HK1101591B - Use of a catalytic system for lactide and glycolide (co)oligomerization - Google Patents

Description

The present invention relates to the use of a system consisting of a strong acid ion exchange resin as a catalyst and a (co) oligomerisation additive as a catalytic system for (co) oligomerisation of the lactide and glycolide by loop opening.

In this respect, lactic and glycolic acid copolymers (GLPAs) are of great interest because they are sensitive to hydrolysis and are degraded in vivo with release of non-toxic by-products. The application of the PLPAs is very broad (Adv. Materphere 8, 1996, Ch. 43, 50 and 49). In the field of pharmaceutical chemistry, they are used for the synthesis of multi-strands, in vitro, in vitro, and in the control of cell release, sutures, and transfer of acids.

For all these applications, the key factor is the rate of degradation of PLGAs which of course depends on their structure (chain length, dispersion, proportion, stereochemistry and monomer sequencing, etc.).

The use of metal systems most often leads to contamination of the copolymers thus obtained by the presence of metal salts, which is sometimes a major limitation depending on the intended applications. The development of non-metallic systems allowing the controlled (co) polymerization of the lactide and glycolide is a major challenge. The present invention is part of this framework and therefore concerns in particular the (co) polymers of the low-mass lactide and glycolide, i.e. the (co) oligomers of the lactide and glycolide. The applicant therefore proposes the use of a simple catalytic system, consisting of a catalyst and a (co) oligomerisation additive, which allows the chain length but also the nature of the chain ends of the prepared (co) oligomers to be controlled.

US 6.355.772 describes the polymerization of lactides.

Err1:Expecting ',' delimiter: line 1 column 528 (char 527)

The term alkyl refers to an alkyl radical with 1 to 20 carbon atoms. This term covers alkyl radicals with 1 to 6 linear or branched carbon atoms and especially alkyl radicals with 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, dry-butyl, and tert-butyl radicals. The term also includes radicals with more than 6 carbon atoms such as heptyl, octyl, non-carbon, decyle, undedecyle, docedecyle, tridedecyle, tetradecyle, heptadecyle, pentadecyle, heptadecyle, and non-ocedecyle.

The term alkoxy refers to radicals in which the alkyl radical is a radical of 1 to 6 carbon atoms as defined above such as the methoxy, ethoxy, propyloxy or isopropyloxy radicals but also linear, secondary or tertiary butoxy, pentyloxy.

The term cycloalkylyl can be chosen from the radicals cyclobutene, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene. The term cycloalkylyl denotes radicals in which the cyclocarbonyl radical is such as the radial radical. The term cycloalkylyl denotes radicals in which the cyclocarbonyl radical is such as the radial radical. The term cycloalkylyl denotes radicals in which the cyclocarbonyl radical is such as the radial radical.

Polycyclic arylic radicals can be monocyclic or polycyclic. Monocyclic arylic radicals can be chosen from among phenyl radicals optionally substituted with one or more allyl radicals such as tolyl, xylyl, mesityl, cumenyl. Polycyclic arylic radicals can be chosen from among naphthyl, anthryl, phenanthryl radicals.

For the purposes of this application, the term (co) oligomerisation means oligomerisation or co-oligomerisation with degrees of polymerisation (DP) below 30, so the (co) oligomerisation of the lactide and the glycolide covers the oligomerisation of the lactide, the oligomerisation of the glycolide but also the oligomerisation of the lactide and the co-oligomerisation of the glycolide.

In a catalytic system according to the present invention, the amount of monomer relative to the (co) oligomerization additive is between 2 and 30 molar equivalents and, very preferably, between 4 and 10 molar equivalents.

The invention relates in particular to the use of a catalytic system as defined above, characterised by the polymer catalyst (1) being a styrene and divinylbenzene macroreticular resin with sulphonic acid functions.

