WO2004099174A2 - Bioreaction continue pour la preparation d'oligomeres cycliques de polyester - Google Patents

Bioreaction continue pour la preparation d'oligomeres cycliques de polyester Download PDF

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WO2004099174A2
WO2004099174A2 PCT/US2003/035176 US0335176W WO2004099174A2 WO 2004099174 A2 WO2004099174 A2 WO 2004099174A2 US 0335176 W US0335176 W US 0335176W WO 2004099174 A2 WO2004099174 A2 WO 2004099174A2
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ceos
enzyme
reaction
leos
reaction mixture
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PCT/US2003/035176
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English (en)
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WO2004099174A3 (fr
Inventor
Edward G. Brugel
Robert Di Cosimo
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E.I. Du Pont De Nemours And Company
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Priority claimed from US10/426,600 external-priority patent/US6979720B2/en
Application filed by E.I. Du Pont De Nemours And Company filed Critical E.I. Du Pont De Nemours And Company
Priority to JP2004571716A priority Critical patent/JP2006524989A/ja
Priority to AU2003287510A priority patent/AU2003287510A1/en
Priority to CA002522409A priority patent/CA2522409A1/fr
Priority to EP03781752A priority patent/EP1618138A2/fr
Publication of WO2004099174A2 publication Critical patent/WO2004099174A2/fr
Publication of WO2004099174A3 publication Critical patent/WO2004099174A3/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
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • 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
    • C12P17/02—Oxygen as only ring hetero atoms
    • C12P17/08—Oxygen as only ring hetero atoms containing a hetero ring of at least seven ring members, e.g. zearalenone, macrolide aglycons

Definitions

  • the present invention relates to a continuous process for the enzyme- catalyzed preparation of cyclic ester oligomers from linear ester oligomers.
  • Cyclic ester oligomers have been known for a long time; see for instance U.S. Patent 2,020,298. They are known to be present in varying, usually small, quantities in many linear polyesters and have been isolated from such linear polyesters; see for example A. G. Harrison, "Analysis of cyclic oligomers of poly(ethylene terephthalate) by liquid chromatography/mass spectrometry", Polymer, 38(10), 2549-2555 (1997) and G. Wick, H. Zeitler, "Cyclic Oligomers in polyesters from diols and aromatic dicarboxylic acids", Angewandte Makromolekulare Chemie, (1983), 112, 59-94.
  • polyesters can be made from dicarboxylic acids or their diesters and diols using enzymes that catalyze (trans)esterification; see for instance X.Y. Wu, et al., Journal of Industrial Microbiology and Biotechnology, vol. 20, p. 328-332 (1998), E. M. Anderson, et al.; Biocatalysis and Biotransformation, vol. 16, p. 181-204 (1998); and H. G. Park, et al., Biocatalysis, vol. 11, p. 263-271 (1994). In some instances, in such reactions the production of small amounts of CEO coproducts has also been reported; see for instance G. Mezoul, et al., Polymer Bulletin, vol.
  • Figure 1 is a schematic diagram of the reactor used in the continuous process described in the Example.
  • degree of polymerization is meant the number of repeat units in an oligomer chain.
  • a repeat unit of the polyester of a dicarboxylic acid and a diol is meant a unit having one dicarboxylic acid derived unit and one diol derived unit.
  • a repeat unit for a hydroxycarboxylic acid is derived from a single hydroxycarboxylic acid molecule.
  • the term "dicarboxylic acid” means an organic compound that has two carboxyl groups and includes those compounds that are derived from a dicarboxylic acid or a simple derivative thereof such as a diester, or a half-acid ester of the dicarboxylic acid, or mixtures thereof.
  • the dicarboxylic acid may be substituted with one or more functional groups such as alkyl, halogen, ether, thioether, and oxo (keto) that do not substantially interfere with the various reactions described in the processes herein.
  • the dicarboxylic acid may include an aromatic ring as part of its structure. An aliphatic dicarboxylic acid may also be used.
