Process for synthesis of poly-4-hydroxybutyrate

Abstract

A process for the synthesis of poly-4-hydroxybutyrates is described, comprising the use of a kit of (i) one or more bases comprising alkali metal cations and (ii) one or more alcohols in said process, as well as the poly-4-hydroxybutyrates obtainable by said process.

Description

[0001] The present application relates to a method for synthesizing poly-4-hydroxybutyrate, comprising the use of (i) one or more bases containing alkali metal cations and (ii) one or more alcohols in the method, and poly-4-hydroxybutyrate obtainable by the method.

[0002] Poly-4-hydroxybutyrate is an important class of aliphatic polyesters. Poly-4-hydroxybutyrate is a biocompatible and biodegradable thermoplastic material and is therefore currently of great interest for replacing other common plastics that are not or barely biodegradable.

[0003] Currently, commercial poly-4-hydroxybutyrate is usually produced by biofermentation using sugar as a raw material. However, these methods have certain disadvantages, such as inefficient use of starting materials due to the metabolism of microorganisms, relatively complex processes, low space-time yields; and difficulty in separating and purifying the product from the fermentation mixture.

[0004] Poly-4-hydroxybutyrate can also be synthesized by catalytic ring-opening polymerization of γ-butyrolactone. The educt γ-butyrolactone is a cheap, readily available material that can be obtained from biomass raw materials. This provides a polymer that is not only biodegradable but also obtainable from renewable resources. However, traditionally, γ-butyrolactone is considered to be non-polymerizable because the strain energy of the five-membered ring is low compared to other easily polymerized lactones such as caprolactone (see: Q. Song et al., Polymer Journal, 2020, 52, 3-11). Due to the development of catalyst systems that can polymerize γ-butyrolactone into poly-4-hydroxybutyrate, some progress has been made in the past few years. However, a low reaction temperature of less than -30 ° C is generally required, the catalyst is quite complex, the yield obtained is only moderate, and the reaction is carried out in a relatively dilute solution, which is disadvantageous from an economic point of view.

[0005] CN 102643301A discloses the polymerization of γ-butyrolactone to poly-4-hydroxybutyrate in an organic solvent at a temperature of 25° C. to 108° C. using a pentacoordinated aluminum complex with an alkoxide ligand. Although high yields of poly-4-hydroxybutyrate up to 95% can be obtained by this process, the reaction mixture to be used is diluted with only 1 g of γ-butyrolactone dissolved in 21 mL of toluene, which makes the processing cost high, since all the toluene must be removed in vacuo before further isolation of the polymer product. Another disadvantage is the complex multi-step synthesis of the aluminum catalyst, starting from the highly pyrophoric AlMe3, which is expensive and notoriously difficult to handle.

[0006] Macromolecules, 2018, 51, 9317-9322 describes the polymerization of γ-butyrolactone to poly-4-hydroxybutyrate in the absence of solvent using specific urea derivatives in combination with alkali metal alkoxides as initiators. At a reaction temperature of -40°C, a conversion of 86% of γ-butyrolactone was obtained at a ratio of 300:3:1 of γ-butyrolactone:phenyl-cyclohexyl-urea:NaOMe. When the reaction temperature was increased to -20°C, the yield dropped to 70% at a ratio of 100:1:1 of γ-butyrolactone:phenyl-cyclohexyl-urea:NaOMe, which is unfavorable from an economic point of view.

[0007] CN 109851765 discloses the polymerization of gamma-butyrolactone to poly-4-hydroxybutyrate in an organic solvent in the presence of specific N-heterocyclic olefins in combination with thiourea derivatives and alcohols. The yield is not reported. The required temperature of -40°C and the specialized synthesis of specific N-heterocyclic olefins and specific thiourea derivatives make the synthesis unfavorable from an economic point of view.

[0008] Polymer Chemistry, 2022, 13, 439-445 describes the polymerization of γ-butyrolactone to poly-4-hydroxybutyrate in the presence of benzyl alcohol combined with a dialkyl magnesium compound and an additional solvent. At a reaction temperature of -50°C, with a ratio of γ-butyrolactone: Ph2CHOH:MgBu2 of 50:1:1, in a relatively dilute 8 mol / L solution in toluene, a maximum conversion of γ-butyrolactone of 72% can be obtained. Since the reaction must be carried out at -50°C, the reaction mixture is relatively dilute, and a relatively large amount of initiator is required to obtain a sufficient yield, this synthesis is disadvantageous from an economic point of view.

[0009] Nature Chemistry, 2016, 8, 42-49 describes the polymerization of γ-butyrolactone to poly-4-hydroxybutyrate in the presence of benzyl alcohol combined with La[N(SiMe3)2]3. By first mixing γ-butyrolactone and benzyl alcohol and then adding La[N(SiMe3)2]3 at a given reaction temperature, a maximum polymer yield of 67% was obtained in THF solution at a reaction temperature of -40°C and a ratio of γ-butyrolactone:PhCH2OH:La[N(SiMe3)2]3 of 100:2:1, using Ph2CHOH (benzyl alcohol) as an initiator. Increasing the reaction temperature to -28°C causes the yield to drop to only 16%. When the process is altered under otherwise identical conditions at -40°C by first dissolving γ-butyrolactone and benzyl alcohol in THF, cooling, and then adding La[N(SiMe3)2]3, the polymer yield is reduced to only 33%. The document also discloses the use of a dedicated lanthanide catalyst with a customized polydentate phenolate ligand. Using this catalyst, the reaction is carried out in the absence of benzyl alcohol. The highest polymer yield of 90% was obtained by using this catalyst at a ratio of γ-butyrolactone:La-catalyst of 100:1 at a reaction temperature of -40°C in a 10M THF solution by first dissolving the catalyst in THF and then adding γ-butyrolactone at a given reaction temperature. But when the catalyst loading was reduced to a ratio of γ-butyrolactone:La-catalyst of 200:1, the polymer yield dropped to 48%. The use of the diol C6H4(CH2OH)2 in combination with the lanthanide catalyst at a ratio of 100:1:1.5 gave a maximum polymer yield of only 33% at -40°C. This is disadvantageous from an economic point of view, since the reaction must be carried out at -40°C to obtain an acceptable yield. In addition, lanthanide compounds are relatively expensive and sensitive, and for acceptable yields, a catalyst loading of at least 1 mol% is required, which is also disadvantageous from an economic point of view.

[0010] Angewandte Chemie International Edition, 2016, 55, 4188-4193 describes the ring-opening polymerization of γ-butyrolactone to poly-4-hydroxybutyrate in the presence of benzyl alcohol combined with a phosphazene base or a strong base. By first mixing γ-butyrolactone and benzyl alcohol and then adding a base at a given reaction temperature, a maximum polymer yield of 90% was obtained with a phosphazene base in a 10 mol / L THF dilute solution at a reaction temperature of -40°C with a ratio of γ-butyrolactone: PhCH2OH: phosphazene of 100:1.5:1. When the reaction temperature was raised to -28°C, the polymer yield dropped significantly to only 20%. When the phosphazene base was replaced by a simpler and cheaper base NaOMe, the yield dropped to 72.8% at a reaction temperature of -40°C, all other conditions being equal. This synthesis is disadvantageous from an economic point of view since the reaction must be carried out at -40 °C to obtain acceptable yields, the reaction mixture is relatively dilute, a sensitive and expensive phosphazene base is required as a catalyst, and relatively large amounts of initiator are required to obtain sufficient yields.

[0011] The related prior art is

[0012] Song Qilei et al.: "Ring-opening polymerization of [gamma]-lactones and copolymerization with other cyclic monomers", Progress in Polymer Science, Pergamon Press, Oxford, GB, vol.110, avialable online 18September 2020 (2020-09-18).

[0013] The main object of the present invention is to provide a process for the synthesis of poly-4-hydroxybutyrate by ring-opening polymerization of γ-butyrolactone, which can be carried out using simple, readily available and inexpensive catalysts, wherein the process provides polymers in high yields. Another object is to provide a process for the ring-opening polymerization of γ-butyrolactone, which does not require temperatures below -25°C, thus requiring less energy for cooling.

[0014] The main object and other objects of the present invention are achieved by a method for synthesizing poly-4-hydroxybutyrate, comprising the following steps:

[0015] (a) preparing a reaction mixture comprising

[0016] (i) one or more bases comprising alkali metal cations

[0017] (ii) one or more alcohols

[0018] as well as

[0019]

[0020] (iii) γ-Butyrolactone (I)

[0021] wherein in the reaction mixture, the molar ratio of γ-butyrolactone (iii) to the total amount of the base (i) comprising an alkali metal cation is 200:1 or more,

[0022] The preparation of the reaction mixture comprises

[0023] (a1) forming a premix, the premix comprising

[0024] (i) one or more bases comprising alkali metal cations

[0025] as well as

[0026] (ii) one or more alcohols

[0027] (a2) providing (iii) γ-butyrolactone at a temperature of -25°C or higher

[0028] (a3) obtaining a reaction mixture by charging the premix formed in step (a1) into the γ-butyrolactone provided in step (a2) at a temperature of -25°C or higher,

[0029] (b) chemically converting the γ-butyrolactone in the reaction mixture into poly-4-hydroxybutyrate by ring-opening polymerization at a temperature of -25°C or higher.

