Patent Application
20050032875
The present invention relates to a process for the preparation of indole derivatives and to novel intermediates.
Indole derivatives of the following formula (1) are known as pharmaceutical active ingredients (e.g. from U.S. Pat. No. 4,739,073) or are important precursors in the preparation thereof. An important indole derivative is fluvastatin, an HMG-CoA reductase inhibitor, that is to say an inhibitor of the biosynthesis of cholesterol, which is used in the treatment of hyperlipoproteinaemia and arteriosclerosis.
Known processes for the preparation of indole compounds of formula (1) do not in all cases meet the requirements in terms of the yield and economic viability of the processes.
The problem underlying the present Application is accordingly to provide a new process for the preparation of indole compounds of formula (1), by means of which those compounds can be obtained in as high a yield as possible combined with good economic viability.
The subject matter of the present invention is accordingly a process for the preparation of compounds of formula
wherein R1 is unsubstituted or substituted C1-C8alkyl,
As C1-C8alkyl radicals there come into consideration for R1, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, or straight-chain or branched pentyl, hexyl, heptyl or octyl. C1-C4Alkyl radicals are preferred. R1 is preferably propyl, especially isopropyl.
As C1-C8alkyl radicals there come into consideration for R2, R3, R4 and R5, for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, or straight-chain or branched pentyl, hexyl, heptyl or octyl. The mentioned alkyl radicals may be unsubstituted or substituted, for example by halogen, such as fluorine. Preference is given to corresponding C1-C4alkyl radicals.
As C1-C8alkoxy radicals there come into consideration for R2, R3, R4 and R5 especially C1-C4-alkoxy radicals, for example methoxy or ethoxy.
As halogen there comes into consideration for R2, R3, R4 and R5, for example, fluorine or chlorine, especially fluorine.
R2, R3 and R5 are preferably hydrogen. R4 is preferably fluorine, especially fluorine bonded in the 4-position.
As protecting groups for Y1, Y2, Y3 and Y4 there may be used the groups customary for that purpose. The usual protecting groups are indicated, for example, in Protective Groups in Organic Synthesis, Th. W. Greene and P. G. M. Wuts, John Wiley & Sons, Second Edition, 1991 (especially pages 118 to 142).
Preferred as protecting groups Y1, Y2, Y3 and Y4 are C1-C4alkylcarbonyl or silyl radicals; there also come into consideration protecting bridges wherein Y1 and Y2 together or Y3 and Y4 together form an unsubstituted or substituted alkylene or silyl radical. Examples of C1-C4-alkylcarbonyl radicals that may be mentioned include methyl- and ethyl-carbonyl. As silyl radicals there come into consideration, for example, radicals of formula —SiR3, wherein the R radicals may have identical or different meanings and are unsubstituted or phenyl-substituted C1-C8alkyl, especially C1-C4alkyl, or unsubstituted or substituted phenyl and wherein the mentioned phenyl radicals may each be further substituted, for example by C1-C4alkyl, halo-substituted C1-C4alkyl, C1-C4alkoxy, nitro or by halogen. The alkylene radicals and silyl radicals mentioned for the protecting bridges may be substituted, for example, by one or two of the R radicals as defined above.
Especially preferred as protecting bridges are radicals of formulae
wherein R7 and R8 are each independently of the other hydrogen, unsubstituted or phenyl-substituted C1-C8alkyl or phenyl, and
R7 and R8 are preferably hydrogen, C1-C4alkyl, benzyl or phenyl, especially C1-C4alkyl, benzyl or phenyl. R7 and R8 are especially preferably methyl, tert-butyl or benzyl.
R9 and R10 are preferably C1-C4alkyl, benzyl or phenyl, especially C1-C4alkyl or benzyl. R9 and R10 are especially preferably methyl, tert-butyl or benzyl.
Preferred protecting bridges are those of formula (5a).
Y1 and Y2 are especially preferably each independently of the other hydrogen or together form a radical of formula (5a) or (5b), especially a radical of formula (5a). More especially Y1 and Y2 are hydrogen.
As organic radicals there come into consideration for X1, for example, unsubstituted or substituted alkyl, alkenyl, alkynyl or phenyl radicals. Special mention may be made of unsubstituted or substituted C1-C12alkyl, C3-C12alkenyl, C3-C12alkynyl or phenyl radicals. In the case of X1 preference is given to unsubstituted or substituted alkyl radicals, especially C1-C12alkyl radicals and preferably C1-C6alkyl radicals. An example of substituents of the alkyl radicals that may be mentioned is, for example, phenyl unsubstituted or further substituted in the phenyl ring by C1-C4alkyl, C1-C4alkoxy, nitro, halogen or by hydroxy. Examples of X1 that may be mentioned include methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, allyl, benzyl, nitrobenzyl and hydroxybenzyl. X1 is especially preferably C1-C4alkyl, especially butyl and preferably tert-butyl.