  • the term "hydroxycarboxylic acid” means an organic compound that has a hydroxy group and a carboxyl group and includes those compounds whose carboxyl group is a carboxylic acid or simple derivative thereof such as an ester.
  • diol an organic compound having 2 hydroxyl groups or a simple derivative thereof.
  • the diol may be substituted with one or more functional groups such as halogen, ether, thioether, and oxo (keto) which do not substantially interfere with the various reactions described in the processes herein.
  • the diol may include an aromatic ring as part of its structure.
  • cyclic ester oligomer is meant a cyclic compound that is derived from at least one dicarboxylic acid and at least one diol, at least one hydroxycarboxylic acid, or a combination of at least one dicarboxylic acid, at least one diol, and at least one hydroxycarboxylic acid.
  • the various diol, dicarboxylic acid, and hydroxycarboxylic acid moieties in the CEO are connected by ester groups.
  • a “dimeric” CEO herein is meant a compound derived from a dicarboxylic acid and diol that has two dicarboxylic acid moieties and two diol moieties present in the CEO, while if the dimeric CEO is made from a hydroxycarboxylic acid it is derived from two such molecules.
  • Trimeric, tetrameric, etc. CEOs have analogous definitions. CEOs may be made from two more different dicarboxylic acids, two or more different diols, and/or two or more hydroxycarboxylic acids. CEOs will preferably have a degree of polymerization (DP) of about 1 to about 20, or preferably, about 1 to about 10, or more preferably, about 1 to about 5.
  • DP degree of polymerization
  • LEO linear ester oligomer
  • LEOs will preferably have a degree of polymerization (DP) of about 1 to about 20, or preferably, about 1 to about 10, or more preferably, about 1 to about 5.
  • LEOs may be made by melt polymerization; solution polymerization; enzyme- catalyzed polymerization; the depolymerization of polyesters, including the thermal depolymerization of polyesters and the alcoholysis (e.g. methanolysis) and hydrolysis of polyesters; or other methods known to those skilled in the art.
  • melt polymerization see F.W. Billmeyer, Textbook of Polymer Science, 3 rd Edition (1984), John Wiley & Sons, pp. 25-48.
  • linear ester oligomer also encompasses mixtures containing both at least one linear compound derived from one or more dicarboxylic acids and one or more diols, one or more hydroxycarboxylic acids, or a combination of one or more dicarboxylic acids, one or more diols, and one or more hydroxycarboxylic acids and CEOs that are naturally present when LEOs are formed by either polymerization or depolymerization in the presence of a transesterification catalyst.
  • the amount of CEOs that will naturally be present is predicted by thermodynamic equilibrium, as taught by H. Jacobson and W. H. Stockmeyer in "Intermolecular Reaction and Polycondensation I. The Theory of Linear Systems", The Journal of Chemical Physics, Vol. 18 Number 12, December 1950.
  • One type of preferred diol from which the LEOs used in the invention are derived is an aliphatic diol, that is a diol in which each hydroxyl group is bound to different alkyl carbon atoms.
  • Other preferred diols include diols of the general formula HOCH 2 (CR 1 R 2 ) n CH 2 OH, wherein R 1 and R 2 are each independently hydrogen or an alkyl group and n is an integer of 0 to 10, and preferably all R 1 and R 2 are hydrogen and especially preferably n is 0 or an integer of 1 to 4, and more preferably is n is 1 or 2.
  • Preferred dicarboxylic acids (or their derivatives including half-acid esters and diesters) from which the LEOs used in the invention are derived are isophthalic acid, substituted isophthalic acids, terephthalic acid, substituted terephthalic acids, and 2,6-naphthalenedicarboxylic acid, and combinations thereof. More preferred carboxylic acids are terephthalic acid and isophthalic acid, and terephthalic acid is especially preferred.
