WO2016176194A1

WO2016176194A1 - Bisphenols and polycarbbonates and the methods of making thereof

Info

Publication number: WO2016176194A1
Application number: PCT/US2016/029335
Authority: WO
Inventors: James Alan Mahood; Jan Henk Kamps; Ruud Van Der Heijden
Original assignee: Sabic Global Technologies B.V.
Priority date: 2015-04-27
Filing date: 2016-04-26
Publication date: 2016-11-03
Also published as: WO2016176194A8

Abstract

Disclosed herein are bisphenol compositions exhibiting minimized endocrine receptor activity. The compositions include phemolic components.

Description

BISPHENOLS AND POLYCARBONATES AND THE METHODS OF MAKING THEREOF

TECHNICAL FIELD

[0001] The present disclosure relates to bisphenol and polycarbonate compounds exhibiting a minimized activity with estrogen receptors.

BACKGROUND

[0002] Bisphenol A (BPA), is an organic synthetic compound represented by the chemical formula (CH₃)₂C(C₆H₄0H)₂ and belonging to the group of diphenylmethane derivatives and bisphenols. BPA is a precursor to a number of plastics and epoxy resins. Polycarbonate (PC) is a prominent example of a BPA derived resin. Polycarbonates represent a class of synthetic thermoplastic resins formed from dihydroxy compounds, such as bisphenols, and phosgenes, or carbonate diesters. Melt, aqueous, interfacial, or non-aqueous solution polymerization are several methods of forming a polycarbonate. In general, polycarbonates are a useful class of polymers having many desired properties. They are highly regarded for optical clarity and enhanced impact strength and ductility at room temperature or below. These materials are employed in a variety of fields including industrial applications, such as pipework, as well as consumer goods, such as food packaging and sports equipment, among many others.

SUMMARY

[0003] The polymerization methods used to make polycarbonates may not always proceed to completion, which can result in residual unreacted monomer in the polymeric material. Should the polymeric material be subjected to conditions effective for polymer degradation, one undesirable effect is the release of precursor monomers. It would be beneficial to have bisphenol monomers for polycarbonate formation that exhibit thermal and hydrolytic stability while remaining inactive or non-binding at certain endocrine receptors. This disclosure relates generally to the preparation of bisphenol compositions that are suitable for use in preparing polycarbonate compositions while exhibiting improved stability and little or no biological activity at a particular estrogen receptor.

[0004] In one aspect, the compositions of the present disclosure can be prepared through the coupling of smaller bisphenol units to provide dimer and higher molecular weight oligomers. In further aspects, the compositions of the present disclosure can also be prepared through the condensation of bisphenol with other organic compounds. The resulting prepared bisphenol compositions can be structurally incompatible with the binding site of the endocrine receptor in that the size and shape of the compositions are incompatible with the binding site thereby reducing the likelihood that the bisphenol composition can bind to an estrogen binding site cavity.

[0005] In yet further aspects, the bisphenol compositions of the present disclosure can be hydrostable under biological conditions. As hydrostable compositions, the likelihood of generating degradation products that can fit into the estrogen binding cavity can be reduced.

[0006] Further aspects of the disclosure can also provide polycarbonate compositions comprising the bisphenol compositions disclosed herein. In still further aspects, the prepared bisphenol compositions can be treated to remove residual bisphenol monomers, thereby preventing the release of potential endocrine active bisphenol monomers should the oligomers and resultant polycarbonate compositions be exposed to hydrolytic conditions, or other degrading conditions.

[0007] In another aspect, the present disclosure also provides various articles of manufacture comprising the bisphenol compositions disclosed herein.

[0008] Still further, when the prepared bisphenol composition is subjected to conditions effective to provide one or more degradation products, the compositions can remain

hydrolytically stable and thus do not degrade.

[0009] Additional advantages will be set forth in part in the description which follows. The advantages will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive, as claimed.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0010] The polymerization methods employed to make polycarbonates may not always proceed to completion, which can result in residual unreacted monomer in a final polymeric material. Where the polymeric material is subjected to conditions that can cause polymer degradation, precursor monomers (that is, polycarbonate starting material monomers) can be released. These bisphenol monomers can have a particular size and shape that allows them to be structurally compatible with estrogen receptor sites. In contrast, the bisphenol compositions of the present disclosure are suitable for use in preparing polycarbonate compositions while exhibiting improved stability and little or no biological activity with respect to certain endocrine receptors. [0011] As noted above, disclosed herein are bisphenol compositions that can be expected to be structurally incompatible with certain estrogen receptors and thus can exhibit relatively little or even no endocrine activity. More specifically, the disclosed bisphenol compositions can exhibit no competitive activity at the alpha or beta estrogen receptor. In various aspects, to limit activity at the estrogen receptor, the disclosed compositions can be incompatible with the binding site of the estrogen receptor. Hence, the compositions can be said to have a limited endocrine activity. In certain aspects, the compositions can be said to exhibit non-binding activity for recombinant human estradiol receptors (rhER) alpha (a) and/or beta 1 (βΐ) in vitro. Limited endocrine activity or minimal binding affinity may be characterized by the compositions exhibiting non-bonding activity for the rhERa and rhER βΐ receptors.

[0012] In various aspects, structural incompatibility of the bisphenol compositions with the alpha or beta estrogen receptor can relate to the molecular size and shape of the bisphenol compositions preventing binding with the receptor. For example, the bisphenol compositions of the present disclosure can have a molecular size that is too large or a structure that is too rigid for the estrogen receptor cavity to accommodate. Moreover, these prepared bisphenol compounds can be thermally and hydrolytically stable. The stability of these compositions can enhance their utility in polycarbonate polymerization processes.

