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WO1993004058A1 - Esters de glutarate chiraux, leur resolution et composes de glutaramide derives - Google Patents

Esters de glutarate chiraux, leur resolution et composes de glutaramide derives Download PDF

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Publication number
WO1993004058A1
WO1993004058A1 PCT/GB1992/001541 GB9201541W WO9304058A1 WO 1993004058 A1 WO1993004058 A1 WO 1993004058A1 GB 9201541 W GB9201541 W GB 9201541W WO 9304058 A1 WO9304058 A1 WO 9304058A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
enantiomer
ethyl
resolution
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
PCT/GB1992/001541
Other languages
English (en)
Inventor
Christopher Thomas Evans
Raymond Mccague
Stephen John Clifford Taylor
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.)
Chiros Ltd
Chirotech Technology Ltd
Original Assignee
Chiros Ltd
Chiroscience Ltd
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
Priority claimed from GB919118149A external-priority patent/GB9118149D0/en
Priority claimed from GB919118151A external-priority patent/GB9118151D0/en
Application filed by Chiros Ltd, Chiroscience Ltd filed Critical Chiros Ltd
Priority to CA002116108A priority Critical patent/CA2116108A1/fr
Priority to AU24774/92A priority patent/AU668692B2/en
Priority to EP92918126A priority patent/EP0599959A1/fr
Priority to JP5504204A priority patent/JPH06510284A/ja
Publication of WO1993004058A1 publication Critical patent/WO1993004058A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/40—Preparation of oxygen-containing organic compounds containing a carboxyl group including Peroxycarboxylic acids
    • C12P7/44—Polycarboxylic acids

