WO2003046054A2

WO2003046054A2 - Copolymer libraries and production and use thereof

Info

Publication number: WO2003046054A2
Application number: PCT/US2002/038173
Authority: WO
Inventors: Alexander K. Andrianov
Original assignee: Parallel Solutions, Inc.
Priority date: 2001-11-29
Filing date: 2002-11-26
Publication date: 2003-06-05
Also published as: AU2002365414A1; WO2003046054A3

Abstract

Combinatorial libraries and methods of making and using same are disclosed, wherein each combinatorial library includes at least three different sublibraries, wherein a sublibrary includes a mixture of copolymers that have the same polymer backbone and at least two different pendant groups on the polymer backbone. In each of the sublibraries, copolymers differ from each other with respect to the relative amounts of the pendant groups present on the polymer backbone. Each of the at least three sublibraries differs from another sublibrary by the copolymers contained therein having at least one pendant group that is different from the pendant groups of the other sublibraries.

Description

COPOLYMER LIBRARIES AND PRODUCTION AND USE THEREOF

This application claims the benefit of U.S. Provisional Application No. 60/334,267 filed November 29, 2001.

This invention relates to copolymer libraries and the production and use thereof. In a preferred embodiment, the invention relates to polyphosphazene copolymer libraries and the production and use thereof.

Copolymers produced from a variety of monomers are generally known in the art. There is a need in the art, however, to provide for improved procedures for producing and analyzing said copolymers for desired properties.

In accordance with one aspect of the present invention there is provided a combinatorial library that includes at least three different sublibraries wherein a sublibrary includes a mixture of copolymers that have the same polymer backbone and at least two different pendant groups on the polymer backbone. In each of the sublibraries, copolymers differ from each other with respect to the relative amounts of the pendant groups present on the polymer backbone. Each of the at least three sublibraries differs from another sublibrary by the copolymers contained therein having at least one pendant group that is different from the pendant groups of the other sublibraries.

In a preferred embodiment, the polymer backbone is a polyphosphazene or a polysiloxane or a polysilane with a polyphosphazene being particularly preferred.

As hereinabove described, the copolymer library contains at least three different sublibraries, with the sublibraries differing from each other by at least one of the pendant groups that is on the polymer backbone. It is to be understood that the combinatorial library may be comprised of more than three sublibraries such as, for example, six or more different sublibraries, ten or more different sublibraries, or fifteen or more different sublibraries, etc. In a sublibrary, each of the copolymers contained therein has the same polymer backbone and each of the copolymers contains at least two different pendant groups (in some cases, three different pendant groups and, in other cases, there may be four or five or six or seven or more different pendant groups), with copolymers in the sublibraries differing from each other by the relative amounts of the pendant groups contained on the polymer backbone.

Thus, for example, in a sublibrary wherein the polymer backbone is substituted with both pendant group A and pendant group B, copolymers in the sublibrary will differ from each other by the relative amounts of groups A and B on the polymer backbone. For example, in such a copolymer mixture, one copolymer may comprise 1% of group A and 99% of group B based on the total pendant groups on the polymer backbone, whereas another copolymer may contain 10% of group A and 90 % of group B, based on the total amount of groups A and B on the polymer backbone. Thus, although the copolymer mixture in each sublibrary contains the same polymer backbone and the same pendant groups, copolymers differ from each other by the relative amounts of the pendant groups on the polymer backbone.

In a preferred embodiment, each sublibrary would include a variety of different copolymers so as to be representative of relative amounts of pendant groups over a desired range of possible pendant group ratios. Thus, for example, if there are two different pendant groups on the polymer backbone, the number of different copolymers in a sublibrary would, for example, be representative of amounts of group A from 1-99% and of group B from 99-1% based on the two pendant groups. The number of copolymers that are representative of such range may vary depending on the use for the library. For example, over such range there may be 99 different copolymers or there may be 50 different copolymers spread out over the range or there may be more or less than 50 or 99 different copolymers. The selection of an appropriate number of copolymers within a sublibrary will be determined by those skilled in the art from the teachings herein.