Preferably, in a catalytic system as defined above, the polymer catalyst (1) is a macroreticilated resin of type Amberlyst® or Dowex®, and very preferably a resin of type Amberlyst®.

According to the present invention, the (co-) oligomerization additive of formula (2) thus used acts as a co-oligomerization initiator (or starter) and is essential because in the absence of such a compound of formula (2), the (co-) oligomerization reactions are much slower, lead to much lower yields, are not reproducible, and are therefore not industrially exploitable.

Err1:Expecting ',' delimiter: line 1 column 390 (char 389)

The invention is specifically intended to use a catalytic system as defined above and characterized by the addition of water or alcohol as the additive of general formula (2) (co-oligomerization). According to the present invention, this alcohol has the formula R2-OH in which R2 is as defined above. Alcohols include, for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-1-butanol, longer-chain alcohols such as dodecanol or substituted alcohols such as ethyl lactate. Preferably, the alcohol used in a catalytic system as defined above is a very preferentially aliphatic alcohol and among the aliphatic alcohols, pentanol and dodecanol-1-alcohol is the aliphatic alcohol.

The invention also relates to a process of (co) oligomerisation of the lactid and glycolide by loop opening, which consists in the presence of the monomer (s) in question, a catalytic system as defined above consisting of a polymeric catalyst of the strong acid ion exchange resin type (1) and a general formula (co) oligomerisation additive (2) in an oligomerisation solvent.

The solvent for the reaction is chosen from solvents that do not interfere with the catalytic reaction itself. Examples of such solvents include aromatic hydrocarbons (such as toluene, xylene or mesylen), possibly substituted by one or more nitro groups (such as nitrobenzene), ethers (such as methyltertiobutyl ether, tetrahydrofuran or dioxane), aliphatic or aromatic halides (such as dichloromethane, chloroform, dichlorobethane or dichlorobenzene).

The reaction time is between 1 hour and 64 hours, preferably between 2 and 48 hours. The amount of monomer in relation to the (co) oligomerization additive is between 2 and 30 molar equivalents and, very preferably, between 4 and 10 molar equivalents. The efficiency of a (co) oligomerization process according to the present invention is generally above 80% and can even reach 100% under relatively mild conditions (40°C, a few hours) as shown in the examples.

The invention also relates in particular to a process of (co) oligomerisation of the lactid and glycolide as defined above with a catalytic system as defined above and the polymer catalyst (1) of which is a styrene- and divinylbenzene-based macroreticular resin with sulphonic acid functions.

Err1:Expecting ',' delimiter: line 1 column 427 (char 426)Err1:Expecting ',' delimiter: line 1 column 223 (char 222)

The invention relates in particular to a process of (co) oligomerisation of the lactide and glycolide as defined above, with a catalytic system in which the (co) oligomerisation additive is either water or an alcohol.

The process of (co) oligomerisation of the lactide and glycolide by loop opening according to the present invention therefore allows the nature of the chain ends of the (co) oligomers to be controlled and is particularly well suited for the production of (co) oligomers of acid-alcohol or ester-alcohol ends as shown in the experimental part. At the end of the reaction, the resin can be separated from the oligomer by simple filtration of the medium and the resin thus recovered can be reused without loss of activity.

The (co) oligomerisation process of the lactide and glycolide according to the present invention is particularly suitable for obtaining (co) oligomers with a mass of 300 to 5 000 Daltons, particularly 500 to 3 000 Daltons.

The (co) oligomerisation process of the lactide and glycolide according to the present invention has many advantages, in particular, the catalytic system consists of a strong acid ion exchange resin and a readily available and inexpensive (co) oligomerisation additive; the use of an additive as a co-oligomerisation initiator not only allows for a very significant improvement in the (co) oligomerisation process but also allows for precise control of the chain length which is virtually equal to the initial monomer to initiator ratio; the use of an additive as a co-oligomerisation additive also allows for control of the nature of the initiator endings of the prepared co-oligomers; the co-oligomerisation can be carried out under relatively low temperature conditions;The reaction times required for a near-total conversion of the monomer (s) are limited to a few hours and up to 48 hours; the mass distribution of the (co) oligomers obtained is very narrow; the polydispersity indices of the (co) oligomers obtained according to the present invention are in fact between 1.0 and 1.4; the (co) oligomers obtained can be easily, quickly and efficiently purified without changing their properties, the resin being quantitatively removed by simple filtration.

