WO2009118750A1 - Hydrolyse stéreosélective pour la résolution de mélanges racémiques à base de (±) -cis-s-acétoxy-1- (4-méthoxyphényl) -4- (2-furyl) -2-azétidinone, de (±) -cis-s-acétoxy-1- (4-méthoxyphenyl) -4- (2-thiényl) -2-azétidinone, ou de (±)-cis-3-acétoxy-4-(1,1-diméthyléthyl)-2-azétidinone - Google Patents

Hydrolyse stéreosélective pour la résolution de mélanges racémiques à base de (±) -cis-s-acétoxy-1- (4-méthoxyphényl) -4- (2-furyl) -2-azétidinone, de (±) -cis-s-acétoxy-1- (4-méthoxyphenyl) -4- (2-thiényl) -2-azétidinone, ou de (±)-cis-3-acétoxy-4-(1,1-diméthyléthyl)-2-azétidinone Download PDF

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WO2009118750A1
WO2009118750A1 PCT/IN2008/000722 IN2008000722W WO2009118750A1 WO 2009118750 A1 WO2009118750 A1 WO 2009118750A1 IN 2008000722 W IN2008000722 W IN 2008000722W WO 2009118750 A1 WO2009118750 A1 WO 2009118750A1
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azetidinone
acetoxy
methoxyphenyl
formula
furanyl
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PCT/IN2008/000722
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English (en)
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Naveen Anand
Surrinder Koul
Subhash Chandra Taneja
Rajinder Parshad
Kuldip Singh Manhas
Rattan Lal Sharma
Ghulam Nabi Qazi
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Council Of Scientific & Industrial Research
University Of Jammu
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Publication of WO2009118750A1 publication Critical patent/WO2009118750A1/fr

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    • 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
    • C12P41/004—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 alcohol- or thiol 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
    • 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
    • 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
    • C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings

