Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-27
2002-11-19
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06482959
ABSTRACT:
The present invention relates to a new process for the preparation of &agr;,&bgr;-unsaturated alcohols by the diasteroselective reduction of &agr;,&bgr;-unsaturated ketones. Representative reactants and products of the present invention are depicted in
FIG. 1
, with compound (I) depicting representative product &agr;,&bgr;-unsaturated alcohols, compound (II) depicting representative &agr;,&bgr;-unsaturated ketones, and compound (III) depicting representative epimers of product &agr;,&bgr;-unsaturated alcohols (I).
&agr;,&bgr;-Unsaturated alcohols of general formula (I) are important key intermediates of prostaglandine derivatives used in veterinary and human medicine.
The synthesis of these compounds is carried out most frequently by reduction of &agr;,&bgr;-unsaturated ketones of formula (II), when a mixture of &agr;,&bgr;-unsaturated alcohols of formula (I) and the epimers of formula (III):
is formed. These two epimer alcohols are separated directly or during some further steps of chemical transformation, usually by chormatographic.
The synthesis of these compounds is carried out most frequently by reduction of &agr;,&bgr;-unsaturated ketones of formula (II), when a mixture of &agr;,&bgr;-unsaturated alcohols of formula (I) and their epimers of formula (III):
The reduction of the keto group of &agr;,&bgr;-unsaturated ketones of general formula (II) was studied in detail in order to enhance the yield and ratio of &agr;,&bgr;-unsaturated alcohols of general formula (I) and at the same time to avoid saturation of the &agr;,&bgr;-double bond. In the prior art the reduction of &agr;,&bgr;-unsaturated ketones of general formula (II) was realized by using borohydride reagents containing a bulky, possibly optically active substituent and in a solvent having ether character (e.g. in tetrahydrofurane, or in a mixture of tetrahydrofurane, diethyl-ether and pentane), at a temperature from −78° C. to −130° C., where the ratio of &agr;,&bgr;-unsaturated epimer alcohols of general formula (I) and of general formula (III) is altered between 1:2-4.5 (J. Am. Chem. Soc. 95, 1491 (1971); J. Am. Chem. Soc. 94, 8616 (1972); U.S. Pat. No. 3,974,183 HU-PS-175.889 Hungarian Patent ). As reducing agents commercially not available lithium—diisopinocam—phenyl-tert-butyl-borohydride, lithium-2-thexyl-8-methyl-2-borobicyclo[3,3,1]nonyl-borohydride, lithium tricyclopentyl-borohydride or lithium-diisobutyl-tert-butyl-aluminumhydride and L-selektride® (lithium-tri-sec-butyl-borohydride) (all containing bulky groups) were used among others.
Some representatives of &agr;,&bgr;-unsaturated ketons of general formula (II) were reduced by applying zinc borohydride too, in 1,2-dimethoxyethane at 0° C. and at room temperature, where the epimers of general formula (I) and general formula (III) were formed in an 1:1 ratio (J. Am. Chem. Soc. 91, 5675 (1969); J. Am. Chem. Soc. 94, 8616 (1972); U.S. Pat. No. 3,970,684;
Using sodium borohydride in ethanol at −30° C. or lithium-trialkyl-borohydride at a temperature lower than −90° C. as reducing agents, the ratio of the epimeric &agr;,&bgr;-unsaturated alcohols of general formula (I) and of general formula (III) fluctuated between the ratios of 50:50 and 60:40 (J. Am. Chem. Soc. 94, 8616 (1972); EP-A-435,443; EP-A-455,448; EP-A-467,564; J. Med. Chem. 24, 1353 (1981). Using sodium borohydride as reducing agent the selectivity of the reduction could be increased when the reduction was carried out at −78° C. in methanol or in a mixture of methanol and dichloromethane, in the presence of cerium (III) chloride (EP-A-219,580; U.S. Pat. No. 4,739,078). Using borane as the reducing agent in the presence of 5-10% air and humidity sensitive oxazaborolydines, a far more favourable diastereomer ratio could be achieved (J. Am. Chem.Soc. 109, 7925 (1987)), but this method can not be applied on a larger scale. Using diisobutyl-aluminum-(2,6-di-tert.butyl-4-methyl phenoxide) (J. Org. Chem. 44, 1363 (1979); Bull.Chem.Soc. Japan 54, 3033 (1981)) at −78° C.; aluminium-isopropoxide in nitrogen atmosphere and in hot toluene (Synthetic Communications 4, 211 (1974)), di(isobornyloxy)-aluminium-isopropoxide or other modified lithium-aluminium-hydrides (J.Am.Chem.Soc. 106, 6717 (1984); Synthetic Communications 9, 799 (1979); Synthetic Communications 9, 483 (1979)) did not represent any advantage either because of difficulties of preparing these reagents, their sensitivity, and/or the costs of preparing them.