The invention also relates to oligomers or co-oligomers of lactide and glycolide obtained or capable of being obtained by the implementation of a process as described above. Such (co) oligomers have a low mass between 300 and 5 000 Dalton, and more particularly between 500 and 3 000 Dalton. Such (co) oligomers may also have controlled acid-alcohol or ester-alcohol ends.

The products of general formula (1) and (2) are commercial or can be manufactured by methods known to the tradesmen.

Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as that commonly understood by a specialist in the field to which the invention relates.

The following examples are presented to illustrate the above procedures and should in no way be considered as limiting the scope of the invention.

Example 1: Preparation of an oligomer of (D,L-lactide) with ester-alcohol ends (Mw close to 1 000 Da)

In a Schlenk tube with a magnetized bar and purged with argon, 3.00 g of D,L-lactide (0.021 mol), 20 mL of dichloromethane, 3.00 g of Amberlyst® 15 resin (0.0135 mol of acid) and 0.41 mL of pentan-1-ol (0.0037 mol) are successively introduced into a Schlenk tube with a magnetized bar. The reaction mixture is left to agitate at 40 °C for 45 hours. The oligomers are characterized by proton NMR; the conversion of the monomer is greater than 95%. The reaction medium is filtered to remove the D,L-lactide (0.021 mol), the evaporated solvent 20 mL. The residue is taken up with dichloromethane (1 mL) and poured on to the pentane (15 mL) under reduced pressure.The surfactant is removed and after vacuum drying, 2.8 g of oligomers (83%) are obtained as a viscous colourless liquid. According to an analysis by GPC (Gel Permeation Chromatography) using calibration from polystyrene (PS) standards of 400-400,000 masses, the sample is composed of oligomers with nearby masses (Mw = 1,036 Dalton, Mw/Mn = 1,22). The nature of the ends of the ester-alcohol chain is determined by mass spectrometry (electrospray ionization, positive ion detection, sample dissolved in the acrylic sample with a trace of ammonium hydroxide).

Example 2: Preparation of an oligomer of (D,L-lactide) with acid-alcohol ends (Mw close to 1 000 Da)

In a Schlenk tube with a magnetized bar and purged with argon, 23.80 g of D,L-lactide (0.165 mol), 200 mL of dichloromethane, 23.73 g of Amberlyst® 15 resin (0.11 mol of acid) and 0.74 mL of water (0.041 mol) are successively introduced into a Schlenk tube. The reaction mixture is left to agitate at 40 °C for 48 hours. The oligomers are characterized by proton NMR; the conversion of the monomer is greater than 95%. The reaction medium is filtered to remove the resin and the reduced solvent is evaporated under pressure.The surfactant is removed and after vacuum drying, 20.1 g of oligomers (82%) are obtained as a viscous colourless liquid. According to an analysis by GPC (Gel Permeation Chromatography) using calibration from polystyrene standards (PS) of 400 to 400,000 masses, the sample is composed of oligomers with nearby masses (Mw = 917 Dalton, Mw/Mn = 1.16).

