Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
1999-04-09
2004-01-27
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S600000
Reexamination Certificate
active
06683197
ABSTRACT:
The invention relates to a process for the production of 4,4-dimethyl-5&agr;-cholesta-8,14,24-trien-3&bgr;-ol (1) and intermediate products in the process
Studies by Byskov et al. (Nature 1995, 374, 559) show that 4,4-dimethyl-5&agr;-cholesta-8,14,24-trien-3&bgr;-ol, formula I, named FF-MAS below, isolated from human follicular fluid, is an endogenous substance that regulates meiosis, to which advantageous hormonal effects are attributed. This substance is thus of importance for pharmaceutical applications, for example to promote fertility.
A first synthesis of this natural substance, which will take place in the biosynthesis of cholesterol from lanosterol, was described by Dolle et al. (J. Am. Chem. Soc. 1989, 111, 278). Starting from ergosterol, FF-MAS is obtained in an 18-step synthesis sequence at great cost. Large parts of the synthesis are dedicated to the partial chemical degradation of the ergosterol side chain, the subsequent creation of the FF-MAS side chain and the protective group chemistry that is necessary to achieve this goal.
A second synthesis of FF-MAS was described by Schroepfer et al. starting from dehydrocholesterol in a 13-step synthesis (Bioorg. Med. Chem. Lett. 1997, 8, 233). Also in this synthesis, a more expensive protection of the diene system must be performed in the side chain degradation. only four steps (epoxidation and rearrangement for protection; reduction and elimination for the regeneration of the diene system) are due to the protective group strategy.
The objects of this invention are new processes for the synthesis of FF-MAS. The subjects of this invention are also the new, previously unknown compounds that are processed within the framework of the syntheses and can be used per se or derivatized as starting materials for the synthesis of other target molecules, for example for the synthesis of FF-MAS analogues (see WO 96/00235) and the use of compounds for the production of 4,4-dimethyl-5&agr;-cholesta-8,14,24-trien-3&bgr;-ol.
This object is achieved by the teaching of the claims.
By the two processes according to the invention, considerably fewer intermediate steps take place than within the known syntheses of Dolle et al. The number of purification steps is considerably lower, and no technically complex devices, such as an ozone generator with the facilities that are necessary for its operation, are required.
Process Variant 1
According to Diagram 1, FF-MAS is produced in a ten-step sequence starting from, for example, 3-oxopregn-4-enoic-21-acid methyl ester (Formula 2 with R
1
=CH
3
) (Helv. Chim. Acta 1939, 22, 1178 and 1184). The compound that is mentioned here as educt is readily accessible in various ways from commercially available steroids. For example, the production of a compound of formula 2 with R
1
=CH
3
in a three-step sequence from 3&bgr;-hydroxyandrost-5-en-17-one (CAS Registry Number 53-43-0; 571-35-7, etc.) via Horner-Wittig (e.g., Synth. Commun. 1977, 7, 215), reduction of the resulting 17-double bond (e.g., Synthesis 1996, 455) and subsequent Oppenauer oxidation (e.g., Helv. Chim. Acta 1939, 22, 1178 and 1884) are described.
Starting from 3&bgr;-acetoxy-androst-5-en-17-one (CAS Registry Number 853-23-6, etc.), a compound of formula 2, with R
1
=CH
3
, can also be produced via condensation with malodinitrile, subsequent reduction of the resulting 17,20-double bond with sodium borohydride, nitrile saponification and decarboxylation with potassium hydroxide in ethylene glycol, esterification of the resulting carboxylic acid (Coll. Czech. Chem. Commun. 1982, 1240) and final Oppenauer oxidation (e.g., Helv. Chim. Acta 1939, 22, 1178 and 1184).
It is familiar to one skilled in the art that R
1
can be varied in compounds of formula 2 according to standard methods. This can happen by using other alcohols in the esterification step, but also by reesterification of an already present ester. R
1
can thus have the meaning of hydrogen, methyl, ethyl, propyl, isopropyl, butyl and the corresponding butyl isomers, pentyl and the corresponding pentyl isomers as well as hexyl and the corresponding hexyl isomers, phenyl, benzyl, ortho-, meta- and para-methyl phenyl.