  • Preferred aliphatic dicarboxylic acids are adipic acid, glutaric acid, succinic acid, sebacic acid, and maleic acid. It is particularly preferred that the dicarboxylic acid used be in the form of a diester. Any combination of preferred dicarboxylic acid and the diols specified in the general formula above may be used to form a preferred LEO for use in the present invention.
  • Preferred combinations of dicarboxylic acids and diols from which the LEOs used in the invention are derived include dimethyl terephthalate with ethylene glycol, 1 ,3-propanediol, 1 ,4-butanediol, di(ethylene glycol), di(butylene glycol), di(propylene glycol), tri(butylene glycol), or mixtures thereof; dimethyl isophthalate with ethylene glycol, 1,3-propanediol, or 1 ,4-butanediol di(ethylene glycol), di(butylene glycol), di(propylene glycol), tri(butylene glycol), or mixtures thereof; dimethyl terephthalate with cyclohexane dimethanol; and dimethyl 2,6-naphthalenedicarboxylate with ethylene glycol, 1,3-propanediol, 1 ,4-butanediol, di(ethylene glycol), di(butylene glycol), di(prop
  • hydroxycarboxylic acids such as p-hydroxybenzoic acid and 2- hydroxyl-6-naphthoic acid will preferably be used as comonomers with diols and dicarboxylic acid. It will be clear that the CEOs formed in the process of the invention will also preferably be formed from the foregoing diols and dicarboxylic acids (or their derivatives including half-acid esters and diesters).
  • LEOs dissolved in a solvent are continuously converted to CEOs in an intramolecular cyclization reaction that is catalyzed by a transesterification/esterification enzyme.
  • the CEOs thus formed are removed from contact with the enzyme, isolated, and collected. Unreacted LEOs are continuously brought back into the presence of the enzyme and are further continuously converted to CEOs.
  • the LEOs used in the process may be made prior to being introduced to the process by any method known to those skilled in the art, such as those listed above.
  • the LEOs may also be made in situ during the process of the present invention.
  • LEOs that are made in situ will preferably be made by the enzyme-catalyzed reaction of dicarboxylic acid and diol and/or hydroxycarboxylic acid monomers.
  • the enzyme used for this reaction may be the same enzyme that is used to convert LEOs to CEOs or may be a different enzyme.
  • LEOs may be both made prior to being introduced to the process of the invention and made in situ from monomers during the process.
  • LEOs may also be generated during the process by the reaction of pre-made LEOs with additional monomers to form LEOs with higher degrees of polymerization.
  • the CEOs formed by the enzyme catalyzed reaction of LEOs may have lower DP's than the LEOs they were formed from. When this is the case, the enzyme-catalyzed intramolecular cyclization of an LEO will generate another LEO or a diol, dicarboxylic acid, or hydroxycarboxylic acid as a byproduct.
  • reactants are dissolved in an organic reaction solvent to prepare a reaction mixture. If necessary, the solvent may be heated to dissolve the reactants.
  • Preferred solvents include toluene, tetrahydrofuran, o- dichlorobenzene, hexane, diphenyl ether, methyl isobutyl ketone, methyl ethyl ketone, or mixtures thereof. More preferred are toluene, o-dichlorobenzene, and methyl isobutyl ketone.
  • the enzyme used in the present reaction is at least one enzyme that can catalyze the esterification of carboxylic acids, the transesterification of esters, and/or the hydrolysis of esters.
  • Typical types of enzymes that may be used include lipases, proteases, and esterases.
  • lipases e.g., lipases, proteases, and esterases.
  • the enzyme is not soluble in the reaction mixture and may be attached to a solid material (supported or immobilized); see for instance G.E.
  • Supports may include materials such as diatomaceous earth, polysaccharides (e.g., chitosan, alginate or carrageenan), titania, silica, alumina, polyacrylates and polymethacrylates, and ion exchange resins, and the enzyme may be adsorbed, covalently attached, or ionically attached, or in the form of crosslinked enzyme crystals (CLECS).