Example 3: Preparation of an oligomer of (D,L-lactide) with ester-alcohol ends (Mw < 1 000 Da)

In a Schlenk tube with a magnetized bar and purged with argon, 3.00 g of D,L-lactide (0.021 mol), 20 mL of dichloromethane, 3.12 g of Amberlyst® 15 resin (0.014 mol of acid) and 0.59 mL of pentane-1-ol (0.0054 mol) are successively introduced into a Schlenk tube with a magnetized bar and purged with argon. The reaction mixture is left to agitate at 40 °C for 40 hours. The oligomers are characterized by proton NMR; the conversion of the monomer is greater than 95%. The reaction medium is filtered to remove the residual and the evaporated solvent is reduced pressure. The residue is taken up with dichloromethane (1 mL) and stirred on the pentane (15 mL).The surfactant is removed and after vacuum drying, 3.2 g of oligomers (89%) are obtained as a viscous colourless liquid. According to an analysis by GPC (Gel Permeation Chromatography) using calibration from polystyrene standards (PS) of 400 to 400,000 masses, the sample is composed of oligomers with nearby masses (Mw = 597 Dalton, Mw/Mn = 1.3). The nature of the ends of the ester-alcohol chain is determined by mass spectrometry (electrospray ionization, positive ion detection, sample dissolved in acetyl with a trace of ammonium hydroxide).

Example 4: Preparation of a co-oligomer (D,L-lactide/glycolide) 80/20 with ester-alcohol ends (Mw < 1 000 Da)

In a Schlenk tube with a magnetized bar and purged with argon, 1.40 g of D,L-lactide (0.0097 mol), 0.30 g of glycolide (0.0026 mol), 15 mL of dichloromethane, 1.20 g of Amberlyst® 15 resin (0.006 mol of acid) and 0.23 mL of pentan-1-ol (0.002 mol) are successively introduced into a Schlenk tube with a magnetized bar. The reaction mixture is agitated at 40 °C for 40 hours. The oligomers are characterized by proton NMR; the conversion of the monomer is greater than 95%. The ratio of the integrals of the signals corresponding to the polylactide part (5.2 ppm) and polyglycolide (4.85 ppm) allows the composition of the copolymers to be evaluated at 79% of the polylactide and 21% of the glycolide.The reaction medium is filtered to remove the resin and evaporated solvent under reduced pressure. The residue is taken up with dichloromethane (1 mL) and poured under agitation onto pentane (15 mL). The surfactant is removed and after vacuum drying, 1.45 g of oligomers (86%) are obtained as a viscous colourless liquid. According to an analysis by GPC (Gel Permeation Chromatography) using a scaling from polystyrene (PS) standards of 400-400,000 masses, the sample is composed of oligomers with nearby masses (Mwalt = 568 Dalton, Mw/Mn = 1.28). The nature of the end of the mass-cooling chain is determined by electrospray spectroscopy (i.e.positive ion detection mode, sample dissolved in acetonitrile with trace of ammonium hydroxide).

Example 5: Preparation of a 50/50 co-oligomer (DL-lactide/glycolide) with n-pentyl alcohol ester ends (Mw > 1000 Da)

In a Schlenk balloon with a magnetized bar and purged with argon, 5.00 g of D,L-lactide (0.035 mol), 5.00 g of glycolide (0.043 mol), 60 mL of dichloromethane, 10.00 g of Amberlyst®15 resin (0.050 mol of acid) and 1.83 mL of pentan-1-ol (0.0168 mol) are successively introduced into a Schlenk balloon with a magnetized bar and purged with argon. The reaction mixture is left to be stirred at reflux (45 °C) for 40 hours. The oligomers are characterized by proton NMR; the conversion of the monomers is greater than 95%. The ratio of the integrals of the signals corresponding to the polylactide part (5.20 ppm) and polyglycolide (4.85 ppm) allows the composition of 49% copymol and 51% glycolide to be evaluated.The reaction medium is filtered to remove the resin and evaporated solvent under reduced pressure. The residue is taken up with dichloromethane (3 mL) and poured under agitation onto pentane (44 mL). The surfactant is removed and after vacuum drying 7.50 g of oligomers (65%) are obtained as a viscous, colorless-white liquid. According to a GPC (Gel Permeation Chromatography) analysis using calibration from polystyrene (PS) standards of 400-400000 masses, the sample is composed of oligomers of near molar masses (Mw = 1550 Dalton, Mw/n = 1.19).The test chemical is used to determine the concentration of the test chemical in the test medium.

