Process for preparing optically active dihydropyrones

Details Process for preparing optically active dihydropyrones Process for preparing optically active dihydropyrones

2002-02-14

2002-12-31

Owens, Amelia (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S417000

Reexamination Certificate

active

06500963

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to a new process for preparing optically active dihydropyrones, new intermediate products which can be obtained by this method of synthesis, and their use as starting compounds in the preparation of pharmaceutically active compounds.
BACKGROUND TO THE INVENTION
5,6-Dihydro-4-hydroxy-2-pyrones are important structural elements in a number of pharmaceutically active compounds. One category of particular interest comprises the 5,6-dihydro-4-hydroxy-2-pyrone-sulphonamides, which may be used as non-peptidic HIV-protease inhibitors. A particularly effective example of a potent and orally bioavailable HIV-protease inhibitor in this category of substances is the compound tipranavir (PNU-140690), which has the following structure
This and other structurally similar compounds are known from the prior art (cf. for example
J. Med. Chem
. 1998, 41, 3467-3476).
A key step in the synthesis of the abovementioned compounds and those structurally similar thereto is the reaction of 5,6-dihydro-4-hydroxy-2-pyrones 1 with suitably substituted carbonyl compounds 2 to form the condensation products 8, as illustrated in Diagram 1.
Diagram 1:
The meanings of the groups R
1
and R
2
which are different from one another can be found in the detailed description of the invention which follows. The groups may vary in their meanings depending on the substitution pattern of the respective target compounds, as described in the prior art.
It is significant according to the invention that the chiral information contained in the starting compounds 1 is retained in the subsequent reaction shown in Diagram 1, as a result of which the compounds 1 have a central importance in the synthesis of the abovementioned pharmaceutically active compounds.
The aim of the present invention is therefore to provide a process which allows 1 to be synthesised in high yields, with high enantiomeric purity, at the lowest possible technical cost and in a high space/time yield.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a new process for preparing optically active dihydropyrones, new intermediate products which can be obtained by this method of synthesis, and their use as starting compounds in the preparation of pharmaceutically active compounds. Each of the aforementioned is described further in the detailed description section below.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that these objectives of the present invention as outline above can be achieved if the chiral 5,6-dihydro-4-hydroxy-2-pyrones 1 are prepared according to the procedure illustrated in Diagram 2.
Diagram 2
For this, racemic 5,6-dihydro-4-hydroxy-2-pyrones 1-rac are converted with chiral aminoalcohols 4 into the salts 1-salt. Surprisingly, the latter can be obtained in the form of crystallising compounds and thus isolated in good yields and with a high degree of purity. Depending on the choice of the optically active aminoalcohols 4 the salts 1-salt of the R- or S-configured compounds 1 are crystallised. The salts 1-salt′ of the unwanted enantiomers of 1 stay in solution during this reaction step. The optically active target compounds are liberated from the crystallised salts 1-salt.
Within the scope of the present invention any reference to compounds of formula 1 should always be taken as a reference to the optically active compounds 1, whereas any reference to compounds of formula 1-rac should be taken as a reference to the racemic mixture of the compounds of formula 1.
Accordingly, the present invention relates to a process for preparing a compound of formula 1
optionally in the form of the tautomers thereof,
wherein
R
1
and R
2
independently of one another denote hydrogen or a group selected from among C
1
-C
4
-alkyl, C
3
-C
8
-cycloalkyl, C
6
-C
10
-aryl and —C
1
-C
4
-alkylene-C
6
-C
10
-aryl, which may optionally be mono-, di- or trisubstituted by one or more groups selected from among hydroxy, halogen, C
1
-C
4
