Anionic exchange-hydrophobic mixed mode chromatography resins

1. A chromatography matrix covalently linked to a ligand having the following formula:

Chromatography matrix-(X)—N(R 1 )—(R 2 -L) n -Ar

or an anionic salt thereof,

wherein:

X is a spacer;

R 1 is hydrogen or C 1 to C 6 alkyl optionally substituted with an —OH;

R 2 is C 2 to C 6 alkyl or C 4 to C 6 cycloalkyl;

L is NR 4 , O, or S;

n=1 or 2; and

Ar is a 6-10 membered ring and:

if Ar is aryl, the aryl is optionally substituted with up to five C 1 to C 3 unsubstituted alkyl, C 3 to C 6 branched alkyl, unsubstituted aryl, or fluorine groups; or

if Ar is heteroaryl, the heteroaryl is optionally substituted with up to four unsubstituted alkyl groups,

with the proviso that when R 1 is hydrogen, R 2 is C 2 alkyl, L is NR 4 or O, and n is 1, Ar is not phenyl.

2. The chromatography matrix of claim 1 , wherein:

X is selected from the group consisting of —O—CH 2 —, —O—CH 2 —CH 2 —, —O—CH 2 —CH 2 —CH 2 —, —O—CH 2 —CH 2 —CH 2 —CH 2 —, —O—CH 2 —CH(CH 2 —OH)—(O—CH 2 —CH(OH)—CH 2 ) 2 —, —O—CH 2 —CH 2 —CH(CH 2 —OH)—(O—CH 2 —CH 2 —CH(OH)—CH 2 ) 2 —, —O—CH 2 —CH(OH)—CH 2 —, —O—CH 2 —CH 2 —CH(OH)—CH 2 —CH 2 —, —O—CH 2 —CH(OH)—CH 2 —O—CH 2 —CH 2 —CH 2 —CH 2 —O—CH 2 —CH(OH)—CH 2 —, and —CO—NH—C(CH 3 ) 2 —CO—;

R 1 is hydrogen or C 1 to C 3 alkyl;

R 2 is C 2 to C 4 alkyl;

L is O;

n=1; and

Ar is a 6 membered ring and:

if Ar is aryl, the aryl is optionally substituted with up to four C 1 to C 2 unsubstituted alkyl, C 3 or C 4 branched alkyl, or fluorine groups; or

if Ar is heteroaryl, the heteroaryl is optionally substituted with up to three unsubstituted alkyl groups,

with the proviso that when R 1 is hydrogen, R 2 is C 2 alkyl, and n is 1, Ar is not phenyl.

3. The chromatography matrix of claim 2 , wherein:

X is selected from the group consisting of —O—CH 2 —, —O—CH 2 —CH 2 —, —O—CH 2 —CH 2 —CH 2 —, —O—CH 2 —CH 2 —CH 2 —CH 2 —, and —O—CH 2 —CH(OH)—CH 2 —;

R 1 is hydrogen or C 1 to C 2 alkyl;

R 2 is C 2 to C 3 alkyl;

L is O;

n=1; and

Ar is phenyl, napthyl, or pyridyl optionally substituted with up to three C 1 to C 2 unsubstituted alkyl,

with the proviso that when R 1 is hydrogen, R 2 is C 2 alkyl, and n is 1, Ar is not phenyl.

4. The chromatography resin of claim 1 , wherein Ar is phenyl substituted with one or two C 1 to C 2 unsubstituted alkyl at the para or meta position relative to Chromatography matrix-(X)—N(R 1 )—(R 2 -L) n -.

5. The chromatography resin of claim 1 , wherein —(X)—N(R 1 )—(R 2 -L) n -Ar is a ligand selected from the group consisting of:

2-(p-Tolyloxy)ethylamine;

2-(o-Tolyloxy)ethylamine;

2-(m-Tolyloxy)ethylamine;

3,5-dimethylphenoxyethanamine;

4-ethylphenoxy ethanamine;

4-isopropylphenoxy ethanamine;

4-t-butylphenoxy ethanamine;

4-phenylphenoxy ethanamine;

1-naphthalenoxy ethanamine;

3-flourophenoxy ethanamine;

4-flourophenoxy ethanamine;

3,5-diflourophenoxy ethanamine;

2,5-diflourophenoxy ethanamine;

3,4-diflourophenoxy ethanamine;

3,4,5-triflourophenoxy ethanamine;

perflourophenoxy ethanamine;

4-pyridinylethanamine;

3-pyridinylethanamine;

4-(2,6-dimethylpyridinyl)ethanamine;

Phenoxypropylamine;

2-phenoxycyclobutylamine;

2-phenoxycyclopentylamine;

4-phenoxycyclohexylamine;

2-(2-phenoxyethoxy)ethanamine;

N-methyl-2-phenoxyethan-1-amine;

N-methyl-3-phenoxypropan-1-amine;

N-methyl(2-phenoxy cyclobutyl)amine;

N-methyl(2-phenoxy cyclopentyl)amine;

N-methyl(4-phenoxy cyclohexyl)amine;

N-methyl-2-(p-tolyloxy)ethan-1-amine;

2-(3,5-dimethylphenoxy)-N-methylethan-1-amine;