Example 6 : Preparation of a 50/50 co-oligomer (D,L-lactide/glycolide) with n-dodecyl-alcohol ester ends (Mw > 1000 Da)

In a Schlenk balloon with a magnetized bar and purged with argon, 5.00 g of D,L-lactide (0.035 mol), 5.00 g of glycolide (0.043 mol), 60 mL of dichloromethane, 10.00 g of Amberlyst® 15 resin (0.050 mol of acid) and 3.82 mL of dodecan-1-ol (0.0168 mol) are successively introduced into a Schlenk balloon with a magnetized bar and purged with argon. The reaction mixture is left to be stirred at reflux (4-5 °C) for 40 hours. The oligomers are characterised by proton NMR; the conversion of the monomer is greater than 95%. The ratio of the signal integrals corresponding to the polylactide (5.20 ppm) and polyglycolide (4.85 ppm) allows the composition of 53% copymol and 47% glycolide to be estimated.The reaction medium is filtered to remove the resin and evaporated solvent under reduced pressure. The residue is taken up with dichloromethane (3 mL) and poured under agitation onto pentane (44 mL). The surfactant is removed and after vacuum drying 9.50 g of oligomers (72%) are obtained as a viscous, colorless, white liquid. According to a GPC (Gel Permeation Chromatography) analysis using calibration from polystyrene (PS) standards of 400-400,000 masses, the sample is composed of oligomers of near molar masses (Mw = 1470 Dalton, Mw/n = 1.17).a power of not more than 50 W,

Example 7: Preparation of an oligomer (D,L-lactide) with n-dodecyl-alcohol ester ends (Mw > 1.000 Da)

The reaction mixture is left to agitate at reflux (45°C) for 40 hours. The oligomers are characterized by NMR of the argon; the conversion of the ester monomer to greater than 95% Mw. The reaction is filtered to remove the evaporating chains and soil under dissolved pressure. The residue is taken up with dimethyl amberlyst®15 (0.025 mol of acid) and agitated in the liquid molecule. The sample is removed by means of a mass sampling of 400 g of iodine and iodine (i.e. 400 g/mL) (i.e. 400 g/mL) after a mass sampling of iodine and iodine (i.e. 1,70 g/mL) in the sample. The samples are obtained by means of a positive electron-transfer spectrometry (GPS) (i.e. a test with a mass of 400 g/mL) (i.e. a test with a mass of 1,70 g/mL).

Example 8: Preparation of an oligomer (D,L-lactide) with n-pentyl alcohol ester ends (Mw > 2000 Da)

The reaction mixture is left to agitate at reflux (45°C) for 168 hours. The oligomers are characterized by NMR of the proton; the conversion of the monomer is greater than 95%. The reaction medium is filtered to remove the resin and solvent dissolved at reduced pressure. The residue is re-metered with dimethyl amberlyst®15 (0.0326 mol of acid) and agitated onto a polymethane compound. The test is carried out on a sample of 400 g of iodine (44 mL) and a sample of iodine (iodine) (iodine) (iodine) (iodine) (iodine) (iodine) is obtained by a positive electron spectrometry (iodine) (iodine) (iodine) (iodine) (iodine) (iodine) (iodine) is obtained from samples of polymers with a mass of 1,27 g/mL).

