Synthesis of hybrid block copolymers and uses thereof

• US 20060172914A1
• Filed: 01/04/2006
• Published: 08/03/2006
• Est. Priority Date: 01/04/2005
• Status: Active Grant

• Current Assignee: Intezyne Technologies
• Original Assignee: Intezyne Technologies
• Inventors: Breitenkamp, Kurt, Sill, Kevin
• Granted Patent: US 7,601,796 B2
• Time in Patent Office: Days
• US Class Current: 510/446
• CPC Class Codes: C08F 283/06 on to polyethers, polyoxymethylenes or polyacetals C08F283/004 takes precedence
• CPC Class Codes: C08F 293/00 Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule on to polymers modified by introduction of unsaturated end groups C08F290/02
• CPC Class Codes: C08F 293/005 using free radical "living" or "controlled" polymerisation, e.g. using a complexing agent
• CPC Class Codes: C08F 297/00 Macromolecular compounds obtained by successively polymerising different monomer systems using a catalyst of the ionic or coordination type without deactivating the intermediate polymer
• CPC Class Codes: C08G 73/0233 Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups
• CPC Class Codes: C08G 73/028 Polyamidoamines
• CPC Class Codes: C08L 2666/02 Organic macromolecular compounds, natural resins, waxes or and bituminous materials
• CPC Class Codes: C08L 51/08 grafted on to macromolecular compounds obtained otherwise than by reactions only involving unsaturated carbon-to-carbon bonds
• CPC Class Codes: C08L 53/00 Compositions of block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Compositions of derivatives of such polymers

Abstract

The present invention relates to the field of polymer chemistry and more particularly to multiblock copolymers and methods of preparing the same.

Claims

1. A method for preparing a multi-block copolymer comprising two or more different poly(amino acid) blocks and one or more synthetic polymer blocks, wherein said method comprises the step of sequentially polymerizing two or more different cyclic amino acid monomers onto a synthetic polymer having a terminal amine salt wherein said polymerization is initiated by said amine salt.

2. The method according to claim 1, wherein said polymerization occurs by ring-opening polymerization of the cyclic amino acid monomers and wherein each cyclic amino acid monomer is an NCA.

3. The method according to claim 2, wherein said terminal amine salt is an acid addition salt formed with an inorganic acid selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid.

4. The method according to claim 2, wherein said terminal amine salt is an acid addition salt formed with an organic acid selected from formic acid, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, or trifluoroacetic acid.

5. The method according to claim 1, wherein said synthetic polymer is a PEG.

6. A method of for preparing a multi-block copolymer comprising one or more different poly(amino acid) blocks and a PEG synthetic polymer block, wherein said method comprises the steps of:

(a) providing a compound of formula I;

wherein;

n is 10-2500;

R¹ is -Z(CH₂CH₂Y)_p(CH₂)_tR³, wherein;

Z is —

O—

, —

S—

, —

C—

C—

, or —

CH₂—

;

each Y is independently —

O—

or —

S—

;

p is 0-10;

t is 0-10; and

R³ is —

N₃, —

CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, a 9-30-membered crown ether, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety, provided that R¹ is other than methyl;

Q is a valence bond or a bivalent, saturated or unsaturated, straight or branched C_1-12 alkylene chain, wherein 0-6 methylene units of Q are independently replaced by -Cy-, —

O—

, —

NH—

, —

S—

, —

OC(O)—

, —

C(O)O—

, —

C(O)—

, —

SO—

, —

SO₂—

, —

NHSO₂—

, —

SO₂NH—

, —

NHC(O)—

, —

C(O)NH—

, —

OC(O)NH—

, or —

NHC(O)O—

, wherein;

-Cy- is an optionally substituted 5-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

A is a suitable acid anion,

(b) polymerizing a first cyclic amino acid monomer onto the amine salt terminal end of formula I;

(c) optionally polymerizing a second cyclic amino acid monomer onto the living polymer end, wherein said second cyclic amino acid monomer is different from said first cyclic amino acid monomer; and

(d) optionally polymerizing additional cyclic amino acid monomers onto the living polymer end.

7. The method according to claim 6, wherein R³ is an optionally substituted group selected from aliphatic or aryl.

8. The method according to claim 7, wherein R³ is an aliphatic group substituted with one or more groups independently selected from CN, N₃, trimethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, N-methyl propiolamido, N-methyl-4-acetylenylanilino, N-methyl-4-acetylenylbenzoamido, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, N-methyl-propargylamino, N-methyl-hex-5-ynyl-amino, N-methyl-pent-4-ynyl-amino, N-methyl-but-3-ynyl-amino, 2-hex-5-ynyldisulfanyl, 2-pent-4-ynyldisulfanyl, 2-but-3-ynyldisulfanyl, or 2-propargyldisulfanyl.

9. The method according to claim 6, wherein R³ is an aryl group substituted with one or more groups independently selected from CN, N₃, NO₂, —

CH₃, —

CH₂N₃, —

CH═

CH₂, —

C≡

CH, Br, 1, F, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, 2-hex-5-ynyloxy-ethyldisulfanyl, 2-pent-4-ynyloxy-ethyldisulfanyl, 2-but-3-ynyloxy-ethyldisulfanyl, 2-propargyloxy-ethyldisulfanyl, bis-benzyloxy-methyl, [1,3]dioxolan-2-yl, or [1,3]dioxan-2-yl.