As hereinabove indicated, each of the sublibraries within a copolymer combinatorial library will have the same polymer backbone, but the copolymers in a sublibrary will differ from the copolymers of other sublibraries by at least one of the pendant groups. Thus, if a first sublibrary includes groups A and B, a second library would include groups that are neither A nor B or groups that include only one of A and B or groups A and B and at least one other group.

Each of the sublibraries may be prepared by the use of a polymer precursor that includes a polymer backbone with a reactable pendant group. Such polymer precursor is then reacted with at least two different reactants that react with the pendant group of the polymer precursor to produce a polymer backbone with two different pendant groups that correspond to the two different reactants. In this manner, there is prepared a copolymer comprising a polymer backbone that corresponds to the backbone of the polymer precursor, with two different pendant groups that correspond to the two different reactants.

In accordance with the present invention, such a reaction between the polymer precursor and at least two different reactants is effected in a manner such that during the reaction the relative amounts of the at least two different reactants is changed, whereby there is produced a mixture of copolymers, each of which is comprised of the polymer backbone and each of which has the same at least two different pendant groups, with the copolymers differing from each other by the relative amounts of the two different pendant groups on the polymer backbone.

In one embodiment, there is provided a reaction in which there is a first feed that includes (either separately or mixed together) the polymer precursor and the at least two different reactants in a predetermined molar-ratio of the first reactant to the second reactant. In addition, the molar-ratio of the combination of the two reactants to the precursor is preferably at least one and more preferably greater than one. Thereafter, preferably in the same reactor, the feed is changed such that there is a change in the molar-ratio of the first reactant to the second reactant, with the molar-ratio of the combined reactants to the polymer precursor again preferably being at least one and more preferably being greater than one. Such a change in the feed then continues so as to provide in the reactor a copolymer mixture wherein each copolymer has the same polymer backbone and each copolymer has the same pendant groups, with copolymers differing from each other in the molar-ratio of the pendant groups on the polymer backbone.

Such a procedure may be accomplished in a single reactor by continuously feeding the polymer precursor and the least two reactants into the reactor with the feed ratio being periodically changed so as to vary the molar-ratio between the at least two different reactants, while maintaining the molar-ratio of the combined at least two reactants to the polymer precursor at a value of at least one.

In another embodiment, instead of having a continuous feed, there is provided a pulsed feed wherein there is introduced into a reactor a first feed as hereinabove described, followed by delivery of no feed, and then followed by delivery of a second feed that includes, separately or in combination, the polymer precursor and a different molar-ratio of reactants for reaction with the precursor polymer with such procedure repeated as many times as required to provide the desired copolymer mixture.

It is to be understood, although as hereinabove described, there are two reactants which are reacted with the polymer precursor, within the spirit and scope of the present invention, there may be used three or more reactants, with the relative molar-ratios between such reactants being varied, with the combined molar ratio of the reactants to the polymer precursor being a value of at least one and preferably greater than one.

Thus, in accordance with an aspect of the present invention, the sublibrary may be produced in a single reactor by changing the feed molar ratio of the at least two reactants that are to be reacted with the pendant groups of the polymer precursor. As should be apparent from the teachings herein, each sublibrary may be produced by a similar procedure in order to produce a combinatorial copolymer library in accordance with the invention.

In accordance with an aspect of the present invention, a chemical sublibrary may be further modified by additional chemical modifications such as a hydrolysis of the pendant groups and or reaction to yield sulfonics.

In a specific embodiment of the invention, there is provided a combinatorial library of polyphosphazene copolymers. Polyphosphazenes are polymers with backbones consisting of alternating phosphorus and nitrogen, separated by alternating single and double bonds. Each phosphorous atom is covalently bonded to two pendant groups ("R"). The repeat unit in polyphosphazenes has the following general formula:

n

wherein n is an integer, and R is a pendant group and each R may be the same or different.

