WO2008131785A2 - Method for the production of the biodegradable polymers - Google Patents

Method for the production of the biodegradable polymers Download PDF

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Publication number
WO2008131785A2
WO2008131785A2 PCT/EE2008/000010 EE2008000010W WO2008131785A2 WO 2008131785 A2 WO2008131785 A2 WO 2008131785A2 EE 2008000010 W EE2008000010 W EE 2008000010W WO 2008131785 A2 WO2008131785 A2 WO 2008131785A2
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WO
WIPO (PCT)
Prior art keywords
lewis
lewis acids
polymerization
catalysts
production
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Application number
PCT/EE2008/000010
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French (fr)
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WO2008131785A3 (en
Inventor
Genrih Markovich Tseilin
Sergey Gennadevich Beksaev
Artem Aleksandrovich Sedov
Valeriy Fedorovich Shvets
Yury Pavlovich Suchkov
Original Assignee
Nordbiochem OÜ
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Nordbiochem OÜ filed Critical Nordbiochem OÜ
Publication of WO2008131785A2 publication Critical patent/WO2008131785A2/en
Publication of WO2008131785A3 publication Critical patent/WO2008131785A3/en

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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/78—Preparation processes
    • C08G63/82—Preparation processes characterised by the catalyst used
    • C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides

Definitions

  • the invention relates to a method for the production a biodegradable polymer of cyclic esters in particular for medical applications.
  • a two-steps method for producing a polylactic acid is described in the patent US5508378.
  • the method includes the steps of (a) polymerizing of lactide used as a main starting material in a molten state to give a polylactic acid; and (b) further polymerizing the polylactic acid obtained in the step (a) in a solid phase by heating at the temperature lower than the melting point of the final polymer product.
  • Tin compounds can be used as a catalyst, such as tin octylate; titanium compounds, such as tetraisopropyl titanate; zirconium compounds, such as zirconium isopropoxide; and antimony compounds, such as antimony trioxide.
  • a catalyst such as tin octylate; titanium compounds, such as tetraisopropyl titanate; zirconium compounds, such as zirconium isopropoxide; and antimony compounds, such as antimony trioxide.
  • the reaction is carried out at a relatively low temperature 120-190°C (preferably 140-170°C) in which decomposition or coloration does not take place.
  • the obtained polylactic acid has an average molecular weight of from 50,000 to 200,000 and contains lactides therein in an amount of from 10 to 50% by weight.
  • the second-step polymerization is carried out in a solid phase.
  • the temperature of the second-step polymerization is 100-175°C, preferably 120-140 0 C.
  • the reaction time is normally from 6 to 90 hours, preferably from 20 to 40 hours.
  • the reaction may be carried out while pressing the reaction mixture under a pressure higher than atmospheric pressure, more specifically at a pressure of from 0.1 to 10 kgf/cm 2 (gauge pressure), preferably from 1 to 3 kgf/cm 2 .
  • the polylactic acid produced on the second step has a molecular weight of from 100,000 to 500,000, preferably from 200,000 to 500,000.
  • a one-step process is described in the patent US5821327.
  • polylactic acid is produced by ring-opening polymerization of lactide in the presence of a polymerization catalyst and a cyclic imide (succinimide, glutarimide and phthalimide) at 100-190 0 C.
  • the amount of the cyclic imide is 1-35% by mole based on the lactide.
  • the metal selected from the group consisting of Group IA, IHA, IVA, MB, IVB and VA of the periodic table, or a compound thereof is used as the catalyst.
  • the amount of the polymerization catalyst is from 0,00001 to 0,1% by mole based on the lactide.
  • the cyclic imide is added to the polymerization reaction system and, therefore, polylactic acid can be efficiently prepared even under the mild conditions of low polymerization catalytic amount and low polymerization temperature. Accordingly, depolymerization of the polymer can be inhibited, and remains of the catalyst in the polymer and coloring of the polymer can be avoided.
  • a method for producing a polylactic acid by ring-opening polymerization of lactide at the presence of a catalyst and a compound capable of inactivating the catalyst is described in the patent US5770682.
  • the polymerization temperature is 120- 18O 0 C.
  • the compound capable of inactivating of the catalyst is selected from the group consisting of (a) phosphoric acid or phosphorous acid, or the derivatives thereof; and (b) aluminium compounds. It compound is added when a weight-average molecular weight of the polylactic acid produced is 50,000 or more.
  • the catalyst is selected from the group consisting of an element of group IA, an element of Group IVA, an element of group IVB, and an element of group VB, of the periodic table, and compounds (preferably, tin lactate, tin tartrate, tin dicaprylate, tin dilaurate, tin dipalmitate, tin distearate, tin dioleate).
  • a method for producing of the copolymer of lactide and ⁇ -caprolactone for medical applications is described in the patent EP0548237.
  • the main steps of the method are: a) purifying said lactide and said ⁇ -caprolactone, b) introducing said purified lactide and said purified ⁇ -caprolactone into a vessel and c) allowing said purified lactide and said purified s-caprolactone to react by bulk synthesis at a temperature 80-160 0 C to form said copolymer.
  • the synthesis is carried out in the presence of the catalysts - Lewis acids.
  • catalysts are tin octoate, antimony trifluoride, zinc powder, dibutyltin oxide and tin oxalate.
  • the amount of the catalyst is 10 "7 to 10 "3 and preferably approximately 10 "5 mol/mol regarding to the monomers.
  • the reaction time is normally from 100 to 400 hours.
  • the amount of the polymerization catalyst is small and the polymerization temperature is low. However, the polymerization proceeds the long period of time.
  • An object of the present invention is a method for producing biodegradable polymers of the cyclic esters having a high molecular weight and which contains substantially no decomposition products or monomers, and is characterized by short time of the polymerization.
  • the bulk polymerization can be carried out at the presence of low catalytic amount of the catalysts - a Lewis acids partially blocked by Lewis bases.
  • the Lewis acids are compound of elements selected from the Group MB, IMB, IVA and IVB of the periodic table and the Lewis bases are amines and heterocyclic compound of nitrogen.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Polyesters Or Polycarbonates (AREA)
  • Biological Depolymerization Polymers (AREA)