10. The method according to claim 6, wherein R³ is a group suitable for Click chemistry.

11. A method for preparing a multi-block copolymer of formula II:

12. The method according to claim 11, wherein one of R^x and R^y is a hydrophilic amino acid side-chain or crosslinkable group and the other of R^x and R^y is a hydrophobic or ionic amino acid side-chain group.

13. The method according to claim 12, wherein said hydrophilic amino acid side-chain group is an aspartic acid side chain, glutamic acid side-chain, lysine side-chain, arginine side-chain, or protected form or mixture thereof, and said hydrophobic amino acid side-chain group is a phenylalanine side-chain, alanine side-chain, or leucine side-chain, and optionally one or more of tyrosine side-chain, serine side-chain, or threonine side-chain.

14. The method according to claim 11, wherein R³ is an aliphatic group optionally substituted with CN, a mono-protected amino group, a di-protected amino group, a protected aldehyde group, a protected hydroxyl group, a protected carboxylic acid group, a protected thiol group, or a detectable moiety.

15. The method according to claim 11, wherein R³ is an aryl group substituted with one or more groups independently selected from CN, N₃, NO₂, —

CH₃, —

CH₂N₃, —

CH═

CH₂, —

C≡

CH, Br, I, F, bis-(4-ethynyl-benzyl)-amino, dipropargylamino, di-hex-5-ynyl-amino, di-pent-4-ynyl-amino, di-but-3-ynyl-amino, propargyloxy, hex-5-ynyloxy, pent-4-ynyloxy, di-but-3-ynyloxy, 2-hex-5-ynyloxy-ethyldisulfanyl, 2-pent-4-ynyloxy-ethyldisulfanyl, 2-but-3-ynyloxy-ethyldisulfanyl, 2-propargyloxy-ethyldisulfanyl, bis-benzyloxy-methyl, [1,3]dioxolan-2-yl, or [1,3]dioxan-2-yl.

16. The method according to claim 11, wherein R³ is a group suitable for Click chemistry.

17. The method according to claim 11, further comprising the step of treating said compound of formula II with a base to form a compound of formula II′

;

18. The method according to claim 17, further comprising the step of treating said compound of formula II′

with a suitable terminating agent to form the compound of formula III;

19. A compound of formula II:

20. A compound of formula III:

21. The compound according to claim 20, wherein R¹ is selected from the group consisting of:

22. The compound according to claim 21, wherein R^2a is selected from the group consisting of:

23. A method of preparing a compound of formula IV:

24. The method according to claim 23, further comprising the steps of:

(a) providing a polymerization initiator of formula B;

wherein;

each of PG¹ and PG² is hydrogen or a suitable amino protecting group, or PG¹ and PG² are taken together to form a cyclic amino protecting group, provided that at least one of PG¹ and PG²is a suitable amino protecting group; and

Q is a valence bond or a bivalent, saturated or unsaturated, straight or branched C_1-12 alkylene chain, wherein 0-6 methylene units of Q are independently replaced by -Cy-, —

O—

, —

NH—

, —

S—

, —

OC(O)—

, —

C(O)O—

, —

C(O)—

, —

SO—

, —

SO₂—

, —

NHSO₂—

, —

SO₂NH—

, —

NHC(O)—

, —

C(O)NH—

, —

OC(O)NH—

, or —

NHC(O)O—

, wherein;

-Cy- is an optionally substituted 5-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

(b) polymerizing ethylene oxide onto said polymerization initiator to provide a compound of formula A;

25. The method according to claim 23, further comprising the steps of:

(a) polymerizing a first cyclic amino acid monomer onto the amine salt terminal end of formula IV, wherein said first cyclic amino acid monomer comprises R^x; and

(b) optionally polymerizing a second cyclic amino acid monomer, comprising R^y, onto the living polymer end, wherein said second cyclic amino acid monomer is different from said first cyclic amino acid monomer to form a compound of formula V;

wherein;

n is 10-2500;

m is 1 to 1000;

m′

is 0 to 1000;

R^x and R^y are each independently a natural or unnatural amino acid side-chain group, wherein R^x and R^y are different from each other;

Q is a valence bond or a bivalent, saturated or unsaturated, straight or branched C_1-12 alkylene chain, wherein 0-6 methylene units of Q are independently replaced by -Cy-, —

O—

, —

NH—

, —

S—

, —

OC(O)—

, —

C(O)O—

, —

C(O)—

, —

SO—

, —

SO₂—

, —

NHSO₂—

, —

SO₂NH—

, —

NHC(O)—

, —

C(O)NH—

, —

OC(O)NH—

, or —

NHC(O)O—

, wherein;

-Cy- is an optionally substituted 5-8 membered bivalent, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered bivalent saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R² is halogen, N₃, CN, a mono-protected amine, a di-protected amine, a protected hydroxyl, a protected aldehyde, a protected thiol, —

NHR⁴, —

N(R⁴)₂, —

SR⁴, —

O(CH₂CH₂O)_q(CH₂)_rR⁵, —

OC(O)R⁴, or —

OS(O)₂R⁴;

q and r are each independently 0-4;

each R⁴ is independently an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10-membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety, or;

two R⁴ on the same nitrogen atom are taken together with said nitrogen atom to form an optionally substituted 4-7 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

R⁵ is hydrogen, halogen, CN, a mono-protected amine, a di-protected amine, a protected aldehyde, a protected hydroxyl, a protected carboxylic acid, a protected thiol, or an optionally substituted group selected from aliphatic, a 5-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a detectable moiety.

26. The method according to claim 25, further comprising the step of treating said compound of formula V with a suitable terminating agent to form the compound of formula VI: