EP1608642A1 - Hydrogenation enantioselective de produits intermediaires lors de la synthese de tipranavir - Google Patents

Hydrogenation enantioselective de produits intermediaires lors de la synthese de tipranavir

Info

Publication number
EP1608642A1
EP1608642A1 EP04721858A EP04721858A EP1608642A1 EP 1608642 A1 EP1608642 A1 EP 1608642A1 EP 04721858 A EP04721858 A EP 04721858A EP 04721858 A EP04721858 A EP 04721858A EP 1608642 A1 EP1608642 A1 EP 1608642A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
ligand
group
aryl
catalyst
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP04721858A
Other languages
German (de)
English (en)
Inventor
Franz Dietrich Klingler
Michael Steigerwald
Richard Ehlenz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim International GmbH
Boehringer Ingelheim Pharma GmbH and Co KG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim International GmbH
Publication of EP1608642A1 publication Critical patent/EP1608642A1/fr
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members

Definitions

  • the present invention relates to a process for the preparation of intermediates in tipranavir synthesis, in particular an enantioselective hydrogenation. Intermediates which serve as starting compounds for the production of pharmaceutically active compounds are easily accessible via this process.
  • Chirality plays a crucial role in many biological processes and has also become increasingly important for the pharmaceutical industry, which is shown, for example, by the fact that over 80% of the drugs currently being developed have chiral properties.
  • the different enantiomers can have completely different effects in the organism, so that only one of the enantiomeric forms is effective and is administered.
  • enzymes whose chiral building blocks represent the amino acids can differentiate between the individual enantiomeric forms.
  • the enantiomers of 5,6-dihydro-4-hydroxy-2-pyrone are important structural elements in a large number of pharmaceutically active compounds, the class of 5,6-dihydro-4-hydroxy-2-pyrone-sulfonamides being of particular importance are.
  • a non-selective synthesis requires an additional separation step of the optical isomers, for example in the form of a final racemate resolution of the two enantiomers either by chemical or enzymatic means. It is therefore clear that selective syntheses that lead to only one optical isomer (either enantiomer or diastereomer) are advantageous. Thus, so-called asymmetric synthesis is increasingly used, i.e. only one optical isomer is preferably formed during a reaction. Enantio- or diastereoselective reactions are used not only in laboratory-scale syntheses, but also increasingly on an industrial scale.
  • a particularly elegant variant, preferably to synthesize an optical isomer, is enantio- or diastereoselective catalysis with chiral catalysts.
  • the catalysts are transition metal complexes with one or more chiral ligands.
  • the number of possible chiral ligands is almost unmanageable, and a large number of combinations of metal and ligand (s) are therefore opened. This range of variation also makes it difficult to find the best combination for the product to be manufactured in a simple manner.
  • Asymmetric catalysis is important for a number of industrial processes and is used, among other things, for the production of amino acids, chiral amines and for ketone reduction.
  • Degussa has developed the DeguPhos catalyst, which is used for the reductive amination of alpha-keto acids to produce L- and D-amino acids.
  • DuPhos [(l, 5-cyclooctadiene) rhodium (I) -l, 2- bis ((2R, 5R) -dimethyl-phospholano) benzene] tetrafluoroborate).
  • WO 00/55150 describes a process for the asymmetric hydrogenation of double bonds.
  • Various intermediates for tipranavir synthesis are produced, using a rhodium catalyst with a chiral ligand containing at least one phosphorus atom.
  • DuPhos (1,2-bis ((2R, 5R) -dimethylphospholano) benzene) or BPE (1,2-bis ((2R, 5R) -dimethylphospholano) ethane) are preferably used as chiral ligands.
  • transition metal complexes of chiral phosphine ligands usually show an insufficient activity in such catalytic processes, combined with only moderate stereoselectivity, so that the use of stoichiometric amounts of chiral hydride reagents would often be preferable. Accordingly, there remains a need to develop a stereoselective hydrogenation catalyst that avoids these disadvantages.
  • the invention is therefore based on the object in further training of the prior art to provide a process which allows an enantio- or diastereoselective hydrogenation in high yields, with high enantio- or diastereoselectivity, with the least possible technical effort and high space-time yield.
  • This process should also be able to be implemented on an industrial scale, ie inexpensively and therefore be carried out in an economical manner.