[0030] Surprisingly, it has been found that

[0031] (i) one or more bases comprising alkali metal cations

[0032] (ii) one or more alcohols

[0033] as well as

[0034] (iii) γ-Butyrolactone combination

[0035] The yield of the ring-opening polymerization has a significant effect, and any deviation from the process defined in substeps (a1) to (a3) ​​will lead to a significant reduction in the yield under otherwise identical conditions.

[0036] It is therefore essential that in step (a) the reaction mixture for the ring-opening polymerization of (iii) γ-butyrolactone (as defined above) is prepared by carrying out the above defined sub-steps (a1) to (a3) ​​in the order defined above.

[0037] In sub-step (a1), a premix is ​​formed, the premix comprising or consisting of:

[0038] (i) one or more bases comprising alkali metal cations

[0039] as well as

[0040] (ii) one or more alcohols.

[0041] Base (i) is a base comprising an alkali metal cation. The anion of base (i) may be a proton acceptor (Brönsted base) and / or an electron pair donor (Lewis base). Preferably, the alkali metal cation is selected from Li + 、Na + , K + , Rb + and Cs + The group consisting of, most preferably selected from Li + 、Na + and K + Composed of groups.

[0042] Without wishing to be bound by any theory, it is currently assumed that the base (i) acts as a catalyst for the ring-opening polymerization of γ-butyrolactone, while the alcohol (ii) acts as an initiator for the ring-opening polymerization of γ-butyrolactone.

[0043] Typically, in step (a1), a premix is ​​formed by:

[0044] (a1.1) providing one or more bases (i) comprising alkali metal cations

[0045] (a.1.2) providing one or more alcohols (ii)

[0046] (a.1.3) mixing the one or more bases (i) comprising alkali metal cations provided in sub-step (a.1.1) with the one or more alcohols (ii) provided in sub-step (a.1.2),

[0047] This results in the premix being obtained.

[0048] In sub-step (a2), (iii) γ-butyrolactone is provided at a temperature of -25°C or higher, preferably at a temperature in the range of -25°C to -10°C. In step (a2), γ-butyrolactone may be provided continuously or discontinuously.

[0049] In sub-step (a3), a reaction mixture for ring-opening polymerization is obtained by charging the premix formed in step (a1) into the γ-butyrolactone provided in step (a2) at a temperature of -25°C or higher.

[0050] In the reaction mixture prepared in step (a), the molar ratio of γ-butyrolactone (iii) to the total amount of (i) the base comprising an alkali metal cation is 200: 1 or more, preferably 200: 1 to 800: 1, and most preferably 200: 1 to 400: 1. Therefore, compared with the prior art process described above, the amount of base (i) as a catalyst for the ring-opening polymerization of a given amount of γ-butyrolactone is considerably low, which is advantageous from an economic point of view.

[0051] In step (b), γ-butyrolactone is chemically converted into poly-4-hydroxybutyrate by ring-opening polymerization in the reaction mixture prepared in step (a) at a temperature of -25°C or higher, preferably at a temperature in the range of -25°C to +50°C, preferably -25°C to +30°C, more preferably at a temperature in the range of -25°C to 0°C, and most preferably at a temperature in the range of -25°C to -10°C.

[0052] Therefore, in the method disclosed herein, the ring-opening polymerization of γ-butyrolactone is carried out at a higher temperature than the prior art method (see, for example, Angewandte Chemie International Edition, 2016, 55, 4188-4193). Therefore, advantageously, less cooling is required, thereby saving energy.

[0053] In step (b), the chemical conversion of gamma-butyrolactone to poly-4-hydroxybutyrate by ring-opening polymerization is typically carried out at ambient pressure.

[0054] In the premix prepared in step (a1), preferably the base (i) comprising an alkali metal cation or one or more bases (i) comprising an alkali metal cation are selected from the group consisting of lithium alkoxide, sodium alkoxide and potassium alkoxide, preferably selected from the group consisting of lithium methoxide, sodium methoxide, potassium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium benzyloxide, sodium benzyloxide and potassium benzyloxide.

[0055] More preferably, in the premix prepared in step (a1), each base (i) comprising an alkali metal cation is selected from the group consisting of lithium alkoxide, sodium alkoxide and potassium alkoxide, preferably selected from the group consisting of lithium methoxide, sodium methoxide, potassium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium benzyloxide, sodium benzyloxide and potassium benzyloxide.

[0056] The most preferred bases (i) are lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and potassium benzyloxide.

[0057] In the premix prepared in step (a1), preferably alcohol (ii) or one or more of the alcohols in alcohol (ii) is selected from the group consisting of:

[0058] -Methanol, ethanol, ethylene glycol, diethylene glycol, polyethylene glycol, 1,2-propylene glycol, dipropylene glycol, polypropylene glycol, 1,3-propylene glycol, 1,4-butylene glycol, polytetramethylene glycol, 1,5-pentanediol, 1,6-hexanediol

[0059] as well as

[0060] -benzyl alcohol according to formula (II)

[0061]

[0062] in

[0063] n is an integer from 1 to 4, preferably 1 or 2

[0064] m is an integer from 0 to 3,

[0065] o is 0 or 1

[0066] m+n+o≤6;

[0067] R 1 and R 2 Independently selected from the group consisting of:

[0068] F, Cl, Br, OH, CN, NH2, NO2,

[0069] C1-C 10 -alkyl

[0070] C3-C 10 - cycloalkyl,

[0071] A C3-C 10 -heterocyclic group,

[0072] C5-C 14 -Aryl,

[0073] A C5-C 10 - heteroaryl,

[0074] Wherein the C1-C 10 -alkyl, C3-C 10 -cycloalkyl, C3-C 10 -heterocyclic group, C5-C 14 -Aryl or C5-C 10 -heteroaryl optionally has one or more additional substituents selected from the group consisting of F, Cl, Br, OH, CN, NH2 and C1-C 10 -alkyl.

[0075] As used herein, C1-C 10-Alkyl is intended to include straight chain C1-C 10 -alkyl and branched C4-C 10 -Alkylalkyl and n-C1-C 10 -alkyl, secondary-C3-C 10 -alkyl and tert-C4-C 10 -alkyl.

[0076] More preferably, in the premix prepared in step (a1 ), each alcohol (ii) is selected from the group defined above.

[0077] Among the benzyl alcohols according to formula (II), preferred are 1,4-benzenedimethanol, 2,6-dichlorobenzyl alcohol, 4-methylbenzyl alcohol and 2,4,6-trimethyl-benzyl alcohol.

[0078] The most preferred alcohols (ii) are methanol, ethanol, polyethylene glycol, 1,4-butanediol, 1,6-hexanediol, benzyl alcohol, 1,4-benzenedimethanol, 2,6-dichlorobenzyl alcohol, 4-methylbenzyl alcohol and 2,4,6-trimethylbenzyl alcohol.

[0079] In the premix prepared in step (a1), most preferably the base (i) comprising an alkali metal cation or one or more of the bases comprising an alkali metal cation (i) is selected from the above-defined group of preferred bases (i), and the alcohol (ii) or one or more of the alcohols (ii) is selected from the above-defined group of preferred alcohols (ii). More preferably, in the premix prepared in step (a1), each base (i) comprising an alkali metal cation is selected from the above-defined group of preferred bases (i), and each alcohol (ii) is selected from the above-defined group of preferred alcohols (ii).

[0080] In a particularly preferred method,

[0081] (i) the base comprising an alkali metal cation is of the formula MOR 3 An alkali metal alkoxide, wherein M is selected from the group consisting of Li, Na and K

[0082] (ii) the alcohol is of formula R 3 OH alcohol

[0083] Where (i) R 3 and (ii) R 3 The same, and are preferably selected from the group consisting of methyl, ethyl, isopropyl, sec-butyl, tert-butyl and benzyl.

[0084] In the reaction mixture prepared in step (a),

[0085] In (i) the total amount of bases including alkali metal cations

[0086] and (ii) the total amount of alcohol

[0087] The molar ratio of is preferably in the range of 1:1 to 10:1, more preferably 1:1 to 8:1, most preferably 1:1 to 5:1.

[0088] In some cases, it is preferred that the reaction mixture prepared in step (a) further comprises one or more solvents (in addition to components (i), (ii) and (iii) described above). In some cases, the reaction mixture prepared in step (a) consists of:

[0089] (i) one or more bases comprising alkali metal cations

[0090] (ii) one or more alcohols

[0091]

[0092] (iii) γ-Butyrolactone (I)

[0093] and one or more solvents.

[0094] Suitable solvents are those in which components (i) to (iii) and the product poly-4-hydroxybutyrate are soluble, respectively, or with which they are miscible. The presence of one or more solvents in the reaction mixture enables a homogeneous distribution of the reactants (i), (ii) and (iii) as defined above and promotes their interaction.

[0095] In the reaction mixture prepared in step (a), preferably the solvent or one or more of the solvents is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

[0096] More preferably, in the reaction mixture prepared in step (a), each solvent is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

[0097] As used herein, the term "hydrocarbon" is intended to include halogenated hydrocarbons.

[0098] Further preferably, in the reaction mixture prepared in step (a), the solvent or one or more of the solvents is selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glycol dimethyl ether, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile.

[0099] Most preferably, in the reaction mixture prepared in step (a), each solvent is selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile.

[0100] To prepare the reaction mixture in step (a), the

[0101] - a premix comprising (i) one or more bases comprising an alkali metal cation and (ii) one or more alcohols and one or more solvents

[0102] and / or

[0103] - a mixture comprising (iii) γ-butyrolactone (I) and one or more solvents.

[0104] The solvent or one or more of the solvents is preferably selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkylsulfoxides and nitriles, most preferably selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethylsulfoxide and acetonitrile.

[0105] More preferably, each solvent is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkylsulfoxides and nitriles, most preferably selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate and acetonitrile.

[0106] In some cases, to prepare the reaction mixture in step (a), a premix may be provided in substep (a1) in the form of a solution comprising (i) one or more bases comprising an alkali metal cation and (ii) one or more alcohols and one or more solvents.

[0107] Preferably, in the premix formed in sub-step (a1), the solvent or one or more of the solvents is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

[0108] More preferably, in the premix prepared in step (a1), each solvent is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

[0109] Further preferably, in the premix formed in sub-step (a1), the solvent or one or more of the solvents is selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile.

[0110] Most preferably, in the premix prepared in step (a1), each solvent is selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile.

[0111] In some cases, in order to prepare the reaction mixture in step (a), a mixture comprising (iii) γ-butyrolactone (I) and one or more solvents may be provided in substep (a2).

[0112] Preferably, in the mixture provided in sub-step (a2), the solvent or one or more of the solvents is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

[0113] More preferably, in the mixture provided in sub-step (a2), each solvent is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

[0114] Further preferably, in the mixture provided in sub-step (a2), the solvent or one or more of the solvents is selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glycol dimethyl ether, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile.

[0115] Most preferably, in the mixture provided in sub-step (a2), each solvent is selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile.

[0116] In a more specific case, in order to prepare the reaction mixture in step (a), providing

[0117] - a premix comprising (i) one or more bases comprising an alkali metal cation and (ii) one or more alcohols and one or more solvents

[0118] and / or

[0119] - a mixture comprising (iii) γ-butyrolactone (I) and one or more solvents.

[0120] The solvent or one or more of the solvents is preferably selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkylsulfoxides and nitriles, most preferably selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethylsulfoxide and acetonitrile.

[0121] More preferably, each solvent is selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkylsulfoxides and nitriles, most preferably selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethylsulfoxide and acetonitrile.

[0122] In some cases, the method defined above further comprises drying the γ-butyrolactone (I) by adding a desiccant, and optionally separating the dried γ-butyrolactone (I) from the desiccant before preparing the reaction mixture. Drying can be achieved by any suitable desiccant.

[0123] The desiccant is preferably selected from the group consisting of:

[0124] CaH2,

[0125] Tosyl isocyanate,

[0126] and oxazolidine.

[0127] The oxazolidine is preferably selected from the group consisting of oxazolidine of formula (III), oxazolidine of formula (IV) and oxazolidine of formula (V).

[0128]

[0129] in

[0130] R 4 , R 5 , R 6 and R 7 Independently selected from H- and C1-C 10 -alkyl group

[0131] And R 8 is a bridging unit comprising 1 to 20 -CH2- units (methylene units) and optionally one or more moieties selected from the group consisting of:

[0132] -NH-,

[0133] -O-(ether bridge),

[0134] -CO-(carbonyl)

[0135] -COO-(Carboxyl)

[0136] and -NH-COO-(polyurethane).

[0137] As used herein, C1-C 10 -Alkyl is intended to include straight chain C1-C 10 -alkyl and branched C4-C10 -Alkylalkyl and n-C1-C 10 -alkyl, secondary-C3-C 10 -alkyl and tert-C4-C 10 -alkyl.

[0138] In certain preferred oxazolidines of formula (V), the bridging unit R 8 for

[0139]

[0140] In certain preferred oxazolidines of formula (III) and (IV), respectively, R 4 Selected from branched alkyl groups, such as secondary-C3-C 10 -alkyl or tert-C4-C 10 , R 5 Select from C1-C 10 -alkyl, and R in formula (IV) 6 It is methyl.

[0141] Most preferably, the oxazolidine has the formula (VI)

[0142]

[0143] The oxazolidine of formula (VI) is sold under the trade name "INCOZOL 2" by the company Incorez.

[0144] The above-mentioned substances can be used as desiccants for γ-butyrolactone.

[0145] Before preparing the reaction mixture, the dried γ-butyrolactone (I) can be separated from the desiccant by distillation to avoid the presence of the desiccant or its reaction product with water in the target product poly-4-hydroxybutyrate. In particular, when CaH2 is used as a desiccant, it is preferred to separate the dried γ-butyrolactone (I) from the used CaH2 by distillation. Regardless of the desiccant used, the distillation must be carried out under a protective atmosphere (e.g., nitrogen or argon) to prevent the dried γ-butyrolactone (I) from absorbing air moisture.

[0146] Preferably, the gamma-butyrolactone provided in step (a2) has a water content of 0.1 wt.% or less, preferably 0.05 wt.% or less, and most preferably 0.01 wt.% or less, as measured by Karl-Fischer titration at 20° C. The low water content can be achieved by applying a desiccant, preferably one of the preferred desiccants described above.

[0147] In some cases, it is preferred that the method for synthesizing poly-4-hydroxybutyrate as defined above further comprises the following steps:

[0148] (c) quenching the ring-opening polymerization by adding a quenching solution comprising one or more acids and one or more solvents to the reaction mixture.

[0149] Using a quench, the base (i) is neutralized. In the absence of a quench, there is a risk of decomposition when the poly-4-hydroxybutyrate obtained is isolated from the reaction mixture at ambient temperature.

[0150] In the quenching solution added in step (c), the acid or one or more of the acids is preferably selected from the group consisting of hydrohalic acids, oxygen-containing acids of Cl, S, N, P and B, alkyl sulfonic acids, aryl sulfonic acids, mono-, di- and tri-functional carboxylic acids. The mono-, di- and tri-functional carboxylic acids include hydroxy-functionalized mono-, di- and tri-functional carboxylic acids and unsaturated mono-, di- and tri-functional carboxylic acids.

[0151] Most preferably, in the quenching solution added in step (c), each acid is selected from the group consisting of hydrohalic acids, oxygen acids of Cl, S, N, P and B, alkyl sulfonic acids, aryl sulfonic acids, mono-, di- and trifunctional carboxylic acids as defined above.

[0152] The most preferred acid is selected from the group consisting of hydrochloric acid HCl, perchloric acid HClO4, nitric acid HNO3, sulfuric acid H2SO4, phosphoric acid H3PO4, boric acid B(OH)3, formic acid, acetic acid, acrylic acid, oxalic acid, propionic acid, lactic acid, citric acid, methanesulfonic acid and toluenesulfonic acid.

[0153] The quenching solution added in step (c) comprises one or more solvents. Suitable solvents are those in which poly-4-hydroxybutyrate is soluble.

[0154] In the quenching solution, the solvent or one or more of the solvents are preferably selected from the group consisting of halogenated aliphatic and aromatic hydrocarbons, ketones, ethers, dialkyl carbonates and dialkyl sulfoxides. Most preferably, in the quenching solution added in step (c), each solvent is selected from the group consisting of halogenated aliphatic and aromatic hydrocarbons, ketones, ethers, dialkyl carbonates and dialkyl sulfoxides.

[0155] As used herein, the term "hydrocarbon" is intended to include halogenated hydrocarbons.

[0156] The most preferred solvents are those selected from the group consisting of chloroform, deuterated chloroform (CDCl3), 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, 1,4-dioxolane, anisole, dimethyl ether, acetone, acetophenone, dihydrolevoglucose, dimethyl carbonate, diethyl carbonate, dimethyl sulfoxide and acetonitrile.

