AU2477492A - Chiral glutarate esters, their resolution and derived glutarimide compounds - Google Patents

Chiral glutarate esters, their resolution and derived glutarimide compounds

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Publication number
AU2477492A
AU2477492A AU24774/92A AU2477492A AU2477492A AU 2477492 A AU2477492 A AU 2477492A AU 24774/92 A AU24774/92 A AU 24774/92A AU 2477492 A AU2477492 A AU 2477492A AU 2477492 A AU2477492 A AU 2477492A
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compound
formula
enantiomer
ethyl
resolution
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AU24774/92A
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AU668692B2 (en
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Christopher Thomas Evans
Raymond Mccague
Stephen John Clifford Taylor
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Chirotech Technology Ltd
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Chiroscience Ltd
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Priority claimed from GB919118149A external-priority patent/GB9118149D0/en
Priority claimed from GB919118151A external-priority patent/GB9118151D0/en
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Publication of AU2477492A publication Critical patent/AU2477492A/en
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    • 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

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

Description

CHIRAL GLUTARATE ESTERS, THEIR RESOLUTION AND DERIVED GLUTARIMIDE COMPOUNDS
Field of the Invention
This invention relates to chiral compounds and their resolution. 5 Background of the Invention
The racemate of 3-ethyl-3-(4-pyridyl)piperidine-2,6- dione (Rogletimide) , also known as pyridoglutethimide (described herein as 4-PG) , has been demonstrated to be effective for the treatment of hormone-dependent breast 0 cancer. As described by Foster et aJL, J. Med. Chem. 28:
200-204 (1985) , the mode of action of 4-PG is thought to be inhibition of the enzyme aromatase and therefore of oestrogen biosynthesis. Derivatives of 4-PG, including 5- alkyl derivatives, may be as good or better aromatase 5 inhibitors; see McCague and Rowlands, J. Med. Chem., in press.
As described by McCague et a_l, J. Chem. Soc. Perkin
Trans. 1: 196-198 (1989), the (R)-enantiomer of 4-PG has been measured to be twenty times as potent an inhibitor of 0 aromatase as the (S)-enantiomer. It is therefore likely that the (R)-isomer is essentially the active component in the racemate.
The separate enantiomers of 4-PG have been prepared, using a camphor-derived chiral auxiliary. This agent is 5 expensive, and makes the method impractical for production of more than gram quantities of product.
Summary of the Invention
According to the present invention, 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. For the purposes of illustration only, the process involved in the invention will now be described with reference to the production of enantiomeric 4-PG, as outlined in the Chart. 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. For the purpose of the invention, the simplest alkyl groups (R,R' = methyl or ethyl) are adequate, and in terms of simplifying the chemical processing, are preferred.
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 (Asperαillus) , esterase 30,000, Rhizopus
Japonicus lipase, F3 lipase, A2 lipase (porcine pancreas) , F6 lipase (from Candida) , pig liver esterase, CE lipase and AY lipase. Cholesterol esterase is an alternative.
One example of a 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.
Conversion of the biotransformation products, which are readily separated by solvent extraction at neutral pH, into enantiomerically-enriched 4-PG is by conventional chemical techniques. Thus, diesters (3.) can be converted into ( 5) by heating with methanolic ammonia under pressure, and ester-acid (4_) can be converted into ( 5.) by heating with urea. 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. In an embodiment of this aspect of the invention, 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.
The following Examples illustrate the invention. 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 MgS04; 0.1 g/l CaCl2; 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. This was used to inoculate production fermenters (using a 10% inoculum): 1.5 1 growth medium per Anglicon fer enter. These were grown at 23°C with agitation; aeration was adjusted to keep the DOT above 50%. After 24 hours, the optical density at 520 nm had reached 2.5. The cells were then harvested at 5000 rpm for 10 min.
Example 2 Biotransformation The cell mass of P3U1 cells, harvested by centrifugation, was resuspended to an optical density of 2
(520 n ) in 10 mM KH2PO/>, pH 7, containing yeast extract (5 g/l). (+)-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. Cells were removed by centrifugation, then diester extracted with ethyl acetate (3 x 1 1) . The aqueous layer was then salted (10% weight NaCl) and the pH adjusted to 2.6 using cone. HCl. The product was then extracted with tetrahydrofuran (THF) . The THF extracts were combined and evaporated under reduced pressure to give
• a brown oil, which was dried by azeotroping with toluene. The toluene solution was mixed with an equal volume of acetone, and the resulting precipitate of inorganic salts filtered off. The solvents were evaporated to give a brown oil which solidified on standing (yield 4.1 g) . This was substantially R-2-ethyl-2-(4-pyridyl)glutaric acid 1- monomethyl ester. Example 3 Cyclisation
Cyclisation to the imide was effected by heating the product from Example 2 with an equal weight of urea for 20 min.
The product was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was dried (MgS04) and then evaporated to give crude 3- ethyl-3-(4-pyridyl)pyridine-2,6-dione (1.1 g) . This was purified by flash chromatraphy on silica (eluting with 2:1 ether:triethylamine) to give pure enantiomerically enriched product (300 mg) . The ee was found to be 56% as determined by HPLC on a Daicel Chiracel OJ column. Example 4 ee Enrichment The purified imide from Example 3 (300 mg) was dissolved in ethyl acetate (10 ml) . To this solution was added lR-(-)-camphorsulphonic acid (1.1 mol equivalent, 352 mg) . After 0.5 hr stirring at ambient temperature the mixture was brought to reflux and sufficient ethanol (3 ml) added to dissolve the solid. The clear solution was allowed to cool slowly to 5°C after which the solid was removed by filtration (190 mg of racemic material) . The enantiomeric excess of the product in the liquors was found to be 96.2%. The solvent was removed and the above recrystallisation process repeated. The final liquors contained R-3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as its R-camphorsulphonate salt in 97.3% enantiomeric excess.
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.
Example 5 Biotransformation
Biotransformation on the same substrate as Example 2 was carried out in a baffled conical flask (500 ml) containing 0.1 M KH2P04 (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
The procedure described in Example 5 was carried out but using Candida cγlindracea lipase as the biocatalyst. After 48 hr, the ee of the remaining diester was 66% in favour of S-enantiomer, at a conversion of 72%. 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
(the growth medium comprised 1 g/l
0.25 g/l MgS04.7H20, 0.1 g/l CaCl2.2H20, 0.1 ml/1 trace element solution, 10 g/l yeast extract, adjusted to pH 7.0 with sodium hydroxide) . This was incubated at 23°C for 24 hours with shaking. The cells were then spun and resuspended in 5 ml reaction buffer in a 20 ml container
(the reaction buffer comprised 10 mM sodium phosphate, 5 g/l yeast extract (Fould Springer) , 50 μl/1 Tween 80, 3 g/l
(+)-dimethyl 2-ethyl-2-(4-pyridylglutarate) . This 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
Chiracel-OJ column. After 22 hours, the residual diester had an ee of 54% in favour of the R configuration.
CO-R racemate
(1) (2)
biocatalyst biocatalyst A B
(3a) (4b) (3b) (4a)
(S)-enantiomer (R)-enantiomer (R) -enantiomer (S)-enantiomer
N 0
H
(5a) R-enantiomer
(5b) S-enantiomer