In general, when the polyphosphazene has more than one type of pendant group, the groups will vary throughout the polymer, and the polyphosphazene is thus a copolymer. Phosphorous can be bound to two like groups, or two different groups. Polyphosphazenes with two or more types of pendant groups can be produced by reacting poly(dichlorophosphazene) with the desired nucleophilic reactants in a desired ratio.

Thus, for example, in the production of a polyphosphazene copolymer sublibrary, there may be introduced into a reactor as the reactive polymer precursor, poly(dichlorophosphazene) as well as two low molecular weight reactants, preferably with the polymer precursor as well as the reactants being in solution. The precursor and the reactants are delivered in a continuous flow into the reaction vessel where the reaction occurs under preset conditions such as temperature, atmosphere and agitation, as known in the art for reacting such a polymer precursor with the modifying reactants. As hereinabove described, the reactants are delivered in different molar ratios during the reaction so that the desired combination of copolymers over a desired composition range may be prepared. During the reaction, in a preferred embodiment, as the molar-ratio of the reactants changes, ratio of the reactants to the polymer precursor is at least one and preferably more than one. As representative but non-limiting examples of reactants that may be employed for modifying a polyphosphazene precursor, there may be mentioned;

H

CH CHg

H₂N H O

: F II

CH_gOCH₂CH₂NH₂ CH₃CH-C- -OCH₂CH₃ HCI CH₃CH₂CH₂CH₂NH₂ CH,

Examples of side groups that can be introduced in polyphosphazene copolymers include aliphatic, aryl, aralkyl, alkaryl, carboxylic acid, heteroaromatic, carbohydrates, including glucose, heteroalkyl, halogen, (aliphatic)amino including alkylamino-, heteroaralkyl, di(aliphatic)amino- including dialkylamino-, arylamino-, diarylamino-, alkylarylamino-, -oxyaryl including but not limited to -oxyphenylCO₂H, -oxyphenylSO₃ H, -oxyphenylhydroxyl and - oxyphenylPO₃ H; -oxyaliphatic including -oxyalkyl, -oxy(aliphatic)CO₂ H, -oxy(aliphatic)SO₃ H, -oxy(aliphatic)PO₃ H, and -oxy(aliphatic)hydroxyl, including oxy(alkyl)hydroxyl; - oxyalkaryl, -oxyaralkyl, -thioaryl, thioaliphatic including -thioalkyl, -thioalkaryl, thioaralkyl, ~ NHC(O)O-(aryl or aliphatic), ~O~[(CH₂)xO]y~CH₂)-O-[(CH₂)xO]y(CH₂)xNH(CH₂) xSO₃ H, and ~O~[(CH₂)xO]y-(aryl or aliphatic), wherein x is 1-8 and y is an integer of 1 to 20.

In one embodiment, the polydichlorophosphazene and the at least one nucleophilic reagent are reacted in the presence of at least of one organic solvent. Organic solvents which may be employed include, but are not limited to, tetrahydrofuran, dioxane, toluene, benzene, DMF, DMSO, and diglyme. In a preferred embodiment, the organic solvent is diglyme. In another embodiment, the organic solvent is a mixture of solvents.

Poly(dichlorophosphazene) concentration is between 0.1%(w/v) and 15%(w/v). Most preferably poly(dichlorophosphazene) concentration is between 0.2%(w/v) and 0.5%(w/v).

The reaction time is typically between 1 hour and 48 hours. Most preferably the reaction time is between 1 and 5 hours.

In one embodiment the reaction temperature is between -20 C and 200C. In a preferred embodiment the reaction temperature is between 100 C and 140 C. The reaction temperature can remain unchanged during the reaction, or alternatively can be increased or decreased over the reaction time. In another embodiment the reaction is carried out at reflux temperature.