[0157] The quenching solution added in step (c) preferably has a temperature in the range of -25°C to 20°C.

[0158] In the quenching solution, the total concentration of the acid is preferably in the range of 0.001 mol / l to 1 mol / L, preferably in the range of 0.016 mol / L to 0.081 mol / L.

[0159] In step (c), the quenching solution is preferably added in such an amount that the acid concentration provided by the quenching solution corresponds to an amount of 1 to 50 equivalents of acid per 1 equivalent of base, preferably in the range of 4 to 20 equivalents of acid per 1 equivalent of base.

[0160] The workup of the reaction mixture and the isolation of the produced poly-4-hydroxybutyrate can be carried out in any conventional manner, for example using filtration or water extraction workup, precipitation, distillation to remove the solvent or a combination of some or all of these steps, such as first a hydrolysis workup to remove the alkaline base and the initiator, followed by removal of the organic solvent and unreacted γ-butyrolactone (I) from the organic phase by evaporation or distillation. By applying these measures or their combination, poly-4-hydroxybutyrate can generally be obtained in a sufficiently pure state so that no additional purification steps are required.

[0161] The reaction can be carried out continuously, semi-continuously or discontinuously. The reaction can be carried out in all reactors suitable for this type of reaction known to those skilled in the art. Suitable reactors are described and reviewed in the relevant literature, for example K. Henkel, "Reactor Types and Their Industrial Applications", Ullmann's Encyclopedia of Industrial Chemistry, 2005, Wiley-VCH Verlag GmbH & Co. KGaA, chapter 3.3: "Reactors for gas-liquid reactions".

[0162] A particularly preferred method for synthesizing poly-4-hydroxybutyrate comprises the following steps:

[0163] (a) preparing a reaction mixture by:

[0164] (a1) forming a premix, the premix comprising

[0165] (i) one or more bases selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and potassium benzyloxide

[0166] as well as

[0167] (ii) one or more selected from the group consisting of methanol, ethanol, polyethylene glycol, 1,4-butanediol,

[0168] Alcohols from the group consisting of 1,6-hexanediol, benzyl alcohol, 1,4-benzenedimethanol, 2,6-dichlorobenzyl alcohol, 4-methylbenzyl alcohol and 2,4,6-trimethylbenzyl alcohol,

[0169] (a2) providing γ-butyrolactone (I) at a temperature in the range of -25°C to -10°C and having a water content of 0.1 wt% or less, wherein the γ-butyrolactone (I) is preferably dried using one or more oxazolidines of formula (III), (IV) or (V) as defined above.

[0170] (a3) forming a reaction mixture by adding the premix formed in step (a1) to the γ-butyrolactone provided in step (a2)

[0171] In the reaction mixture

[0172] - the molar ratio of γ-butyrolactone to the total amount of base (i) defined above is in the range of 200:1 to 400:1

[0173] and

[0174] - the molar ratio of the total amount of the base (i) defined above to the total amount of the alcohol (ii) defined above is in the range of 1:1 to 1:8

[0175] The reaction mixture further comprises a compound selected from the group consisting of dichloromethane, toluene, 2-methyltetrahydrofuran, 1,4-dioxolane, glycol dimethyl ether, diglycol dimethyl ether, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile and mixtures thereof.

[0176] Solvent (b) is used to polymerize the reaction mixture by ring-opening polymerization at a temperature in the range of -25°C to -10°C.

[0177] Chemical Conversion of γ-butyrolactone to Poly-4-hydroxybutyrate (c) The ring-opening polymerization is quenched by adding a quenching solution to the reaction mixture.

[0178] The quenching solution comprises an acid selected from the group consisting of hydrochloric acid HCl, perchloric acid HClO4, nitric acid HNO3, sulfuric acid H2SO4, phosphoric acid H3PO4, boric acid B(OH)3, formic acid, acetic acid, acrylic acid, oxalic acid, propionic acid, lactic acid, citric acid, methanesulfonic acid and toluenesulfonic acid

[0179] The acid is dissolved in a solvent selected from chloroform, deuterated chloroform (CDCl3),

[0180] The solvent is a solvent of the group consisting of 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, 1,4-dioxolane, anisole, dimethyl ether, acetone, acetophenone, dihydrolevoglucose ketone, dimethyl carbonate, diethyl carbonate, dimethyl sulfoxide, acetonitrile and mixtures thereof.

[0181] In the dose,

[0182] The quenching solution has a temperature in the range of -25°C to 20°C.

[0183] In a particularly preferred process according to the invention, the base (i) is potassium tert-butoxide and the alcohol (ii) is selected from the group consisting of benzyl alcohol, polyethylene glycol, 1,4-butanediol, 1,6-hexanediol, benzyl alcohol, 1,4-benzenedimethanol, 4-methylbenzyl alcohol and 2,4,6-trimethylbenzyl alcohol.

[0184] In a particularly preferred process according to the invention, the base (i) is potassium benzyloxide and the alcohol (ii) is selected from the group consisting of benzyl alcohol, polyethylene glycol, 1,4-butanediol, 1,6-hexanediol, benzyl alcohol, 1,4-benzenedimethanol, 4-methylbenzyl alcohol and 2,4,6-trimethylbenzyl alcohol.

[0185] In another aspect, the use of a kit in a method for synthesizing poly-4-hydroxybutyrate as defined above is disclosed, the kit comprising

[0186] (i) one or more bases comprising alkali metal cations

[0187] (ii) one or more alcohols.

[0189] Specific and preferred bases (i) comprising alkali metal cations are as described above. Specific and preferred alcohols (ii) are as described above. Specific and preferred combinations of bases (i) comprising alkali metal cations and alcohols (ii) are as described above. Preferably, the kit is used in one of the specific and preferred methods for synthesizing poly-4-hydroxybutyrate defined above.

[0190] In another aspect, poly-4-hydroxybutyrate obtainable by a process as defined above is disclosed. Preferably, poly-4-hydroxybutyrate is obtainable by one of the specific and preferred processes defined above.

[0191] The poly-4-hydroxybutyrate obtainable by the process defined above preferably has one or more of the following properties:

[0192] - The number average molecular weight (Mn) determined by gel permeation chromatography (GPC) is in the range of 4000 g / mol to 10000 g / mol

[0193] - Weight average molecular weight (Mn) determined by gel permeation chromatography (GPC) in the range of 6000 g / mol to 16000 g / mol

[0194] - Molecular weight distribution determined by gel permeation chromatography (GPC)

[0195] (Mw / Mn) in the range of 1.4 to 2.0

[0196] - Decomposition onset temperature (T5%) determined by thermogravimetric analysis (TGA) is in the range of 220°C to 250°C

[0197] - Glass transition temperature (Tg) determined by differential scanning calorimetry in the range of -40°C to -60°C

[0198] - Crystallization temperature (Tc) determined by differential scanning calorimetry in the range of 10°C to 20°C

[0199] - The melting temperature (Tm) determined by differential scanning calorimetry is in the range of 50 to 60°C.

[0200] Methods for determining the above parameters are known in the art. See the Examples section for details.

[0201] Preferred poly-4-hydroxybutyrates obtainable by the process defined above are soluble in one or more solvents selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, acetone, acetonitrile, dichloromethane, dimethyl sulfoxide (=DMSO), chlorobenzene, chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, dimethylformamide, ethyl acetate, γ-butyrolactone (=GBL), dimethyl carbonate, diethyl carbonate, dimethoxyethane (=glyme), dihydrolevoglucosone (=cyrene) and toluene.

[0202] Potential applications of the poly-4-hydroxybutyrate obtainable by the above method include the manufacture of fibers suitable for reinforcing a matrix made of another polymer, i.e., fibers for forming fiber-reinforced polymers. Such fiber-reinforced polymers made of poly-4-hydroxybutyrate have advantages in terms of the ability to be recycled, since the reinforcing fibers can be easily removed by depolymerizing the poly-4-hydroxybutyrate and distilling the resulting γ-butyrolactone from the melt of the matrix polymer, thereby obtaining γ-butyrolactone as a reusable monomer and a fiber-free matrix polymer.

[0203] Further areas of application of the poly-4-hydroxybutyrates obtainable by the process defined above relate to adhesives, for example hot-melt adhesives or compostable adhesives, or the encapsulation of crop protection products.

[0204] The polymers of the present invention can be used in seed treatment compositions and methods for treating seeds. Therefore, the present invention also relates to the use of these polymers in seed treatment compositions. Seed treatment is a method of applying active ingredients to seeds to support germination and / or growth. Seed treatment is applicable to a variety of crops. Typical examples include the application of pesticides, such as fungicides, insecticides and plant growth regulators, and other active ingredients, such as fertilizers.

