Thiazole derivatives, method for their production and use

Details Thiazole derivatives, method for their production and use Thiazole derivatives, method for their production and use

2000-06-14

2002-05-07

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S204000

Reexamination Certificate

active

06384230

ABSTRACT:

The invention relates to the subject that is characterized in the claims, i.e., thiazole derivatives, process for their production and their use for the production of epothilone A, epothilone B or derivatives thereof.
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 action. According to references for an in vitro activity against breast and intestinal tumor cell lines, this compound class appears particularly advantageous for the formation of a pharmaceutical agent. Various working groups are therefore concerned with the synthesis of these macrocyclic compounds. The working groups start from different fragments of the macrocycle to synthesize the desired natural substances. Danishefsky et al. intends to synthesize from three fragments C(1)-C(2)+C(3)-C(9)+C(10)-C(20). The C(10)-C(20) fragment is a thiazole derivative, which could not be obtained free of diastereomers in a 15-stage synthesis (JOC, 1996, 61, 7998-7999). Freedom from diastereomers is often decisive, however, for the action and a requirement for the production of a pharmaceutical agent.
The object was therefore to prepare, in a manner free of diastereomers, suitable fragments, from which the macrocyclic compounds and derivatives thereof can be synthesized.
It was now found that the thiazole derivatives of formula II
in which
R
1
means C
1
-C
4
alkyl,
R
2
means any protective group that can be chelated,
R
3
means hydrogen or C
1
-C
4
alkyl,
Y means CO
2
R
4
, CHO, CH═CH
2
or CH
2
R
5
,
 whereby
R
4
stands for C
1
-C
4
alkyl or an optionally substituted benzyl group,
R
5
stands for halogen, hydroxy, p-toluenesulfonate or —OSO
2
B and
B stands for C
1
-C
4
alkyl or C
1
-C
4
perfluoroalkyl,
can be produced free of diastereomers, and are suitable for the production of epothilone A and epothilone B and derivatives thereof.
C
1
-C
4
alkyl for R
1
, R
3
, R
4
and B is defined as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
Any protective group R
2
that can be chelated is defined as, for example, benzyl radicals such as, e.g., benzyl, p-methoxybenzyl (PMB), silyl radicals such as, e.g., trimethyl-silyl, 2-(trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, methoxymethyl, benzyloxymethoxymethyl, benzoyl, acetyl.
Substituted benzyl group R
4
can be, e.g., p-methoxybenzyl, 2,4-dimethoxybenzyl or a benzyl radical that is substituted by another electron-pushing substituent.
Halogen is defined as fluorine, chlorine, bromine and iodine, whereby bromine and iodine are preferred.
C
1
-C
4
Perfluoroalkyl is defined as straight-chain or branched, completely fluorinated alkyl radicals, such as, for example, CF
3
, C
2
F
5
, C
3
F
7
, C
4
F
9
.
Compounds II can be produced according to the process that is shown in diagram I, in which the synthesis is depicted by way of example for compound IIa with R
2
=p-methoxybenzyl, R
3
=methyl and Y=CO
2
Et.
Starting from the naturally occurring (S)-malic acid (III), the &agr;-hydroxy acid function with trifluoroacetic acid anhydride/methanol (a) is converted into the mono-methylester. The acidic function that still remains is then reduced to alcohol with diborane in tetrahydrofuran (b). The (S)-(−)-methyl-2,4-dihydroxyester that is thus obtained is converted into the cyclic acetal (IV) with p-methoxybenzyldimethylacetal with camphersulfonic acid in toluene under reflux (c). The methylketone (V) is obtained from the methylester by reaction with one equivalent of methyllithium in 2 hours at −100° C. (d). Reaction with a C
2
-, C
3
- or C
4
-organometallic compound, e.g., of a Grignard compound under common reaction conditions, results in the other radicals R
1