In one embodiment additional reactant can be added to the substituted polyphosphazene copolymers upon completion of the substitution reaction. In one embodiment, the substituted polyphosphazene copolymer is reacted with a base, in the presence of water, to produce a polyphosphazene polyacid or acid salt. When one reactant is sodium propyl paraben, after the production of the substituted polyorganophosphazene, the ester function of polyphosphazene copolymer is hydrolyzed with base to produce a copolymer of poly[di(carboxylatophenoxy)phosphazene]. In another embodiment, the substituted polyphosphazene copolymer can be reacted with concentrated sulfuric acid to produce polyphosphazene sulfonic acid.

The combinatorial copolymer libraries of the present invention may then be employed to screen for desired properties. Such screening may be initially accomplished without the necessity of isolating or separating the individual copolymers of a sublibrary. Thus, each sublibrary is screened to determine which, if any, of the sublibraries has the desired property or properties. The identified sublibraries will then be analyzed to determine which of the copolymers in the sublibrary has the desired property or properties, and which of any copolymers in the sublibrary that have the desired property is best suited for the desired application. The individual copolymer or copolymer' s within a sublibrary that have the desired property or that is best suited for a desired use may be determined by separating the copolymers in a sublibrary into individual polymers. Alternatively, an array of individual polyphosphazene copolymers corresponding to the sublibrary of interest can be synthesized and then screened for the desired characteristics individually.

The present invention will be further described with respect to the following examples:

EXAMPLES

Example 1.

A combinatorial library of polyphosphazene copolymers containing two copolymer sublibraries is synthesized as follows.

Building Blocks.

Sodium propyl 4-hydroxybenzoate (reactant A, to introduce carboxylatophenoxy- side groups), sodium salt of 2-(2-methoxyethoxy)ethanol (reactant B, to introduce methoxyethoxyethoxy- side groups), and sodium salt of methoxyethanol (reactant C, to introduce methoxyethoxy- side groups) are prepared by reacting them with 40% sodium hydride dispersion in mineral oil at room temperature in diglyme (1 : 1 molar ratio). Sublibrary 1. [PN(A)(B)] - Poly[(carboxylatophenoxy)(methoxyethoxyethoxy)phosphazene] copolymer mixture.

0.002M of polymer precursor - polydichlorophosphazene (25 ml of 0.08 M solution in diglyme) is fed into a single reactor continuously over a period of 4 hours with a feed rate of approximately 8.3 mkM/min (0.1 ml/min). 0.001 M of reactant A (25 ml of 0.04M solution in diglyme) and 0.001 M of reactant B (25 ml of 0.04 M solution in diglyme) are fed to a reactor continuously over a period of 4 hours. The feed rate of each reactant A and B was periodically changed to vary the molar ratio between reactant, and the total feed rate of A and B is maintained at 8.3 mkM/min. For example, the starting feed rate (time - 0 min) is 8.3 mkM/min (0.2 ml/min) for reactant A and 0 mkM/min (0.0 ml/min) for reactant B, whereas the final feed rate (time - 240 min) is 0 mkM/min (0.0 ml/min) for reactant A and 8.3 mkM/min (0.2 ml/min) for reactant B. The reaction is carried out under nitrogen upon continuous vertical agitation and the temperature is maintained at 120-130° C.

Reaction mixture is then cooled to 90°C and 0.004 M of potassium hydroxide solution in water (10 ml) is added. Aqueous phase is then collected and purified by preparative size exclusion chromatography.

Sublibrary 2. [PN(A)(B)] - Poly[(carboxylatophenoxy)(methoxyethoxy)phosphazene] copolymer mixture.

Sublibrary 2 is synthesized using the same procedure as for sublibrary 1, but reactant C is used instead of reactant B.

Sublibrary 3. [PN(B)(C)] - Poly[(methoxyethoxyethoxy)(methoxyethoxy)phosphazene] copolymer mixture.

Sublibrary 3 is synthesized using the same procedure as for sublibrary 1, but reactant C is used instead of reactant A. Example 2.