When the radical X1 is a cation, the cation may be, for example, sodium or potassium, especially sodium.
X1 is preferably hydrogen, unsubstituted or phenyl-substituted C1-C8alkyl or a cation. Especially preferably X1 is a cation, such as sodium or potassium, especially sodium.
Z1 is preferably bromine, chlorine, iodine, —OSO2CF3, —COCl, —B(OH)2 or a mono- or di-ester derived from —B(OH)2. Especially preferably Z1 is bromine, chlorine or iodine, especially bromine, or —B(OH)2 or a mono- or di-ester derived from —B(OH)2. Bromine is of particular interest.
As mono-or di-ester derived from —B(OH)2 there come into consideration for R6 and Z1 both cyclic and acyclic esters. Suitable mono- or di-ester derivatives of —B(OH)2 are, for example, those of formula —B(OR′)2, where the two R′ radicals may have identical or different meanings and are hydrogen, unsubstituted or phenyl-substituted C1-C8alkyl or unsubstituted or substituted phenyl, or wherein the two R′ radicals together form a C1-C8alkylene radical. Examples of substituents of the phenyl radical that may be mentioned include C1-C4alkyl, C1-C4alkoxy, amino, N-mono- or N,N-di-C1-C4alkyl, halogen, hydroxy and nitro. The R′ radicals are preferably hydrogen or C1-C4alkyl, preference being given to ethyl and especially methyl. It is also preferred that the two R′ radicals together form a C1-C8alkylene radical, especially a C4-C8alkylene radical. An example of such an alkylene radical that may be mentioned is the radical of formula —C(CH3)2—C(CH3)2—.
R6 is preferably hydrogen, bromine, chlorine or iodine, especially hydrogen or iodine, preferably hydrogen.
As compound of formula (2) there is preferably used a compound of formula
wherein the meanings and preferred definitions given above for Z1 apply. Z1 is especially bromine, —B(OH)2 or a mono- or di-ester derived from —B(OH)2, preferably bromine.
As compound of formula (3) there is preferably used a compound of formula
wherein the meanings and preferred definitions given above for R6, R7, R8 and X1 apply. R6 is especially preferably hydrogen, bromine, chlorine or iodine, especially hydrogen. R7 and R8 are especially preferably each independently of the other hydrogen, unsubstituted or phenyl-substituted C1-C8alkyl or phenyl. It is more especially preferred to use the compound of formula (7) together with a compound of formula (6).
Compounds of formula (2) can be obtained, for example, by halogenating suitable compounds wherein Z1 is hydrogen. The halogenation can be carried out according to generally customary methods. For bromination, mention may be made, for example, of Houben-Weyl, Methoden der organischen Chemie, volume 5/4, pages 233 ff, Georg Thieme Verlag, Stuttgart, 1960. Suitable for the bromination are, for example, elemental bromine, N-bromosuccinimide, pyridinium bromide perbromide or triphenylphosphine dibromide, in an inert, preferably halogenated, solvent, such as carbon tetrachloride, chloroform, chlorobenzene or dichlorobenzene. The bromination is generally carried out at a temperature of from −5 to 25° C., in the case of N-bromosuccinimide at about from 40 to 85° C. The starting compounds wherein Z1 is hydrogen are known or can be obtained analogously to known processes, for example the processes indicated in U.S. Pat. No. 4,739,073. Compounds of formula (2) wherein Z1 is —B(OH)2 or a mono- or di-ester derived from —B(OH)2 can be obtained analogously to known processes (e.g. starting from the compound of formula (2) wherein Z1 is bromine).
Compounds of formula (3) are known (e.g. from U.S. Pat. No. 4,808,621) or can be obtained analogously to known processes.
As palladium catalyst there are preferably used olefinic palladium complex compounds.
Examples of such palladium catalysts that may be mentioned include compounds of formula
wherein L is a neutral ligand having electron donor properties, Z is an anionic ligand and D denotes substituents, and p is an integer from zero to five and defines the number of substituents on the allyl group;
and compounds of formula
wherein
L is a neutral ligand having electron donor properties. Suitable ligands are, for example, phosphine ligands of the tertiary phosphine type.
A suitable tertiary phosphine preferably contains from 3 to 40, especially from 3 to 18, carbon atoms. It preferably corresponds to the formula:
PR23R24R25 (11)
wherein R23, R24 and R25 are each independently of the others C1-C20alkyl, C3-C12cycloalkyl, C2-C11heterocycloalkyl, C6-C16aryl, C7-C16aralkyl or C2-C15heteroarylalkyl, it being possible for those radicals to be substituted by substituents selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C6-C16aryl, —NO2, SO3−, ammonium and halogen. The radicals R23 and R24 together can be unsubstituted or C1-C6alkyl-, C1-C6haloalkyl-, —NO2— or C1-C6alkoxy-substituted tetra- or penta-methylene, which have been fused to one or two bivalent 1,2-phenylene radicals, R25 being as defined above.
