Keto reduction of carbacyclin intermediates

Details Keto reduction of carbacyclin intermediates Keto reduction of carbacyclin intermediates

1991-07-31

1993-04-06

Chan, Nicky

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

549336, 549332, 556441, 560119, 562501, C07F 704

Patent

active

052005305

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a new process for the reduction of 15-keto carbacyclin intermediates (PG nomenclature) in the presence of cerium(III) salts.
In the syntheses of pharmacologically effective carbacyclin analogs Iloprost, Cicaprost or Eptaloprost, reduction of the 15 keto group to the 15alpha hydroxy group is a very important step. Reduction with technically easily available reagents such as sodium borohydride leads to a mixture with undesirable 15beta hydroxy isomers. The two isomers must be separated from one another by chromatography. (For economical reasons the 15beta isomer must be reoxidized to the initial ketone and again reduced and separated into the 15 isomers, etc.) The expense necessary for the separation (adsorbent, amount of solvent) is higher, the more 15beta hydroxy isomer must be separated.
According to present processes the portion of undesirable 15beta hydroxy isomers is always high, if reduction with simple hydride reagents is involved.
Moreover, Iloprost, which represents a diastereomer mixture of 16-methyl compounds in a ratio of 16alpha:16beta=54:46, so far is obtained in this way only if said reoxidation is performed once or twice and all 15alpha hydroxy products (which by themselves exhibit different diastereomeric compositions), obtained after reduction and chromatography, are further processed together. The chemical reaction, as can easily be seen, requires exceptionally high expenses.
In Iloprost synthesis the 15-keto group (3a, diagram 1) can also be reduced microbiologically (to 4a). But the total expense of performing a microbiological reduction, working up and purification of the product up to separation of the undesirable accompanying substances is very high.
Microbiological reduction cannot be performed in the case of Cicaprost and Eptaloprost intermediate step 1.
It cannot be performed in the case of 3b either. 3b can be produced by simultaneously filed syntheses by 3alpha-hydroxy-cis-bicyclo[3.3.0]octan-7-one-2beta-carboxylic acid methyl ester derivatives, especially 7,7-neopentyl ketal, in a substantially simpler way than present precursor 3a. ##STR1##
The ketone 3c obtainable from the THP ether precursors (instead of said silyl ethers) leads, in the case of sodium borohydride reduction, to poorer yields and to an unsatisfactory 16-diastereomer distribution. Moreover, the 15-isomers can be separated only after cleavage of the protecting groups, which makes the usability of the 15beta portion by reoxidation difficult. The route by 3c therefore is less favorable than by 3b.
The object therefore was to improve the chemical reduction of the 15-keto group in the synthesis of carbacyclin analogs relative to the yield of 15alpha-hydroxy product and also in Ilosprost synthesis relative to the 16-diastereomer composition.
Thus, the invention relates to a process for the production of alpha-hydroxy-bicyclo[3.3.0]octane derivatives of formula I ##STR2## in which
A means the double bond radical --O--X--O-- with X as straight-chain or branched-chain alkylene with 1-7 C atoms or the radicals .dbd.CH--(CH.sub.2).sub.3 --COOR', .dbd.CH--CH.sub.2 --O--CH.sub.2 --COOR' or .dbd.CH--(CH.sub.2).sub.3 --O--CH.sub.2 --CH.sub.2 -COOR' with R' as C.sub.1 -C.sub.7 alkyl,
R means ##STR3## with R" as hydrogen or phenyl or the radical --SiR.sub.1 R.sub.2 R.sub.3, and R.sub.1 , R.sub.2 and R.sub.3 can be the same or different and represent a straight-chain or branched-chain alkyl group with 1-7 C atoms or phenyl,
B means a trans-CH.dbd.C(X) group with X as hydrogen or bromine, and the trans-configuration relates to the C chain, and
D means an alkyl group with 1-10 C atoms, an alkenyl group with 2-10 C atoms or an alkynyl group with 2-10 C atoms,
characterized in that, keto-bicyclo[3.3.0]octane derivatives of formula II ##STR4## is the presence of cerium(III) salts.
In attaining this object, two effects are important, which, individually, but especially combined with one another, are advantageous. cerium(III) chloride leads to a marked yield increase in the desired 15alpha-hydroxy product.


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