[0205] The poly-4-hydroxybutyrate obtainable by the process defined above can be used in the form of a blend with one or more other polymers, in such a way as to increase the content of renewable materials in the final part.

[0206] Besides these applications, the poly-4-hydroxybutyrates obtainable by the process defined above can be used as intermediates for the preparation of other polymers or elastomers, for example for home care or cosmetic applications or for technical polymers such as polyurethanes.

[0207] In particular, the difunctional poly-4-hydroxybutyrates obtainable by the process defined above can be used for the preparation of

[0208] - thermoplastic polyurethane, e.g. for extrusion applications, preferably for extruded articles, more preferably for extruded articles selected from the group consisting of cable sheathing, pipes and hoses, injection molding applications, preferably for injection molded articles, more preferably for injection molded articles selected from the group consisting of rollers, gaskets, seals, rail pads and conveyor belts, preferably with improved compression set, with improved heat resistance and creep properties,

[0209] -Polyurethane foam

[0210] -Casting elastomers

[0211] -Thermoplastic copolyesters and other specialty polymers.

[0212] The poly-4-hydroxybutyrate obtainable by the process defined above can also be used as a binder in coating applications such as

[0213] - Conventional primer,

[0214] - Water-based paint layer,

[0215] - liquid primers, which are essentially free of solvents and water (so-called 100% systems),

[0216] - solid waterless primers such as powder coatings and pigmented powder coatings,

[0217] - Solvent-free, possibly pigmented powder coating dispersions, such as powder slurry primers.

[0218] Such coatings can be hardened by heat treatment, radiation or dual-cure hardening methods. They are self-crosslinking or crosslinked by external crosslinking agents.

[0219] These coatings are suitable for coating substrates such as wood, paper, textiles, leather, nonwovens, plastics, glass, ceramics, mineral products, for example for construction such as cement slabs or fiber cement boards, and in particular metals or coated metals.

[0220] The coating process is carried out according to methods known in the art, wherein at least one coating according to the invention, i.e. a coating containing poly-4-hydroxybutyrate obtainable by the method defined above, is applied to a substrate in the desired thickness and then the volatile components are removed. If necessary, the process can be repeated one or more times. The coating can be applied to the substrate according to known methods, such as spraying, stopping, coating with a coating knife, brushing, rolling or casting. The strength of the coating is generally 3 to 1000 g / m 2 , and preferably 10 to 200 g / m 2 .

[0221] The poly-4-hydroxybutyrates obtainable by the process defined above can also be used in the production of printing inks or printed coatings, as additives such as dispersing aids, stabilizers or binders. A preferred application is as binder for printing inks or printed coatings.

[0222] Furthermore, the poly-4-hydroxybutyrates obtainable by the process defined above can also be employed in cosmetic and dermatological preparations as rheology modifiers, in particular as thickeners, in particular as oil-thickening polymers suitable for cosmetic applications. Example:

[0223] The following examples are intended to further explain and illustrate the present invention, but not to limit the scope thereof.

[0224] Testing of different bases (i) and alcohol initiators (ii) (Examples 1 to 20)

[0225] Preparation 6.5 mmol scale (Examples 4 to 7, 12 to 14, see Table 1) :

[0226] Ring-opening polymerization of γ-butyrolactone (GBL) was carried out in a sealed 10 mL vial. In an argon-filled glove box, GBL (500 μL, 6.50 mmol, 1.0 eq) was charged into a 10 mL vial and sealed with a septum. The base indicated in Table 1 (0.125 mol% to 0.5 mol%, relative to GBL, see Table 1) was charged into a separate 1 mL vial, followed by the solvent 2-MeTHF (65 μL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and the alcohol initiator indicated in Table 1 (0.5 mol% to 1.0 mol%, relative to GBL, see Table 1), and sealed (step (a1)). The obtained premix base / initiator / solvent was homogenized for 5 min. If the solid components of the premix are not completely dissolved, the premix is ​​used as a suspension. The vial is taken out of the glove box. The vial containing GBL is immersed in a cooling bath at -20°C (step (a2)). After equilibration at the desired temperature for 30 min, a reaction mixture was formed (step (a3)), and the ring-opening polymerization of GBL was initiated by dropwise addition of the premixed base / initiator / solvent via a gas-tight syringe (step (b)). After 4 h or 14 h at -20°C (as indicated in Table 1), the polymerization was quenched (step (c)) by adding 4 mL of cold (-20°C) acetic acid / CHCl3 (5 μL / mL) solution until the precipitated polymer was redissolved at -20°C. 1 The quenched reaction mixture was analyzed by H-NMR to obtain the percentage and yield of monomer converted.

[0227] Preparation 130 mmol scale (Examples 1 to 3, 8 to 11, 15 to 20, see Table 1) :

[0228] Ring-opening polymerization of γ-butyrolactone was carried out in a flame-dried 100 mL round-bottom flask. In an argon-filled glove box, GBL (10 mL, 130 mmol, 1.0 eq) was charged into a flask and sealed with a septum. The base indicated in Table 1 (0.125 mol% to 0.25 mol%, relative to GBL, see Table 1) was charged into a separate 4 mL vial, followed by the solvent 2-MeTHF (1.3 mL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and the alcohol initiator indicated in Table 1 (0.5 mol% to 1.0 mol%, relative to GBL, see Table 1), and sealed (step (a1)). The obtained premix alkali / initiator / solvent was homogenized for 5 min. If the solid components of the premix are not completely dissolved, the premix is ​​used as a suspension. The reactor and vial are taken out of the glove box. The round-bottom flask is immersed in a cooling bath at -20°C (step (a2)). After equilibration at the desired temperature for 40 min, a reaction mixture was formed (step (a3)), and the ring-opening polymerization of GBL was initiated by dropwise addition of the premix base / initiator / solvent via a gas-tight syringe (step (b)). After 4 h or 24 h at -20°C (as indicated in Table 1), the polymerization was quenched (step (c)) by adding 40 mL of cold (-20°C) acetic acid / DCM (5 μL / mL) solution until the precipitated polymer redissolved at -20°C. The quenched reaction mixture was washed with distilled water (3×100 mL), and then the volatile components were evaporated using a rotary evaporator (at 35°C until 20 mbar was reached). The remaining viscous liquid was precipitated using cold MeOH:H2O 9:1, filtered, washed with cold MeOH:H2O 9:1, and dried under high vacuum (0.1 mbar) for 24 h.

[0229]

[0230] [a] By using hexamethyldisiloxane as an internal standard 1 H-NMR to determine;

[0231] [b] Isolation yield;

[0232] [c] Potassium tert-butoxide, 2M (25% w / w) - solution in 2-MeTHF;

[0233] [d]M n (Number average molar mass in g / mol) of pure polymer 1 H-NMR, by adding benzyl alcohol [5.12ppm], 1,4-BDM [5.09ppm], 1,4-BDO

[0234] The integral of the signals of [3.66 ppm], 1,6-HDO [3.66 ppm], and MeOH [3.47 ppm] was defined as A, and compared with the integral of the CH2 signal from poly-4-hydroxybutyrate at 4.12 ppm as B to determine the result.

[0235] M n The following formula is used to calculate the protons, where N is the number of protons for A and B. A and N B :M n =

[0236] ((B / N B ) / (A / N A ))*Mw(γ-butyrolactone)+Mw(initiator).

[0237] [e] Determined by GPC in THF

[0238] Note: M determined by NMR n The value is usually different from the M determined via GPC. n As the skilled person knows, GPC gives relative values ​​depending on the standards applied.

[0239] "ND" means parameter not determined.

[0240] Testing of different solvents for the reaction mixture

[0241] Preparation on 6.5 mmol scale (Examples 4 and 21 to 29) :

[0242] Ring-opening polymerization of γ-butyrolactone (GBL) was carried out in a sealed 10 mL vial. In an argon-filled glove box, GBL (500 μL, 6.50 mmol, 1.0 eq) was charged into a 10 mL vial and sealed with a septum. The base potassium tert-butoxide (0.25 mol % relative to GBL) was charged into a separate 1 mL vial, followed by the solvent indicated in Table 2 (65 μL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and the initiator benzyl alcohol (1.0 mol % relative to GBL) and sealed (step (a1)). The obtained premix base / initiator / solvent was homogenized for 5 min. If the solid components of the premix were not completely dissolved, the premix was used as a suspension. The vial was taken out of the glove box. The vial containing GBL was immersed in a cooling bath at -20°C (step (a2)). After equilibration at the desired temperature for 30 min, a reaction mixture was formed (step (a3)), and the ring-opening polymerization of GBL was initiated by dropwise addition of the premixed base / initiator / solvent via a gas-tight syringe (step (b)). After 4 h or 14 h at -20°C (as indicated in Table 2), the polymerization was quenched (step (c)) by adding 4 mL of cold (-20°C) acetic acid / CHCl3 (5 μL / mL) solution until the precipitated polymer was redissolved at -20°C. 1 The quenched reaction mixture was analyzed by H-NMR to obtain the percentage and yield of monomer converted.