-alkoxy and CF
3
,
with the proviso that R
1
and R
2
cannot simultaneously have the same meaning,
characterised in that in a first step a compound of formula 1-rac
wherein R
1
and R
2
may have the meanings given hereinbefore, is reacted in a suitable solvent with one or more, preferably one chiral aminoalcohol of formula 4
wherein
R
3
, R
3′
, R
4
and R
4
′ which may be identical or different denote hydrogen or a group selected from among C
1
-C
4
-alkyl, C
3
-C
8
-cycloalkyl, C
6
-C
10
-aryl and —C
1-C
4
-alkylene-C
6
-C
10
-aryl, which may optionally be mono-, di- or trisubstituted by one or more groups selected from among hydroxy, halogen, C
1
-C
4
-alkoxy, —S—C
1
-C
4
-alkyl, —SO
2
-C
1
-C
4
-alkyl, NO
2
and CF
3
, with the proviso that if R
3
and R
3
′ have the same meaning, the groups R
4
and R
4
′ cannot have the same meaning, and with the proviso that if R
4
and R
4
′ have the same meaning, the groups R
3
and R
3
′ cannot have the same meaning,
to form a salt of formula 1-salt
wherein the groups R
1
, R
2
, R
3
, R
3
′, R
4
and R
4
′ may have the meanings given hereinbefore, the resulting crystalline compound 1-salt is isolated and the target compound is liberated therefrom.
A preferred process according to the invention is a process for preparing a compound of formula 1 optionally in the form of the tautomers thereof,
wherein
R
1
and R
2
independently of one another denote a group selected from among methyl, ethyl, propyl, butyl, phenyl, benzyl, phenylethyl and phenylpropyl which may optionally be monosubstituted by a group selected from among hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy and CF
3
with the proviso that R
1
and R
2
cannot simultaneously have the same meaning,
characterised in that in a first step a compound of formula 1-rac wherein R
1
and R
2
may have the meanings given hereinbefore is reacted in a suitable solvent with one or more, preferably one chiral aminoalcohol of formula 4 wherein R
3
, R
3
′, R
4
and R
4
′ which may be identical or different denote hydrogen or a group selected from among methyl, ethyl, propyl, phenyl, benzyl and phenylethyl, which may optionally be mono- or trisubstituted by one or two groups selected from among hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy, Me-S—, Me-SO
2
—, Et-S—, Et-SO
2
—, NO
2
and CF
3
, with the proviso that if R
3
and R
3
′ have the same meaning, the groups R
4
and R
4
′ cannot have the same meaning, and with the proviso that if R
4
and R
4
′ have the same meaning, the groups R
3
and R
3
′ cannot have the same meaning,
to form a salt of formula 1-salt, wherein the groups R
1
, R
2
, R
3
,R
3
′,R
4
and R
4
may have the meanings given hereinbefore, the resulting crystalline compound 1-salt is isolated and the target compound 1 is liberated therefrom.
Particularly preferred according to the invention is a process for preparing a compound of formula 1 optionally in the form of the tautomers thereof,
wherein
R
1
and R
2
independently of one another denote a group selected from among methyl, ethyl, propyl, butyl, phenyl, benzyl, phenylethyl and phenylpropyl, with the proviso that R
1
and R
2
cannot simultaneously have the same meaning,
characterised in that in a first step a compound of formula 1-rac, wherein R
1
and R
2
may have the meanings given hereinbefore, is reacted in a suitable solvent with one or more, preferably one chiral aminoalcohol of formula 4
wherein
R
3
, R
3
′, R
4
and R
4
′ which may be identical or different denote hydrogen or a group selected from among methyl, ethyl, propyl, phenyl and benzyl, which may optionally be monosubstituted by a group selected from among hydroxy, methoxy, Me—S—, Me—SO
2
—and NO
2
, with the proviso that if R
3
and R
3
′ have the same meaning, the groups R
4
and R
4
′ cannot have the same meaning, and with the proviso that if R
4
and R
4
′ have the same meaning, the groups R
3
and R
3
′ cannot have the same meaning,
to form a s

Affiliated with

Also associated with

Rating

Process for preparing optically active dihydropyrones 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 preparing optically active dihydropyrones, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for preparing optically active dihydropyrones will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2988498