[0013] In various aspects, the molecular size and structure of the bisphenol compositions disclosed herein can inhibit binding of the compositions at the alpha or beta estrogen receptor. In one aspect, the bisphenol composition can have a structure unfavorable for binding at an estrogen binding cavity. For example, the bisphenol compositions can be too large in size or too rigid in structure to fit into the estrogen binding site cavity. In other aspects, the estrogen binding site cavity can be too small to accommodate the large or rigid bisphenol structures of the present disclosure. Indeed, to permit binding with the estrogen receptor, a molecule can have a molecular size of less than 450 cubic Angstroms (A³), as 450 A³, or less than about 450 A³ is the probe accessible volume of the alpha and beta estrogen receptor binding cavities. In various aspects of the present disclosure, the bisphenol compositions herein can have a molecular size of greater than 450 A³ or greater than about 450 A³ As a further figurative example, the distance from an end of the molecule to an opposite end of the molecule stretched to full length can render the molecule too large for the estrogen binding cavity.

[0014] As molecular size of the composition can prevent binding at an estrogen binding site, structural conformation likewise can impede binding. It is well known in the art that rigidity can be attributed to structural elements that minimize the number of possible structural

conformations a molecule can assume. Compared to flexibility, rigidity in the molecular structure can relate to the resistance of the molecule to assume another structural form (or conformation) because of limited rotation of atoms about chemical bonds within the structure. Often, a rigid molecule can have a single dominant conformation. In one example, the limitation in the number of structural conformations available to the composition can make it less likely that the composition will assume a conformation compatible with binding at an estrogen receptor. These conformational restrictions coupled with the larger size of the composition can further contribute to the likelihood of limited binding with the estrogen receptor. By means of example, and not intended to be limiting, one skilled in the art might also appreciate that rigidity in the molecular structure can be attributed to the following structural elements: ring systems (both aliphatic and aromatic), double bonds, conjugated systems, and larger atoms or groups.

[0015] In various aspects, the bisphenol compositions disclosed can have a rigid structure. This rigidity in structure can prevent the bisphenol compositions from assuming a structural conformation that allows binding at an estrogen receptor site. The bisphenol compositions can thus be unable to adopt a structural conformation that would fit into the alpha or beta estrogen receptor binding site. Further, even if smaller than 450 A³, a rigid bisphenol composition can be prevented from binding because of its structural constraints. In one aspect, a bisphenol composition can exhibit rigidity owing to the presence of four or more aromatic rings. As a further example, the bisphenol composition can comprise the BP A hydroquinone oligomer, 4,4'- bis(hydroxyphenyl)diphenyl ether comprising four aromatic rings (1).

[0016] The composition 4,4'-bis(hydroxyphenyl)diphenyl ether can be obtained from the reaction of a phenylether and a boronic acid, such as bis(4-bromophenyl)ether and 4- hydroxyphenyl boronic acid. In one example, prepared 4,4'-bis(hydroxyphenyl)diphenyl was found to be a non-binder for both rhERa and rhER up to the limits of the concentrations tested, which was a concentration of 2.5 x 10^"5 molar (M).

[0017] In various aspects of the present disclosure, the bisphenol compositions can be appropriate for preparing polycarbonate materials. Their usefulness as polycarbonate building blocks is further supported by their structural attributes and processing conditions that can enhance both thermal and hydrolytic stability. This stability can provide compositions that are less likely to degrade, whether that degradation is induced by heat or by hydrolysis. Such a resistance to degradation can deter the formation of smaller degradation products that could be suitable for binding with the estrogen receptor.

[0018] In one aspect, the bisphenol compositions can exhibit thermal stability. Thermal stability can relate to the ability of a molecule to resist degradation at an elevated temperature. Upon heating, thermally unstable compositions can breakdown, forming color impurities and degradation bodies. It is noted that certain structural characteristics of a given chemical composition can contribute to the composition's thermal stability. In one aspect, a composition can tend to be less thermally stable where the composition comprises multiple benzylic protons. Benzylic protons are hydrogens on a saturated carbon atom adjacent to an aromatic ring. These protons can be reactive and can tend to make a composition less thermally stable. The enhanced reactivity at the benzylic positions of a given molecule can be attributed to the low bond dissociation energy exhibited at benzylic C-H bonds. In an aspect, the bisphenol compositions disclosed herein can be free or substantially free of benzylic protons. As defined herein, "substantially free of may mean where benzylic protons are not present in the chemical structure of the compositions. In one aspect, benzylic protons are present in an amount of less than about 10 ppm, specifically less than 1 ppm, more specifically less than about 0.1 ppm, more specifically less than or equal to about 0.01 ppm, and more specifically less than or equal to about 0.001 ppm, based on the total weight of all components in the bisphenol compositions.

[0019] In various aspects, the bisphenol compositions can be resistant to biological hydrolysis. That is, the compositions disclosed herein can exhibit hydrolytic stability. As an example, the compositions can comprise hydrolytically stable components that can resist bond scission when subjected to hydrolytic conditions. As one skilled in the art might appreciate, certain chemical bonds can be less susceptible to cleavage, or scission, than others. For example, more hydrophobic groups or structures can be less susceptible to polymer hydrolysis. The same can generally follow for higher molecular weight compositions. It is also appreciated in the art that the ease of hydrolysis can vary among different chemical functional groups based upon molecular and structural factors. Rates of hydrolysis can decrease across the following functional group scheme: anhydrides > esters > amides > ethers. For instance, a carbonate bond or ester bond can be more likely to be cleaved in a hydrolysis reaction than the more stable aromatic ether bond. Carbon-carbon double bonds can also be more resilient facing hydrolytic cleavage.