Combinatorial library of polyphosphazene copolymers is prepared as described in Example 1, except that the addition of poly(dichlorophosphazene), reactants A, B, and C is carried out in 24 pulses with 10 min intervals between additions.

Example 3.

Combinatorial library, synthesized as in example 1, was then screened for useful properties, such as copolymer solubility in different solvents. Sublibraries are analyzed for solubility in water and methanol. Two samples of each sublibrary copolymer mixtures are placed in 3 dual dissolution baths (Hanson SR8-Plus Dissolution Bath). Water and methanol are then added to each dissolution bath so each sublibrary is tested separately for its solubility in water and methanol. The system allowed control over dissolution parameters, such as dissolution temperature and agitation rate. At programmed time intervals, aliquots from the dissolution baths are periodically removed and transferred for the analysis in the Waters Alliance Dissolution System. The analysis of each aliquot is performed using UV and Refractive Index detection so that the amount and composition of dissolved copolymers can be estimated based on the extinction coefficient and refractive index of the corresponding homopolymers. Dissolution plot is then obtained for each sublibrary showing the amount and composition of dissolved copolymers over time, and a copolymer composition with the appropriate solubility characteristics is determined.

Numerous modifications and variations of the present invention are possible in light of the above teachings and, therefore, within the scope of the appended claims, the invention may be practiced otherwise then as particularly described.

Claims

What is claimed is:

1. A combinatorial library, comprising: at least three sublibraries, each of said at least three sublibraries comprising a sublibrary mixture of copolymers having the same polymer backbone and at least two different pendant groups, with copolymers of said sublibrary differing from other copolymers in the sublibrary by the ratio of one pendant group to the other pendant group on the polymer backbone, with one sublibrary differing from another sublibrary of the at least three sublibraries by at least one of the pendant groups on the polymer backbone.

2. The combinatorial library of claim 1, wherein the polymer backbones are selected from the group consisting of polyphosphazene, polysiloxane, and polysilane.

3. The combinatorial library of claim 1, wherein said pendant groups are selected from nucleophiles corresponding to the group consisting of: aliphatic; aryl; aralkyl; alkaryl; carboxylic acid; heteroaromatic; carbohydrates, including glucose, heteroalkyl; halogen; (aliphatic)amino including alkylamino-; heteroaralkyl; di(aliphatic)amino- including dialkylamino-, arylamino-, diarylamino-, alkylarylamino-; -oxyaryl including but not limited to - oxyphenylCO₂H, -oxyphenylSO₃ H, -oxyphenylhydroxyl and -oxyphenylPO₃ H; -oxyaliphatic including -oxyalkyl, -oxy(aliphatic)CO₂ H, -oxy(aliphatic)SO₃ H, -oxy(aliphatic)PO₃ H, and - oxy(aliphatic)hydroxyl, including oxy(alkyl)hydroxyl; -oxyalkaryl, -oxyaralkyl, -thioaryl, thioaliphatic including -thioalkyl, -thioalkaryl, thioaralkyl; ~NHC(O)O-(aryl or aliphatic), --O-- [(CH₂)xO]y~CH₂)-O-[(CH₂)xO]y(CH₂)xNH(CH₂)xSO₃ H, and ~O-[(CH₂)xO]y-(aryl or aliphatic), wherein x is 1-8 and y is an integer of 1 to 20.

4. The combinatorial library of claim 1, whereiri said pendant groups are nucleophiles selected from the group consisting of: H

H₂N H O ² '>, f I I

CH₃OCH₂CH₂NH₂ CH₃ CH - C — C - OCH₂CH₃ HCI CH₃Cπ₂CH2θHπ H2

CH,

5. The combinatorial library of claim 1, wherein each sublibrary includes a variety of different copolymers, said variety being representative of relative amounts of pendent groups over a desired range.