R23, R24 and R25 as C1-C20alkyl are, for example, methyl, ethyl, n- or iso-propyl or n-, sec- or tert-butyl or straight-chain or branched pentyl, hexyl, heptyl, octyl, isooctyl, nonyl, tert-nonyl, decyl, undecyl or dodecyl.
R23, R24 and R25 as C3-C12cycloalkyl are, for example, cyclopropyl, dimethylcyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
R23, R24 and R25 as C2-C11heterocycloalkyl preferably contain 4 or 5 carbon atoms and one or two hetero atoms from the group O, S and N. Examples include the substituents derived from oxirane, azirine, 1,2-oxathiolane, pyrazoline, pyrrolidine, piperidine, piperazine, morpholine, tetrahydrofuran and tetrahydrothiophene.
R23, R24 and R25 as C6-C16aryl are, for example, mono-, bi- or tri-cyclic, e.g. phenyl, naphthyl, indenyl, azulenyl or anthryl.
R23, R24 and R25 as C2-C15heteroarylalkyl are preferably such radicals that are, as heteroaryl, monocyclic or fused to a further heterocycle or to an aryl radical, e.g. phenyl, and preferably contain one or two, in the case of nitrogen up to four, hetero atoms from the group O, S and N. Examples of such heteroaryl radicals that may be mentioned include: furan, thiophene, pyrrole, pyridine, bipyridine, picolylimine, γ-pyran, γ-thiopyran, phenanthroline, pyrimidine, bipyrimidine, pyrazine, indole, coumarone, thionaphthene, carbazole, dibenzofuran, dibenzothiophene, pyrazole, imidazole, benzimidazole, oxazole, thiazole, dithiazole, isoxazole, isothiazole, quinoline, isoquinoline, acridine, chromene, phenazine, phenoxazine, phenothiazine, triazine, thianthrene, purine and tetrazole. C2-C15Heteroarylalkyl consists preferably of the mentioned heterocycles which substitute, for example, C1-C4alkyl radicals, depending on the length of the carbon chain where possible in the terminal position but alternatively in the adjacent position (1-position) or in the α-position (2-position).
R23, R24 and R25 as C7-C16aralkyl preferably contain from 7 to 12 carbon atoms, e.g. benzyl, 1- or 2-phenethyl or cinnamyl.
Preference is also given to sterically demanding radicals R23, R24 and R25, for example cyclic or branched, especially α,α-dibranched, and more especially α-branched, alkyl groups.
Special preference is given to those compounds (8) or (10) in which R23, R24 and R25 are methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl, 1-, 2- or 3-pentyl, 1-, 2-, 3- or 4-hexyl, cyclopentyl, cyclohexyl, phenyl, naphthyl or benzyl, e.g. (iso-C3H7)3P, (C5H9)3P, (C6H11)3P and (C6H5)3P.
As organic group there comes into consideration for the substituents of the compound of formula (10), for example, C1-C20alkyl, C3-C12cycloalkyl, C6-C16aryl or C2-C15heterocyclyl. As examples of such radicals, reference may be made to the corresponding radicals mentioned above for R23, R24 and R25. Examples of substituents of such radicals that may be mentioned include: C1-C4alkyl, halo-substituted C1-C4alkyl, for example trifluoromethyl, C6-C16aryl, especially phenyl or naphthyl (C6-C16aryl, especially phenyl or naphthyl, being unsubstituted or substituted by halogen, carboxy, C1-C4alkoxycarbonyl, hydroxy, C1-C4alkoxy, phenyl-C1-C4alkoxy, C1-C4alkanoyloxy, C1-C4alkanoyl, amino, N—C1-C4alkylamino, N,N-di-C1-C4-alkylamino, N-phenyl-C1-C4alkylamino, N,N-bis(phenyl-C1-C4alkyl)amino, C1-C4alkanoyl-amino, halo-substituted C1-C4alkyl, for example trifluoromethyl, sulfo, cyano and nitro), hydroxy, C1-C4alkoxy, phenyl-C1-C4alkoxy, C1-C4alkanoyloxy, amino, N—C1-C4alkylamino, N,N-di-C1-C4alkylamino, N-phenyl-C1-C4alkylamino, N,N-bis(phenyl-C1-C4alkyl)amino, C1-C4alkanoylamino, carbamoyl-C1-C4alkoxy, N—C1-C4alkylcarbamoyl-C1-C4alkoxy or N,N-di-C1-C4alkylcarbamoyl-C1-C4alkoxy, amino, mono- or di-C1-C4alkylamino, halogen, for example fluorine, chlorine or bromine, carboxy, C1-C4alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-C1-C4alkoxycarbonyl, for example benzyloxycarbonyl, C1-C4alkanoyl, sulfo, C1-C4-alkanesulfonyl, for example methanesulfonyl (CH3—S(O)2—), phosphono (—P(═O)(OH)2), hydroxy-C1-C4alkoxyphosphoryl or di-C1-C4alkoxyphosphoryl, carbamoyl, mono- or di-C1-C4alkylcarbamoyl, sulfamoyl, mono- or di-C1-C4alkylaminosulfonyl, nitro and cyano.