Definitions

  • the present invention relates to a stereoselective enzymatic process for the resolution of a mixture of ( ⁇ )-cis-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2- azetidinone, ( ⁇ )-cis-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thiophenyl)-2-azetidinone and ( ⁇ )-cis-3-acetoxy-4-(1 ,1-dimethylethyl)-2-azetidinone into their optically pure forms.
  • the present invention relates to a process for the resolution of a mixture of ( ⁇ )-cis-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2- azetidinone, ( ⁇ )-cis-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thiophenyl)-2-azetidinone and ( ⁇ )-cis-3-acetoxy-4-(1 ,1-dimethylethyl)-2-azetidinone into their optically pure forms by using a lipase enzyme.
  • the invention discloses the use of a native lipase enzyme preparation Arthrobacter simplex (MTCC 5125) in a highly efficient resolution process for the separation of two enantiomers of ( ⁇ )-c/s-3-acetoxy-1-(4- methoxyphenyl)-4-(2-furanyl)-2-azetidinone, ( ⁇ )-c/s-3-acetoxy-1-(4-methoxyphenyl)- 4-(2-thiophenyl)-2-azetidinone and ( ⁇ )-c/s-3-acetoxy-4-(1 ,1-dimethylethyl)-2- azetidinone through stereoselective hydrolysis of their acetyl esters in presence of an organic co-solvent.
  • MTCC 5125 native lipase enzyme preparation Arthrobacter simplex
  • paclitaxel [Taxol®], a complex polycyclic diterpene, exhibits a unique mode of action on microtubule proteins responsible for the formation of the spindle during cell division. Paclitaxel inhibits the depolymerization process of microtubulin.
  • Various types of cancers have been treated with paclitaxel and results in the treatment of ovarian cancer and metastatic breast cancer are very promising.
  • Paclitaxel was originally isolated from the bark of the yew Taxus brevifolia and has also been found in other Taxus sp. in relatively low yield.
  • Paclitaxel is 1000 times more potent compared to 10- deacetyl baccatin-lll and its higher activity is due to C-13 side chain comprising N-benzoyl-(2f?,3S)-3-phenylisoserine moiety (Wani et al JAm Chem Soc. 93, 2325- 7 1971).
  • paclitaxel Due to the poor solubility of paclitaxel, various groups are involved in the development of more water soluble taxane analogs and other molecules having more efficacy than parent molecule. Higher water soluble taxol derivative have also been developed, which when given orally was as effective as i.v dose. Paclitaxel and was also found active in a human, hormone-dependent, prostate tumor model CWR-22 and just as effective in anti-androgen chemotherapy (Patel et al, Tetrahedron: Asymmetry, 2003, 14, 3673-3677).
  • Optically enriched (+)-c/s-(3R,4f?)-3-acetoxy-1 -(4-methoxyphenyl)-4-(2- furanyl)-2-azetidinone of formula 1a, (+)-c/s-(3R,4R)-3-acetoxy-1-(4- methoxyphenyl)-4-(2-thiophenyl)-2-azetidinone of formula 2a and (+)-c/s-(3R,4S)-3- acetoxy-4-(1 ,1-dimethylethyl)-2-azetidinone of formula 3a are the key side chain intermediates used in the synthesis of modified side-chain of new generation analogues of anticancer drug Paclitaxel.
  • Amano PS- 30 Pseudomonas cepacia
  • Amano GC-20 Geotrichum candidum
  • Amano APF Aspergillus niger Amano AK (Pseudomonas sp.)
  • Amano Lipase P-30 Pseudomonas sp.
  • Amano P Pseudomonas fluorescens
  • Amano AY-30 Candida cylindracea
  • Amano N Rhizopus niveus
  • Amano R Piericillium sp.
  • Amano FAP Rhizopus oryzae
  • Amano AP-12 Aspergillus nige ⁇ , Amano MAP (Mucor meihei), Amano GC-4 (Geotrichum candidum), Sigma L-0382 and L-3126 (porcine pancrease), Lipase OF (Sepracor), Esterase 30,000 (Gist-Brocard
  • Holtan et al. (US Patent No. 6548293) patented a process comprising selective hydrolyses of the ester of one of the enantiomers of ⁇ -lactam by combining the mixture with homogenized avian or mammalian liver.
  • MTCC 5125 for the kinetic resolution of ( ⁇ )- c/s-3-acetoxy-1 -(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone, ( ⁇ )-c/s-3-acetoxy-1 - (4-methoxyphenyl)-4-(2-thiophenyl)-2-azetidinone, ( ⁇ )-c/s-3-acetoxy-4-(1 , 1 - dimethylethyl)-2-azetidinone of the formulae 1-3 is novel and has not been reported in the literature or known in the art of synthesis of precursors of taxol side chain.
  • the present invention thus discloses in detail the application of Arthrobacter simplex (RRL-1) lipase for the kinetic resolution of racemic ( ⁇ )-c/s-3-acetoxy-1-(4- methoxyphenyl)-4-(2-furanyl)-2-azetidinone, ( ⁇ )-c/s-3-acetoxy-1-(4-methoxyphenyl)- 4-(2-thiophenyl)-2-azetidinone, ( ⁇ )-c/s-3-acetoxy-4-(1 ,1 -dimethylethyl)-2- azetidinone of the formulae 1-3 defined as above.