[0020] In a further aspect, the bisphenol compositions of the present disclosure can comprise fewer hydrolysable linkages. In view of the foregoing, hydrolysable linkages can refer to bonds that are likely to be cleaved in a hydrolysis reaction. It follows that the bisphenol compositions can feature fewer carbonate groups and comprise more aromatic ether and carbon-carbon double bond groups. The hydrostability of the disclosed bisphenol compositions can allow the compositions to be stable, or intact, under biological conditions. The hydrostability of the bisphenol compositions disclosed herein can reduce the likelihood of the generation of a potential endocrine active degradation product. When subjected to certain conditions, large bisphenol A polymers, such as polycarbonates, can undergo hydrolytic degradation to yield hydrolysis degradants or reaction products. The resulting degradants commonly correspond to the monomeric starting materials initially used to manufacture the polycarbonate. These degradants can potentially be smaller products that would themselves be biologically active. The hydrolytically stable compositions of the present disclosure can retain their larger size and/or rigidity in structure thereby preventing the compositions from binding at estrogen receptor binding sites. To provide hydrolytic and thermal stability, the bisphenol compositions can thus be free or substantially free of hydroly sable linkages and free of benzylic protons.

Alternatively, the compositions disclosed herein can have linkages that are less susceptible to hydrolysis and the compositions can have benzylic protons that are only present as an impurity in the composition.

[0021] In various aspects, the bisphenol compositions of the present disclosure can be prepared under conditions that provide improved stability. These compositions can be prepared in a number of ways. In an aspect, smaller bisphenol compositions can be coupled together under appropriate reaction conditions to provide dimers or other higher molecular weight oligomers. The coupling can provide compositions that can be both hydrolytically and thermally stable, thereby facilitating optimal performance of the bisphenol compositions as polycarbonate precursors.

[0022] In one aspect, the disclosed bisphenol compositions can be condensed with other organic compounds to provide larger bisphenol compositions. These larger compositions can include bisphenol oligomers. As an example, to provide the endocrine-inactive larger bisphenol compositions, smaller bisphenols can be coupled into dimers or higher molecular weight oligomers. The coupling can provide compositions that can be both hydrolytically and thermally stable, thereby facilitating optimal performance of the bisphenol compositions. In a further example, the coupling can result in a product free of benzylic protons which can reduce thermal stability during melt polymer processing of an ultimate polycarbonate product.

[0023] In various aspects, isolation of the prepared bisphenol composition as well as an additional purification step can be performed to provide the non-binding properties disclosed herein. For example, the condensation of BP A and other organic compounds to form larger bisphenol compositions (that is, compositions having a molecular size greater than 450 A³) can be accompanied by the presence of residual free BPA. Typically, when used to prepare a polycarbonate, this residual free BPA could be incorporated into the polymer backbone. Then, should the polymer be subjected to hydrolysis, the residual BPA could be released. The small size of the residual BPA could allow the molecule to bind at the estrogen endocrine receptor. Accordingly, the bisphenol compositions disclosed herein can be isolated and additionally purified to extract residual BPA prior to polymerization of the bisphenol composition.

[0024] In a further example, coupled bisphenol oligomer can be obtained from a condensation of bisphenol and dichlorodiphenylsulfone. The bisphenol and dichlorodiphenylsulfone condensation can provide an oligomeric product that can then be isolated and purified to remove any residual BPA. The isolated product can then be polymerized to yield an endocrine incompatible BPA sulfone polycarbonate. For example, the prepared bisphenol

dichlorodiphenyl sulfone oligomer can have a molecular size greater than 450 A³ as well as more than four aromatic ring systems (3).

For the smallest oligomer, where n is 1 , the bisphenol composition can be non-binding with the alpha or beta estrogen receptor. The bisphenol composition can be polymerized and then purified to remove residual BPA to less than 1000 ppm, or less than about 1000 ppm providing a poly ether carbonate with a Tg of 177 °C, or about 177 °C.

[0025] In one example, a purified BPA sulfone oligomer at a degree of polymerization of n is 1 exhibits non-binding for both rhERa and rhER{$ up to the limits of the concentrations tested, which was a concentration of 2.5 x 10^"6 M.

[0026] In various aspects of the present disclosure, the size of the bisphenol composition suitable for preparing a polycarbonate polymer can be limited. In many aspects, the bisphenol composition can be an oligomer. The size of the oligomer can limited according to the number of repeating monomer units therein. In one example, n can be less than 15, or less than about 15. In other examples, n can be less than 7, or less than about 7. The size can also be limited according to the molecular weight of the bisphenol oligomer composition. For example, the bisphenol composition can have a molecular weight of less than 4000 grams, or less than about 4000 grams per mole (g/mol) [0027] In other aspects, the disclosed bisphenol compositions can be derived from phenolic monomers. These phenolic monomers can comprise dihydric phenols, mono phenols, bisphenols, phenolic blocks, or a combination thereof. Specific examples of the disclosed phenolic compounds can include, without limitation, resorcinol, hydroquinone, methyl hydroquinone, t-butyl hydroquinone, di-t-butyl hydroquinones (DTBHQ), biphenols, tetramethyl bisphenol-A, spiro biindane bisphenols (SBIBP), bis-(hydroxy aryl)-N-aryl isoindolinones, hydroxy benzoic acids, or any combination thereof. As a further example, the phenolic components comprise phenolic blocks. The phenolic blocks can be linked via ether or carbonate bonds, and derived from hydroxyl or halogenated starting materials, comprising: hydroquinone; resorcinol or catechol; biphenol; [l,l':4',l"-terphenyl]-4,4"-diol; l,l':3',l"-terphenyl, 4,4"-diol; 2,2-bis(4-hydroxyphenyl)propane; l,l-bis(3-methyl-4-hydroxyphenyl)cyclohexane; 4,4'-(l- methylethylidene)bis[2,6-dimethyl-phenol; 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine; 4, 4'-(l-phenylethylidene)bisphenol; spiro biindane bisphenols; l,l'-sulfonylbis[4- hydroxybenzene]; 1,3-cyclobutanediol, 2,2,4,4-tetramethyl-; isosorbide, 1,4- cyclohexanedimethanol, l,4-bis(l-(4-hydroxyphenyl)-l-methylethyl)benzene; 4,4'-[l,3- phenylenebis(l-methylethylidene)]bisphenol; 4-hydroxyphenyl boronic acid; 4,4'-dihydroxy- 3,3'-dimethoxydiphenylmethane, hydrogenated and or substituted forms thereof.