Abstract

The invention relates to a method for the production a biodegradable polymer of cyclic esters in particular for medical applications. The method is carried out by bulk polymerization with the catalysts, wherein the catalysts are Lewis acids partially blocked by Lewis bases. According to the method the Lewis acids are compound of elements selected from the Group IIB, IIIB, IVA and IVB of the Periodic Table.

Description

Method for the production of the biodegradable polymers
DESCRIPTION OF THE INVENTION
The invention relates to a method for the production a biodegradable polymer of cyclic esters in particular for medical applications.
BACKGROUND OF THE INVENTION
A two-steps method for producing a polylactic acid is described in the patent US5508378. The method includes the steps of (a) polymerizing of lactide used as a main starting material in a molten state to give a polylactic acid; and (b) further polymerizing the polylactic acid obtained in the step (a) in a solid phase by heating at the temperature lower than the melting point of the final polymer product.
Tin compounds can be used as a catalyst, such as tin octylate; titanium compounds, such as tetraisopropyl titanate; zirconium compounds, such as zirconium isopropoxide; and antimony compounds, such as antimony trioxide.
In the first step of polymerization process of the present invention, the reaction is carried out at a relatively low temperature 120-190°C (preferably 140-170°C) in which decomposition or coloration does not take place. The obtained polylactic acid has an average molecular weight of from 50,000 to 200,000 and contains lactides therein in an amount of from 10 to 50% by weight.
The second-step polymerization is carried out in a solid phase. The temperature of the second-step polymerization is 100-175°C, preferably 120-1400C. The reaction time is normally from 6 to 90 hours, preferably from 20 to 40 hours.
In order to inhibit the sublimation of the unreacted lactide, the reaction may be carried out while pressing the reaction mixture under a pressure higher than atmospheric pressure, more specifically at a pressure of from 0.1 to 10 kgf/cm2 (gauge pressure), preferably from 1 to 3 kgf/cm2.
The polylactic acid produced on the second step has a molecular weight of from 100,000 to 500,000, preferably from 200,000 to 500,000. A one-step process is described in the patent US5821327. According to the patent polylactic acid is produced by ring-opening polymerization of lactide in the presence of a polymerization catalyst and a cyclic imide (succinimide, glutarimide and phthalimide) at 100-1900C. The amount of the cyclic imide is 1-35% by mole based on the lactide. The metal selected from the group consisting of Group IA, IHA, IVA, MB, IVB and VA of the periodic table, or a compound thereof is used as the catalyst. The amount of the polymerization catalyst is from 0,00001 to 0,1% by mole based on the lactide.
According to the present invention, the cyclic imide is added to the polymerization reaction system and, therefore, polylactic acid can be efficiently prepared even under the mild conditions of low polymerization catalytic amount and low polymerization temperature. Accordingly, depolymerization of the polymer can be inhibited, and remains of the catalyst in the polymer and coloring of the polymer can be avoided.
A method for producing a polylactic acid by ring-opening polymerization of lactide at the presence of a catalyst and a compound capable of inactivating the catalyst is described in the patent US5770682. The polymerization temperature is 120- 18O0C.
The compound capable of inactivating of the catalyst is selected from the group consisting of (a) phosphoric acid or phosphorous acid, or the derivatives thereof; and (b) aluminium compounds. It compound is added when a weight-average molecular weight of the polylactic acid produced is 50,000 or more.
The catalyst is selected from the group consisting of an element of group IA, an element of Group IVA, an element of group IVB, and an element of group VB, of the periodic table, and compounds (preferably, tin lactate, tin tartrate, tin dicaprylate, tin dilaurate, tin dipalmitate, tin distearate, tin dioleate).
At the final step of the process to remove unchanged lactide from the polylactic acid pressure was reduced and/or inert gas was passed through the reactor.
A method for producing of the copolymer of lactide and ε-caprolactone for medical applications is described in the patent EP0548237. The main steps of the method are: a) purifying said lactide and said ε-caprolactone, b) introducing said purified lactide and said purified ε-caprolactone into a vessel and c) allowing said purified lactide and said purified s-caprolactone to react by bulk synthesis at a temperature 80-1600C to form said copolymer.
The synthesis is carried out in the presence of the catalysts - Lewis acids. Examples of such catalysts are tin octoate, antimony trifluoride, zinc powder, dibutyltin oxide and tin oxalate. The amount of the catalyst is 10"7 to 10"3 and preferably approximately 10"5 mol/mol regarding to the monomers. The reaction time is normally from 100 to 400 hours.
In this polymerization process, it is preferred that the amount of the polymerization catalyst is small and the polymerization temperature is low. However, the polymerization proceeds the long period of time.
SUMMARY OF THE INVENTION
An object of the present invention is a method for producing biodegradable polymers of the cyclic esters having a high molecular weight and which contains substantially no decomposition products or monomers, and is characterized by short time of the polymerization.
According to the present invention, the bulk polymerization can be carried out at the presence of low catalytic amount of the catalysts - a Lewis acids partially blocked by Lewis bases.
Preferably, the Lewis acids are compound of elements selected from the Group MB, IMB, IVA and IVB of the periodic table and the Lewis bases are amines and heterocyclic compound of nitrogen.
The invention is illustrated with the aid of the following examples, without being restricted thereto.
EXAMPLE 1
7 mol L-Lactide, 8,8 mol Caprolactone and 6 g solution of the catalyst in ethyl acetate (tin octoate - 1 ,5 mmol; BF3 - 0,07 mmol and tributylamine - 0,08 mmol) were added to the reactor. The polymerization reaction was conducted by heating with stirring at 120-1250C and under a nitrogen gas flow. The reaction was carried out during 120 min. Copolymers with an average molecular weight 206 000 were obtained.
EXAMPLES 2-13
Process of polymerization was carried out according to the same manner as that described in Example 1. Glycolide, Propiolactone, Trimethylene carbonate were used as the monomers. Different Lewis acids and a Lewis bases were used as the catalysts. Results of polymerization are given in Table 1.
Figure imgf000006_0001