Claims (20)

1. A method for preparing, in the form of at least predominantly one enantiomer thereof, a chiral compound of formula I
wherein X and Z are each H or an organic group and Y is a cyclic group, which comprises cyclising by a idation a corresponding enantiomeric form of a chiral compound of formula II
ROOC COOR'
wherein R and R' are the same or different esterifying radicals.
2. A method according to claim 1, wherein X, R and R1 are each a C,.10 alkyl group.
3. A method according to claim 2, wherein X is ethyl.
4. A method according to any preceding claim, wherein Y is 4-pyridyl.
5. A method according to any preceding claim, wherein Z is H.
6. A method according to any preceding claim, wherein the compound of formula I is an aromatase inhibitor.
7. A method according to claim l, wherein the compound of formula I is (R)-4-pyridoglutethimide.
8. A method according to any preceding claim, wherein R and R' are each methyl or ethyl.
9. A method according to any preceding claim, wherein cyclisation comprises reaction with urea or ammonia.
10. A method according to any preceding claim, which comprises the prior steps of contacting racemic formula II compound with an enantiospecific esterase; further resolution (if desired) ; and separating the compound of formula II from the acid formed by the esterase reaction.
11. A method according to claim 10, wherein the esterase has the characteristics of Trichosporon ENZA 1-3, IMI 348917 or Of PU31, NCIMB 40517.
12. A method according to claim 10 or claim 11, wherein further resolution is conducted, using a camphorsulphonate salt or other resolution agent.
13. A compound of formula II as defined in any of claims 1 to 8.
14. A compound according to claim 13, wherein X is ethyl and Y is 4-pyridyl.
15. A compound according to claim 13 or claim 14, in the form of a mixture of enantiomers of which one is in enantiomeric excess of at least 50%.
16. A compound according to claim 13 or claim 14, in the form of one enantiomer substantially free of the other enantiomer.
17. A compound according to claim 15 or claim 16, wherein the one enantiomer is the (R)-enantiomer.
18. A compound according to claim 17, which corresponds to (R)-4-pyridoglutethimide.
19. Trichosporon ENZA 1-3, IMI 348917, except for use in the enantiospecific conversion of a monocarboxylic arylalkanoic acid ester to the acid.
20. The strain P3U1, NCIMB 40517.
AU24774/92A 1991-08-22 1992-08-21 Chiral glutarate esters, their resolution and derived glutarimide compounds Ceased AU668692B2 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB9118151 1991-08-22
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
GB9118149 1991-08-22
PCT/GB1992/001541 WO1993004058A1 (en) 1991-08-22 1992-08-21 Chiral glutarate esters, their resolution and derived glutarimide compounds

Publications (2)

Publication Number Publication Date
AU2477492A true AU2477492A (en) 1993-03-16
AU668692B2 AU668692B2 (en) 1996-05-16

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AU24774/92A Ceased AU668692B2 (en) 1991-08-22 1992-08-21 Chiral glutarate esters, their resolution and derived glutarimide compounds

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

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9410721D0 (en) * 1994-05-27 1994-07-13 Chiroscience Ltd Chiral compounds and their resolution
AR022725A1 (en) * 1999-02-26 2002-09-04 Schering Corp ENZYMATIC HYDROLYSIS ENANTIOSELECTIVA OF ESTERES 3-SUBSTITUTES OF GLUTARIC ACID

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3224019C1 (en) * 1982-06-28 1984-02-16 Takara Shuzo Co., Ltd., Kyoto Process for the preparation of alkyl beta -(S)-aminoglutarates
DE3724520C2 (en) * 1986-07-31 1996-01-11 Madaus Ag New 3-aryl-3-cycloalkyl-piperidine-2,6-dione derivatives
NZ242054A (en) * 1991-03-22 1993-11-25 British Tech Group Pyridine derivatives having a bridged alicyclic group; medicaments

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EP0599959A1 (en) 1994-06-08
JPH06510284A (en) 1994-11-17
AU668692B2 (en) 1996-05-16
WO1993004058A1 (en) 1993-03-04
CA2116108A1 (en) 1993-03-04

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