[0028] It should be understood that, in view of this disclosure, any bisphenol compositions can be used that exhibit a lack of estrogen binding activity characterized by a molecular size of less than 450 A³, a rigid molecular structure, and hydrolytic and thermal stability in that it is free of hydrolysable linkages and benzylic protons.

[0029] In some aspects, a phenolic monomer can be used to prepare the polycarbonate starting material and endocrine incompatible compositions of the present disclosure. In one example, biphenol and a dichlorodiphenyl sulfone can be combined. The prepared composition can have a molecular siz

[0030] The composition can be treated to remove residual biphenol to less than 1000 ppm, or less than about 1000 ppm, and then polymerized to provide a polycarbonate having a Tg of about 194 °C. [0031] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0032] Various aspects relate to the preparation of polycarbonate compositions comprising the bisphenol compositions disclosed herein. As used herein, the term "polycarbonate" can include homopoly carbonates and copoly carbonates have repeating structural carbonate units. In one aspect, a polycarbonate can comprise any polycarbonate material or mixture of materials, for example, as recited in U. S. Patent No. 7,786,246, which is hereby incorporated in its entirety for the specific purpose of disclosing various polycarbonate compositions and methods.

[0033] In an aspect, a polycarbonate can be prepared from the bisphenol compositions of the present disclosure. In one example, a polycarbonate, as disclosed herein, can be an aliphatic-diol based polycarbonate. In another aspect, a polycarbonate can comprise a carbonate unit derived from a dihydroxy compound, such as for example a bisphenol composition that differs from the aliphatic diol. Suitable bisphenol compounds can include the bisphenol compositions disclosed herein that exhibit structural incompatibility at the alpha or beta estrogen receptors.

[0034] In one aspect, the polycarbonates herein can be prepared using an interfacial phase transfer process or melt polymerization. Although the reaction conditions for interfacial polymerization can vary, an exemplary process can generally involve dissolving or dispersing a dihydric phenol reactant in aqueous caustic soda or potash, adding the resulting mixture to a water-immiscible solvent medium such as for example methylene chloride, and contacting the reactants with a carbonate precursor (such as phosgene) in the presence of a catalyst such as, for example, triethylamine or a phase transfer catalyst salt, under controlled pH conditions of, for example, from about 8 to about 10.

[0035] The polycarbonate compounds and polymers disclosed herein can also, in various aspects, be prepared by a melt polymerization process. Generally, in the melt polymerization process, polycarbonates are prepared by co-reacting, in a molten state, the dihydroxy reactant(s) (i.e., isosorbide, aliphatic diol and/or aliphatic diacid, and any additional dihydroxy compound) and a diaryl carbonate ester, such as diphenyl carbonate, or more specifically in an aspect, an activated carbonate such as bis(methyl salicyl)carbonate, in the presence of a transesterification catalyst. In one aspect, volatile monohydric phenol can be removed from the molten reactants by distillation and the polymer is isolated as a molten residue. The melt polymerization can include a transesterification catalyst comprising a first catalyst, also referred to herein as an alpha catalyst. Exemplary transesterification catalysts can include, but are not limited to, lithium hydroxide, sodium hydroxide, sodium formate, potassium formate, sodium acetate, lithium carbonate, sodium carbonate, lithium methoxide, sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, sodium phenoxide, potassium phenoxide, potassium sulfate, or a combination comprising at least one of the foregoing. In another aspect, a second transesterification catalyst, also referred to herein as a beta catalyst, can optionally be included in the melt polymerization process, provided that the inclusion of such a second transesterification catalyst does not significantly adversely affect the desirable properties of the polycarbonate.

ASPECTS

[0036] The disclosed compositions and methods include at least the following aspects.

[0037] Aspect 1. A method comprising: forming a phenolic component from a monomer or oligomer that is structurally incompatible with one or more of an alpha and beta estrogen receptor, wherein the phenolic component exhibits minimized binding activity at an alpha or beta estrogen receptor and the phenolic component is hydrolytically and thermally stable; and forming a polycarbonate composition from the phenolic component.

[0038] Aspect 2. The method of aspect 1 , wherein the phenolic component is free of or substantially free of hydroly sable linkages.

[0039] Aspect 3. The method of any of aspects 1 -2, wherein the phenolic component is free of or substantially free of benzylic protons.

[0040] Aspect 4. The method of any of aspects 1 -3 further comprising forming an article from the polycarbonate.

[0041] Aspect 5. The method of any of aspects 1 -4, wherein the polycarbonate composition comprises

wherein n is an integer greater than or equal to 1 and less than or equal to fifteen.

[0042] Aspect 5. A composition comprising: a polycarbonate component derived from a phenolic component; wherein the phenolic component is structurally incompatible with one or more of an alpha and beta estrogen receptor; and wherein the phenolic component exhibits hydrolytic stability; and wherein the phenolic component exhibits thermal stability.