As C1-C20alkyl preference is given to C1-C8alkyl, especially C1-C4alkyl. As C3-C12cycloalkyl preference is given to unsubstituted or C1-C4alkyl-substituted cyclohexyl, especially unsubstituted cyclohexyl. As C6-C16aryl preference is given to phenyl or naphthyl, especially phenyl, it being possible for those radicals to be substituted as indicated above.
As unsubstituted or substituted quinolylene ring system in formula (10) there comes into consideration, for example, a quinolin-1,8-ene ring system, which may be substituted as indicated above for the organic radicals. Preference is given to the corresponding unsubstituted ring systems.
As unsubstituted or substituted pyridylene ring system in formula (10) there comes into consideration, for example, a pyridin-1,2-ylene ring system, which may be substituted as indicated above for the organic radicals. Preference is given to the corresponding unsubstituted ring systems.
As unsubstituted or substituted naphthylene ring system in formula (10) there comes into consideration, for example, a naphthyl-1,8-ene ring system, which may be substituted as indicated above for the organic radicals. Preference is given to the corresponding unsubstituted ring systems.
As unsubstituted or substituted phenylene in formula (10) there comes into consideration, for example, ortho-phenylene, which may be substituted as indicated above for the organic radicals. Preference is given to the corresponding unsubstituted phenylene.
In cases in which R15 and R16 do not form an unsubstituted or substituted quinolylene or pyridylene ring system and R15 and R16, instead of being hydrogen or an organic radical, can also together form unsubstituted or substituted alkylene, which forms a ring together with the nitrogen atom, the alkylene is preferably C1-C8alkylene, especially C3-C6alkylene and preferably pentamethylene (in which case a piperidine ring is formed).
An anionic ligand is, for example, the hydride ion (H−), or a ligand derived, for example, from inorganic or organic acids by removal of protons, e.g. halides (F−, Cl−, Br− and I− or anions of oxyacids or derivatives thereof, for example SnCl3−, SnCl5−, BF4−, B(aryl)4−, PF6−, SbF6− or AsF6−.
Anions of oxyacids are, for example, sulfate, phosphate, perchlorate, perbromate, periodate, antimonate, arsenate, nitrate, carbonate, the anion of a C1-C8carboxylic acid, for example formate, acetate, propionate, butyrate, benzoate, phenylacetate, mono-, di- or tri-chloro- or -fluoro-acetate, sulfonates, for example mesylate, ethanesulfonate, propanesulfonate, n-butanesulfonate, trifluoromethanesulfonate (triflate), unsubstituted or C1-C4alkyl-, C1-C4-alkoxy- or halo-substituted, especially fluoro-, chloro- or bromo-substituted, benzene-sulfonate or p-toluenesulfonate, e.g. benzenesulfonate, tosylate, p-methoxy- or p-ethoxy-benzenesulfonate, pentafluorobenzenesulfonate or 2,4,6-triisopropylbenzenesulfonate.
Especially preferred anionic ligands are H−, F−, Cl−, Br−, BF4−, PF6−, SnCl3−, SbF6−, AsF6−, CF3SO3−, C6H5—SO3−, 4-methyl-C6H5—SO3−, 3,5-dimethyl-C6H5—SO3−, 2,4,6-trimethyl-C6H5—SO3− and 4-CF3—C6H5—SO3−, acetate and cyclopentadienyl (Cp−). Special preference is given to acetate, Cl−, Br− or I−. Acetate is more especially preferred.
Suitable substituents D remain unchanged under the conditions of the coupling reactions. The substituents may be selected as desired. Suitable substituents D are selected from the group of functional groups or derivatised functional groups consisting of amino, C1-C4alkyl-amino, C1-C4dialkylamino, hydroxy, oxo, thio, —NO2, carboxy, carbamoyl, sulfo, sulfamoyl, ammonio, amidino, cyano, formylamino, formamido and halogen or are saturated or unsaturated, aliphatic, cycloaliphatic or heterocycloaliphatic radicals, carbocyclic or heterocyclic aryl radicals, fused carbocyclic, heterocyclic or carbocyclic-heterocyclic radicals, which may in turn be combined as desired with further of those radicals and substituted by the mentioned functional groups or derivatised functional groups.