[0243] Table 2

[0244]

[0245] [a] By using hexamethyldisiloxane as an internal standard 1 confirmed by H-NMR.

[0246] Preparation on 6.5 mmol scale (Examples 30 to 32, see Table 3) :

[0247] Ring-opening polymerization of γ-butyrolactone (GBL) was carried out in a sealed 10 mL vial. In an argon-filled glove box, GBL (500 μL, 6.50 mmol, 1.0 eq) was charged into a 10 mL vial and sealed with a septum. The base potassium tert-butoxide (0.25 mol % relative to GBL) was charged into a separate 1 mL vial, followed by the solvent indicated in Table 3 (65 μL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and (except for Example 30 as a comparative example) the initiator indicated in Table 3 (1 mol % relative to GBL) and sealed (step (a1)). The obtained premix alkali / initiator / solvent was homogenized for 5 min. The vial was taken out of the glove box. The vial containing GBL was immersed in a cooling bath at -20°C (step (a2)). After equilibration at the desired temperature for 30 min, a reaction mixture was formed (step (a3)), and the ring-opening polymerization of GBL was initiated by dropwise addition of the premixed base / initiator / solvent via a gas-tight syringe (step (b)). After 4 h at -20°C, the polymerization was quenched (step (c)) by adding 4 mL of cold (-20°C) acetic acid / CHCl3 (5 μL / mL) solution until the precipitated polymer was redissolved at -20°C. 1 The quenched reaction mixture was analyzed by H-NMR to obtain the percentage and yield of monomer converted.

[0248] Preparation 130 mmol scale (Example 33, see Table 3) :

[0249] Ring-opening polymerization of γ-butyrolactone (GBL) was carried out in a flame-dried 100 mL round-bottom flask. In an argon-filled glove box, GBL (10 mL, 130 mmol, 1.0 eq) was charged into the flask and sealed with a septum. The base potassium tert-butoxide (0.25 mol % relative to GBL) was charged into a separate 4 mL vial, followed by the solvent ethyl acetate (1.3 mL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and the initiator benzyl alcohol (1.0 mol % relative to GBL) and sealed (step (a1)). The obtained premix alkali / initiator / solvent was homogenized for 5 min. The reactor and vial were taken out of the glove box. The round-bottom flask was immersed in a cooling bath at -20 ° C (step (a2)). After equilibration at the desired temperature for 40 min, a reaction mixture was formed (step (a3)), and the ring-opening polymerization of GBL was initiated by dropwise addition of the premix base / initiator / solvent via a gas-tight syringe (step (b)). After 4 hours at -20°C, the polymerization was quenched (step (c)) by adding 40 mL of cold (-20°C) acetic acid / DCM (5 μL / mL) solution until the precipitated polymer redissolved at -20°C. The quenched reaction mixture was washed with distilled water (3×100 mL), and then the volatile components were evaporated using a rotary evaporator (at 35°C until 20 mbar was reached). The remaining viscous liquid was precipitated using cold MeOH:HO 9:1, filtered, washed with cold MeOH:HO 9:1, and dried under high vacuum (0.1 mbar) for 24 hours.

[0250] Table 3

[0251]

[0252] [a] By using hexamethyldisiloxane as an internal standard 1 H-NMR to determine;

[0253] [b] Isolation yield

[0254] Testing of different solvents for quenching in step (c) (Examples 4 and 34 to 47)

[0255] Preparation on a 6.5 mmol scale (Examples 4, 34 to 39 and 41 to 47, see Table 4) :

[0256] Ring-opening polymerization of γ-butyrolactone (GBL) was carried out in a sealed 10 mL vial. In an argon-filled glove box, GBL (500 μL, 6.50 mmol) was loaded into a 10 mL vial and sealed with a septum. The base potassium tert-butoxide (1.83 mg, 0.016 mmol) was loaded into a separate 1 mL vial, followed by the solvent 2-MeTHF (65.0 μL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and the initiator benzyl alcohol (6.7 μL, 0.065 mmol) and sealed (step (a1)). The obtained premix alkali / initiator / 2-MeTHF was homogenized for 5 min. The vial was taken out of the glove box. The vial containing GBL was immersed in a cooling bath at -20 ° C (step (a2)). After equilibration at the desired temperature for 30 min, a reaction mixture was formed (step (a3)) and the ring-opening polymerization of GBL was initiated by dropwise addition of the premix base / initiator / 2-MeTHF via a gas-tight syringe (step (b)). After 4 hours at -20°C, the polymerization was quenched (step (c)) by adding a cold (-20°C) quenching solution containing 4 mL of acetic acid (acid concentration 5 mol% relative to GBL) in the solvent indicated in Table 4 until the precipitated polymer redissolved at -20°C. If the polymer did not redissolve at -20°C, the reaction mixture was warmed to +22°C. By 1 The quenched reaction mixture was analyzed by H-NMR to obtain the percentage and yield of monomer converted.

[0257] Preparation 130 mmol scale (Example 40, see Table 4) :

[0258] Ring-opening polymerization of γ-butyrolactone was carried out in a flame-dried 100 mL round-bottom flask. In an argon-filled glove box, γ-butyrolactone (10 mL, 130 mmol, 1.0 eq) was charged into a flask and sealed with a septum. The base potassium tert-butoxide (0.25 mol% relative to GBL) was charged into a separate 4 mL vial, followed by the solvent 2-MeTHF (1.3 mL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and the initiator benzyl alcohol (1.0 mol% relative to GBL) and sealed (step (a1)). The premix alkali / initiator / solvent was homogenized for 5 min. The reactor (i.e., flask) and vial were taken out of the glove box. The round-bottom flask was immersed in a cooling bath at -20 ° C (step (a2)). After equilibration at the desired temperature for 40 min, a reaction mixture was formed (step (a3)) and the ring-opening polymerization of GBL was initiated by dropwise addition of the premix base / initiator / solvent via a gas-tight syringe (step (b)). After 4 hours at -20°C, the polymerization was quenched (step (c)) by adding 40 mL of cold (-20°C) acetic acid / acetone (5 μL / mL) solution and warmed to +22°C until the polymer redissolved. The quenched reaction mixture was washed with distilled water (3×100 mL) and then the volatile components were evaporated using a rotary evaporator (at 35°C until 20 mbar was reached). The remaining viscous liquid was precipitated using cold MeOH:HO 9:1, filtered, washed with cold MeOH:HO 9:1, and dried under high vacuum (0.1 mbar) for 24 hours.

[0259] Table 4

[0260]

[0261]

[0262] [a] By using hexamethyldisiloxane as an internal standard 1 H-NMR to determine;

[0263] [b] Isolation yield;

[0264] [c]M n (number average molar mass in Da) of pure polymer 1 H-NMR was determined by comparing the integration of the CH2 signal from benzyl alcohol at 5.12 ppm A with the integration of the CH2 signal from poly-4-hydroxybutyrate at 4.12 ppm B, since only one benzyl alcohol molecule is present per polymer chain.

[0265] M n It is calculated by the following formula, where protons are not considered because two CH2 are compared:

[0266] M n =(B / A)*Mw(γ-butyrolactone)+Mw(benzyl alcohol)

[0267] [d] 1,2-DCE = 1,2-dichloroethane [e] 1,1,2,2-TCE = 1,1,2,2-tetrachloroethane

[0268] Testing of different acids for quenching in step (c) (Examples 4 and 48 to 61)

[0269] Preparation on 6.5 mmol scale (Examples 4 and 48 to 61, see Table 5) :

[0270] Ring-opening polymerization of γ-butyrolactone (GBL) was carried out in a sealed 10 mL vial. In an argon-filled glove box, GBL (500 μL, 6.50 mmol) was loaded into a 10 mL vial and sealed with a septum. The base potassium tert-butoxide (1.83 mg, 0.016 mmol) was loaded into a separate 1 mL vial, followed by the solvent 2-MeTHF (65.0 μL, resulting in a GBL concentration of 100 M in the reaction mixture to be formed) and the initiator benzyl alcohol (6.7 μL, 0.065 mmol) and sealed (step (a1)). The obtained premix alkali / initiator / 2-MeTHF was homogenized for 5 min. The vial was taken out of the glove box. The vial containing GBL was immersed in a cooling bath at -20 ° C (step (a2)). After equilibration at the desired temperature for 30 min, a reaction mixture was formed (step (a3)) and the ring-opening polymerization of GBL was initiated by dropwise addition of the premix base / initiator / 2-MeTHF via a gas-tight syringe (step (b)). After 4 hours at -20°C, the polymerization was quenched (step (c)) by adding 4 mL of a cold (-20°C) quenching solution containing the acid indicated in Table 5 (acid concentration was 1 to 5 mol% relative to GBL) in 4 mL of the solvent indicated in Table 5 until the precipitated polymer redissolved at -20°C. If the polymer did not redissolve at -20°C, the reaction mixture was warmed to +22°C. By 1 The quenched reaction mixture was analyzed by H-NMR to obtain the percentage and yield of monomer converted.