[0043] Aspect 6. A composition formed from a phenolic component structurally incompatible with one or more of an alpha and beta estrogen receptor; wherein the phenolic component is capable of being polymerized to form a polycarbonate; wherein the phenolic component exhibits hydrolytic stability.

[0044] Aspect 7. The composition of aspect 5 or 6, wherein the phenolic component comprises a monomer.

[0045] Aspect 8. The composition of aspect 5 or 6, wherein the phenolic component comprises an oligomer.

[0046] Aspect 9. The composition of any of aspects 5-8, wherein the phenolic components form repeating units, the number of repeating units is less than fifteen and the repeating units have a molecular weight of less than 4,000 grams per mole.

[0047] Aspect 10. The composition of any of aspects 5-9, wherein when the composition is subjected to degradation conditions and the composition releases components as a result of degradation, the components released are less likely to bind with the alpha and beta estrogen receptor or are structurally incompatible with the alpha and beta estrogen receptor.

[0048] Aspect 1 1. The composition of any of aspects 5-10, wherein the phenolic component has a molecular size of greater than 450 A³. [0049] Aspect 12. The composition of any of aspects 5-11, wherein the composition has a rigid molecular structure.

[0050] Aspect 13. The composition of any of aspects 5-12, wherein the composition has at least four ring systems.

[0051] Aspect 14. The composition of any of aspects 5-13, wherein the phenolic component comprises a bisphenolic compound.

[0052] Aspect 15. The composition of any of aspects 5-14, wherein the composition is free of or substantially free of hydroly sable linkages.

[0053] Aspect 16. The composition of any of aspects 5-15, wherein the composition exhibits thermal stability.

[0054] Aspect 17. The composition of any of aspects 5-16, wherein the composition is free of or substantially free of benzylic protons.

[0055] Aspect 18. The compositions of any of aspects 5-17, wherein the phenolic components comprise phenolic blocks, the phenolic blocks linked via ether or carbonate bonds, and derived from hydroxyl or halogenated starting materials, comprising: hydroquinone; resorcinol or catechol; biphenol; [l,r:4',l"-terphenyl]-4,4"-diol; l,r:3',l"-terphenyl, 4,4"-diol; 2,2-bis(4- hydroxyphenyl)propane; l,l-bis(3-methyl-4-hydroxyphenyl)cyclohexane; 4,4'-(l- methylethylidene)bis[2,6-dimethyl-phenol; 2-phenyl-3,3-bis(4-hydroxyphenyl)phthalimidine; 4, 4'-(l-phenylethylidene)bisphenol; spiro biindane bisphenols; l,l'-sulfonylbis[4- hydroxybenzene]; 1,3-cyclobutanediol, 2,2,4,4-tetramethyl-; isosorbide, 1,4- cyclohexanedimethanol, l,4-bis(l-(4-hydroxyphenyl)-l-methylethyl)benzene; 4,4'-[l,3- phenylenebis(l-methylethylidene)]bisphenol; 4,4'-dihydroxy-3,3'-dimethoxydiphenylmethane, hydrogenated and or substituted forms thereof.

[0056] Aspect 19. The composition of any of aspects 5-18, further comprising one or more additives and wherein each of the one or more additives does not exhibit estrogenic activity at alpha or beta in vitro estrogen receptors.

[0057] Aspect 20. The composition of aspect 19, the one or more additives

comprising a stabilizer, antioxidant, colorant, impact modifier, flame retardant, branching agent, cross linking agent, hardeners, curing agents, UV screening additive, anti-drip additive, mold release additive, lubricant, plasticizer, filler, mineral, reinforcement additive, or any combination thereof.

[0058] Aspect 21. An article formed from the composition of any of aspects 5-20.

EXAMPLES [0059] Detailed embodiments of the present disclosure are disclosed herein; it is to be understood that the disclosed embodiments are merely exemplary of the disclosure that may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limits, but merely as a basis for teaching one skilled in the art to employ the present disclosure. The specific examples below will enable the disclosure to be better understood. However, they are given merely by way of guidance and do not imply any limitation.

Preparation of 4,4 '-bis(hydroxyphenyl)diphenyl ether

[0060] To a mixture of bis(4-bromophenyl)ether (7.00 grams (g), 21.34 millimol (mmol)), 4- hydroxyphenylboronic acid (8.57 g, 62.13 mmol), sodium bicarbonate (NaHCC^ 13.48 g,160.46 mmol), 1,4-dioxane (200 milliliters (ml)) and water (100 ml) was added

tetrakis(triphenylphosphine)palladium(0) (Pd(PPl¾)4, 987 mg, 0.85 mmol) under nitrogen N2 atmosphere in a 500 ml three neck round bottom flask with condenser and magnetic stirring. The reaction mixture was heated at 90 °C overnight under N2-flow using an oil heating bath. Thin layer chromatography (hexane: ethyl acetate at a 1 : 1 ratio) showed full conversion to the desired product (Rf = 0.53, UV). The reaction mixture was allowed to reach room temperature by removing the oil heating bath and then poured into a mixture of water (500 ml) and

dichloromethane (500 ml). After vigorous stirring for 15 minutes, the mixture was filtered. The residue was washed with water (2 x 200 ml), followed by dichloromethane (2 x 200 ml) to give 8.21 g crude product as a dark brown solid. The crude product was refluxed at 80°C in ethyl acetate (500 ml) overnight and filtered while still hot. The procedure was repeated with the residue. This time 350 ml ethyl acetate was used. The filtrates were combined and concentrated to give the title compound as an off-white solid (6.03 g, 80%). Proton nuclear magnetic resonance (1H-NMR, 400 MHz, deuterated dimethyl sulfoxide, DMSO-d6): δ 9.42 (broad s, 2H, OH), 7.59 (d, J = 8.6 Hz, 4H, Ar-H), 7.46 (d, J = 8.6 Hz, 4H, Ar-H), 7.08 (d, J = 8.6 Hz, 4H, Ar- H), 6.86 (d, J = 8.6 Hz, 4H, Ar-H); LC-MS: m/z 353.1, [M-H]^", 355.1 [M+H]⁺.