Claims (15)

1. Use of a catalytic system constituted by

   (a) a strongly acidic ion-exchange resin-type polymeric catalyst (1), and

   (b) a (co)oligomerization additive of general formula (2)         R¹-E-R²     (2) in which

   E represents an element of group 16;

   R¹ represents a hydrogen or deuterium atom;

   R² represents a hydrogen or deuterium atom, or a group of formula -E₁₄(R₁₄)(R'₁₄)(R"₁₄);

   E₁₄ is an element of group 14;

   R₁₄, R'₁₄ and R"₁₄ represent, independently, the hydrogen atom; the deuterium atom; one of the following substituted or non-substituted radicals: alkyl, cycloalkyl or aryl, and in which said substituent or substituents are chosen from: halo, hydroxy, alkyl, alkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, carboxy, alkoxycarbonyl, cycloalkoxycarbonyl and aryloxycarbonyl,

   for the (co)oligomerization of lactide and glycolide by ring opening, characterized in that the quantity of monomer relative to the (co)oligomerization additive is comprised between 2 and 30 molar equivalents.
2. Use according to claim 1, characterized in that the quantity of monomer relative to the (co)oligomerization additive is comprised between 4 and 10 molar equivalents.
3. Use according to one of the preceding claims, characterized in that the polymeric catalyst (1) is a styrene and divinylbenzene-based macroreticular resin with sulphonic acid functions.
4. Use according to one of the preceding claims, characterized in that the polymeric catalyst (1) is a macroreticular resin of the Amberlyst^® or Dowex^®type.
5. Use according to claim 4, characterized in that the polymeric catalyst (1) is a resin of the Amberlyst^® type.
6. Use according to one of the preceding claims, characterized in that the compound of general formula (2) is such that

   E represents an oxygen or sulphur atom;

   R¹ represents a hydrogen atom;

   R² represents a hydrogen atom or a group of formula -E₁₄(R₁₄)(R'₁₄)(R"₁₄);

   E₁₄ is a carbon or silicon atom;

   R₁₄, R'₁₄ and R"₁₄ represent, independently, the hydrogen atom, or one of the following substituted or non-substituted radicals: alkyl, cycloalkyl or aryl, in which said substituent or substituents are chosen from: halo, alkyl, cycloalkyl, phenyl, naphthyl, carboxy and alkoxycarbonyl.
7. Use according to one of the preceding claims, characterized in that the compound of general formula (2) is such that

   E represents an oxygen atom;

   R¹ represents a hydrogen atom;

   R² represents a hydrogen atom or a group of formula -E₁₄(R₁₄)(R'₁₄)(R"₁₄);

   E'₁₄ is a carbon atom;

   R₁₄, R'₁₄ and R"₁₄ represent, independently, the hydrogen atom, or a substituted or non-substituted alkyl radical in which said substituent or substituents are chosen from alkyl, carboxy and alkoxycarbonyl.
8. Use according to one of the preceding claims, characterized in that the compound of general formula (2) is such that

   E represents an oxygen atom;

   R₁ a hydrogen atom;

   R² a hydrogen atom or a group of formula -E₁₄(R₁₄)(R'₁₄)(R"₁₄) in which E₁₄ represents a carbon atom and R₁₄, R'₁₄ and R"₁₄ represent, independently, the hydrogen atom or an alkyl radical.
9. Use according to one of the preceding claims, characterized in that the compound of general formula (2) is either water or an alcohol.
10. Use according to claim 9, characterized in that the alcohol is an aliphatic alcohol.
11. Use according to claim 10, characterized in that the aliphatic alcohol is chosen from isopropanol, pentan-1-ol and dodecan-1-ol.
12. A (co)oligomerization process of lactide and glycolide by the ring-opening, said process which consists in bringing together the monomer or monomers considered, a catalytic system as defined in one of claims 1 to 11, and an oligomerization solvent.
13. Process according to claim 12, characterized in that the temperature is comprised between -20°C and approximately 150°C.
14. Process according to claim 13, characterized in that the process is carried out in solution at a temperature comprised between 20°C and 80°C.
15. Process according to one of claims 12 to 14, characterized in that the reaction time is comprised between one hour and 64 hours, and preferably between 14 hours and 48 hours.