Claims

Claims
1. A method for the production of the biodegradable polymers of a cyclic esters by bulk polymerization with the catalysts, wherein the catalysts are Lewis acids partially blocked by Lewis bases.
2. A method according to claim 1 , wherein the Lewis acids are compound of elements selected from the Group MB, IMB, IVA and IVB of the Periodic Table.
3. A method according to claim 1 , wherein the Lewis bases are amines and heterocyclic compound of nitrogen.
4. A method according to claim 2, wherein the Lewis acids are tin octoate and boron trifluoride or its mixtures.
5. A method according to claim 3, wherein the Lewis bases are alkylamines, piperidines and pyridines.
6. A method according to claim 1 , wherein the bulk polymerization is conducted at 110-15O0C.
7. A method according to claim 1 , an amount of Lewis acids is from 0,007 to 0,011% by mole based on cyclic esters.
8. A method according to claim 1 , an amount of Lewis bases is from 4,2 to 9,4 % by mole based on Lewis acids.
PCT/EE2008/000010 2007-04-30 2008-04-30 Method for the production of the biodegradable polymers WO2008131785A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EEP200700020 2007-04-30
EEP200700020A EE200700020A (en) 2007-04-30 2007-04-30 Method for the preparation of biodegradable polymers

Publications (2)

Publication Number Publication Date
WO2008131785A2 true WO2008131785A2 (en) 2008-11-06
WO2008131785A3 WO2008131785A3 (en) 2009-01-08

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WO (1) WO2008131785A2 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106496538A (en) * 2016-10-19 2017-03-15 安徽红太阳新材料有限公司 A kind of synthetic method of high molecular polycaprolactone
CN110498916A (en) * 2019-05-30 2019-11-26 华南理工大学 A kind of method of cyclic ester and the copolymerization of epoxy monomer sequence controlled block

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3284417A (en) * 1963-11-13 1966-11-08 Union Carbide Corp Process for the preparation of lactone polyesters
US3682865A (en) * 1968-05-22 1972-08-08 Laporte Industries Ltd Polymerisation process

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3284417A (en) * 1963-11-13 1966-11-08 Union Carbide Corp Process for the preparation of lactone polyesters
US3682865A (en) * 1968-05-22 1972-08-08 Laporte Industries Ltd Polymerisation process

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106496538A (en) * 2016-10-19 2017-03-15 安徽红太阳新材料有限公司 A kind of synthetic method of high molecular polycaprolactone
CN110498916A (en) * 2019-05-30 2019-11-26 华南理工大学 A kind of method of cyclic ester and the copolymerization of epoxy monomer sequence controlled block
CN110498916B (en) * 2019-05-30 2021-09-21 华南理工大学 Method for controllable block copolymerization of cyclic ester and epoxy monomer sequences

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EE200700020A (en) 2008-12-15

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