Preparation of BP A hydroquinone oligomer (n = 1)

[0061] Oligomers were prepared using a modification of the method of Laskoski et al, as described in Example 1 of US Patent No. 7,723,420. To a 250 ml three-necked flask equipped with thermocouple, Dean- Stark trap, magnetic stirring, and nitrogen pad was charged dimethylsulfoxide (50 ml), BP A (10 g, 0.044 mol), and KOH (4 g, 0.071 mol). The slurry was heated to 100 °C with stirring as the solids disappeared. Toluene (60 ml) was then added and the solution was heated to reflux. Water was removed via azeotropic distillation using the Dean- Stark trap and then the toluene was distilled off by heating the reactor to 145 °C. 1,4- Dibromobenzene (8.6 g, 0.036 mol) and copper (I) iodide (0.6 g) were then added and the reaction held at 145 °C overnight. The product mix was cooled and added to 400 ml water. Acetic acid was added until the pH of the aqueous layer was slightly acidic (greater than pH 7). The water was decanted, leaving the product as a gummy black layer. Methylene chloride (400 ml) was added to dissolve the product layer. This solution was then extracted again with 400 ml fresh water to remove residual DMSO. The methylene chloride was then removed under vacuum atmosphere to leave the oligomeric product.

Polycarbonate of purified BP A hydroquinone

[0062] Crude oligomers from above were purified by column chromatography (CI 8 silica packing using an isocratic 75 wt. % / 25 wt. % acetonitrile /water eluent) to give the n=l oligomer as a white solid. The melt range was 150 °C to 152 °C. 1H NMR (d₆-DMSO): δ 1.56 ppm (6H, s), 6.66 ppm (2H, d, J = 8.56 Hz), 6.85 ppm (2H, d, 8.78 Hz), 6.98 ppm (4H, s), 7.00 ppm (2H, d, J = 8.57 Hz), 7.16 ppm (2H, d, J = 8.79 Hz), 9.17 ppm, (2H, s).

Preparation of BP A sulfones oligomers

[0063] To a 2 liter (L) Morton flask equipped with mechanical stirrer, condenser, subsurface gas inlet, and pH controller was charged methylene chloride (75 ml), deionized water (725 ml), and purified BPA hydroquinone oligomer (n=l) (Sg, 0.0094 moles), Phosgene (Sg, 0.051 moles) was added subsurface at a rate of 1 g/min with vigorous stirring while a solution of 33 wt. % sodium hydroxide (NaOH) in water was added at a rate to maintain the reaction mixture at pH=7-8. Any vapors that passed the condenser were scrubbed and neutralized with caustic to prevent any release of phosgene. After the phosgene addition was complete, the reaction mix was purged with nitrogen for 10 minutes until no residual phosgene could be detected. Triethylamine (0.06 ml) was added and the mixture was stirred for 10 minutes while a solution of 33 wt. % NaOH in water was added at a rate to maintain the reaction mixture at pH=9-10. Additional phosgene (3 g, 0.03 moles) was added subsurface at a rate of 1 g/min with vigorous stirring while a solution of 33 wt. % NaOH in water was added at a rate to maintain the reaction mixture at pH=9-10. After the phosgene addition was complete, the reaction mix was purged with nitrogen for 10 minutes until no residual phosgene could be detected. Stirring was stopped and the reaction mix allowed to phase separate. Additional methylene chloride (50 ml) was added. The methylene chloride layer was removed, washed with normal hydrochloric acid (IN HCl) (500 ml) and then with deionized water (3 times 500 ml) until the washings were greater than pH 5. The clean polymer solution was then precipitated into hot water and air dried at 60 °C for 18 hours. The polymer showed no detectable free BPA (detection limit of 5 ppm) and gave Tg of 143 °C by differential scanning calorimetry (DSC). Gas permeation chromatography (GPC) showed a weight average molecular weight (Mw) of 77,078 Daltons and a number average molecular weight (Mn) of 5,952 Daltons measured against a polycarbonate standard.

Preparation of BPA sulfones polycarbonate

[0064] To a 2L Morton flask equipped with mechanical stirrer, condenser, subsurface gas inlet, and pH controller was charged methylene chloride (500 ml), deionized water (300 ml), BPA sulfone oligomer (25 g), and phenol (0.09 g, 0.001 moles). Phosgene (10 g, 0.101 moles) was added subsurface at a rate of 1 g/min with vigorous stirring while a solution of 33 wt. % NaOH in water was added at a rate to maintain the reaction mixture at pH of 6-7. Any vapors that passed the condenser were scrubbed and neutralized with caustic to prevent any release of phosgene. After the phosgene addition was complete, additional 33 wt.% NaOH in water was added to increase the reactor to pH 9. The reaction mix was purged with nitrogen for 10 minutes until no residual phosgene could be detected. Triethylamine (0.2 ml) was charged and then 33 wt. % NaOH in water was added as necessary to maintain pH 9-10. Additional phosgene (3 g, 0.0303 mol) was then added while a solution of 33 wt.% NaOH in water was added at a rate to maintain the reaction mixture at pH=6.9-10. After purging to remove residual phosgene, stirring was stopped and the reaction mix allowed to phase separate. The methylene chloride layer was removed, washed with IN HC1 (500 ml) and then with DI water (3 x 500 ml) until the washings were greater than pH 5. The clean polymer solution was then precipitated into hot water and air dried at 60 °C for 18 hours. DSC on the dried powder gave Tg 177.2 °C. Ultra performance liquid chromatography (UPLC) analysis of the polymer showed no detectable free BPA (test detection limit of 5 ppm). GPC indicated a Mw of 29,340 Daltons and a Mn of 11,037 Daltons measured against polycarbonate standard. Similar methods were used to prepare 4,4' -bisphenol sulfone oligomers, purify to remove residual bisphenol, and then convert these to bisphenol sulfone polycarbonates. The resulting bisphenol sulfone polycarbonates gave Tg 194 °C and a Mw of 23,274 Daltons and a Mn of 10,827 Daltons measured against a polycarbonate standard.