Definitions

  • This invention relates to chiral compounds and their resolution. 5 Background of the Invention
  • 4-PG 4-PG
  • 5- alkyl derivatives may be as good or better aromatase 5 inhibitors; see McCague and Rowlands, J. Med. Chem., in press.
  • the problem of producing enantiomers of 4-PG and its analogues is solved by their preparation from precursors, in enantiomeric form, that can be resolved much more easily.
  • the novel method that is practical for the bulk production of a single enantiomer of 4-PG, is based on the microbial or enzymic biotransformation of an ester precursor.
  • the enantiomeric products of the invention are of formula I, and the novel precursors are of formula II, these formulae being defined in claim l.
  • Racemic formula II compound may be contacted with an enantiospecific esterase that enriches the mixture in terms of one enantiomer, by reacting with the other enantiomer to form the corresponding acid (which may be separated) ; partial enrichment may be enhanced by further resolution with a conventional camphor-derived chiral auxiliary. Biotransformation can be conducted using a known esterase. Description of the Invention
  • 4-PG is the compound of formula I when X is ethyl, Y is 4-pyridyl and Z is hydrogen.
  • the Chart also shows how compounds of formula II (specifically formula 2) may be prepared by sequential alkylation of an alkyl 4-pyridylacetate (1) with iodoethane, e.g. in the presence of potassium t-butoxide and t-butyl alcohol and then with an alkyl aerylate.
  • R and R' are esterifying groups, suitably alkyl residues containing up to 10 carbon atoms consisting of straight-chain alkyl, branched alkyl, arylalkyl, and aryl optionally substituted with, for example, halogen.
  • R,R' methyl or ethyl
  • the subsequent step shown in the Chart is characteristic of the invention. It is based on the discovery of biocatalysts that preferentially hydrolyse one enantiomer of a racemic diester (2) to give optically- enriched residual diester (3.) and the onoester (4.) . There are biocatalysts that produce the R-enantiomer of the ester-acid (i.e. biocatalysts A in the Chart) and those that produce the ⁇ -enantiomer (biocatalysts B) .
  • Suitable esterase activities may be available from acylase I (Asper ⁇ illus) , esterase 30,000, Rhizopus
  • biocatalyst suitable for the biotransformation is the microbial strain P3U1 which can produce R-ester acid of greater than 60% ee.
  • Another suitable biocatalyst (of type B) is Trichosporon ENZA 1-3, whose characteristics, including its enantiospecificity for the conversion of aralkanoic acid esters into the acid, £•_?• (S)-Ketoprofen, are described in International Patent Application No. PCT/EP92/01892, also claiming priority from British Patent Application No. 9118149.5.
  • Strain ENZA 1-3 has been deposited under the terms of the Budapest Treaty, on 20th August 1991, with the International Mycological Institute, Kew, UK; the accession number is 348917.
  • Strain P3U1 has also been deposited, under the terms of the Budapest Treaty, on 20th August 1992, at NCIMB; the accession number is 40517.
  • a further feature of the invention is the discovery of a process for producing essentially optically pure (5.) from optically-enriched material derived from the biotransformation. It is therefore not essential that the biotransformation is absolutely specific for enantiomerically pure (5_) to be manufactured.
  • the optically- enriched (5_) is converted (in the case of (R)-enantiomer) to the (lR)-(-)-10-camphorsulphonate salt and the salt recrystallised, for example from ethyl acetate:ethanol (10:1) whereupon material that has 0 to 50% ee in favour of (R or S)-glutarimide crystallises and leaves almost optically pure (j5) salt in solution. Release of (5 from its salt and subsequent recrystallisation of the almost optically pure (5 can raise it to optical purity.
  • Example 1 Growth of P3U1
  • the strain P3U1 was streaked onto nutrient agar plates and 5 g/l glucose, and incubated at 23°C for 60 hours.
  • Seed flasks containing 150 ml growth medium (1 g/l (NH 2 S0 4 /' 2 9 1 KH . PO,; 0-25 g/l MgS0 4 ; 0.1 g/l CaCl 2 ; 0.1 ml TES; 10 ml YE) per 500 ml flask, were inoculated from the nutrient agar plates and shaken at 23°C, 350 rpm for 24 hours. After 24 hours the optical density at 520 nm had reached 2.1.
  • (+)-Dimethyl 2-ethyl-2-(4-pyridyl)glutarate was added to a final concentration of 3 g/l.
  • the cells were stirred at 23°C without aeration or pH control.
  • the enantio eric excess (ee) of the substrate was monitored as the hydrolysis progressed (extraction of the diester into cyclohexane, followed by HPLC analysis of the cyclohexane layer on a Chiracel-OJ-column) . After 72 hours, the ee of the remaining diester was 66%, and the biotransformation was harvested.
  • Cyclisation to the imide was effected by heating the product from Example 2 with an equal weight of urea for 20 min.
  • the R-enriched R-camphorsulphonate salt solution was concentrated to dryness then suspended in water (5 ml) .
  • the mixture was basified to pH 9 with 2 N sodium hydroxide solution.
  • the product was extracted into ethyl acetate and the organic extracts dried (MgSO .
  • the final product was isolated and purified by flash chromatography as described in Example 3.
  • Biotransformation on the same substrate as Example 2 was carried out in a baffled conical flask (500 ml) containing 0.1 M KH 2 P0 4 (100 ml) adjusted to pH 7, cyclohexane (100 ml) , dimethyl ester (1 g) and Mucor iavanicus lipase (700 mg) .
  • the flask contents were shaken at 23°C, and the ee of the remaining substrate in the cyclohexane layer monitored by HPLC. After 48 hours, the ee of the remaining substrate was 46% (enriched in the pro- R diester) , at a conversion of 84%.
  • Example 6 Biotransformation
  • Example 7 Biotransformation
  • ENZA 13 was inoculated from a freshly-grown YM (Difco) agar plate into 5 ml growth medium in a 20 ml container
  • reaction buffer comprised 10 mM sodium phosphate, 5 g/l yeast extract (Fould Springer) , 50 ⁇ l/1 Tween 80, 3 g/l
  • (+)-dimethyl 2-ethyl-2-(4-pyridylglutarate) was shaken for 41 hours.
  • the enantiomeric excess (ee) was measured by extraction of the diester into cyclohexane followed by HPLC analysis of the cyclohexane layer on a