  • the main objective of the present invention is to separate optically pure ester (+)-c/s-(3fi,4R)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone of formula 1a, (+)-c/s-(3R,4f?)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thiophenyl)-2- azetidinone of formula 2a and (+)-c/s-(3R,4S)-3-acetoxy-4-(1 ,1-dimethylethyl)-2- azetidinone of formula 3a from the racemic mixture using Arthrobacter simplex (RRL-1) lipase.
  • RRL-1 Arthrobacter simplex
  • Another objective of the present invention is provide stereoselective hydrolysis of respective racemic esters i.e. hydrolysis of ( ⁇ )-c/s-3-hydroxy-1-(4- methoxyphenyl)-4-(2-furanyl)-2-azetidinone of formula 1, ( ⁇ )-c/s-3-hydroxy-1-(4- methoxyphenyl)-4-(2-thiophenyl)-2-azetidinone of formula 2 and ( ⁇ )-c/s-3-hydroxy- 4-(1 ,1-dimethylethyl)-2-azetidinone of formula 3.
  • the present invention provides a process for stereoselective enzymatic resolution of a racemic mixture of ( ⁇ )-c/s-3-acetoxy-1-(4- methoxyphenyl)-4-(2-furanyl)-2-azetidinone (1 ), ( ⁇ )-c/s-3-acetoxy-1 -(4- methoxyphenyl)-4-(2-thiophenyl)-2-azetidinone (2) or ( ⁇ )-c/s-3-acetoxy-4-(1 ,1- dimethylethyl)-2-azetidinone (3), which comprises incubating the racemic compound selected from the structural formulae 1-3 shown in the drawing accompanying this specification with a crude wet pellet of whole cell preparations or cell free preparation or isolated/partially purified lipase enzyme (RRL-1)
  • Arthrobacter simplex in an aqueous buffer phase in presence of an organic co-solvent for effecting stereoselective hydrolysis of racemic acyl derivatives, at a temperature of 10-40 0 C, for a period of period of 12-15 hrs, followed by separation of unhydrolysed ester and hydrolyzed alcohol from the resultant mixture by known chromatography methods to obtain the deired resolved products (+)-c/s-(3R,4R)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone of formula 1a and hydrolysed alcohol (-)-c/s-(3S,4S)-3-hydroxy-1-(4- methoxyphenyl)-4-(2-furanyl)-2-azetidinone of formula 1b; unhydrolysed ester (+)- CiS-(ZRAR)-S-ZCeXoXy-I -(4-methoxyphenyl)
  • the racemic mixture used is selected from the compounds of formulae 1-3.
  • aqueous buffer phase used is selected from the group consisting of phosphate buffer, tris buffer and acetic acid buffer.
  • the organic co-solvent used is selcted from selected from the group consisting of hexane, cyclohexane, benzene, toluene, dichloromethane, acetone, acetonitrile, dimethylformamide, dimethyl sulphoxide, methanol and ethanol.
  • concentrations of organic co-solvent used is in the range of 10-90%.
  • reaction temperature used is preferably in the range of 20-35 0 C.
  • the pH of the reaction mixture is in the range of 5-8.
  • the product obtained after resolution has >99% enantiomeric excess.
  • racemic mixtures of the title compounds of formulae 1-3 were initially synthesised by 2+2 cycloaddition reaction of acetoxyacetyl chloride and an imine in presence of a base in an organic solvent at a specified temperature by the method known in the art of its synthesis.
  • Arthrobacter simplex is a bacteria which is gram positive, obligate aerobe and it grows as rod (motile) and coccai (Non motile) form. Under microscope the cells appears as chevrons (V- shape).
  • racemic substrate of formulae 1-3 is incubated with crude wet pellet of whole cell or cell free preparation or isolated/partially purified enzyme of Arthrobacter simplex (RRL-1) in an aqueous phosphate buffer selected from buffers such as phosphate, tris and acetic acid and the like at pH in the range of 5 to 8.
  • aqueous phosphate buffer selected from buffers such as phosphate, tris and acetic acid and the like at pH in the range of 5 to 8.
  • the stereoselective hydrolysis of the racemic substrate of formulae 1-3 is most efficiently effected in presence of an organic co-solvent which not only improves the enantioselectivity but also significantly improves the rate of hydrolysis.
  • the co-solvent used are selected from non polar as well as polar solvents such as toluene, benzene, hexane, cyclohexane, xylene, dimethylformamide, acetonitrile, dimethyl sulphoxide, dichloromethane, diethyl ether and the like, whereas the preferred co-solvents are dimethylformamide, acetonitrile or dimethyl sulphoxide.
  • the biphasic solvent system preferably comprises the preferred ratios of the two phases in the range between 10 to 90 percent by volume of organic phase and between about 90 to 10 percent by volume of aqueous phase, more suitably a biphasic medium comprising 90 and 10 percents by volume of buffer and organic co-solvent respectively.
  • the pH of the buffer medium is suitably adjusted at 5-8, more suitably at 6- 7.5 and most suitably at 7.
  • the temperature of the reaction is selected between 10- 4O 0 C, more suitably at 20-35 0 C and most suitably at 26 ⁇ 1°C.