Biological Testing [0065] Estradiol binding activity of various compounds and potential polymer hydrolysis or thermolysis products were tested using a conventional in vitro competitive binding assay, and quantified by the half maximal inhibitory concentration (IC₅₀) value. The (IC₅₀) binding concentrations for the alpha (a) and/or beta 1 (βΐ) in vitro estradiol receptors were tested. Tests were conducted by displacement of radiolabeled 17b-estradiol.

[0066] The compound to be evaluated, for example 4,4'-bis(hydroxyphenyl)diphenyl ether, was tested as to its binding affinity for recombinant human estradiol receptors (rhER) alpha (a) and/or beta 1 (βΐ) in vitro. 17 -estradiol (E2) was used a standard whose relative binding affinity was defined as 100%. Competitive binding assays were performed by incubating rhER alpha (a) and/or beta 1 (βΐ) with 10 nM [3H] estradiol (the radio ligand) in the presence or absence of increasing concentrations, 0.25 to 250,000 nM, of the sample compound (nM is nano molar). Each data point is the average of at least two assays. Compounds were diluted 10 fold in binding buffer and then 1 :4 in the final assay mix. The final concentration of ethanol or

dimethylsulfoxide in the assay was 5%. Samples of 4,4'bis(hydroxyphenyl)diphenyl ether and the BP A sulfone oligomer (at a degree of polymerization of n=l) were found to be non-binders for both rhERa and rhER up to the limits of the concentrations tested which was 2.5 x 10^"5 M and 2.5 x 10^"6 M, respectively. The IC50 is the concentration of test compound at which about 50% of the radio labeled estradiol was displaced from the estradiol receptor.

DEFINITIONS

[0067] Ranges can be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as "about" that particular value in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0068] It is to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. As used in the specification and in the claims, the term "comprising" can include the embodiments "consisting of and "consisting essentially of." Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined herein.

[0069] As used herein, the terms "number average molecular weight" or "Mn" can be used interchangeably, and refer to the statistical average molecular weight of all the polymer chains in the sample and is defined by the formula:

where M; is the molecular weight of a chain and N; is the number of chains of that molecular weight. Mn can be determined for polymers, such as polycarbonate polymers or polycarbonate- PMMA copolymers, by methods well known to a person having ordinary skill in the art.

[0070] As used herein, the terms "weight average molecular weight" or "Mw" can be used interchangeably, and are defined by the formula:

where M; is the molecular weight of a chain and N; is the number of chains of that molecular weight. Compared to Mn, Mw takes into account the molecular weight of a given chain in determining contributions to the molecular weight average. Thus, the greater the molecular weight of a given chain, the more the chain contributes to the Mw. Mw can be determined for polymers, such as polycarbonate polymers, by methods well known to a person having ordinary skill in the art.

[0071] Compounds are described using standard nomenclature. For example, any position not substituted by any indicated group is understood to have its valency filled by a bond as indicated, or a hydrogen atom. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, the aldehyde group --CHO is attached through the carbon of the carbonyl group.

[0072] The term "aliphatic" refers to anarray of atoms that may be linear, branched, or cyclic or a combination thereof and has a valence of at least one. Aliphatic groups are defined to comprise at least one carbon atom. The array of atoms may include heteroatoms such as nitrogen, sulfur, silicon, selenium and oxygen or may be composed exclusively of carbon and hydrogen ("Alkyl"). Aliphatic groups may be substituted or unsubstituted. Exemplary aliphatic groups include, but are not limited to, methyl, ethyl, isopropyl, isobutyl, chloromethyl, hydroxymethyl (~CH₂OH), mercaptomethyl (~CH₂SH), methoxy, methoxycarbonyl (CH₃OCO- -), nitromethyl (--CH2NO2), and thiocarbonyl.

[0073] The term "alkyl group" as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. A "lower alkyl" group is an alkyl group containing from one to six carbon atoms.

[0074] The term "ring system" can be any saturated or unsaturated carbon based cyclic structure or compound. A ring system can be heterocyclic, wherein the ring atoms comprise more than one element, or homocyclic, wherein the ring atoms comprise a single element. A ring system can also refer to an aromatic ring.

[0075] The term "aromatic ring" as used herein can refer to an"aryl group" and can be any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc. The term "aromatic" also includes "heteroaryl group," which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms can include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy.

[0076] The term "carbonate group" or "carbonate" as used herein is represented by the formula -OC(0)OR, where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.

[0077] The term "carbonyl group" as used herein is represented by the formula C=0.

[0078] As used herein, "endocrine activity," or its derivatives such as endocrine active, can refer to the ability of a composition to bind at an estrogen receptor in a biological system.

Specially, endocrine activity can refer to the ability to bind at the alpha or beta estrogen receptor.