The mentioned substituents and radicals may also be interrupted by one or more bivalent radicals from the group —O—, —S—, —C(═O)—O—, —O—C(═O)—, —C(═O)—N(C1-C4alkyl)-, —N(C1-C4alkyl)-C(═O)—, —S(═O)—, —S(═O)2—, —S(═O)—O—, —S(═O)2—O—, —O—S(═O)—, —O—S(═O)2—, —S(═O)—N(C1-C4alkyl)-, —S(═O)2—N(C1-C4alkyl)-, —(C1-C4alkyl)N—S(═O)—, —(C1-C4-alkyl)N—S(═O)2—, —P(═O)—, —P(═O)—O—, —O—P(═O)— and —O—P(═O)—O—.
As aliphatic radicals there come into consideration for D, for example, the radicals mentioned above for R15, R16 and R17 as C1-C20alkyl.
As cycloaliphatic radicals there come into consideration for D, for example, the radicals mentioned above for R15, R16 and R17 as C3-C12cycloalkyl.
As heterocycloaliphatic radicals there come into consideration for D, for example, the radicals mentioned above for R15, R16 and R17 as C2-C11heterocycloalkyl.
As carbocyclic or heterocyclic aryl radicals there come into consideration for D, for example, the radicals mentioned above for R15, R16 and R17 as C6-C16aryl, C7-C16aralkyl and C2-C15-heteroarylalkyl.
The radicals D are especially preferably hydrogen, C1-C4alkyl, halogen or phenyl, which may be substituted as indicated above.
Preferably the index p has the values 0, 1 or 2, especially 0.
Suitable olefinic palladium complex compounds (8) having substituents on the allyl group are illustrated by the following structural formulae:
wherein Z and L are as defined and are preferably tricyclohexyiphosphine or triisopropylcyclophosphine and halogen, for example chlorine, bromine or iodine.
The substituents of the allyl group may, however, also be bonded with one another to form polynuclear bridged complexes according to the following structure:
Preference is given to olefinic palladium complex compounds (8) without substituents on the allyl group, which is bonded to palladium (index p is zero), and wherein L is the tricyclohexyl-phosphine or triisopropyilcyclophosphine group and X is halogen, for example chlorine, bromine or iodine.
In addition to the compounds of formula (8) there also come into consideration those of formula
wherein the meanings and preferred definitions given above for D, X and p apply. The compounds of formula (8a) are added together with the ligand, the palladium complex being formed in situ.
Suitable palladium catalysts of formulae (8) and (8a) are known (e.g. from WO-A-99/47474) or can be obtained analogously to known palladium catalysts.
Examples of substituents of the phenyl rings A and B of the compounds of formula (9) that may be mentioned include C1-C4alkyl, C1-C4alkoxy, C5-C8cycloalkyl, C1-C4alkylcarbonyloxy, C1-C4alkoxycarbonyl, amino, N-mono- or N,N-di-C1-C4alkylamino, phenyl and halogen. As those substituents, preference is given to C1-C4alkyl, C5-C8cycloalkyl, such as cyclohexyl, or phenyl.
R11, R12, R11′ and R12′ are preferably each independently of the others hydrogen, C1-C4alkyl, C5-C8cycloalkyl, such as cyclohexyl, or phenyl.
R13, R14, R13′ and R14′ are preferably each independently of the others C1-C8alkyl, especially C1-C4alkyl, C5-C8cycloalkyl such as cyclohexyl, or unsubstituted or C1-C4alkyl-substituted phenyl.
For X there come into consideration the meanings and preferred definitions given above for the anionic ligand Z.
Palladium catalysts of formula (9) are known (e.g. from EP-A-0 690 046) or can be obtained analogously to known palladium catalysts.
Suitable palladium complex compounds of formula (10) are illustrated by the following structural formula:
wherein the meanings and preferred definitions given above for R15, R16, Z and L apply. In those formulae preferably R15 and R16 are C1-C4alkyl, especially methyl, L is P(phenyl)3 or P(isopropyl)3 and Z is OAc.
In addition to the compounds of formula (10) there also come into consideration those of formula
wherein for the substituents the meanings and preferred definitions given above apply.
The compounds of formula (12) are added together with the ligand, the palladium complex being formed in situ.
Special preference is given to suitable compounds of formula
The compounds of formula (10) can be obtained analogously to known processes. For example, they may be obtained by the reaction of a compound of formula
wherein the substituents are as defined above,
with a palladium salt of formula
Pd(Z)2 (15),
wherein Z is as defined above, in a suitable solvent, especially a halogenated, preferably chlorinated, hydrocarbon, preference being given to C1-C4alkylhalides, such as chloroform or methylene chloride, at a temperature of, for example, from 0 to 50° C., especially from 20 to 30° C., and isolation of the resulting complex (generally, especially in the case when Z is C1-C4alkylcarbonyl, a dimeric compound of formula (12) bridged by way of Z is obtained). The resulting compound can then be reacted with a ligand
L (16),
wherein the meanings given above apply, optionally directly in situ in the reaction mixture used for the catalysis. The reaction is carried out in a suitable solvent, for example an ether, such as tetrahydrofuran, at a temperature of, for example, from 0 to 50° C., especially from 20 to 30° C. The resulting complex can then be used either directly or after isolation.