The reaction of a compound of formula 2 to a compound of formula 3 is carried out according to processes that are known in the art (e.g., Helv. Chim. Acta 1980, 63, 1554, J. Am. Chem. Soc. 1954, 76, 2852). For example, a compound of formula 2 is reacted in the presence of bases such as, for example, the alkali salts of lower alcohols, but preferably potassium tert-butylate, with an alkylating agent such as, for example, dimethyl sulfate, dimethyl carbonate or else methyl iodide in a solvent or solvent mixture. As solvents, lower, preferably tertiary alcohols as well as ethers, for example methyl tert-butyl ether or tetrahydrofuran and their mixtures can be used. The use of tert-butanol or a mixture of tert-butanol and tetrahydrofuran is preferred. The reaction is performed in a temperature range of 0° C. to 65° C., but preferably in a temperature range of 15° C. to 50° C.
The reaction of a ketone of formula 3 to the corresponding 3-alcohol of formula 4 can be performed with a considerable number of reducing agents. As examples, there can be mentioned: BH
3
complexes (e.g., with tert-butylamine or trimethylamine), selectrides, sodium and lithium borohydride, inhibited lithium aluminum hydrides (e.g., LiAl (O′Bu)
3
H); microorganisms such as, e.g., baker's yeasts or enzymes, for example, 3&bgr;-hydroxy steroid dehydrogenase, can also be used.
It is known to one skilled in the art that depending on the reagent that is used, various solvents or solvent mixtures and reaction temperatures can be used. Preferred here, however, are borohydrides, such as, for example, sodium borohydride in suitable solvents, such as, for example, lower alcohols or mixtures of alcohols with aprotic solvents, for example dichloromethane or tetrahydrofuran. The reactions are performed in a temperature range of −20° C. to 40° C., but preferably in the range of 0° C. to 30° C.
Before the introduction of the 7,8-double bond (5→6), the 3-OH group of a compound of formula 4 is provided with a protective group R
2
that is suitable for this reaction. As protective groups, for example, esters of aliphatic and aromatic carboxylic acids, e.g., acetic- and benzoic acid esters, acetal protective groups, such as, for example, tetrahydropyranyl-, methoxymethyl- or methoxyethoxymethyl ethers, but also other ether protective groups, for example, silyl ethers, such as, for example, trimethylsilyl-, triethylsilyl- or triisopropylsilyl; triphenylsilyl; dimethyl(1,1-dimethylethyl)silyl-ether, are suitable.
Depending on the desired protective group, the reaction conditions and reaction temperatures vary. The introduction of the respective protective group is carried out according to processes that are known to one skilled in the art. As an example, the esterification of a compound of formula 4 with acetyl chloride in the presence of a base such as triethylamine or pyridine with or even without the addition of an inert solvent, for example dichloromethane in a temperature range of 0° C. to 60° C., can be mentioned. The introduction of a silyl protective group is carried out preferably by reaction of a compound of formula 4 with a silyl halide, but preferably dimethyl-(1,1-dimethylethyl)silyl-chloride or triethylsilyl chloride in the presence of a base, for example imidazole, in a suitable solvent such as, for example, dimethylformamide in a temperature range of 10° C. to 140° C., but preferably between 20° C. and 100° C. The introduction of the 7,8-double bond into a compound of formula 5 (→6) can be carried out in a two-step process. First, it is bromated in an allylic manner to the 5,6-double bond in the 7-position, and then a compound of formula 6 is obtained by eliminating the hydrogen bromide. The bromine compound does not need to be isolated, but can generally be used directly in the next step. The bromation is carried out according to processes that are known in th
Blume Thorsten
Esperling Peter
Kuhnke Joachim
Badio Barbara P.
Millen White Zelano & Branigan, P. C.
Schering Aktiengesellschaft
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