Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-01
2003-08-12
Gerstl, Robert (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06605726
ABSTRACT:
This application is a 371 of PCT EP99/07746
This invention relates to a process for the production of epothilone B and derivatives as well as intermediate products for this process.
It is known that the natural substances epothilone A (R=H) and epothilone B (R=methyl) (compound I, DE 195 42 986 A1, DE 41 38 042 C2)
have a fungicidal and cytotoxic effect. According to indications for in vitro activity against mammary and intestinal tumor cell lines, this family of compounds appears especially advantageous for the development of a pharmaceutical agent. Various working groups have successfully endeavored to synthesize these macrocyclic compounds. The working groups start from various fragments of the macrocycle to synthesize the desired natural substances.
In any case, diastereomer-pure fragments as starting products and intermediate products are required for a successful epothilone synthesis. Diastereomer purity is often decisive for the action and reliability of a pharmaceutical agent and thus a requirement for its production.
The total synthesis of epothilone A is described by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 1997, 109, No. 5, pp. 543-544).
Epothilone derivatives were already described by Höfle et al. in WO 97/19086. These derivatives were produced starting from natural epothilone A or B.
Another synthesis of epothilone and epothilone derivatives was described by Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172. Nicolaou et al. also described the synthesis of epothilone A and B and several epothilone analogs in Nature, Vol. 387, 1997, pp. 268-272, and the synthesis of epothilone A and its derivatives in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7960-7973, as well as the synthesis of epothilone A and B and several epothilone analogs in J. Am. Chem. Soc., Vol. 119, No. 34, 1997, pp. 7974-7991.
Nicolaou et al. also describe in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 the production of epothilone A analogs using combinative solid-phase synthesis. Several epothilone B analogs are also described there.
The object of this invention is to provide a process for the production of epothilone B and derivatives, in which epothilone is built up from fragments that can be obtained at a reasonable price and enantioselectively as starting products.
Another object is the provision of epothilone B or its derivatives in higher yields than according to the previously known processes.
The production of epothilone B according to this invention is based on the linkage of three partial fragments 2, 3, and 4 according to the diagram below:
means a C1-C6 fragment (epothilone numbering system) of general formula:
in which
PG
21
and PG
22
, independently of one another, in each case mean a hydroxy protective group and
R
6
means a straight-chain or branched-chain alkyl group with up to 6 carbon atoms, a cycloalkylalkyl group with up to 10 carbon atoms, or a phenyl group, 1- or 2-naphthyl group, heteroaryl group, benzyl group or methylheteroaryl group.
3 stands for a C7-C10 fragment (epothilone numbering system) of general formula:
in which
PG
3
means a hydroxy protective group, and
FG
3
means a phenylsulfonyl group.
4 stands for a C11-C20 fragment (epothilone numbering system) of general formula:
in which
FG
4
means an iodine atom or another leaving group, and
PG
4
means a hydroxy protective group.
Synthesis
Production of 2
According to this invention, partial fragment 2 is obtained with use of the following synthesis route enantioselectively from very reasonably-priced starting compounds in an efficient way with high enantiomer excesses.
The substituents have—unless otherwise indicated—the meanings that are already indicated above in the individual fragments:
Steps a and b
The protected 3-hydroxypropanal (2-I), which was produced analogously to the literature (Kiyooka et al., J. Org. Chem., 1991, 56, 2276-2278) from 1,3-propanediol by monoprotection and oxidation, is reacted under chiral catalysis with a silylketenacetal of general formula
(R
2
=methyl, ethyl, etc.) with mediation by N-tosylvaline/diborane to form (2-II), with high enantiomeric excess. In compound (2-II), the 3-hydroxy group is then protected according to methods that are known to one skilled in the art for the production of the compound of general formula (2-III).
As alkyl, silyl and acyl radicals for the protective groups PG
21
, PG
22
, PG
3
and PG
4
, the radicals that are known to one skilled in the art are considered. Alkyl or silyl radicals that can be easily cleaved from the corresponding alkyl and silyl ethers, such as, for example, the methoxymethyl, methoxyethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, trimethylsilyl, triethylsilyl, tert-butyl-dimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, triisopropylsilyl, benzyl, para-nitrobenzyl, or para-methoxybenzyl radical, and alkylsulfonyl and arylsulfonyl radicals, are preferred. As acyl radicals, e.g., formyl, acetyl, propionyl, isopropionyl, pivalyl, butyryl or benzoyl, which can be substituted with amino and/or hydroxy groups, are suitable.
A survey on protective groups is found in, e.g., “Protective Groups in Organic Synthesis,” Theodora W. Green, John Wiley and Sons.
In this case, those protective groups are preferred that can be cleaved under the action of fluoride, such as, e.g., trimethylsilyl, tert-butyldimethylsilyl, triisopropyl, triethylsilyl, tert-butyldiphenylsilyl radicals, and of the latter especially the tert-butyldimethylsilyl radical, triisopropylsily radical, and the tert-butyldiphenylsilyl radical.
Steps c and d
Compound (2-III) is converted into methylketone (2-IV) by reaction with trimethylsilylmethyllithium and is then reacted to form the compound of general formula 2, according to the methods known to one skilled in the art, with an alkyl, cycloalkylalkyl, aryl, heteroaryl, methylaryl or methylheteroaryl halide of formula (2-X), R
6
-Hal, in which R
6
means a straight-chain or branched-chain alkyl group with up to 6 carbon atoms, a cycloalkylalkyl group with up to 10 carbon atoms, a phenyl group, 1- or 2-naphthyl group, heteroaryl group, benzyl group or methylheteroaryl group, and Hal means a halogen atom (chlorine, bromine or iodine).
As an alternative, compound (2-III) can also be reduced to alcohol, according to methods that are known to one skilled in the art, selectively oxidized to aldehyde and then reacted with an organometallic compound Me-CH
2
—R
6
(Me stands for a lithium atom or for a radical MgHal, Hal=Cl, Br: R
6
has the above-indicated meaning). Subsequent oxidation then also yields a compound of general formula 2.
As C
1
-C
6
alkyl groups for R
6
, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, or hexyl group is suitable.
For a cycloalkylalkyl group R
6
with up to 10 carbon atoms, for example, the cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl group can be mentioned.
The heteroaryl radical, either as R
6
or in methylheteroaryl group R
6
, can be, for example, a furyl, thienyl, pyridyl, pyrazolyl, pyrimidinyl, oxazolyl, pyridazinyl, pyrazinyl, quinolyl, or thiazolyl radical.
The radicals that are possible above for R
6
can be substituted in one or more places by halogen, OH, O-alkyl, CO
2
H, CO
2
-alkyl, —NH
2
, —NO
2
, —N
3
, —CN, C
1
-C
20
alkyl, C
1
-C
20
acyl, or C
1
-C
20
acyloxy groups. Heteroatoms in the heteroaryl radicals can be oxidized.
Production of 3
The substituents have—if not otherwise indicated—the meanings that are already indicated above in the individual fragments.
Partial fragment 3 can be produced in high optical purity from the hydroxyisobutyric acid methyl ester that can be obtained inexpensively.
Steps a and b
Compound (3-I) is available in a known way by monoprotection and reduction from the commercially available hydroxyisobutyric acid-methyl ester. Compound (3-I) is reacted with tosyl chloride to form compound (3-II) (thus conversion of the hydroxy group into a better leaving group
Mantoulidis Andreas
Mulzer Johann
Öhler Elisabeth
Gerstl Robert
Millen White Zelano & Branigan P.C.
Schering AG
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