, 92; A. S. Gopalan et al., Tetrahedron Lett. 1989, 5705; A. G. Tolstikov et al., Bioorg. Khim. 1990, 16, 1670; L. Dasaradhi et al., J. Chem. Soc., Chem. Commun. 1990, 729; A. S. Gopalan et al., J. Chem. Perkin Trans. 1 1990, 1897; EP 0487986 A2, 14.11.91; B. Adger et al., J. Chem. Soc., Chem. Commun. 1995, 1563; Y. R. Santosh Laxmi and D. S. Iyengar, Synthesis, 1996, 594).
Of these, the resolution of the racemate via the formation of diastereomeric salts of &agr;-lipoic acid with optically active a-methylbenzylamine (DE-A 4137773.7, 16.11.91 and DE-A 4427079.8, 30.07.94) represents the most economical variant up to now. Since the racemate separation only takes place in the last stage of the synthesis sequence, however, high yields cannot be attained.
The only known chemocatalytic asymmetric process for the preparation of enantiomerically pure &agr;-lipoic acid (DE-A 3629116.1, 27.08.86) is based on the Sharpless epoxidation of allyl alcohols, but is uneconomical because of the high costs of the starting compounds.
Among the biocatalytic synthesis routes described, the asymmetric reduction of 3-oxooctanedioic acid diesters III with baker's yeast is to be emphasized (EP 0487986 A2, 14.11.91). The disadvantages of this process, however, are that the space-time yield is extremely low, a high enantiomeric excess can only be achieved when using the isobutyl ester (R
1
=iBu) and always only the (S)-enantiomer (S)-I is formed.
The object of the invention is therefore alternatively to make both enantiomers of &agr;-lipoic acid available in high chemical and optical space-time yield when using inexpensive starting substances. According to the invention, this is achieved by asymmetric chemocatalytic hydrogenation of 3-oxooctanedioic acid diesters of the formula III, in which R
1
and R
2
in each case independently of one another are a C
1
-C
20
-alkyl group, C
3
-C
12
-cycloalkyl group, C
7
-C
12
-aralkyl group or a mono- or binuclear aryl group, in the presence of complexes of ruthenium and optically active phosphines or of Raney nickel and optically active tartaric acid as catalysts.
In this case, independently of the nature of the ester groups (R
1
, R
2
), constant high optical and chemical yields of 3-hydroxyoctanedioic acid diesters I are attained. Unlike the biocatalytic variants, the reaction can be carried out at very high substrate concentrations.
The compounds III are known and obtainable especially by acylation of Meldrum's acid with monoalkyl adipoyl chloride and subsequent alcoholysis (H. Thoma and G. Spiteller, Liebigs Ann. Chem. 1983, 1237; EP 0487986 A2, 14.11.91). Under certain reaction conditions, according to the invention preferably also the alkyl 6-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene) 6-hydroxyhexanoates of the formula IV (R
1
=C
1
-C
20
-alkyl, C
3
-C
12
-cycloalkyl, C
7
-C
12
-aralkyl and/or mono- or binuclear aryl) which are intermediately formed and can be isolated can be used for the asymmetric hydrogenation. They can be prepared as described (H. W. Schmidt and M. Klade, Org. Prep. Proced. Int. 1988, 20, 184) or prepared in an analogous manner.
Of particular interest as catalysts for the asymmetric hydrogenation are ruthenium-diphosphine complexes. As typical examples but not as a restriction, the ruthenium complexes of the following formulae V to XI may be mentioned:
[RuHal
2
D]
1,2
(L)
x
V
[RuHalAD]
+
Y
−
VI
RuD
n
OOCR
3
OOCR
4
VII
[RuH
x
D
n
]
m+
Y
m
−
VIII
[RuHal(PR
5
2
R
6
)D]
2+
Hal
2
−
IX
[RUHHalD
2
]
X
[DRu(acac)
2
]
XI
in which:
acac is acetylacetonate,
D is a diphosphine of the general formula XII,
Hal is halogen, in particular iodine, chlorine or bromine,
R
3
and R
4
are identical or different and are alkyl having up to 9 C atoms, preferably up to 4 C atoms, which is optionally substituted by halogen, in particular fluorine, chlorine or bromine or are phenyl which is optionally substituted by alkyl having 1 to 4 C atoms or are &agr;-aminoalkanoic acid preferably having up to 4 C atoms, or jointly form an alkylidene group having up to 4 C atoms,
R
5
and R
6
in each case are identical or different and are optionally substituted phenyl, preferably substituted by alkyl having 1 to 4 C atoms or halogen,
Y is Cl, Br, I, ClO
4
, BF
4
or PF
4
,
A is an unsubstituted or substituted benzene ring such as p-cymene,
L is a neutral ligand such as acetone, a tertiary amine or dimethylformamide,
n and m in each case are 1 or 2,
x is 0 or 1,
where in formula VIII n is 1 and m is 2 if x=0, and n is 2 and m is 1 if x=1.
The complexes of the formulae V to XI can be prepared by methods known per se (V and X: EP 174057 and J. P.Genet et al., Tetrahedron Asymmetry 1994, 5, 675; VI: EP 366390; VII: EP 245959 and EP 272787; VIII: EP 256634; IX: EP 470756; XI: P. Stahly et al., Organometallics 1993, 1467).
Optically active diphosphine ligands which can be used are compounds of the general formula XII:
in which:
Q is a group bridging the two P atoms having 2 to 24 carbon atoms and optionally 1 to 4 heteroatoms, preferably O, S, N and Si, the bridge being formed by at least 2 of the carbon atoms and optionally 1 to 4 of the heteroatoms,
R
7
-R
10
in each case are identical or different and are alkyl groups having 1 to 18 C atoms, cycloalkyl groups having 5 to 7 C atoms or aryl groups having 6 to 12 C atoms.
As particularly preferred chiral diphosphines which can be used in enantiomerically pure form, the following ligands can be mentioned as examples:
The ligands mentioned above as racemic structures for the sake of simplicity are known compoun

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