Process for the preparation of hydroxylactones

Details Process for the preparation of hydroxylactones Process for the preparation of hydroxylactones

2001-08-24

2003-01-28

Rotman, Alan L. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S295000

Reexamination Certificate

active

06512127

ABSTRACT:

The present invention is directed towards a process for the preparation of 4-hydroxymethyl-&ggr;-butyrolactone (I)
and towards the use thereof.
Enantiomerically enriched (I) is an important intermediate for the preparation of medicaments, it is used especially for the preparation of particular enzyme inhibitors (Synth. Commun. 2000, 30, 1955f.; EP617968). From those specifications, methods of preparing the medicaments starting from (I) and the synthesis of (I) are also described.
The object of the present invention is to provide a further process for the preparation of enantiomerically enriched (I). In particular, that process is to be readily usable on a large scale and is to be superior to the processes of the prior art from an ecological and an economic point of view.
Those objects are achieved by a process having the features of claim 1. Claims 2 to 9 are directed towards preferred embodiments of the process according to the invention. Claim 10 protects a particular use.
By reacting racemic epoxide of the general formula (II)
wherein R represents a (C
1
-C
8
)-alkyl radical, a (C
8
-C
16
)-aryl radical, by kinetic racemate cleavage with a nucleophile and a catalyst that contains as the reaction center a tetradentate enantiomerically enriched metal-salene complex, and then carrying out the conversion to (I), there is obtained a process which ensures the preparation of (I) on an industrial scale in high yields and with high enantiomeric excesses.
There is preferably used in the racemate cleavage a catalyst that contains an enantiomerically enriched complex of the general formula (III)
wherein
M=Cr, Co,
A represents a counter-ion or nucleophile,
R
1
, R
2
, R
1′
, R
2′
each independently of the others represents H, (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
-C
8
)-alkyl-(C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
18
)-heteroaryl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl,
wherein at least one of the radicals may not be H, or R
1
and R
1′
are bonded via a (C
3
-C
5
)-bridge that may be mono- or poly-substituted by (C
1
-C
8
)-alkyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl and/or may contain hetero atoms such as N, O, P, S in the ring,
R
3
, R
8
each independently of the other represents H, (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkoxy, (C
6
-C
18
)-aryl, R
4
, R
5
, R
6
, R
7
each independently of the others represents H, (C
1
-C
8
)-alkyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl, (C
1
-C
8
)-acyloxy, (C
1
-C
8
)-acyl, (C
6
-C
18
)-aryl, (C
7
-C
19
)-aralkyl, (C
3
-C
18
)-heteroaryl, (C
4
-C
19
)-heteroaralkyl, (C
1
-C
8
)-alkyl- (C
6
-C
18
)-aryl, (C
1
-C
8
)-alkyl-(C
3
-C
18
)-heteroaryl, (C
3
-C
8
)-cycloalkyl, (C
1
-C
8
)-alkyl-(C
3
-C
8
)-cycloalkyl, (C
3
-C
8
)-cycloalkyl-(C
1
-C
8
)-alkyl, or R
4
and R
5
and/or R
6
and R
7
are bonded via a (C
3
-C
5
)-bridge that may contain one or more double bonds and/or may be mono- or poly-substituted by (C
1
-C
8
)-alkyl, (C
1
-C
8
)-acyl, (C
1
-C
8
)-alkoxy, (C
2
-C
8
)-alkoxyalkyl and/or may contain hetero atoms such as N, O, P, S in the ring. Most particularly preferred is a catalyst that contains an enantiomerically enriched complex of the general formula (IV)
wherein
m=from 0 to 4,
M=Cr, Co,
A=Cl, BF
4
, SbF
6
, (C
1
-C
8
)-acyl, OH, H
2
O, OC(CF
3
)
3
, O(C
6
-C
18
)-aryl, and
R
9
=(C
1
-C
8
)-alkyl, (C
6
-C
18
)-aryl.
The kinetic racemate cleavage may in principle be carried out without a solvent or in any organic solvent that is inert towards the reaction in question, such as, for example, an ether, especially THF, MTBE.
The temperatures during the racemate cleavage may be from −40° to 50° C., preferably from −20° to +30° C., particularly preferably from −5° to +10° C.
There may in principle be used as the nucleophile any compound that comes into consideration for that purpose to the person skilled in the art. The use of water for that purpose in the kinetic racemate cleavage is, however, most particularly preferred.