The starting materials for the preparation of the compound of formula (10) are known or can be obtained analogously to known processes.
As palladium catalysts special preference is given to those of formulae (8), (8a), (10) and (12), especially those of formulae (10) and (12). Those of formula (10) are of particular interest.
The reaction conditions for the coupling reactions of the compounds of formula (2) with those of formula (3) are described in the literature and correspond to the reaction conditions known for so-called Suzuki and Heck coupling reactions.
The process according to the invention can be carried out by using either the compound of formula (2) or the compound of formula (3) as initial charge, or by introducing both compounds.
The term “catalytic amount” preferably means an amount of about from 0.0001 to 15 mol %, especially from 0.01 to 10 mol % and more especially from 0.1 to 10 mol %, based on the amount of substrate used.
The molar ratio of the reaction partners in the coupling reactions of compounds of formula (2) to the compounds of formula (3) is generally in the range from 0.5:1 to 1:10, a ratio in the range from 0.5:1 to 1:5 being preferred. A ratio of from 1:1 to 1:2 is especially preferred. The reaction is carried out at a temperature ranging from with cooling up to the boiling temperature of the solvent, especially from room temperature up to the boiling temperature of the solvent (reflux conditions). Preference is given to temperatures of from 25 to 170° C., especially from 50 to 150° C. and preferably from 100 to 150° C. Suitable solvents are customary, especially relatively high-boiling, solvents, for example nonpolar aprotic solvents, e.g. xylene or toluene, or polar aprotic solvents, e.g. dimethylformamide. The obtainable reaction product can be worked up and isolated in a manner known per se. Mention may be made of customary purification methods, for example removal of the solvent and optionally subsequent separation processes, e.g. fine distillation, recrystallisation, preparative thin-layer chromatography, column chromatography, preparative gas chromatography etc.
Subsequent to the preparation of the compound of formula (4), the radicals Y3 and Y4 can be converted into the radicals Y1 and Y2 where Y1 and Y2 are hydrogen. That removal of the protecting groups can be carried out in conventional manner, for example by reaction under basic or acidic conditions. Removal of the protecting groups is preferably carried out subsequent to the preparation of the compound of formula (4).
When X1 is hydrogen or an organic radical, X1 can be converted into a cation, for example by hydrolysis.
The hydrolysis can be carried out, for example, by conventional basic hydrolysis of the esters. For that purpose, the compound of formula (4) is treated with about one mole of an inorganic base, for example an alkali metal hydroxide, e.g. potassium hydroxide or especially sodium hydroxide, in a mixture of water and a water-miscible organic solvent, for example a lower alcohol or an ether, such as methanol, ethanol or tetrahydrofuran, at a temperature of, for example, from 0 to 80° C. It is also possible to carry out the operation with slightly less than a stoichiometric amount of base and then to remove the excess ester by means of extraction with an organic solvent that is not miscible with water, e.g. tert-butyl methyl ether; freeze-drying can then be carried out. In order to form the free acid, the ester can also be hydrolysed in an acidic medium, it being possible for that hydrolysis to be carried out according to processes known per se. Hydrolysis is preferably carried out, preferably using sodium hydroxide, subsequent to the preparation of the compound of formula (4).
In dependence upon the optical purity of the compound of formula (3) used, the compounds of formula (1) can be obtained in the form of racemates or in the form of stereoisomerically pure compounds. Stereoisomerically pure compounds are to be understood here and hereinafter as compounds that are at least 60%, especially 80% and preferably 90%, pure. Such compounds are especially preferably at least 95%, preferably 97.5% and more especially 99% in stereoisomerically pure form.
For example, when corresponding stereoisomerically pure compounds of formula (3) are used, compounds of formula (1) can be obtained in pure form, especially in the (3R,5S) configuration given below:
Further stereoisomers that may be mentioned include those of the corresponding (3R,5R), (3S,5S) and (3S,5R) configurations.
When a racemate is used as compound of formula (3), separation of the racemate can also be effected subsequent to the preparation of the compound of formula (1). The racemate can be separated into the optically pure antipodes, for example, by known processes for separating enantiomers, for example by means of preparative chromatography on chiral supports (HPLC) or by esterification and crystallisation with optically pure precipitants, e.g. with D-(−) or L-(−)-mandelic acid or (+)- or (−)-10-camphorsulfonic acid.
The present invention relates also to compounds of formula
wherein for R′ the meanings and preferred definitions given above apply. The two R′ radicals preferably have identical or different meanings and are hydrogen, unsubstituted or phenyl-substituted C1-C8alkyl or unsubstituted or substituted phenyl, or the two R′ radicals together form a C1-C8alkylene radical.