. In the Wittig reaction (c), the 2-methyl-4-thiazolylmethyltriphenylphosphonium bromide, which is accessible in two stages from 1,3-dichloropropanone, is combined first with sodium hexamethyldisilazide at −78° C. in tetrahydrofuran before the ketone is added to it. After 1 hour and after heating to −40° C., the reaction results in an E/Z-mixture (E/Z=3.6:1). The E-isomer (VI) can be separated by simple flash chromatography. Regioselective release of the terminal hydroxy group by reductive opening of the acetal with 4 equivalents of diisobutylaluminum hydride in methylene chloride in 4 hours at −20° C. (f) produces a readily separable mixture (5.6:1 for the desired regioisomer) of the alcohol. After separation, the alcohol is converted into the corresponding aldehyde by Swern oxidation in one hour while being heated from −78° C. to 0° C. (g), and the aldehyde is reacted immediately to Wadsworth-Horner-Emmons condensation under Still's conditions (h) with ethyl-2-diethoxyphosphinylopropionate or the Horner reagent that is suitable corresponding to the desired radical R
3
with the addition of potassium hexamethyldisilazide, 18-crown-6 at −78° C. for one hour in tetrahydrofuran. An E/Z-mixture (E/Z=6.2:1) of the &agr;,&bgr;-unsaturated ester is obtained, from which the Z-isomer (IIA) can be separated in a good yield. The use of the trifluoroethylphosphonate derivative results in a better selectivity of 15:1.
The compound of general formula IIa represents a central component of the synthesis of epothilone derivatives and epothilone itself.
The ester function in 11-position can be converted into any functionality that is required for the subsequent ring closure.
Derivatizations in 12- and 13-position (epothilone numbering system) are possible from the double bond. Thus, for example, conversion by Sharpless oxidation into the epoxide that is itself present in the epothilone:
In this respect, ester IIa is reduced with 3 equivalents of diisobutylaluminum hydride in tetrahydrofuran at −20° C. (i) into a &agr;,&bgr;-unsaturated alcohol, and then the double bond of the allyl alcohol is epoxidated in a diastereo-selective manner with 4 Å molecular sieve, titanium tetraisopropylate, D-(−)-diisopropyltartrate, tert-butylhydroperoxide in methylene chloride for 3 hours at −30° C. (k).
The hydroxy group in 15-position that is still present in protected form also allows derivatizations at this point or can be cleaved under conditions that are known in the literature.
Compounds with Y—CHO can be obtained by Dibal reduction of compound IIa in a way that is known in the literature.
Subsequent Wittig reaction results in compounds with Y=CH═CH
2
.
The compounds with Y=CH
2
R
5
with R
5
=p-toluenesulfonate, (C
1
-C
4
)alkylsulfonate or (C
1
-C
4
)perfluoroalkylsulfonate can be obtained from alcohol (VII).
The compounds with Y=CH
2
-halogen can be obtained from, e.g., the compound with Y=CH
2
-p-toluenesulfonate or Y=OH in the usual way.
In contrast to the process of Danishefsky et al., only 10 stages are required for the synthesis up to the stage of the epoxide, and the thiazole derivative of formula IIa can be obtained free of diastereomers just like the epoxide. Another advantage consists in that the natural starting material that is used and the reactions of the synthesis allow larger amounts to be produced.
The further processing of the compounds according to the invention to epothilone A and B can be carried out as indicated in the reaction sequence below. The compound of general formula XI is further processed into epothilone B analogously to known processes by cleavage of the primary protective group, oxidation in 1-position, selective release of the 15-hydroxy group, as they are described by, for example, K. C. Nicolaou et al. In Nature, Vol.38-, 1997, pp. 268-272 and J. Am. Chem. Soc. 1997, 119, pp. 7960-7973:
f) (i) iodide formation; (ii) sulfone coupling, 76.5%; g) desulfonation, 70%; h) desilylation, 98%; i) aldol reaction.
The examples below are used for a more detailed explanation of the subject of the invention, without intending that it be limited to these examples.
PREOPERATIVE METHODS
All reactions of org

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