  • the enzyme may also be used without prior immobilization on a support and may be suspended in the stirred reaction mixture.
  • the specific activity of the immobilized enzyme is preferably about 0.1 lU/g immobilized enzyme to about 2000 lU/g immobilized enzyme, more preferably about 10 lU/g immobilized enzyme to about 500 lU/g of immobilized enzyme.
  • Preferred enzymes for use in the present invention are bacterial and fungal enzyme catalysts that are derived from organisms of the genera Aspergillus, Arthrobacter, Alcaligenes, Bacillus, Brevibactehum, Pseudomonas, Chromobacterium, Candida, Fusahum, Geotrichum, Humicola, Mucor, Pichia,
  • Penicillium, Rhizomucor, Rhizopus or Thermus are particularly preferred bacterial and fungal enzyme catalysts are derived from the genera and species Arthrobacter sp., Alcaligenes sp., Aspergillus niger, Aspergillus oryzae, Bacillus cereus, Bacillus licheniformis, Bacillus subtilis, Bacillus coagulans, Brevibactehum ammoniagenes, Burkholde a plantarii, Candida antartica, Candida cylindracea, Candidia lipolytica, Candida utilis, Candida rugosa, Chromobacterium viscosum, Fusahum solani, Geotrichum candidum, Humicola lanuginosa, Mucor sp., Mucor japonicus, Mucor javanicum, Mucor miehei, Pichia miso, Rhizomucor miehei, Rhizopus sp., Rhizopus nigricans, Rhizopus oryzae, Rhizopus arr
  • the most preferred lipases are derived from Candida antartica, such as Candida antartica B-Iipase "CALB" (Anderson et al., Biocatalysis and Biotransformation, 16:181-204 (1998)).
  • Candida antartica B-Iipase "CALB” Anderson et al., Biocatalysis and Biotransformation, 16:181-204 (1998).
  • suitable, commercially-available, catalysts derived from C. antartica include, but are not limited to, Novozym® 435 (Product # L4777, Sigma-Aldrich, MO) and CHIRAZYME L-2, c-f C2, lyo (ID# 2207257, Biocatalytics, Pasadena, CA).
  • the reaction mixture is preferably continuously purged during the process, preferably with an inert gas, to remove the byproducts of the transesterification/esterification process, such as any alcohols that are formed.
  • the purging process may also remove water, requiring that water levels be maintained by the addition of water throughout the process in order to maintain enzyme activity. If the purging process removes solvent, additional solvent may have to be added throughout the process as well.
  • the process of the present invention comprises continually contacting LEOs with the enzyme in a reaction vessel under conditions in which the reactants will be partially or fully converted to CEOs.
  • the enzyme may be attached to a solid support, or used unsupported. It may be present as a fixed bed or may be suspended in the stirred reaction mixture and the reaction vessel will be maintained at a temperature (the "reaction temperature") at which the enzyme will catalyze the formation of CEOs from LEOs.
  • the reaction mixture is continuously fed to a separation apparatus where all or a portion of the CEOs formed are, using any method known to those skilled in the art, removed and, if necessary, purified.
  • separation apparatus is meant any vessel or other apparatus, such as a filter, extractor, etc. in which CEOs are removed from the reaction mixture.
  • the remaining reaction mixture depleted in CEOs is then continuously brought back into contact with the enzyme.
  • Additional LEOs and/or monomers may be added to the reaction mixture before or when it is brought back into contact with the enzyme in a reaction vessel. At least a portion of added monomers will react, catalyzed by the enzyme, to generate LEOs.
  • Monomers present may also react with LEOs already present to generate LEOs with a higher degree of polymerization. When there is more diol than dicarboxylic acid present, or vice versa, the monomers may also react with LEOs to lower the degree of polymerization of the LEOs.
  • the CEOs formed will preferably have a degree of polymerization of 2 to about 30, or more preferably 2 to about 10.
  • the enzyme continuously catalyzes the conversion of all or a portion of LEOs present to CEOs.