  • Racemic ( ⁇ )-c/s-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone (1g) of formula 1 was added to biphasic system of aqueous phosphate buffer (22.5ml, 0.1 M. pH 7.0) and organic solvent dimethylformamide (2.5ml).
  • aqueous phosphate buffer (22.5ml, 0.1 M. pH 7.0) and organic solvent dimethylformamide (2.5ml).
  • RRL- 1g Arthrobacter simplex
  • TLC was performed on silica gel coated glass plates, using ethyl acetate: hexane (40:60) as mobile phase.
  • Chiral HPLC was performed on Shimadzu HPLC using (R, R) Whelk-O1 chiral column and hexane: isopropyl alcohol: acetic acid, 97:3:0.1 as mobile phase.
  • the reaction was terminated by adding ethyl acetate and centrifuging the mixture at 10,000 to 15,00Og to remove enzyme and the suspended particles. The clear solution was decanted and the centrifuged mass was extracted separately with ethyl acetate (3 x 50ml).
  • Racemic ( ⁇ )-c/s-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thiophenyl)-2-azetidinone (200mg) of formula 2 was added to biphasic system of aqueous phosphate buffer (9ml, 0.1 M. pH 7.0) and organic solvent dimethylformamide (1ml).
  • aqueous phosphate buffer 9ml, 0.1 M. pH 7.0
  • organic solvent dimethylformamide 1ml
  • RRL- 1 Arthrobacter simplex
  • TLC was performed on silica gel coated glass plates, using ethyl acetate: hexane (40:60) as mobile phase.
  • Chiral HPLC was performed on Shimadzu HPLC using (R, R) Whelk-O1 chiral column and Hexane:isopropyl alcohol: acetic acid, 97:3:0.1 as mobile phase.
  • the reaction was terminated by adding ethyl acetate and centrifuging the mixture at 10,000 to 15,00Og to remove enzyme and the suspended particles. The clear solution was decanted and the centrifuged mass was extracted separately with ethyl acetate (3 x 50ml). The organic layer was combined and washed with water.
  • Racemic ( ⁇ )-c/s-3-acetoxy-4-(1 ,1-dimethylethyl)-2-azetidinone (135 mg of formula 3 was added to biphasic system of aqueous phosphate buffer (9.0ml, 0.1 M. pH 7.0) and organic dimethylformamide (1.0ml).
  • aqueous phosphate buffer 9.0ml, 0.1 M. pH 7.0
  • organic dimethylformamide 1.0ml
  • TLC was performed on silica gel coated glass plates, using ethyl acetate:hexane (40:60) as mobile phase.
  • Chiral HPLC was performed on Shimadzu HPLC using Diacel OJ-H column and Hexane:ethyl alcohol, 98:2 as mobile phase. After completion of the reaction (2-4h., approx., 50% conversion), the reaction was terminated by adding ethyl acetate and was extracted separately with ethyl acetate (3 x 25ml). The organic layer was combined and washed with water.
  • Racemic ( ⁇ )-c/s-3-acetoxy-1 -(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone (0.5g) of formula 1 was added to biphasic system of aqueous phosphate buffer (12ml, 0.1 M. pH 7.0) and organic solvent dimethylformamide (1.5ml).
  • aqueous phosphate buffer (12ml, 0.1 M. pH 7.0) and organic solvent dimethylformamide (1.5ml).
  • RRL-1 Arthrobacter simplex
  • RRL-1 Arthrobacter simplex
  • HPLC chiral high performance liquid chromatography
  • TLC was performed on silica gel coated glass plates, using ethyl acetate: hexane (40:60) as mobile phase.
  • Chiral HPLC was performed on Shimadzu HPLC using (R, R) Whelk-O1 chiral column and hexane: isopropyl alcohol: acetic acid, 97:3:0.1 as mobile phase.
  • the reaction was terminated by adding ethyl acetate and was extracted separately with ethyl acetate (3 x 20ml). The organic layer was combined and washed with water.
  • Racemic ( ⁇ )-c/s-3-acetoxy-1 -(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone (0.5g) of formula 1 was added to biphasic system of aqueous phosphate buffer (12ml, 0.1 M. pH 7.0) and organic solvent dimethylformamide (1.5ml).
  • aqueous phosphate buffer (12ml, 0.1 M. pH 7.0) and organic solvent dimethylformamide (1.5ml).
  • lypholysed cell free preparation of Arthrobacter simplex (RRL- 1) 0.25g, (2060 units/mg) was added. During the course of the reaction temperature was maintained at 30 ⁇ 1°C.
  • Thin layer chromatography (TLC) and chiral high performance liquid chromatography (HPLC) was carried out to monitor the progress of the reaction after every hour.
  • TLC was performed on silica gel coated glass plates, using ethyl acetate: hexane (40:60) as mobile phase.
  • Chiral HPLC was performed on Shimadzu HPLC using (R, R) Whelk-01 chiral column and hexane: isopropyl alcohol: acetic acid, 97:3:0.1 as mobile phase.
  • the reaction was terminated by adding ethyl acetate and was extracted separately with ethyl acetate (3 x 20ml). The organic layer was combined and washed with water.
  • Arthrobacter simplex Advantage of using Arthrobacter simplex is that the enzymatic preparation is highly stereoselective that hydrolyses only one of the enantiomers, thereby furnishing both the enantiomers in high optical purity (enantiomeric excess, ee ⁇ 99%) with high time space yields.