6. The combinatorial library of claim 5, wherein the desired range of one pendant group is from about 1% to about 99%.

7. A process for producing a mixture of copolymers, comprising; reacting a polymer precursor comprising a polymer backbone and a reactable pendant group with at least two different reactants that react with the pendant group of the polymer precursor to produce a polymer backbone with at least two different pendant groups, wherein during the reaction the ratio of the at least two different reactants is changed to thereby produce a copolymer mixture.

8. The process of claim 7, wherein the polymer said polymer precursor is selected from the group consisting of polyphosphazene, polysiloxane, and polysilane.

9. The process of claim 7, wherein said polymer precursor is poly(dichlorophosphazene).

10. The process of claim 9, wherein the concentration of said poly(dichlorophosphazene) is between 0.1%(wv) and 15%(w/v).

11. The process of claim 9, wherein the concentration of said pory(dichlorophosphazene) is between 0.2%(wv) and 0.5%(w/v).

12. The process of claim 7, wherein the reaction time is between 1 hour and 48 hours.

13. The process of claim 7, wherein the reaction time is between 1 hour and 5 hours.

14. The process of claim 7, wherein the reaction temperature is between -20°C and 200°C.

15. The process of claim 7, wherein the reaction temperature is between 100°C and 140°C.

16. The process of claim 7, wherein said reactants are selected from the group consisting of: aliphatic; aryl; aralkyl; alkaryl; carboxylic acid; heteroaromatic; carbohydrates, including glucose, heteroalkyl; halogen; (aliphatic)amino including alkylamino-; heteroaralkyl; di(aliphatic)amino- including dialkylamino-, arylamino-, diarylamino-, alkylarylamino-; -oxyaryl including but not limited to -oxyphenylCO₂H, -oxyphenylSO₃ H, -oxyphenylhydroxyl and - oxyphenylPO₃ H; -oxyaliphatic including -oxyalkyl, -oxy(aliphatic)CO₂ H, -oxy(aliphatic)SO₃ H, -oxy(aliphatic)PO₃ H, and -oxy(aliphatic)hydroxyl, including oxy(alkyl)hydroxyl; - oxyalkaryl, -oxyaralkyl, -thioaryl, thioaliphatic including -thioalkyl, -thioalkaryl, thioaralkyl; ~ NHC(O)O-(aryl or aliphatic), -O~[(CH₂)xO]y~CH₂)~O~[(CH₂)xO]y(CH₂)xNH(CH₂)xSO₃ H, and ~O~[(CH )xO]y-(aryl or aliphatic), wherein x is 1-8 and y is an integer of 1 to 20.

17. The process of claim 7, wherein said reactants are selected for the group consisting of:

CH₃CH₂CH CH₂OH CH_gCH

CH₃OCH₂CH₂OH

CH,OCH,CH,OCH H.OH

^H ,

CH₃OCH₂CH₂NH₂ CH_gCH-C—^H C ?l-OCH₂CH₃ HCI CH₃CH₂CH₂CH₂NH₂ CH,

18. The process of claim 7, wherein the reaction comprises first and second feeds wherein said first feed includes said polymer precursor and said at least two different reactants such that said at least two different reactants are present in a first predetermined molar-ratio in relation to each other while the molar-ratio of said reactants to said precursor is at least one, and wherein said second feed includes said polymer precursor and said at least two different reactants such that said at least two different reactants are present in a second predetermined molar-ratio in relation to each other that is different from said first predetermined molar-ratio while the molar ratio of said reactants to said precursor is at least one.

19. The process of claim 18, wherein the molar-ratio of said reactants to said precursor is greater than one in said first feed.

20. The process of claim 18, wherein the molar-ratio of said reactants to said precursor is greater than one in said second feed.

21. The process of claim 18, wherein the molar-ratio of said reactants to said precursor is greater than one in both said first feed and said second feed.

22. The use of the combinatorial library of claim 1, for the purpose of screening copolymers for desired properties.

23. The use of claim 22 wherein the desired property is one of solubility.