As examples of substituents of the phenyl radical there may be mentioned C1-C4alkyl, C1-C4-alkoxy, amino, N-mono- or N,N-di-C1-C4alkyl, halogen, hydroxy and nitro. The R′ radicals are preferably hydrogen, benzyl or C1-C4alkyl, preference being given to ethyl or especially methyl. It is also preferred that the two R′ radicals together form a C1-C8alkylene radical, especially a C4-C8alkylene radical. As an example of such an alkylene radical there may be mentioned the radical of formula —C(CH3)2—C(CH3)2—.
The present invention relates also to compounds of formula
wherein for R7, R8 and X1 the meanings and preferred definitions given above apply. R7 and R8 are especially each independently of the other hydrogen, unsubstituted or phenyl-substituted C1-C8alkyl or phenyl, especially C1-C4alkyl or benzyl, preferably C1-C4alkyl. X1 is preferably C1-C4alkyl.
The following Examples illustrate the invention:
20 g (78.95 mmol) of 3-(4-fluoro-phenyl)-1-isopropyl-1H-indole, 200 ml of THF and 200 ml of chlorobenzene are introduced into a 1.5 liter sulfonating flask equipped with an anchor stirrer, thermometer and nitrogen supply, and the mixture is cooled to 3° C. with stirring. 26.58 g (78.95 mmol) of pyridinium bromide perbromide are then added, and stirring is carried out for 1.25 hours at 3° C. Thereafter, in the course of 10 minutes, 680 g of a 5% sodium hydrogen carbonate solution are added dropwise. The phases are separated and the aqueous phase is extracted three times with 150 ml of chlorobenzene. The combined organic phases are washed twice with 340 ml of 5% sodium hydrogen carbonate solution and twice with 220 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. The brown residue is dissolved in 125 ml of methylene chloride; 125 ml of 94% ethanol are added, and the methylene chloride is distilled off at normal pressure. The solution is cooled slowly to room temperature, and then to 3° C., and the precipitate is filtered off, washed three times with 10 ml of ice-cold 94% ethanol and dried overnight at RT/125 T. Beige crystals are obtained having a melting point of from 110 to 111.5° C. Elemental analysis: found 4.95% H; 61.23% C; 4.04% N; 22.9% Br; 5.67% F. Theory 4.55% H; 61.46% C; 4.22% N; 24.05% Br; 5.72% F.
5.5 ml of a 1.6M solution of n-butyllithium in hexane are added, at a temperature of −78° C., to a solution of the above indole bromide (2.65 g) in 60 ml of a mixture of dry tetrahydro-furan/diethyl ether (ratio by volume 1:1). Stirring is carried out at a temperature of −78° C. for 15 minutes. A solution of 2-ethoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4 ml) in diethyl ether (2 ml) is then added. The reaction mixture is heated to room temperature in the course of about 2.5 hours and then diluted with diethyl ether. The organic phase is washed with saturated sodium chloride solution, dried over Na2SO4 and is then concentrated by evaporation. The desired product is obtained in the form of yellowish crystals (3.0 g, 100%).
1H-NMR (CDCl3): 1.27 (s, 12H); 1.69 (d, J=7.0, 6H); 5.08-5.20 (m, 1H); 7.05-7.12 (m, 3H); 7.21-7.26 (m, 1H); 7.44-7.49 (m, 2H); 7.55-7.61 (m, 2H).
A solution of the above aldehyde (990 mg) and CHl3 (2.26 g) in tetrahydrofuran (18 ml) is added at a temperature of 0° C., under argon, to a suspension of dry CrCl2 (2.83 g) in dry tetrahydrofuran (36 ml). The reaction mixture is stirred at room temperature for 16 hours. The reaction is then stopped by the addition of water and extraction is carried out with diethyl ether. The organic phase is washed with saturated sodium chloride solution and dried over Na2SO4, and the solvent is removed under reduced pressure. The crude product is purified by chromatography (hexane/AcOethyl 1:1). The vinyl iodide (470 mg, 32%) is obtained in the form of a yellow oil (7:3 ratio of E/Z).
1H-NMR (CDCl3): 1.21-1.39 (m, 1H); 1.40 (s, ˜3H); 1.44 (s, 6.3H); 1.45 (s, ˜3H); 1.46 (s, 2.7H); 1.53 (s, 0.3H); 1.56-1.78 (m, 1H); 2.29 (dd, J=15.4, 6.3, 0.7H); 2.32 (dd, J=15.0, 6.2, 0.3H); 2.44 (dd, J=15.3, 7.1, 1H); 4.21-4.38 (m, ˜2H); 6.23 (dd, J=7.3, 7.3, 0.3 H, Z); 6.34 (dd, J=7.9. 0.9, 0.3H, Z); 6.39 (dd, J=14.7, 0.9, 0.7H, E); 6.52 (dd, J=14.7, 5.6, 0.7H, E).
