EP0763023A1 - Composes chiraux et leur resolution - Google Patents

Composes chiraux et leur resolution

Info

Publication number
EP0763023A1
EP0763023A1 EP95920162A EP95920162A EP0763023A1 EP 0763023 A1 EP0763023 A1 EP 0763023A1 EP 95920162 A EP95920162 A EP 95920162A EP 95920162 A EP95920162 A EP 95920162A EP 0763023 A1 EP0763023 A1 EP 0763023A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
enantiomer
nitrophenyl
ethyl
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.)
Withdrawn
Application number
EP95920162A
Other languages
German (de)
English (en)
Inventor
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.)
Chirotech Technology Ltd
Original Assignee
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
Application filed by Chiroscience Ltd filed Critical Chiroscience Ltd
Publication of EP0763023A1 publication Critical patent/EP0763023A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • 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

Definitions

  • This invention relates to chiral compounds that are useful as intermediates in the synthesis of pharmaceutically-active glutari ides, and to their resolution.
  • Racemates of 3,3-disubstituted glutarimides such as 3- ethyl-3- (4-aminophenyl) piperidine-2 , 6-dione (aminoglutethimide) and 3-ethyl-3-(4-pyridyl)piperidine- 2,6-dione (rogletimide) have been shown to be effective for the treatment of hormone-dependent breast cancer; see Smith et al. Lancet ii:646 (1978), and Foster et al , J.Med. Chem. 2j8:200 (1985) .
  • the mode of action of these compounds is considered to be inhibition of the enzyme aromatase that catalyses the formation of estrogens from androgens; thus the compounds inhibit tumours whose growth is promoted by estrogens.
  • O-A-9304058 discloses a process for the manufacture of such glutarimide compounds, by way of biocatalytic resolution of glutarate diester ⁇ . Only the less hindered ester function is hydrolysed by an appropriate biocatalyst, with a degree of enantiospecificity showing that the biocatalyst can distinguish aryl, ethyl and carboxylic ester substituents borne on a quarternary carbon atom. While only moderate specificity was observed in the case of precursors .of rogletimide, the biotransformation products were easily converted into rogletimide and means to then increase the enantiomeric excess was found. Summary of the Invention
  • R is an esterifying group, suitably an alkyl residue containing up to 10 carbon atoms, e.g. straight-chain alkyl, branched alkyl, arylalkyl and aryl optionally substituted with, for example, halogen.
  • R may be H; alternatively, depending on the enantiomer that is desired, R may be unchanged.
  • X and Z are each H or an organic group.
  • X may be, for example, C.*_ 10 alkyl such as ethyl.
  • Z is preferably H or a ,_., ( , alkyl group, e.g. to give a 5-alkyl product.
  • the compound of formula I may also be an intermediate for hypotensive agents such as verapamil.
  • Y is thus defined; in general, Y (or Ar in the Chart) is a cyclic group, either an aryl, carbocyclic or heterocyclic radical, e.g. of up to 12 C atoms, including any substituents.
  • Y is preferably dimethoxyphenyl, 4-pyridyl, 4-aminophenyl (optionally N- protected) , isopropyl-phenyl or cyclohexylphenyl.
  • Y is thus defined; in general, Y (or Ar in the Chart) is a cyclic group, either an aryl, carbocyclic or heterocyclic radical, e.g. of up to 12 C atoms, including any substituents.
  • Y is preferably dimethoxyphenyl, 4-pyridyl, 4-aminophenyl (optionally N- protected) , isopropyl-phenyl or cyclohexylphenyl.
  • Y is aminophen
  • Y may also be nitrophenyl; (R) -3- ethyl-3-(4-nitrophenyl)piperidine-3,6-dione is a novel compound. Compounds of formula II in which Y is nitrophenyl give especially good biotransformation yields.
  • the first step shown in the Chart is a characteristic of the invention. It is based on the use of biocatalysts that preferentially hydrolyse one enantiomer of a racemic nitrile (1) to give optically-enriched residual ester (2) and the acid (3) . There are biocatalysts that produce the R-enantiomer of the ester (i.e. biocatalysts A in the Chart) and those that produce the ⁇ -enantiomer (biocatalysts B) .
  • Suitable esterase activities may be available from acylase I (Aspergillus) , esterase 30,000, Rhizopus Japonicus lipase, F3 lipase, A2 lipase (porcine pancreas) , F6 lipase (from Candida) , pig liver esterase, CE lipase and
  • Cholesterol esterase is an alternative.
  • biocatalysts A are Candida cylindracae lipase and enzyme activities of the genera in Examples 8 to 10.
  • biocatalyst suitable for the biotransformation is the microbial strain P3U1, NCIMB 40517, which can produce R-ester acid of greater than 60% ee.
  • Another suitable biocatalyst (of type B) is Trichosporon ENZA 1-3, IMI 348917, whose characteristics, including its enantiospecificity for the conversion of aralkanoic acid esters into the acid, e.g. (S)-ketoprofen, are described in WO-A-9304189.
  • ⁇ -Chymotrypsin is another suitable biocatalyst of category B.
  • a further biocatalyst is obtainable from any fungus of the type described in WO-A-9420634 for the enantiospecific hydrolysis of arylpropionic acid esters.
  • a specific fungus of this type is Ophiostoma novo-ulmi , IMI 356050.
  • the same substrate with esterase derived from the given fungus Ophiostoma novo-ulmi also gave transformation with the opposite specificity.
  • nitrile esters Conversion of such nitrile esters to the glutarimides was accomplished easily under such conditions as heating with acid, e.g. a mixture of acetic acid and sulphuric acid, to provide the optically-active glutarimide compounds. These conditions are known in the conversion of racemic nitrile-esters into the racemic glutarimides, aminoglutethimide and rogletimide.
  • the following Examples 1 and 4 illustrate the preparation of nitrile-esters (II) that are substrates for biotransformation, and Example 6 illustrates a relevant reduction.
  • Examples 2, 5 and 8 to 10 illustrate biotransformations, and Examples 3 and 7 illustrate cyclisation reactions, in accordance with the invention. Examples 1 to 3, and Examples 4 to 7, provide different routes to the same product.
  • a 500 ml jacketed biotransformation vessel was charged with 0.1M KH 2 P0 4 , pH 7.0 (250 ml) and methyl 4-(4- aminophenyl)4-cyanohexanoate (5.0 g, 20.3 mmol).
  • Candida cylindracea lipase CCL; 5.0 g
  • Temperature was maintained at 30°C with the aid of a ther ocirculator and the pH controlled by a probe linked to an autotitrator.
  • the biotransformation was allowed to proceed until 10 ml of IM NaOH had been added (equivalent to 50% conversion). This took about 3 hours.
  • a l l jacketed biotransformation vessel was charged with 0.05 M KH 2 P0 4 , pH 7.5 (500 ml) and methyl 4-cyano-4-(4- nitrophenyl)hexanoate (20 g, 72 mmol).
  • -Chymotrypsin (ex. Aldrich; 4 g) was introduced and the mixture was agitated using an overhead stirrer. Temperature was maintained at 37°C with the aid of a thermocirculator and the pH controlled by a probe linked to an autotitrator. The biotransformation was allowed to proceed until 18 ml of IM NaOH had been added (equivalent to 50% conversion) .
  • a loopful of Candida rugosa was used to inoculate 50 ml of sterile pH 6.0 aqueous medium [containing (g/1) yeast extract (5), (NH 4 ) 2 S0 4 (1), KH 2 P0 4 (5), MgS0.7H 2 0 (0.2) and glucose (10)] in 500 ml Erlenmeyer flasks shaken at 250 rpm with a one inch (25 mm) throw for 24 hours at 25°C. The cells were then harvested by centrifugation at 1200 g for 10 minutes. The cells were resuspended to one fifth of their original harvest volume in 50 mM potassium phosphate pH 6.0.
  • a 50 mg/ml emulsion of ethyl 4-cyano-4-(4-nitrophenyl)hexanoate in 50 mM potassium phosphate + 0.1% Tween 80 was prepared by sonication for 10 minutes (cycles of 10 seconds on, 3 seconds off) at an amplitude of 18 ⁇ m in a Soniprep 150. 400 ⁇ l of this substrate emulsion was added to 1.6 ml of the resuspended cells in a 20 ml glass vial. The biotransformation reaction mixture was then incubated with shaking at 25°C, 250 rpm for 69 hours. After this time the reaction was stopped by the addition of 2 ml ethyl acetate.
  • Fusarium oxysporum IMI 329662 was cultured on 25 ml of sterile ptt 6.0 aqueous medium [containing (g/1) yeast extract (20), (NH 4 ) 2 S0 4 (4) , KH 2 P0 4 (5), MgS0 4 .7H 2 0 (0.3) , Na 2 HP0 4 .2H 2 0 (5), CaCl 2 .2H 2 0 (0.2) and glucose (40) ], in 250 ml point-baffled Erlenmeyer flasks shaken at 250 rpm with a one inch (25 mm) throw for 72 hours at 25°C.
  • Example 10 Penicillium pinophilum IMI 114933 was cultured as described in Example 9 but with the inclusion of 10 g/1 tributyrin in the medium. Cells were harvested, resuspended to original volume in 50 mM potassium phosphate and used in biotransformation as in Example 8.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Wood Science & Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