[0079] The term "ester" as used herein is represented by the formula— C(0)OA, where A can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

[0080] The term "ether" as used herein is represented by the formula AOA¹, where A and A¹ can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

[0081] As used herein, the term "hydrostability," and its derivatives such as "hydrostable," refers to the degree to which a given composition can resist hydrolysis. [0082] As used herein, the term "polycarbonate" includes homopolycarbonates and copoly carbonates have repeating structural carbonate units. In one aspect, a polycarbonate can comprise any polycarbonate material or mixture of materials, for example, as recited in U.S. Patent No. 7,786,246, which is hereby incorporated in its entirety for the specific purpose of disclosing various polycarbonate compositions and methods.

[0083] As defined herein, "substantially free of can mean that a given component is present in an amount of less than about 10 ppm, specifically less than 1 ppm, more specifically less than about 0.1 ppm, more specifically less than or equal to about 0.01 ppm, and more specifically less than or equal to about 0.001 ppm, based on the total weight of all components.

As used herein, "hydrolysis," or "hydrolytic cleavage," can refer to a chemical transformation wherein a covalent bond is cleaved due to the reaction with water.

[0084] Various combinations of elements of this disclosure are encompassed by this disclosure, e.g. combinations of elements from dependent claims that depend upon the same independent claim.

[0085] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH₂CH₂0- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more -CO(CH2)gCO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

Claims

CLAIMS What is Claimed:

1. A method comprising:

forming a phenolic component from a monomer or oligomer having a size of greater than 450 A³, or having a size of less than 450 A³ and having structural rigidities, wherein the phenolic component is structurally incompatible with one or more of an alpha and beta estrogen receptor and wherein the phenolic component exhibits minimized binding activity at an alpha or beta estrogen receptor and the phenolic component is hydrolytically and thermally stable; and

forming a polycarbonate composition from the phenolic component.

2. The method of claim 1 , wherein the phenolic component is free of or substantially free of hydrolysable linkages.

3. The method of any of claims 1 -2, wherein the phenolic component is free of or

substantially free of benzylic protons.

4. The method of any of claims 1 -3 further comprising forming an article from the

polycarbonate.

5. The method of any of claims 1 -4, wherein the structural rigidities comprises four or more ring systems present within the phenolic structure.

6. The method of any of claims 1 -4, wherein the polycarbonate composition comprises

7. A composition comprising: a polycarbonate component derived from a phenolic component having a size of greater than 450 A³, or having a size of less than 450 A³ and having structural rigidities;

wherein the phenolic component is structurally incompatible with one or more of an alpha and beta estrogen receptor; and

wherein the phenolic component exhibits hydrolytic stability; and

wherein the phenolic component exhibits thermal stability.

8. A composition formed from

a phenolic component having a size of greater than 450 A³, or having a size of less than 450 A³ and having structural rigidities, wherein the phenolic component is structurally incompatible with one or more of an alpha and beta estrogen receptor; wherein the phenolic component is capable of being polymerized to form a

polycarbonate;

wherein the phenolic component exhibits hydrolytic stability.

9. The composition of claim 7 or 8, wherein the phenolic component comprises a monomer.

10. The composition of 7 or 8, wherein the phenolic component comprises an oligomer.

11. The composition of any of claims 7-8, wherein the phenolic components form repeating units, the number of repeating units is less than fifteen and the repeating units have a molecular weight of less than 4,000 grams per mole.

12. The composition of any of claims 7-9, wherein when the composition is subjected to degradation conditions and the composition releases components as a result of degradation, the components released are less likely to bind with the alpha and beta estrogen receptor or are structurally incompatible with the alpha and beta estrogen receptor.

13. The composition of any of claims 7-10, wherein the structural rigidities comprises four or more ring systems present in the phenolic component .

14. The composition of any of claims 7-13, wherein the phenolic component comprises a bisphenolic compound.

15. The composition of any of claims 7-14, wherein the composition is free of or

substantially free of hydrolysable linkages.

16. The composition of any of claims 7-15, wherein the composition exhibits thermal

stability.

17. The composition of any of claims 7-16, wherein the composition is free of or

substantially free of benzylic protons.

18. The compositions of any of claims 7-17, wherein the phenolic components comprise phenolic blocks, the phenolic blocks linked via ether or carbonate bonds, and derived from hydroxyl or halogenated starting materials, comprising: hydroquinone; resorcinol or catechol; biphenol; [l,r:4', l "-terphenyl]-4,4"-diol; l,r:3', l "-terphenyl, 4,4"-diol; 2,2- bis(4-hydroxyphenyl)propane; l , l-bis(3-methyl-4-hydroxyphenyl)cyclohexane; 4,4'-(l - methylethylidene)bis[2,6-dimethyl-phenol; 2-phenyl-3,3-bis(4- hydroxyphenyl)phthalimidine; 4,4'-(l -phenylethylidene)bisphenol; spiro biindane bisphenols; l, l'-sulfonylbis[4-hydroxybenzene] ; 1,3-cyclobutanediol, 2,2,4,4- tetramethyl-; isosorbide, 1 ,4-cyclohexanedimethanol, l ,4-bis(l -(4-hydroxyphenyl)-l- methylethyl)benzene; 4,4'-[l,3-phenylenebis(l -methylethylidene)]bisphenol; 4,4'- dihydroxy-3,3'-dimethoxydiphenylmethane, hydrogenated and or substituted forms thereof.

19. The composition of any of claims 7-18, further comprising one or more additives and wherein each of the one or more additives does not exhibit estrogenic activity at alpha or beta in vitro estrogen receptors, the one or more additives comprising a stabilizer, antioxidant, colorant, impact modifier, flame retardant, branching agent, cross linking agent, hardeners, curing agents, UV screening additive, anti-drip additive, mold release additive, lubricant, plasticizer, filler, mineral, reinforcement additive, or any combination thereof.

20. An article formed from the composition of any of claims 7-19.