  • any suitable method may be used in a separation apparatus to remove CEOs from the reaction mixture. If CEOs and the rest of the reaction mixture (e.g., LEOs and monomers, if any) have different solubilities in the reaction solvent at temperatures below the reaction temperature, when removed from the enzyme, the reaction mixture is fed to a vessel that is maintained at a temperature at which either the CEOs formed in the reaction or the LEOs and monomers are at least partially insoluble and where at least a portion of them precipitate out of solution. In the former case, the insoluble, precipitated CEOs are removed from the process and collected by any suitable means, such as filtration, and the resulting CEO-depleted reaction mixture is continuously brought back into contact with the enzyme at the reaction temperature.
  • any suitable means such as filtration
  • the CEO-containing solution is removed from the vessel and the CEOs are collected by any suitable means.
  • examples of methods of isolating CEOs include: removal of the solvent by evaporation or distillation; adding a cosolvent to precipitate the CEOs and collecting the precipitate; and extracting the CEOs into another solvent and isolating them from that solvent by precipitation or removal of the second solvent by evaporation or distillation.
  • Any insoluble, precipitated LEOs are collected by any appropriate method, such as by using a continuous rotary filter and are redissolved in the reaction solvent and brought back into contact with the enzyme at the reaction temperature.
  • Another method is applicable where the CEOs and the LEOs and any monomers present have different solubilities in a solvent that is not miscible with the reaction solvent.
  • this method some or all of the CEOs or LEOs and monomers are removed from the reaction mixture by counter-current extraction with the non- miscible solvent.
  • this solvent stream is removed from the process and the extracted CEOs are collected by any suitable means, such as precipitation, extraction, evaporation, and crystallization, while the remainder of the reaction mixture is brought back into contact with the enzyme at the reaction temperature.
  • the solution containing the CEOs is removed from the process and the CEOs are isolated.
  • the extracted LEOs and monomers are brought back into contact with the enzyme at the reaction temperature. They may be subjected to a second counter-current extraction with the reaction solvent, the extracted solution may be diluted with the reaction solvent, or the non-miscible solvent may be removed and the isolated LEOs and monomers may be redissolved in the reaction solvent before they are brought back into contact with the enzyme.
  • an additional solvent that causes either some or all of the CEOs or some or all of the LEOs and monomers present to precipitate from solution is added.
  • the CEO- enriched solution is removed and the CEOs are collected.
  • the insoluble LEOs and monomers are collected by any appropriate method, such as by using a continuous rotary filter, and are redissolved in the reaction solvent and brought back into contact with the enzyme.
  • the insoluble CEOs are removed from the process and collected and the remaining LEOs and monomers are brought back into contact with the enzyme, after removing them from the second solvent by any suitable method such as counter-current extraction, evaporation, crystallization, and redissolution, or dilution with the reaction solvent.
  • CEOs are isolated by crystallization, melt crystallization, or the addition of a solvent in which either CEOs or LEOs and monomers are soluble at the temperature used.
  • CEOs may also be removed from the reaction mixture or other solution containing LEOs and monomers by other means such as selective crystallization; passing the solution through a semi-permeable membrane; a distillation technique such as short-path distillation; sublimation; using an adsorbant selective for CEOs or LEOs and monomers; or other methods known to those skilled in the art.
  • CEOs remaining with LEOs and monomers are brought back into contact with the enzyme and can react further or can be isolated later in the process.
  • the purity of the CEOs collected from the process of the present invention will be at least 50 percent by weight, or preferably at least 75 percent by weight, or more preferably, at least 90 percent by weight.
  • Impurities may comprise LEOs and/or monomers.
  • the CEOs may be further purified by any known purification technique such as chromatography or recrystallization.
  • One embodiment of the continuous process of the present invention uses a recirculating reactor. An initial reaction mixture is brought into contact with the enzyme in a reaction vessel.