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Abstract

La présente invention concerne un traitement enzymatique stéréosélectif destiné à la résolution d'un mélange à base de (±)-cis-3-acétoxy-1-(4-méthoxyphényl)-4-(2-furanyl)-2- azétidinone, de (±)-cis-3-acétoxy-1-(4-méthoxyphényl)-4-(2-thiophényl)-2-azétidinone ou de (±)-cis-3-acétoxy-4-(1,1-diméthyléthyl)-2-azétidinone dans leur formes optiquement pures au moyen d'une lipase. L'invention concerne en l'occurrence l'utilisation d'un simplex d'Arthrobacter à lipase native (MTCC 5125) dans un processus de résolution hautement efficace destiné à la séparation de deux énantiomères de (±)-c/s-3-acétoxy-1-(4-méthoxyphényl)-4- (2-furanyl)-2-azétidinone, de (±)-c/s-3-acétoxy-1-(4-méthoxyphényl)-4-(2-thiophényl)-2- azétidinone et de (±)-c/s-3-acétoxy-4-(1,1-diméthyléthyl)-2-azétidinone par une hydrolyse stéréosélective de leurs acétyl-esters en présence d'un co-solvant organique.
PCT/IN2008/000722 2008-03-26 2008-10-31 Hydrolyse stéreosélective pour la résolution de mélanges racémiques à base de (±) -cis-s-acétoxy-1- (4-méthoxyphényl) -4- (2-furyl) -2-azétidinone, de (±) -cis-s-acétoxy-1- (4-méthoxyphenyl) -4- (2-thiényl) -2-azétidinone, ou de (±)-cis-3-acétoxy-4-(1,1-diméthyléthyl)-2-azétidinone WO2009118750A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0552041A2 (fr) * 1992-01-15 1993-07-21 E.R. Squibb & Sons, Inc. Procédés enzymatiques pour la résolution d'un mélange d'énantiomères efficaces comme intermédiaires dans la préparation de taxanes
US6548293B1 (en) * 1999-10-18 2003-04-15 Fsu Research Foundation, Inc. Enzymatic process for the resolution of enantiomeric mixtures of β-lactams

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0552041A2 (fr) * 1992-01-15 1993-07-21 E.R. Squibb & Sons, Inc. Procédés enzymatiques pour la résolution d'un mélange d'énantiomères efficaces comme intermédiaires dans la préparation de taxanes
US6548293B1 (en) * 1999-10-18 2003-04-15 Fsu Research Foundation, Inc. Enzymatic process for the resolution of enantiomeric mixtures of β-lactams

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANAND, N. ET AL.: "(3R,4S)-cis-3-Acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)azetidin-2-one", ACTA CRYSTALLOGRAPHICA SECTION E, vol. 6, no. 7, July 2004 (2004-07-01), pages 1215 - 1216, XP002521282, Retrieved from the Internet <URL:http://scripts.iucr.org/cgi-bin/paper?S1600536804014540> [retrieved on 20090325] *
ANAND, N. ET AL.: "Arthrobacter sp.: a lipase of choice for the kinetic resolution of racemic arylazetidinone precursors of taxanoid side chains", TETRAHEDRON ASYMMETRY, vol. 18, no. 9, 7 June 2007 (2007-06-07), pages 1059 - 1069, XP022107696 *

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