On prépare des glutarimides énantiomères tels que l'aminoglutéthimide et le roglétimide par cyclisation d'un ester-nitrile correspondant constituant un bon substrat pour la biotransformation à l'aide d'une estérase énantiospécifique.
EP95920162A 1994-05-27 1995-05-30 Composes chiraux et leur resolution Withdrawn EP0763023A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9410721 1994-05-27
GB9410721A GB9410721D0 (en) 1994-05-27 1994-05-27 Chiral compounds and their resolution
PCT/GB1995/001228 WO1995032947A1 (fr) 1994-05-27 1995-05-30 Composes chiraux et leur resolution

Publications (1)

Publication Number Publication Date
EP0763023A1 true EP0763023A1 (fr) 1997-03-19

Family

ID=10755860

Family Applications (1)

Application Number Title Priority Date Filing Date
EP95920162A Withdrawn EP0763023A1 (fr) 1994-05-27 1995-05-30 Composes chiraux et leur resolution

Country Status (9)

Country Link
EP (1) EP0763023A1 (fr)
JP (1) JPH10500861A (fr)
CN (1) CN1151731A (fr)
AU (1) AU2572495A (fr)
CA (1) CA2191363A1 (fr)
FI (1) FI964709A (fr)
GB (1) GB9410721D0 (fr)
NO (1) NO965551L (fr)
WO (1) WO1995032947A1 (fr)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000055122A1 (fr) * 1999-03-16 2000-09-21 Eisai Co., Ltd. Derives de nitrile
US6884791B2 (en) 1999-07-06 2005-04-26 Methylgene, Inc. Inhibitors of β-lactamase
ATE311397T1 (de) 1999-07-06 2005-12-15 Methylgene Inc Sulfonamidomethyl phosphonat beta-lactamase inhibitoren
WO2006128590A1 (fr) * 2005-05-31 2006-12-07 Dsm Ip Assets B.V. Hydrolases, acides nucleiques codant pour ces hydrolases et methodes de fabrication et d'utilisation

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2848455A (en) * 1955-07-18 1958-08-19 Ciba Pharm Prod Inc Alpha-(p-amino-phenyl)-alpha-lower alkyl glutarimides
DE3724520C2 (de) * 1986-07-31 1996-01-11 Madaus Ag Neue 3-Aryl-3-Cycloalkyl-piperidin-2,6-dion-Derivate
AU668692B2 (en) * 1991-08-22 1996-05-16 Chiroscience Limited Chiral glutarate esters, their resolution and derived glutarimide compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9532947A1 *

Also Published As

Publication number Publication date
JPH10500861A (ja) 1998-01-27
NO965551D0 (no) 1996-12-23
FI964709A0 (fi) 1996-11-26
FI964709A (fi) 1996-11-26
GB9410721D0 (en) 1994-07-13
CA2191363A1 (fr) 1995-12-07
CN1151731A (zh) 1997-06-11
WO1995032947A1 (fr) 1995-12-07
NO965551L (no) 1997-01-09
AU2572495A (en) 1995-12-21

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