  • This initial reaction mixture comprises a solution of any of the reactants used in the present invention.
  • the reaction vessel is maintained at a temperature at which all components of the initial reaction mixture as well as any LEOs and CEOs that are formed in the course of the reaction are soluble.
  • the reaction vessel is preferably continuously stirred.
  • the enzyme catalyzes the esterification/transesterification of the reactants to generate a reaction mixture enriched in CEOs.
  • the reaction mixture from the reaction vessel is removed from contact with the enzyme by any known method, such as continuous filtration, extraction, Soxhlet extraction, centrifugation, etc., and is continuously fed to a separation apparatus, which may also be a continuously stirred vessel.
  • CEOs are removed from the reaction mixture in the separation apparatus using a method such as one of those described above and the resulting reaction mixture depleted in CEOs is returned to the reaction vessel where it is brought back into contact with the enzyme and where further reaction occurs. Additional reaction mixture may be added throughout the process to replenish the amounts of reactants present.
  • the reaction mixture may be transferred between the reaction vessel and separation apparatus by tubing, piping or other means that permits liquid transport.
  • the reaction mixture may be pumped or gravity fed between the reaction vessel and separation apparatus and additional vessels and apparatus may be included in the loop.
  • a second embodiment of the present invention uses a linear reactor that comprises a plurality of reaction vessels/separation apparatus connected in series.
  • An initial reaction mixture is brought into contact with the enzyme in a first reaction vessel.
  • This initial reaction mixture may comprise a solution of any combination of reactants capable of reacting to form CEOs in the presence of the enzyme.
  • the first reaction vessel is maintained at a temperature at which all components of the initial reaction mixture as well as any LEOs and CEOs that are formed in the course of the reaction are soluble.
  • the first vessel is preferably L continuously stirred.
  • the enzyme catalyzes the esterification/transesterification of the reactants to generate a reaction mixture enriched in CEOs.
  • the reaction mixture from the first reaction vessel is removed from contact with the enzyme and is continuously fed to a first separation apparatus.
  • CEOs are removed from the reaction mixture in the separation apparatus using a method such one of those described above and the resulting reaction mixture depleted in CEOs is optionally continuously passed to a second reaction vessel that is maintained at a temperature at which all components of the reaction mixture are soluble and which contains the enzyme.
  • the reaction mixture in turn is optionally continuously fed to a second separation apparatus in which CEOs are removed from the process.
  • many reaction vessels and separation apparatus as desired may be linked in this fashion, where the reaction mixture is continuously fed from a reaction vessel containing enzyme to a separation apparatus containing no enzyme and in which CEOs are removed.
  • the number of reaction vessels and separation apparatus used will depend on the degree of conversion of reactants or amount of product desired. It is not necessary that the method of separation of the CEOs from the reaction mixture be the same in each separation apparatus.
  • reaction mixture may be added throughout the process to replenish the amounts of reactants present.
  • the reaction mixture may be transferred between the reaction vessels and separation apparatus by tubing, piping or other means that permits liquid transport.
  • the reaction mixture may be pumped or gravity fed between the reaction vessels and separation apparatus and additional vessels and apparatus may be included in the series.
  • the second embodiment is preferred over the first when the LEOs are less soluble than the CEOs in the reaction solvent at temperatures below the reaction temperature.
  • Preferred CEOs formed by the process of this invention are the dimer derived from 1 ,4-butanediol and dimethyl terephthalate (3,8,15,20- tetraoxatricyclo[20.2.2.210,13]octacosa-10,12,22,24,25,27-hexaene-2,9,14,21- tetrone) (structure 1); the trimer formed from 1,4-butanedioI and dimethyl terephthalate (3,8,15,20,27,32-hexaoxatetracyclo[32.2.2.210,13.222,25]dotetraconta- 10,12, 22,24,34,36,37,39,41-nonaene-2,9,14,21,26,33-hexone); the dimer formed from 1,3-propanedi
  • the CEOs formed by the process of the present invention may be polymerized to higher molecular weight polyesters, which have many applications in injection molding, blow molding, extrusion molding, fibers, filaments, and films and are useful for making durable and disposable goods.