Under the conditions of catalytic hydrogenation, e.g. using charcoal containing palladium catalyst of 5% metal content, the carbon-carbon double bond of the &agr;,&bgr;-unsaturated ketons of general formula (II) saturates without the reduction of the ketone group (EP-A-289,349; Synthetic Communications 19, 245 (1989); EP-A-435,443.
It is the object of this invention to provide an industrially feasible process, which is suitable at room temperature and without applying special additives, extreme conditions and reagents for the preparation of compounds of general formula (I) by diastereomeric reduction of ketones of general formula (II) in higher yields them in any known processes. The base of this new process achieving this object is the unexpected finding that &agr;,&bgr;-unsaturated alcohols of general formula (I)—wherein R means an alkyl group containing 1-4 carbon atoms, or in a given case benzoyl group substituted with phenyl group; R
1
means hydrogen atom or an alkyl group containing 1-4 carbon atoms; R
2
means hydrogen atom or alkyl group containing 1-4 carbon atoms; R
3
means in a given case an alkyl group containing 1-6 carbon atoms substituted with phenyl group or with cycloalkyl group containing 5-7 carbon atoms, or in a given case phenoxy group substituted with halogen atom or a cycloalkyl group containing 5-7 carbon atoms, R
4
means hydrogen atom or halogen atom—are formed diastereoselectively upon reduction of &agr;,&bgr;-unsaturated ketones of general formula (II)—wherein the meanings of R, R
1
,R
2
,R
3
, and R
4
are as given above—if alkali borohydrides of small space demand are applied and the reaction is carried out in a heterogen phase, in an aprotic solvent in the presence of inorganic substances which are dissoluble in the reaction mixture and their particle sizes are small.
According to our experiences within the conditions described above and within the temperature range of −10° C. and +30° C. diastereoselectivity barely fluctuated. Thus the reaction can be carried out at about the room temperature. The term of inorganic substances dissoluble in the reaction mixture and having small particle sizes means farourably silicium compounds and/or aluminium compounds or mixtures thereof These are preferably the silica gels, different types of aluminium oxide, in the first place the “active” aluminium oxides which can be acidic, basic, or neutral in their reaction, the adsorptive capacity of which can be determined by the Brockmann scale./Römp Chemical Encyclopedia Vol. I. p. 116-117 (Müszaki Könyvkiadó=Technical Publishing House. Bp.1982)/. The term of silica gels which are useful in the claimed new process means silicic acid gels as defined in Römp Chemical Encyclopedia Vol.II. P. 977-978 /Müszaki Könyvkiadó, Budapest. 1982/. These are for example Silica gel 60, Silica gel G. “Small particle sizes” means 0.01-10000 micrometer preferably the particle size range is from 1 &mgr;m to 1000 &mgr;m.
Applicable aprotic solvents preferably halogenated hydrocarbons as chlorobenzene, methylene chloride, carbon tetrachloride, chloroform, 1,1,2,2-tetrachloroctane; alkane carboxylic acid esters as ethyl acetate, methyl acetate, methyl propionate; hydrocarbons as xylene, or toluene; alkyl nitriles as acetonitrile; ethers as tetrahydrofurane or diethyl-ether can be used. If we use ethanol as solvent for the reduction, or we carry out the reduction without the presence of silica gel, then diasteroeselectivity decreases substantially. The presence of small quantity of alcohol of short carbon chain e.g. methanol however faci
Baloghne Kardos Zsuzsanna
Benno Nandor
Beresne Povarny Magdonla
Dalmadi Gyula
Ebinger Katalin
Birch & Stewart Kolasch & Birch, LLP
Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt.
Galambos Attila
Robinson Binta
Rotman Alan L.
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