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pyridine Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Des énantiomères de composés chiraux tels que 3-éthyl-3-(4-pyridyl) pipéridine-2, 6-dione (Rogletimide) sont préparés par cyclisation des diesters correspondants tels que diéthyl-2-éthyl-2-(4-pyridil) glutarate, qui sont eux-mêmes préparés par biotransformation énantiospécifique du diester racémique.
PCT/GB1992/001541 1991-08-22 1992-08-21 Esters de glutarate chiraux, leur resolution et composes de glutaramide derives Ceased WO1993004058A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002116108A CA2116108A1 (fr) 1991-08-22 1992-08-21 Esters de glutarate chiraux, leur isolation et glutarimide derive
AU24774/92A AU668692B2 (en) 1991-08-22 1992-08-21 Chiral glutarate esters, their resolution and derived glutarimide compounds
EP92918126A EP0599959A1 (fr) 1991-08-22 1992-08-21 Esters de glutarate chiraux, leur resolution et composes de glutaramide derives
JP5504204A JPH06510284A (ja) 1991-08-22 1992-08-21 キラルグルタレートエステル、それらの分割および誘導されるグルタルイミド化合物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB919118149A GB9118149D0 (en) 1991-08-22 1991-08-22 Araylalkanoic acid resolution
GB919118151A GB9118151D0 (en) 1991-08-22 1991-08-22 Chiral compounds and their resolution
GB9118151.1 1991-08-22
GB9118149.5 1991-08-22

Publications (1)

Publication Number Publication Date
WO1993004058A1 true WO1993004058A1 (fr) 1993-03-04

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PCT/GB1992/001541 Ceased WO1993004058A1 (fr) 1991-08-22 1992-08-21 Esters de glutarate chiraux, leur resolution et composes de glutaramide derives

Country Status (5)

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EP (1) EP0599959A1 (fr)
JP (1) JPH06510284A (fr)
AU (1) AU668692B2 (fr)
CA (1) CA2116108A1 (fr)
WO (1) WO1993004058A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032947A1 (fr) * 1994-05-27 1995-12-07 Chiroscience Limited Composes chiraux et leur resolution
WO2000050628A1 (fr) * 1999-02-26 2000-08-31 Schering Corporation Hydrolyse enzymatique enantioselective d'esters 3-substitue d'acide glutarique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3224019C1 (de) * 1982-06-28 1984-02-16 Takara Shuzo Co., Ltd., Kyoto Verfahren zur Herstellung von ß-(S)-Aminoglutarsäuremonoalkylestern
EP0258617A1 (fr) * 1986-07-31 1988-03-09 MADAUS Aktiengesellschaft Dérivés 3,3-disubstitués de la pipéridinedione-2,6

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ242054A (en) * 1991-03-22 1993-11-25 British Tech Group Pyridine derivatives having a bridged alicyclic group; medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3224019C1 (de) * 1982-06-28 1984-02-16 Takara Shuzo Co., Ltd., Kyoto Verfahren zur Herstellung von ß-(S)-Aminoglutarsäuremonoalkylestern
EP0258617A1 (fr) * 1986-07-31 1988-03-09 MADAUS Aktiengesellschaft Dérivés 3,3-disubstitués de la pipéridinedione-2,6

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
AGRICULTURAL AND BIOLOGICAL CHEMISTRY. vol. 51, no. 7, July 1987, TOKYO JP pages 1833 - 1838 G.M. RAMOS TOMBO ET AL 'Application of microbes and microbial esterase to the preparation of optically active N-acetylindoline-2-carboxylic acid' *
JOURNAL OF THE CHEMICAL SOCIETY. 1989, LETCHWORTH GB pages 196 - 198 RAYMOND MCCAGUE ET AL. 'Synthesis of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione and its enantiomers.' cited in the application *
TETRAHEDRON, (INCL. TETRAHEDRON REPORTS) vol. 45, no. 18, 1989, OXFORD GB pages 6011 - 6016 AILEEN M.BOSS ET AL. 'A concise synthesis of racemic pyridoglutethimide and its resolution using chiral stationary phase HPLC' *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032947A1 (fr) * 1994-05-27 1995-12-07 Chiroscience Limited Composes chiraux et leur resolution
WO2000050628A1 (fr) * 1999-02-26 2000-08-31 Schering Corporation Hydrolyse enzymatique enantioselective d'esters 3-substitue d'acide glutarique

Also Published As

Publication number Publication date
AU668692B2 (en) 1996-05-16
JPH06510284A (ja) 1994-11-17
CA2116108A1 (fr) 1993-03-04
AU2477492A (en) 1993-03-16
EP0599959A1 (fr) 1994-06-08

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