2-(4-ethylphenoxy)-N-methylethan-1-amine;

2-(4-isopropylphenoxy)-N-methylethan-1-amine;

2-(4-(tert-butyl)phenoxy)-N-methylethan-1-amine;

2-([1,1′-biphenyl]-4-yloxy)-N-methylethan-1-amine;

N-methyl-2-(naphthalen-1-yloxy)ethan-1-amine;

2-((2-phenoxyethyl)amino)ethan-1-ol;

2-(3-fluorophenoxy)-N-methylethan-1-amine;

2-(4-fluorophenoxy)-N-methylethan-1-amine;

2-(2,5-difluorophenoxy)-N-methylethan-1-amine;

2-(3,4-difluorophenoxy)-N-methylethan-1-amine;

2-(3,5-difluorophenoxy)-N-methylethan-1-amine;

N-methyl-2-(3,4,5-trifluorophenoxy)ethan-1-amine;

N-methyl-2-(perfluorophenoxy)ethan-1-amine;

N-methyl-2-(pyridin-4-yloxy)ethan-1-amine;

N-methyl-2-(pyridin-3-yloxy)ethan-1-amine;

2-((2,6-dimethylpyridin-4-yl)oxy)-N-methylethan-1-amine; and

N-methyl-2-(2-phenoxyethoxy)ethan-1-amine.

6. The chromatography resin of claim 1 , wherein Ar is heteroaryl and a heteroatom in the heteroaryl is N.

7. The chromatography resin of claim 1 , wherein the anionic salt is a hydrochloride salt, a phosphate salt, or a sulfate salt.

8. The chromatography resin of claim 1 , wherein X is attached to chromatography matrix via an amine, ether or amide bond.

9. A chromatography resin prepared by reacting a ligand with a chromatography support comprising an aldehyde group, epoxide group, or an azalactone group, said ligand being selected from the group consisting of:

2-(p-Tolyloxy)ethylamine;

2-(o-Tolyloxy)ethylamine;

2-(m-Tolyloxy)ethylamine;

3,5-dimethylphenoxyethanamine;

4-ethylphenoxy ethanamine;

4-isopropylphenoxy ethanamine;

4-t-butylphenoxy ethanamine;

4-phenylphenoxy ethanamine;

1-naphthalenoxy ethanamine;

3-flourophenoxy ethanamine;

4-flourophenoxy ethanamine;

3,5-diflourophenoxy ethanamine;

2,5-diflourophenoxy ethanamine;

3,4-diflourophenoxy ethanamine;

3,4,5-triflourophenoxy ethanamine;

perflourophenoxy ethanamine;

4-pyridinylethanamine;

3-pyridinylethanamine;

4-(2,6-dimethylpyridinyl)ethanamine;

Phenoxypropylamine;

2-phenoxycyclobutylamine;

2-phenoxycyclopentylamine;

4-phenoxycyclohexylamine;

2-(2-phenoxyethoxy)ethanamine;

N-methyl-2-phenoxyethan-1-amine;

N-methyl-3-phenoxypropan-1-amine;

N-methyl(2-phenoxy cyclobutyl)amine;

N-methyl(2-phenoxy cyclopentyl)amine;

N-methyl(4-phenoxy cyclohexyl)amine;

N-methyl-2-(p-tolyloxy)ethan-1-amine;

2-(3,5-dimethylphenoxy)-N-methylethan-1-amine;

2-(4-ethylphenoxy)-N-methylethan-1-amine;

2-(4-isopropylphenoxy)-N-methylethan-1-amine;

2-(4-(tert-butyl)phenoxy)-N-methylethan-1-amine;

2-([1,1′-biphenyl]-4-yloxy)-N-methylethan-1-amine;

N-methyl-2-(naphthalen-1-yloxy)ethan-1-amine;

2-((2-phenoxyethyl)amino)ethan-1-ol;

2-(3-fluorophenoxy)-N-methylethan-1-amine;

2-(4-fluorophenoxy)-N-methylethan-1-amine;

2-(2,5-difluorophenoxy)-N-methylethan-1-amine;

2-(3,4-difluorophenoxy)-N-methylethan-1-amine;

2-(3,5-difluorophenoxy)-N-methylethan-1-amine;

N-methyl-2-(3,4,5-trifluorophenoxy)ethan-1-amine;

N-methyl-2-(perfluorophenoxy)ethan-1-amine;

N-methyl-2-(pyridin-4-yloxy)ethan-1-amine;

N-methyl-2-(pyridin-3-yloxy)ethan-1-amine;

2-((2,6-dimethylpyridin-4-yl)oxy)-N-methylethan-1-amine; and

N-methyl-2-(2-phenoxyethoxy)ethan-1-amine.

10. The chromatography resin of claim 9 , wherein the chromatography matrix comprises an aldehyde group.

11. The chromatography resin of claim 9 , wherein the chromatography matrix comprises an epoxide group.

12. The chromatography resin of claim 9 , wherein prior to reacting the chromatography matrix with the ligand, the chromatography matrix is reacted with allylglydicylether and bromine; 1,4-butanedioldiglycidyl; or epichlorohydrin.