  • the CEOs may also be polymerized directly in a mold. Examples
  • FIG. 10 is a 600 mL jacketed reaction vessel containing Chirazyme® L-2 lipase supported on polymer beads, and a 0.1 M solution of dimethyl terephthalate and di(ethylene glycol) in toluene.
  • 11 is a 600 mL reaction vessel that is maintained at room temperature. Each reactor is equipped with running stirrers 12. The temperature of the solvent in vessel 10 is maintained at 50-55 °C using hot silicone oil that is heated by heater 14 and circulated through jacket 15 of vessel 10. The reaction solution is pumped by pump 16 into vessel 11 via tubing 17, the lipase being held in place by fritted glass filter 13.
  • the desired CEO product of the reaction the cyclic dimer derived from dimethyl terephthalate and di(ethylene glycol) (CPEOT) (structure 3), precipitates out in vessel 11 and is collected on fritted filter 18.
  • the filtered, room-temperature reaction solution is pumped by pump 19 to the top of vessel 10 through tubing 20. Meanwhile, sufficient dimethyl terephthalate and di(ethylene glycol) dissolved in toluene is added to the top of vessel 10 via opening 21 to maintain the concentration of starting materials in vessel 10 as well as a constant volume.
  • the reaction solution is continuously purged with a 50 mL/min nitrogen flow and 1 ⁇ l/min of water is continuously added. The reaction is run continuously as long as desired.
  • vessel 11 is emptied and the collected CPEOT is collected. Its purity is greater than 90% as measured by HPLC and can be further purified by column chromatography on silica gel.
  • Samples are analyzed by LCMS using the following technique. Approximately 10 drops of the reaction mixture are placed in 1.5 ml of o-cresol. The o-cresol mixture is heated at 100 to 125 °C for 5 min, with stirring. Then, 5 drops of the o- cresol solution are added to 3 ml of chloroform and the mixture is shaken and filtered through a 0.45 micron filter (Acrodisc® CR 25 mm syringe filter, Gelman Laboratory) into a liquid chromatograph sample vial. Analysis is carried out using a Hewlett- Packard® 1100 Liquid Chromatograph equipped with a HP G1315A UV Diode array detector and a HP G1946A Mass Spectrometer detector.

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Abstract

Cette invention concerne un processus continu de préparation par catalyse enzymatique d'oligomères cycliques d'ester à partir d'oligomères d'ester linéaires. Ce processus peut être mené à bien au moyen d'un réacteur linéaire ou de recirculation.
PCT/US2003/035176 2003-04-30 2003-10-31 Bioreaction continue pour la preparation d'oligomeres cycliques de polyester WO2004099174A2 (fr)

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JP2004571716A JP2006524989A (ja) 2003-04-30 2003-10-31 ポリエステル環状オリゴマーを製造するための連続バイオリアクター方法
AU2003287510A AU2003287510A1 (en) 2003-04-30 2003-10-31 Continuous bioreactor process for the preparation of polyester cyclic oligomers
CA002522409A CA2522409A1 (fr) 2003-04-30 2003-10-31 Bioreaction continue pour la preparation d'oligomeres cycliques de polyester
EP03781752A EP1618138A2 (fr) 2003-04-30 2003-10-31 Bioreaction continue pour la preparation d'oligomeres cycliques de polyester

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US10/426,600 US6979720B2 (en) 2002-05-03 2003-04-30 manufacture of certain cyclic ester oligomers
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Cited By (1)

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JP2008545439A (ja) * 2005-06-07 2008-12-18 イー・アイ・デュポン・ドウ・ヌムール・アンド・カンパニー 酵素触媒による大環状ポリエステルオリゴマーの製造方法

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AU2003287510A8 (en) 2004-11-26
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