  • R 1 and R 2 independently represent hydrogen or a radical which is selected from the group consisting of Ci-C ⁇ alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, and C ⁇ alkylene -Ce-o-aryl, optionally with one, two or three substituents, selected from the group consisting of OH, NH 2 , NH-CO-CH 3 or N (-CO-CH 3 ) 2 , halogen, -Gi- Alkoxy and CF 3 , where R 1 and R 2 do not have the same meaning at the same time;
  • R 3 represents an aryl which is substituted in the meta position and optionally has at least one further substituent, the substituents being selected from the group consisting of F, Cl, Br, I, OH, O-SO 2 -CF 3 , NO 2 , NH 2 , NH-SO 2 - (4-trifluoromethylpyridin-2-yl), N (-CH 2 -aryl) 2 , NY! Y 2 with Yi and Y 2 selected from H, COO-alkyl, COO- CH 2 aryl, CO alkyl, and CO aryl;
  • R 4 is selected from the group consisting of H and Ca alkyl
  • R 5 is selected from the group consisting of H, Si (CH 3 ) 3 , Li, Na, K, Cs,
  • R ' N (R ') 4 , where all R' may be the same or different and are selected from Ci-C ⁇ -alkyl, and CH 2 - aryl;
  • radicals R 1 to R 5 can have the meanings given above, in
  • Presence of a catalyst which has at least one ligand in the form of a chiral 1,2-bis (phospholano) maleic anhydride Presence of a catalyst which has at least one ligand in the form of a chiral 1,2-bis (phospholano) maleic anhydride.
  • the starting compounds of the general formula I are intermediates in the production of tipranavir and related products which are used as
  • Starting compounds are used for the production of pharmaceutically active compounds.
  • Mixtures of E / Z isomers (based on the double bond to be hydrogenated) can be used, of which surprisingly only one isomer is then hydrogenated.
  • a mixture of about 50% E and about 50% Z isomer is preferably used.
  • R 1 and R 2 can be selected independently of one another from the group consisting of methyl, ethyl, propyl, butyl, phenyl, benzyl, cyclohexyl, phenylethyl and phenylpropyl, optionally with a Substituents selected from the group consisting of Hydroxy, fluorine, chlorine, bromine, methoxy, ethoxy and CF 3 .
  • R 1 is particularly preferably phenylethyl and R 2 is propyl or R 1 is propyl and R 2 is phenylethyl.
  • R and R are selected from phenylethyl and propyl, R represents optionally substituted phenyl with an NO 2 group in the meta position, R 4 means methyl and R 5 means hydrogen. If there is a further substituent in addition to the meta substituent in R 3 , it is preferred that this is selected from F, Cl, Br, I, OH or O-SO 2 -CFs s
  • alkyl groups even if they are part of other radicals, unless otherwise defined, are to be understood as meaning branched and unbranched alkyl groups having 1 to 4 carbon atoms.
  • the following hydrocarbon radicals are mentioned as examples: methyl, ethyl, propyl, 1-methylethyl (Isopropyl), n-butyl, 2-methylpropyl (iso-butyl), 1-methylpropyl (sec-butyl), 1,1-dimethylethyl (tert-butyl).
  • the definitions of propyl and butyl include the respective isomeric forms. If necessary, the common abbreviations Me for methyl, Et for ethyl, prop for propyl and but for butyl are also used for the alkyl groups mentioned above.
  • branched and unbranched alkylene bridges with 1 to 4 carbon atoms are regarded as alkylene groups.
  • alkylene groups include: methylene, ethylene, propylene and butylene.
  • propylene and butylene encompass all of the possible isomeric forms. Accordingly, the term propylene includes the isomeric bridges n-propylene, methylethylene and dimethylmethylene and the term butylene the isomeric bridges n-butylene, 1-methylpropylene, 2-methylpropylene, 1,1-dimethylethylene and 1,2-dimethylethylene.
  • the cycloalkyl group is intended to represent a saturated cyclic hydrocarbon radical having 3 to 8 carbon atoms.
  • Cyclic hydrocarbons having 3 to 6 carbon atoms are preferred. Examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • Alk loxy which may also be referred to as alkoxy, means within the scope of the invention a straight-chain or bonded via an oxygen atom branched alkyl group with 1 to 4 carbon atoms.
  • the methoxy group is particularly preferred.
  • aryl stands for an aromatic ring system with 6 to 10 carbon atoms.
  • Preferred aryl radicals are naphthyl and phenyl, with the phenyl radical being particularly preferred. Abbreviations may be used for naphthyl and for phenyl Ph.
  • aryl-alkylene or alkylene-aryl are understood to mean aryl groups which are linked via an alkylene bridge, the definitions given above applying to alkylene groups and aryl groups.
  • alkylene aryl groups preferred according to the invention are benzyl, 2-phenylethyl and 3-phenylpropyl.
  • Halogen in the context of the present invention represents fluorine, chlorine, bromine or iodine, with fluorine, chlorine and bromine being preferred, unless otherwise defined.
  • the starting compounds of the general formula I shown above are selectively hydrogenated enantio in the presence of a catalyst. It is known that the hydrogenation of a molecule is influenced by other centers of chirality present in the molecule. However, this is not the case with the present compounds of formula I. According to the invention, the catalyst is therefore of major importance in this enantioselective hydrogenation. This enables the synthesis of the compounds of the above formula I directly from the compounds of the formula II, without further intermediate steps or a complicated separation of the isomeric forms.
