Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1989-11-13
1992-03-03
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
540 32, 540116, 552625, 552641, 549341, 549345, 560119, 560217, C07J 100, C07J 7500, C07C40500, C07C17700
Patent
active
050934902
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The invention relates to a process for the production of (+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid esters.
Bicyclo[3.3.0]octane-3,7-dione-2 carboxylic acid esters represent important intermediate products for the production of carbacyclin derivatives and sesquiterpenes and can easily be produced according to a new process (German patent application P 3702385.3).
It has now been found that in the transesterification of these bicyclo[3.3.0]octane-3,7-dione-2 carboxylic acid esters with naturally configured steroids, which contain a free 17beta hydroxyl group, surprisingly only the derivatives with the absolute configuration represented in formula I crystallize out, while the corresponding diastereomeric esters IV remain in solution and can be recovered from the mother liquors in high optical yields. ##STR7##
The object of the invention is thus the optical resolution of the racemic D,L-bicyclo[3.3.0]octane-3,7-dione carboxylic acid ester derivatives II by transesterification with steroids with a free 17beta hydroxyl group, especially with aromatic A ring, of formula III and subsequent crystallization to steroid esters, and only the enantiomers, with the absolute configuration indicated in general formula I, crystallize out in a nearly optically pure manner, while steroid esters IV, diastereomeric to I, can be recovered in optical yields of about 90% from the mother liquor.
Thus the invention relates to a process for the production of (+)-bicyclo[3.3.0]octan-3-one-2 carboxylic acid steroid esters of formula I ##STR8## in which X means oxygen or the radicals --O--(CH.sub.2).sub.n --O-- or --O--CH.sub.2 --C(CH.sub.3).sub.2 --CH.sub.2 --O--, ##STR9## and X and X.sub.1 have the meanings indicated above, characterized in that D,L-bicyclo[3.3.0]octan-3-one-2 carboxylic acid esters of formula II ##STR10## in which X has the meaning indicated above and R is an alkyl group with 1-4 carbon atoms, with optically active steroids with a free 17beta hydroxy group of formula III ##STR11## in which R.sub.2 and the radical ##STR12## have the meanings indicated above, in the presence of a nucleophilic or acid catalyst is converted into the diastereomeric steroid esters and the optically pure steroid esters of formula I are obtained as crystallizates.
The radicals methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl and tert-butyl are suitable as alkyl groups with 1-4 C atoms.
Estradiol methyl ether as well as compounds of the equilin type or of the equilenin type are suitable as steroids of formula III, which carry a 17beta hydroxy group. As further steroids there can be mentioned those in which gamma=X or X.sub.1.
The preferred reactions are explained by the following diagram I: Thus D,L-bicyclo[3.3.0]octane-3,7-dione-2 carboxylic acid methyl ester VI is transesterified with estradiol methyl ether VII in the presence of 4-dimethylaminopyridine (DMAP) or 4-pyrrolidinopyridine (PPY) according to the method of D. F. Taber et al., J.O.C. 50, 3618 (1985) or by acid-catalyzed transesterification in the presence of camphorsulfonic acid acid, p-toluenesulfonic acid or methanesulfonic acid in toluene in about 80-90% yield. In this case, almost optically pure ester VIII crystallizes out in 35-40% yield, while the ester (cf. IV) diastereomeric to VIII remains in solution. With the selective ketalization with neopentyl glycol, VIII yields the steroid ester ketal X. The optically active ketal ester X can also be recovered analogously from D,L-neopentylketal monoethyl ester IX by transesterification with estradiol methyl ether VII in the presence of DMAP or PPY in crystalline form and practically optically pure in about 35-40% yield, and the diastereomer of X remains in the mother liquor. ##STR13##
Reduction of X with sodium borohydride in methyl tert-butyl ether H.sub.2 O yields the crystalline alcohol XI, whose optical purity of more than 98% can be determined with the help of HPLC on an analytical acid (ODS-Hypersil) with the system acetonitrilemethanol H.sub.2 O=33:29:38.
Reduction of the amorphous diastereo
REFERENCES:
patent: 2154272 (1939-04-01), Hildebrandt et al.
patent: 4912251 (1990-03-01), Skuballa
Schering Aktiengesellschaft
Shah Mukund J.
Ward E. L.
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