[0271] Table 5

[0272]

[0273] [a] By using hexamethyldisiloxane as an internal standard 1 confirmed by H-NMR.

[0274] Testing of Different Water Scavengers for γ-Butyrolactone (Examples 62 to 68)

[0275] Prepared on a 130 mmol scale, including drying of GBL by addition of CaH2 (Example 62) :

[0276] Ring-opening polymerization of γ-butyrolactone (GBL) was carried out in a 50 mL Schlenk round-bottom flask previously dried overnight at 120° C. in an oven under N2 atmosphere. Calcium hydride (112 mg, 1 wt %) and GBL (10.0 mL, 130.1 mmol) were charged into the flask and flushed with N2 and sealed. The mixture in the sealed flask was then heated to 60° C. over a period of 2 hours. After cooling to room temperature, the sealed flask was immersed in a cooling bath at -20° C. for 30 min (step (a2)). Base (anhydrous solution of potassium tert-butoxide in 2-MeTHF, 2M, 25 wt%, 0.170 mL, 0.25 mol% relative to GBL), initiator (anhydrous benzyl alcohol, 0.135 mL, 1.30 mmol) and anhydrous Me-THF (1.130 mL, resulting in a concentration of 100 M GBL in the reaction mixture to be formed) were charged into separate dry vials and sealed (step (a1)). The obtained premix base / initiator / solvent was homogenized for 5 min and cooled to -20°C for 10 minutes. The ring-opening polymerization of GBL was initiated by rapidly adding the premix to the cold GBL via a gas-tight syringe (step (b)), forming a reaction mixture (step (a3)). After 4 hours at -20°C, the polymerization was quenched by adding a cold (-20°C) quenching solution containing acetic acid (2 mol.% relative to GBL) dissolved in 40 mL of dichloromethane (step (c)), and then the white solid polymer formed was gently crushed. The quenched reaction mixture was filtered and washed with distilled water (3×80 mL), and then the volatile components were evaporated using a rotary evaporator (40° C. until 20 mbar was reached). The remaining viscous liquid was precipitated using cold MeOH, filtered, washed with cold MeOH, and dried on a rotary evaporator under vacuum to obtain 4-hydroxybutyrate (3.443 g, 40.0 mmol, 30% yield).

[0277] Prepared on a 65.05 mmol scale using Incozol 2 (Formula (IV) (Examples 63 to 68) :

[0278] Ring-opening polymerization of γ-butyrolactone was carried out in a 50 mL Schlenk flask previously dried overnight in an oven at 120° C. under N2 atmosphere. After 3 cycles of high vacuum / N2, the dried flask was sealed and GBL (5.0 mL, 65.05 mmol) was charged via a gas-tight syringe. The water scavenger Incozol 2 (Incorez, 0.1 to 0.3 mol.%) was added to the GBL, and the resulting mixture was stirred at ambient temperature for 1 hour. The sealed flask was then immersed in a cooling bath at -20° C. for 30 min (step (a2)). A base (an anhydrous solution of potassium tert-butoxide in 2-MeTHF, 2M, 25 wt%, 0.35 to 0.6 mol% relative to GBL, see Table 6), an initiator (anhydrous benzyl alcohol or polyethylene glycol M indicated in Table 6) was added to the flask. w =400 (PEG 400), 0.25 to 1.0 mol% relative to GBL, see Table 6) and anhydrous Me-THF (65.0 μL, resulting in a concentration of 100 M GBL in the reaction mixture to be formed) were charged into separate dry vials and sealed (step (a1)). The obtained premix base / initiator / solvent was homogenized for 5 min and cooled to -20°C for 10 minutes. The ring-opening polymerization of GBL was started by quickly adding the premix to the cold GBL via a gas-tight syringe (step (b)), forming a reaction mixture (step (a3)). After 4 hours at -20°C, the polymerization was quenched by adding a cold (-20°C) quenching solution containing acetic acid (2 mol% relative to GBL) dissolved in 40 mL of dichloromethane (step (c)), and then the white solid polymer formed was gently crushed. The quenched reaction mixture was washed with distilled water (3 x 50 mL) and then the volatile components were evaporated using a rotary evaporator (40 °C until 20 mbar was reached). The remaining viscous liquid was precipitated using cold MeOH, filtered, washed with cold MeOH, and dried on a rotary evaporator under vacuum to obtain the corresponding poly-γ-butyrolactone.

[0279] Table 6

[0280]

[0281] [a] GBL was mixed with CaH2 (1 wt%) and heated to 60°C before adding the base / initiator / solvent premix.

[0282] Up to 2 hours [b] Isolation yield

[0283] The physical parameters of the 4-hydroxybutyrate esters synthesized in Examples 62 to 68 in the presence of a water scavenger are summarized in Table 7. "ND" means the parameter was not determined.

[0284] Table 7 :

[0285]

[0286] Determination of M from GPC in THF n 、M w and

[0287] The decomposition onset temperature (T 5％ ).

[0288] The glass transition temperature (T) was measured by DSC. g ), crystallization temperature (T c ) and melting temperature (T m ).

[0289] method :

[0290] The number average molecular weight (M) was determined by gel permeation chromatography (GPC). n ), weight average molecular weight (M w ) and molecular weight distribution The measurements were performed on an Agilent 1260 Infinity II GPC instrument equipped with two PLgel 3 μm mixed E columns at 40°C with THF as eluent and a flow rate of 1 mL / min. The polymer concentration in THF was 4 mg / mL and 1,2-dichlorobenzene was used as a reference. Conventional calibration with polystyrene standards was used for molecular weight determination.

[0291] At METTLER TOLEDO STAR e Thermogravimetric analysis (TGA) was performed on a DSC / TGA analyzer. The polymer samples were heated from 20°C to 500°C at a rate of 10°C / min in a N2 atmosphere.

[0292] Differential Scanning Calorimetry (DSC) measurements were performed on a Netzsch DSC 200F3 Maia instrument under N2 atmosphere at a flow rate of 30 mL / min. After the first scan allowing the thermal history to reset, a second heating was performed from -80°C to 120°C at a heating and cooling rate of 10°C / min.

[0293] Comparative Example 1 (non-inventive): Rapid addition of GBL to cold base / initiator / solvent

[0294] Ring-opening polymerization of γ-butyrolactone was carried out in a flame-dried 100 mL round-bottom flask. In an argon-filled glove box, the base potassium tert-butoxide (0.036 g, 0.325 mmol, 0.25 mol% relative to GBL) was charged into the flask, followed by the solvent 2-MeTHF (1.301 mL, resulting in a concentration of 100 M GBL in the reaction mixture to be formed) and the initiator benzyl alcohol (0.135 mL, 1.301 mmol, 1.0 mol% relative to GBL) and sealed with a septum. GBL (10 mL, 130 mmol, 1.0 eq.) was charged into a separate 20 mL sealed vial. The premix base / initiator / solvent was homogenized for 5 min. The reactor (i.e., flask) and vial were taken out of the glove box. The round-bottom flask with base / initiator / solvent was immersed in a cooling bath at -20°C. After equilibration at the desired temperature for 40 min, a reaction mixture was formed and polymerization was initiated by rapid addition of γ-butyrolactone via a syringe. After 4 h at -20 °C, the polymerization was quenched by adding 40 mL of cold (-20 °C) acetic acid / CHCl3 (2 μL / mL) solution until the precipitated polymer redissolved at -20 °C. The quenched reaction mixture was washed with distilled water (3×100 mL) and then a rotary evaporator was used to evaporate the volatile components (at 35 °C until 20 mbar was reached). The remaining viscous liquid was precipitated with cold MeOH:H2O 9:1, filtered, washed with cold MeOH:H2O 9:1, and dried under high vacuum (0.1 mbar) for 24 h to give the corresponding poly-γ-butyrolactone (5.72 g, 66.4 mmol, 51% yield, M n =7161 g / mol).