Water (6 ml), K3PO4 (427 mg) and Pd(dppf)Cl2 (18 mg) [dppf=1,1′-bis(diphenylphosphino)-ferrocene] are added to a solution of the boronate (303 mg) and vinyl iodide (458 mg) in dimethoxyethane (6 ml). The reaction mixture is stirred under argon at a temperature of 60° C. for 40 hours. After cooling to room temperature, the reaction mixture is poured into water and extracted with AcOethyl. The combined organic phases are washed with saturated sodium chloride solution, dried over Na2SO4 and concentrated. The crude product is purified by chromatography (hexane/AcOethyl, 5:1). The desired product (235 mg, 46%) is obtained in the form of a yellowish foam (7:3 ratio of E/Z).
1H-NMR (CDCl3): 1.43 (s, 3H); 1.46 (s, 9H); 1.51 (s, 3H); 1.55-1.63 (m, 2H); 1.67 (d, J=7.0, 6H); 2.04 (dd, J=15.0, 5.0, 0.3H); 2.20 (dd, J=15.0, 7.8, 0.3H); 2.31 (dd, J=15.4, 6.2, 0.7H); 2.46 (dd, J=15.2, 7.0, 0.7H); 3.78-3.89 (m, 0.3H); 4.18-4.34 (m, 1H); 4.43-4.48 (m, 0.7H); 4.68-4.80 (m, 0.3H); 4.78-4.90 (m, 0.7H); 5.67 (dd, J=16.4, 5.9, 0.7H); 5.74 (dd, J=11.4, 8.2, 0.3H); 6.53 (d, J=11.1, 0.3H); 6.62 (d, J=16.1, 0.7H); 7.04-7.23 (m, 4H); 7.37-7.46 (m, 2H); 7.52-7.56 (m, 1.4H); 7.67 (d, J=8.0, 0.6H).
In the following Examples, reference is made to the following compounds:
General process procedure:
Compound A (1 molar equivalent) and compound B (1.2 molar equivalents, based on compound A) are dissolved in the respective solvent (10% solution) indicated in the following Tables 1(a) to 1(c). The base and the palladium catalyst are also added thereto. The reaction mixture is heated to the temperature shown in the Tables. After the reaction time indicated, the conversion and the yield are determined by means of HPLC. The results and reaction conditions are shown in the following Tables 1(a) to 1(c). The yield is determined by means of HPLC.
Generally used abbreviations:
DME: dimethoxyethane
In a 5 ml round-bottomed flask, 0.1 g of erythro-(±)-E-(6-{2-[3-(4-fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-vinyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-acetic acid tert-butyl ester and 8 mg of pyridinium p-toluenesulfonate are dissolved in 1.5 ml of acetonitrile; 0.1 ml of water is added and the clear solution is stirred at room temperature for 24 hours. The reaction mixture is then diluted with ethyl acetate, washed twice with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation. 0.1 g of a beige solid is obtained, which, according to TLC, HPLC and NMR, corresponds to the product prepared as reference in the form of the tert-butyl ester analogously to U.S. Pat. No. 4,739,073, Example 5.
In a 10 ml three-necked round-bottomed flask equipped with a magnetic stirrer, thermometer, septum, syringe and nitrogen supply, 0.49 g of erythro-(±)-E-7-[3-(4-fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3,5-dihydroxy-hept-6-enoic acid tert-butyl ester is hydrolysed according to O. Tempkin, Tetrahedron 31, 10659 (1997), there being obtained 0.35 g (77% of the theory) of a pale beige powder, the NMR of which corresponds to that of the commercial product.
Preparation Example for Palladium Catalyst:
0.67 g of N,N-dimethylbenzylamine is slowly added to a solution of 1 g of Pd(OAc)2 in 30 ml of chloroform. The reaction mixture is stirred for 2 hours and then filtered (silica). The resulting yellow solution is concentrated in vacuo and the resulting oil is suspended in a few ml of hexane. The yellow suspension is centrifuged and the resulting yellow powder is dried in vacuo. The compound of the symbolic formula
is obtained in quantitative yield. That dimer is dissolved in 10 ml of tetrahydrofuran, and 1 equivalent of triphenylphosphine is added. The reaction mixture is then stirred for 1 hour.
The resulting suspension is concentrated in vacuo and the white powder is washed with hexane. The desired product is obtained in a 90% yield in the form of a yellowish powder.
1H NMR (δ in CDCl3): 7.75 and 7.35 (2m, 15, PPh3); 6.93 (d), 6.8 (t), 6.34 (m) (4, aromatic-H); 4.02 (d, 2.05 Hz, 2, CH2N); 2.79 (d, 2.34 Hz, 6, NMe2); 1.27 (s, 3, OAc).
31P NMR (δ in CDCl3): 43
For preparation, see also Ryabov et al. in J. Chem. Soc., Perkin Trans. 1983, pages 1503-1508.
| Number | Date | Country | Kind |
|---|---|---|---|
| 01810817.5 | Aug 2001 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP02/09046 | 8/13/2002 | WO |