  • enantioselective hydrogenation should also include diastereoselective hydrogenation, since a further chiral center can be located in the compounds of general formula I.
  • a further chiral center can be located in the compounds of general formula I.
  • the catalyst of the invention contains a transition metal ion such as rhodium (I), ruthenium (I), iridium (I) or another suitable transition metal, with rhodium (I) preferably being present.
  • This transition metal is coordinated with at least one ligand in the form of a chiral 1,2-bis ( ⁇ hospholano) maleic anhydride.
  • this 1,2-bis (phospholano) maleic anhydride should particularly preferably be understood to mean the system of the general formula III
  • R L1 and R L2 are identical or different branched ess ooddeerr and branched C 1 -C 8 alkyl, preferably C 1 -C 4 alkyl, particularly preferably methyl, ethyl or isopropyl.
  • R L1 and R L2 have the same meanings, particularly preferably both methyl.
  • the last preferred compound of the formula III, in which ' R L1 and R 2 both denote methyl, is also known under the name MalPhos in the prior art.
  • the chiral 1,2-bis (phospholano) maleic anhydride presented above represents an optionally substituted bidentate bisphospholane system, i.e. Two five-membered saturated rings, each with a phosphorus atom in the ring - the so-called phospholane systems - are bonded to the double bond of a maleic anhydride via the two phosphorus atoms.
  • ligands are known under the trade name MalPhos.
  • the transition metal forms a complex with the ligand, which can be used as a hydrogenation catalyst.
  • the catalyst has the following structure:
  • Ligand 1 means the chiral 1,2-bis (phospholano) maleic anhydride of the formula EU shown above.
  • Ligand 2 is preferably an unsaturated cyclic hydrocarbon having 3 to 12 carbon atoms, cyclopentadiene, benzene, cyccloheptatriene or cyclooctadiene systems being preferably used. 2 cyclopentadiene or 1,5-cyclooctadiene (COD) is particularly preferably used as a ligand.
  • Ligand 2 can be substituted with one or more organic groups. In a preferred embodiment according to the invention, ligand 2 is unsubstituted.
  • Ci-C ⁇ -alkyl groups in particular C 1 -C 4 -alkyl groups, are suitable as substituents.
  • an anion as counterion to the transition metal cation complex such as BF 4 " , CF3-CO-O “ , Cl “ , Br “ or I “ , of which the BF 4 " adduct is preferred.
  • the hydrogenation catalyst which is particularly preferred in the process according to the invention, the MalPhos-Rhodium-l, 5-cycclooctadiene-tetrafluoroborane adduct, is shown below:
  • Catalyst influenced, but predictions about structure-activity relationships in such complex systems are only possible in a few individual cases.
  • the steric conditions play a role, such as a certain conformational rigidity of the complex.
  • the electronic properties of the donor atoms are a second parameter, which significantly determines the properties of catalytically active transition metal complexes determine.
  • the overall electronic character of the ligand appears to be important. It is indeed possible to fine-tune the conformational, steric and electronic properties of the ligands with considerable effort, but due to the numerous different influences, it is not easy to draw a systematic conclusion about the effectiveness and usefulness of a particular catalyst.
  • the starting compounds according to the general formula I above are intermediates on the way to tipranavir synthesis, which can be processed further after the enantioselective hydrogenation has taken place.
  • the starting compound of the formula I can be used either in the form of an isomer or as a mixture of E and Z isomers.
  • the base is preferably selected from the group consisting of a hydroxide, C 1 -C 5 alkoxide, bicarbonate, carbonate, di- and tribasic phosphate, borate, fluoride, optionally amine substituted with C 1 -C 4 alkyl or aryl, optionally with C 1 -C 3 alkyl substituted silane.
  • the base is particularly preferably an alkali or alkaline earth metal methanolate, ethanolate or carbonate, particularly preferably a carbonate.
  • alkali or alkaline earth alcoholates or carbonates are those of sodium, potassium, calcium or magnesium, those of sodium and potassium, in particular sodium, being of outstanding importance according to the invention.
  • the base is used in an amount of about 1 mol% to about 20 mol%, preferably about 5 mol% to about 15 mol%.
  • Nitrogen gas or a noble gas such as argon are suitable for this, nitrogen being preferred for cost reasons.
  • the hydrogenation according to the invention is advantageously carried out in a solvent.
  • the solvents conventionally used for hydrogenation reactions can be used as solvents. Examples include: methanol, ethanol, acetone, methylene chloride, ethyl acetate, toluene, xylene and acetonitrile. Methanol and ethanol are particularly preferably used as solvents.
  • the amount of catalyst used is preferably about 0.001 mol% to about 5 mol%, preferably about 0.01 mol% to about 0.5 mol%, in particular about 0.05 mol% to about 0.15 mol%. This results in the ratio (in moles) of substrate / catalyst of about 200/1 to 5000/1, preferably about 500/1 to about 3000/1, in particular about 1000/1 to about 2000/1.
  • the catalyst is first dispersed or dissolved in a solvent and then added to the reaction mixture containing the compound to be hydrogenated, solvent and optionally a base. The same is then preferred for the catalyst and the reaction mixture Solvent used.
  • the catalyst can also be added without a solvent.
  • the hydrogenation according to the process of the invention is preferably carried out in one
  • Temperature interval from about 20 ° C to about 100 ° C, preferably about 40 ° C to about 80 ° C, particularly preferably between about 50 ° C and about 70 ° C, most preferably at about 60 ° C. It is recommended to ' ⁇ sbesondere when delicate Retechnischs phenomenon in the molecule, that the temperature is about 100 ° C, in some cases, about 80 ° C does not exceed. For example, a nitro group present in the molecule is reduced to the amino group at temperatures above about 80 ° C, which can be undesirable. Temperatures below about 20 ° C slow the reaction so that this is no longer of economic interest.
  • the level of the set pressure is not particularly limited. This essentially serves to increase the reaction rate. However, it is expedient to set the hydrogen pressure in the hydrogenation in the range from approximately 2 bar to approximately 200 bar, preferably approximately 10 bar to approximately 50 bar, particularly preferably between approximately 15 bar and approximately 40 bar.
  • the hydrogenation according to the invention is preferably carried out for a reaction time of about 1h to about 100h, particularly preferably about 5h to about 40h, particularly preferably about 10h to about 30h. According to the invention, it is therefore possible, with a relatively short reaction time of about 24 hours, to achieve an enantioselectivity of over about 90%, preferably over about 95%, in particular even over 98%. This shows the clear superiority over the systems known to date in the prior art, which do not show this selectivity to this extent.
  • the hydrogenated product obtained can be subjected to an additional purification, for example one or more washing steps and / or recrystallization in the solvent used, and can be separated off and worked up in a conventional manner.
  • the process according to the invention enables easy access to isomers which have hitherto been relatively difficult to access, which is also possible on an industrial scale with excellent productivity.
  • the process according to the invention makes it possible to provide the desired product not only in high yields but also with very high enantioselectivity. No additional cleaning steps are required, the products can be processed directly as they are.
  • the hydrogenation catalyst used according to the invention has a high performance, in particular in the form of excellent activity and stability, and is highly enantioselective, so that the desired products can be obtained in a simple manner. According to the method according to the invention, a
  • a complex separation into the two isomers can thus be avoided; rather, only the desired isomer is obtained in hydrogenated form, this not only working on a laboratory scale, but also in large-scale industrial plants.
  • the catalyst according to the invention are thus largely met by the catalyst according to the invention.
  • the catalysts used in the hydrogenation process of the invention are inexpensive to manufacture.
  • the starting products for the production of MalPhos are significantly cheaper compared to the starting materials for DuPhos, so that the production of the catalyst is much cheaper.
  • the efficiency of the catalyst system used according to the invention is also clearly superior to that of the prior art.
  • reactions catalyzed with rhodium-malphos systems run faster and with higher enantioselectivity compared to the corresponding DuPhos systems.
  • the non-peptide HJV protease inhibitors such as tipranavir, so that the technical teaching of the invention is a valuable enrichment for the pharmaceutical sector.
  • the hydrogenation solution was rinsed with 14 ml of methanol in a glass reactor, warmed to about 50 ° C. and adjusted to a pH of about 1.4 with hydrochloric acid (32%). 61 ml of water were added dropwise at about 50 ° C. over 2 hours. The mixture was then at 20 ° C for 3 h cooled, stirred at this temperature for 1.5 h and finally the crystalline product was suction filtered. It was washed with 133 ml of methanol / water (2: 1) and dried at about 45 ° C. i.vac, which gave about 50.5 g (about 80%) of the hydrogenated compound 1.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)
  • Pyrane Compounds (AREA)

Abstract

L'invention concerne un procédé de production des composés de la formule générale (I) par hydrogénation énantiosélective des composés de la formule (II) en présence de cacalysateurs d'hydrogénation spéciaux. L'invention se distingue par une énantiosélectivité élevée, ce qui permet d'obtenir facilement une classe de substances de médicaments importants.
EP04721858A 2003-03-24 2004-03-19 Hydrogenation enantioselective de produits intermediaires lors de la synthese de tipranavir Ceased EP1608642A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10313118 2003-03-24
DE10313118A DE10313118A1 (de) 2003-03-24 2003-03-24 Enantioselektive Hydrierung von Intermediaten bei der Tipranavir-Synthese
PCT/EP2004/002894 WO2004085427A1 (fr) 2003-03-24 2004-03-19 Hydrogenation enantioselective de produits intermediaires lors de la synthese de tipranavir

Publications (1)

Publication Number Publication Date
EP1608642A1 true EP1608642A1 (fr) 2005-12-28

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Application Number Title Priority Date Filing Date
EP04721858A Ceased EP1608642A1 (fr) 2003-03-24 2004-03-19 Hydrogenation enantioselective de produits intermediaires lors de la synthese de tipranavir

Country Status (6)

Country Link
US (1) US7002017B2 (fr)
EP (1) EP1608642A1 (fr)
JP (1) JP2006520748A (fr)
CA (1) CA2520129A1 (fr)
DE (1) DE10313118A1 (fr)
WO (1) WO2004085427A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004051456A1 (de) * 2004-10-22 2006-04-27 Degussa Ag Neue Bisphosphankatalysatoren

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Publication number Priority date Publication date Assignee Title
PL193240B1 (pl) 1997-09-11 2007-01-31 Upjohn Co Sposób wytwarzania hydroksylaktonu i związki pośrednie stosowane w tym sposobie
DE60000660T2 (de) 1999-03-18 2003-06-26 Upjohn Co Verbesserte verfahren fur assymmetrische hydrogenation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2004085427A1 *

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Publication number Publication date
JP2006520748A (ja) 2006-09-14
US7002017B2 (en) 2006-02-21
DE10313118A1 (de) 2004-10-07
US20040224990A1 (en) 2004-11-11
WO2004085427A1 (fr) 2004-10-07
CA2520129A1 (fr) 2004-10-07

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