[0295] M n (average mass in g / mol or Da) of pure polymer 1 H-NMR, determined by comparing the integration of the CH2 signal from benzyl alcohol at 5.12 ppm A with the integration of the CH2 signal from poly-4-hydroxybutyrate at 4.12 ppm B, since there is only one benzyl alcohol molecule per polymer chain. n The following formula is used for calculation, protons are not considered here because two CH2 are compared:

[0296] M n =(B / A)*Mw(γ-butyrolactone)+Mw(benzyl alcohol)

Claims

1. A method for synthesizing poly-4-hydroxybutyrate, the method comprising the following steps (a) preparing a reaction mixture, the reaction mixture comprising (i) one or more bases comprising alkali metal cations (ii) one or more alcohols as well as (iii) γ-Butyrolactone (I) wherein in the reaction mixture, the molar ratio of γ-butyrolactone (iii) to the total amount of the base (i) comprising an alkali metal cation is 200:1 or more, wherein preparing the reaction mixture comprises (a1) forming a premix, the premix comprising (i) one or more bases comprising alkali metal cations as well as (ii) one or more alcohols (a2) providing (iii) γ-butyrolactone at a temperature of -25°C or higher (a3) obtaining the reaction mixture by charging the premix formed in step (a1) into the γ-butyrolactone provided in step (a2) at a temperature of -25°C or higher, (b) chemically converting the γ-butyrolactone in the reaction mixture into poly-4-hydroxybutyrate by ring-opening polymerization at a temperature of -25°C or higher.

2. The method according to claim 1, wherein (i) The one or more bases comprising an alkali metal cation are selected from the group consisting of lithium alkoxide, sodium alkoxide and potassium alkoxide, preferably lithium methoxide, sodium methoxide, potassium methoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium benzyloxide, sodium benzyloxide and potassium benzyloxide.

3. The method according to any one of claims 1 and 2, wherein (ii) the one or more alcohols are selected from the group consisting of methanol, ethanol, ethylene glycol, diethylene glycol, polyethylene glycol, 1,2-propylene glycol, dipropylene glycol, polypropylene glycol, 1,3-propylene glycol, 1,4-butylene glycol, polytetramethylene glycol, 1,5-pentanediol, 1,6-hexanediol and benzyl alcohol according to formula (II) in n is an integer from 1 to 4, preferably 1 or 2 m is an integer from 0 to 3, o is 0 or 1 m+n+o≤6; R 1 and R 2 Independently selected from the group consisting of: F, Cl, Br, OH, CN, NH2, NO2, C1-C 10 -alkyl, C3-C 10 - cycloalkyl, A C3-C 10 -heterocyclic group, C5-C 14 -Aryl, A C5-C 10 - heteroaryl, Wherein the C1-C 10 -alkyl, C3-C 10 -cycloalkyl, C3-C 10 -heterocyclic group, C5-C 14 -Aryl, C5-C 10 -heteroaryl groups each optionally have one or more additional substituents selected from the group consisting of: F, Cl, Br, OH, CN, NH2 and C1-C 10 -alkyl, Wherein the benzyl alcohol according to formula (II) is preferably selected from the group consisting of benzyl alcohol, 1,4-benzenedimethanol, 2,6-dichlorobenzyl alcohol, 4-methylbenzyl alcohol and 2,4,6-trimethyl-benzyl alcohol.

4. A method according to any preceding claim, wherein (i) the base comprising an alkali metal cation is of the formula MOR 3 Alkali metal alkoxide, wherein M is selected from the group consisting of Li, Na and K (ii) the alcohol is of formula R 3 OH alcohol Where (i) R 3 and (ii) R 3 The same, and are preferably selected from the group consisting of methyl, ethyl, isopropyl, sec-butyl, tert-butyl and benzyl.

5. A method according to any preceding claim, wherein step (b) Chemical conversion of γ-butyrolactone (I) to poly-4-hydroxybutyrate via ring-opening polymerization It is carried out at a temperature in the range of -25°C to +50°C, preferably -25°C to -10°C.

6. A process according to any preceding claim, wherein in the reaction mixture prepared in step (a), the molar ratio of γ-butyrolactone (I) to the total amount of (i) base comprising an alkali metal cation is in the range of 200:1 to 800:1, preferably 200:1 to 400:

1.

7. A process according to any preceding claim, wherein the reaction mixture prepared in step (a) (i) Total amount of base including alkali metal cations and (ii) The molar ratio of the total amount of alcohol is in the range of 1:1 to 10:1, preferably 1:1 to 5:

1.

8. A process according to any preceding claim, wherein the reaction mixture prepared in step (a) further comprises one or more solvents The one or more solvents are preferably selected from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

9. A process according to any preceding claim, wherein for the preparation of the reaction mixture in step (a), providing - a premix comprising (i) one or more bases comprising an alkali metal cation and (ii) one or more alcohols and one or more solvents and / or a mixture comprising (iii) gamma-butyrolactone (I) and one or more solvents, Therein, the one or more solvents are preferably selected in each case from the group consisting of aliphatic hydrocarbons, aromatic hydrocarbons, ethers, esters, N,N-dialkylamides, dialkyl sulfoxides and nitriles.

10. A method according to any preceding claim, further comprising: drying the γ-butyrolactone (I) by adding a desiccant, and optionally separating the dried γ-butyrolactone (I) from the desiccant before preparing the reaction mixture, Wherein the desiccant is preferably selected from the group consisting of: CaH2, Tosyl isocyanate, and oxazolidine The oxazolidine is preferably selected from the group consisting of oxazolidine of formula (III), oxazolidine of formula (IV) and oxazolidine of formula (V). Where R 4 , R 5 , R 6 and R 7 Independently selected from H- and C1-C 10 -alkyl group, and R 8 is a bridging unit comprising 1 to 20 -CH2- units and optionally one or more moieties selected from the group consisting of: -NH-, -O-, -CO-, -COO- and -NH-COO-.

11. The process according to any preceding claim, wherein the γ-butyrolactone provided in step (a2) has a water content of 0.1 wt% or less, preferably 0.05 wt% or less and most preferably 0.01 wt% or less, as measured by Karl-Fischer titration.

12. The method according to any preceding claim, further comprising the steps of: (c) quenching the ring-opening polymerization by adding a quenching solution comprising one or more acids and one or more solvents to the reaction mixture, in - the one or more acids are preferably selected from the group consisting of hydrohalic acids, oxyacids of Cl, S, N, P and B, alkylsulfonic acids, arylsulfonic acids, mono-, di- and trifunctional carboxylic acids, - The one or more solvents are preferably selected from the group consisting of halogenated aliphatic and aromatic hydrocarbons, ketones, ethers, dialkyl carbonates, dialkyl sulfoxides and nitriles - The quenching solution preferably has a temperature in the range of -25°C to 20°C.

13. A method according to any preceding claim, comprising the steps of: (a) preparing a reaction mixture by: (a1) forming a premix, the premix comprising (i) one or more bases selected from the group consisting of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and potassium benzyloxide as well as (ii) one or more selected from the group consisting of methanol, ethanol, polyethylene glycol, 1,4-butanediol, 1,6-hexanediol, benzyl alcohol, 1,4-benzenedimethanol, 2,6-dichlorobenzyl alcohol, Alcohols of the group consisting of 4-methylbenzyl alcohol and 2,4,6-trimethylbenzyl alcohol, (a2) providing γ-butyrolactone (I) at a temperature in the range of -25°C to -10°C and having a water content of 0.1 wt% or less (a3) forming a reaction mixture by adding the premix formed in step (a1) to the γ-butyrolactone provided in step (a2) wherein in the reaction mixture - The molar ratio of γ-butyrolactone to the total amount of base (i) is in the range of 200:1 to 400:1 and - the molar ratio of the total amount of base (i) to the total amount of alcohol (ii) is in the range of 1:1 to 1:8 wherein the reaction mixture further comprises a solvent selected from the group consisting of dichloromethane, toluene, 2-methyl-tetrahydrofuran, 1,4-dioxolane, glyme, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide and acetonitrile and mixtures thereof (b) chemically converting the γ-butyrolactone in the reaction mixture into poly-4-hydroxybutyrate by ring-opening polymerization at a temperature in the range of -25°C to -10°C (c) quenching the ring-opening polymerization by adding a quenching solution to the reaction mixture, The quenching solution comprises an acid selected from the group consisting of hydrochloric acid, perchloric acid, nitric acid, sulfuric acid, phosphoric acid, boric acid, formic acid, acetic acid, acrylic acid, oxalic acid, propionic acid, lactic acid, citric acid, methanesulfonic acid and toluenesulfonic acid. The acid is dissolved in a solvent selected from the group consisting of chloroform, deuterated chloroform, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chlorobenzene, 1,4-dioxolane, anisole, dimethyl ether, acetone, acetophenone, dihydrolevoglucose, dimethyl carbonate, diethyl carbonate, dimethyl sulfoxide, acetonitrile and a mixture thereof, The quenching solution has a temperature in the range of -25°C to 20°C.

14. Use of a kit comprising the following in a method according to any one of claims 1 to 13 (i) one or more bases comprising alkali metal cations (ii) one or more alcohols.

15. Poly-4-hydroxybutyrate obtainable by the process according to any one of claims 1 to 13.

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