Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2002-05-01
2003-11-25
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
active
06653492
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method of providing bile acids from non-animal starting materials.
BACKGROUND OF THE INVENTION
Bile acids occur in conjugation with glycine or taurine in bile of most vertebrates and some of them find use in medicine. Thus, some bile acids—due to their inherent pharmacological properties—are used as cholerectics (see, for example, James E F Reynolds (editor) Martindale The Extra Pharmacopoeia, 30
th
Edition, The Pharmaceutical Press, London (1993), page 1341). Due to their surface-active properties bile acid salts have been tested as absorption enhancers in pharmaceutical compositions (GB 1,527,605, Takeda). Also, bile acids can be used to make derivatives of therapeutic peptides with the purpose of influencing the profile of action of the peptides (WO 95/07931; WO 98/08871, both Novo Nordisk).
Traditionally, bile acids have been obtained from animal sources. However, the wide distribution of serious diseases such as HIV, AIDS and Bovine Spongiform Encephalopathy (BSE) has caused a wide spread fear that material of animal origin may cause infection. Even though the fear may not be well founded in all cases it is desirable to avoid—as far as practicable—to have any components of animal origin in medicaments in order to eliminate any danger and fear of danger. Bile acids have quite complicated molecular structures and they cannot be synthesized at a commercially acceptable price from simple starting materials.
DEFINITIONS
The designation “optionally substituted derivatives” of lithocholic acid and the intermediates used for its preparation is used to designate closely related products and intermediates which differ from lithocholic acid or the intermediates leading to lithocholic acid by having one or two further hydroxy groups (deoxycholic acid, chenodeoxycholic acid, cholic acid).
DESCRIPTION OF THE INVENTION
Natural products having some structural resemblance to the bile acids are found in the vegetable world and they are available at a price that does not from the outset forbid their use as starting materials in a large-scale synthesis of bile acids.
Accordingly, the present invention provides a method of providing lithocholic acid of Formula (I)
or an optionally substituted derivative thereof which comprises
step a) catalytic hydrogenation of ethyl-3-oxo-4,22-choladienate (Formula (II)) or an optionally substituted derivative thereof
to give ethyl-3-oxocholanate (Formula (III)) or the corresponding substituted derivative thereof:
followed by:
step b) hydrolysis of the C-24 ester group of the intermediate of formula (III), obtained in step a), or the corresponding substituted derivative thereof, to give 3-oxocholanic acid (Formula (IV)) or the corresponding substituted derivative thereof,
and reduction of the 3-keto group of this intermediate to give lithocholic acid
(Formula (I)) or the corresponding substituted derivative thereof, or, as an alternative to step b):
step c) reduction of the 3-ketogroup of the intermediate (III), obtained in step a), or the corresponding substituted derivative thereof, to give the intermediate of formula (V):
followed by hydrolysis of the C-24 ester group to give lithocholic acid (Formula (I)) or the corresponding substituted derivative thereof.
Stigmasterol is a sterol that can be isolated from soybeans. The above-mentioned starting material of formula (II) can be obtained from stigmasterol by oxidation and ozonolysis to 3-ketobisnor-4-cholenaldehyde as described by J A Campbell et al., J Am Chem Soc 79 (1957) 1127-129, followed by reaction of the aldehyde with triethylphosphonoacetate as described by E D Bergmann et al., Steroids 27 (1976) 431-437.
The catalytic hydrogenation according to step a) above can be carried out in any suitable solvent conventionally used for catalytic hydrogenations e.g. alcohols and ethers. In one embodiment of the invention, the solvent used is 99% ethanol.
The catalyst used in step a) can be any catalyst that will provide specific reduction of the carbon—carbon double bonds in the 4-position and in the 22-position of the compound of formula (II) or a corresponding substituted derivative e.g. 5% palladium on carbon or 10% palladium on carbon. In one embodiment of the present invention the catalyst used for the reduction of the compound of formula (II) is 10% palladium on carbon.
The reduction described in step a) can be carried out in the presence of a base, such as an alkali metal hydroxide or an alkaline earth metal hydroxide or other metal hydroxide or such as an aliphatic amine, e.g. tert-butylamine. In a particular embodiment, the reduction is carried out in the presence of potassium hydroxide.
The reduction described in step a) can be carried out at various temperatures. In one embodiment of the present invention, the reduction is carried out at a temperature between 0° C. and 80° C. In a more specific embodiment the reduction is carried out at room temperature e.g. between 15° C. and 30° C.
The hydrogen pressure under which the reduction according to step a) is carried out can be selected within a wide range. Thus, in one embodiment, the pressure can be in the range from atmospheric pressure to 10 atmospheres. Other embodiments are at atmospheric pressure or in the range from atmospheric pressure to 2 atmospheres.
The hydrolysis of the ester group carried out according to step b) and step c) can be carried out under various conditions. Thus it can be carried out at room temperature in an alkaline mixture of water and a water miscible solvent e.g. an alcohol. When step b) is used, the base can conveniently be the base added before the catalytic hydrogenation was carried out. However, for the ester group hydrolysis a further amount of the same or another base can be added to the reaction mixture. When step c) is used, the reaction mixture in which the intermediate (V) is formed can be made strongly alkaline after dilution with water and hydrolysis of the ester group can be performed in this mixture. Alternatively, the intermediate (V) can be isolated and purified and subsequently the ester group can be hydrolysed e.g. using sodium hydroxide or potassium hydroxide in aqueous ethanol.
For the reduction of the 3-keto group in the intermediates of formula (III) and (IV) is used reducing agents that will provide a specific reduction of this group. Examples of such agents are lithium tri-tert-butoxyaluminiohydride, sodium borohydride and sodium borohydride combined with a modifying agent, e.g. cerium(III) chloride. The reductions are carried out starting at ice-bath temperature. Subsequently, the temperature is allowed to raise to room temperature. A convenient solvent when lithium tri-tert-butoxyaluminiohydride is used as the reducing agent is tetrahydrofuran. Other options are dioxane, ethylene glycol dimethyl ether and diethylene glycol dimethyl ether. A convenient solvent when sodium borohydride or sodium borohydride combined with a modifying agent is used as the reducing agent is methanol or ethanol optionally containing water.
REFERENCES:
patent: 2471697 (1949-05-01), Minlon
patent: 1527 605 (1978-10-01), None
patent: WO 95/07931 (1995-03-01), None
patent: WO 98/08871 (1998-03-01), None
Martindale, The Extra Pharmacopoeia, CAS Apr. 25, 1981; 11006-55-6; pp. 1341-1342, 1993.
Campbell et al., J Am Chem Soc. vol. 79, pp. 1127-1129 (1957).
Bergman et al., Steroids, vol. 27, No. 3, pp. 431-437 (Mar. 1976).
Fieser et al., Steroids, p. 346 (1967).
JP 53108961 (WPI) Abstract, 1978.
Badio Barbara P.
Began, Esq. Marc A.
Boak, Esq. Richard W.
Green, Esq. Reza
Novo Nordick A/S
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