When water is used as the nucleophile, there is ideally obtained from the kinetic racemate cleavage by the process according to the invention 0.5 eq. of an enantiomerically enriched diol of the general formula (V)
and 0.5 eq. of the unreacted epoxide (II)
wherein R in each case may be as defined above.
Under the indicated conditions, (V) immediately cyclises in situ to form the desired enantiomerically enriched lactone (I).
It is, however, within the scope of the invention to separate the two compounds obtainable in the kinetic racemate cleavage and to convert the unreacted enantiomerically enriched epoxide of the general formula (II)
with acid catalysis, especially with acids such as TFA, HClO
4
, H
2
SO
4
, H
3
PO
4
or polymerically bonded acids, to enantiomerically enriched 4-hydroxymethyl-&ggr;-butyrolactone (I). It is also possible to initiate that cyclisation by basic ester cleavage.
Since that reaction yields the same optical enantiomer of (I) as the cyclisation of the diol (V) (Davies et al. Synthesis, 1983, 462), very special preference is given to a process in which the transesterification of the enantiomerically enriched diol (V) and the acid catalysed cyclisation of the enantiomerically enriched epoxide (II) are carried out together in one reaction container.
The scheme below illustrates the possible procedures.
Of course, the enantiomeric series is rendered accessible by use of the enantiomeric catalyst.
In a further embodiment, the invention is directed towards the use of the 4-hydroxymethyl-&ggr;-butyrolactone (I) prepared by the process according to the invention in the preparation of substances having biological activity, especially pharmaceuticals.
The preparation of the racemic starting material is known in the literature (Tetrahedron 1984, 40, 2781-2788; Helv. Chim Acta 1979, 62, 135-139; Indian J. Chem. 1985, 24, 1085-1087).
The present reaction may be carried out using catalysts whose molecular weight has been increased by bonding to a polymer. That bonding may in principle be carried out in a manner known to the person skilled in the art. The bonding is advantageously carried out via one of the substituents R
4
to R
7
in (III) or R
9
in (IV), but it may also be attached at a different position in the molecule. That is dependent on the effect which the bonding to the polymer has on the enantioselective reaction, which can be determined in routine experiments. The compounds according to the invention to be bonded are advantageously coupled to a suitable polymer via a linker, in order to eliminate any disadvantageous interactions between the polymer and the complex (III) or (IV) that may affect the catalytic reaction. With regard to possible linkers, the nature and manner of the bonding to the polymer, and the complex, as well as with regard to suitable polymers, reference is made to specifications DE 100 296 01, DE 100 031 10, DE 100 029 73 and DE 100 029 76 as well as JACS 1999, 121, 4147f. When its molecular weight has been increased in that manner, the homogeneously soluble or heterogenised complex (III) or (IV) may be used particularly advantageously in a membrane reactor, giving rise to the possibility of a quasi-continuous or continuous catalytic reaction (DE 199 10 691.6; Wandrey et al., Tetrahedron Asymmetry 1999, 10, 923-928). That is particularly advantageous on an industrial scale from the point of view of cost.
Within the scope of the invention, enantiomerically enriched denotes the presence of an optical antipode in admixture with the others in an amount >50 mol. %.
(C
1
-C
8
)-Alkyl radicals are to be regarded as being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl or octyl, including all their isomers formed due to different positions of the double bond. The radical (C
1
-C
8
)-alkoxy corresponds to the radical (C
1
-C

Affiliated with

Also associated with

Rating

Process for the preparation of hydroxylactones does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of hydroxylactones, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of hydroxylactones will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3053947