# US 7,411,084 B2 · Method of preparing phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof via a dicarboxylate intermediate

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- Number: US 7,411,084 B2
- Document ID: US7411084B2
- Status: Granted
- Kind: B2
- Application number: 10/489,727
- Filed: 2002-09-26
- Published: 2004-09-02
- Granted: 2008-08-12
- Earliest claimed: 2001-09-26
- Assignees: Emisphere Technologies, Inc.
- Inventors: Joseph N. Bernadino
- Web page: https://patentgrep.com/patent/US7411084B2

## CPC

- C07C 51/38: by decarboxylation
- C07C 51/09: from carboxylic acid esters or lactones
- C07C 51/412: {by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part}
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to a method of preparing a phenoxy alkanoic, alkenoic, or alkynoic acid or a salt thereof from a phenoxy containing compound via a dicarboxylate intermediate. The phenoxy alkanoic, alkenoic, and alkynoic acids and salts thereof prepared by this method are suitable for use in composition for delivering active agents via oral or other routes of administration to animals. Furthermore, the present invention relates to phenoxy dicarboxylic acids and their salts for delivering active agents, such as biologically or chemically active agents, to a target.

## Claims

### Claim 1

A method of preparing an alkylated phenoxy containing compound from a phenoxy containing compound, the method comprises the steps of (a) alkylating the phenoxy containing compound with a dicarboxylate alkylating agent to form a dicarboxylated phenoxy containing compound, and (b) decarboxylating the dicarboxylated phenoxy containing compound to form the alkylated phenoxy containing compound,
wherein the dicarboxylate alkylating agent has the formula
wherein
R7 is a linear or branched C7-C12 alkylene;
R7 is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C1-C4 alkoxy, aryl, heteraryl, or vinyl;
R7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
R8 and R11 are independently C1-C4 alkyl or C1-C4 haloalkyl; and
X is a suitable leaving group.

### Claim 2 (depends on 1)

The method of claim 1, wherein the molar ratio of phenoxy containing compound to dicarboxylate alkylating agent is from about 1:1 to about 1:0.5.

### Claim 3 (depends on 1)

The method of claim 1, wherein the alkylating step is performed in the presence of a base.

### Claim 4 (depends on 3)

The method of claim 3, wherein the molar ratio of base to phenoxy containing compound is greater than 1.

### Claim 5 (depends on 4)

The method of claim 4, wherein the base is pyridine, picoline, tetramethylguanidine, triethylamine, diisopropylethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, or any combination of any of the foregoing.

### Claim 6 (depends on 5)

The method of claim 5, wherein the base is sodium carbonate.

### Claim 7 (depends on 1)

The method of claim 1, wherein the alkylating step is performed at a temperature of from about 40 to about 80° C.

### Claim 8 (depends on 7)

The method of claim 7, wherein the alkylating step is performed at a temperature of from about 60 to about 80° C.

### Claim 9 (depends on 1)

The method of claim 1, further comprising hydrolyzing one or more carboxyl moieties of the alkylated phenoxy carboxylic acid compound after step (a) to form the free acid of the alkylated phenoxy carboxylic acid compound.

### Claim 10 (depends on 9)

The method of claim 9, wherein the decarboxylating step is performed after the hydrolyzing step.

### Claim 11 (depends on 1)

The method of claim 1, wherein decarboxylating comprises heating the dicarboxylated phenoxy containing compound in an organic solvent to a temperature ranging from about 140 to about 200° C.

### Claim 12 (depends on 11)

The method of claim 11, wherein the organic solvent has a boiling point of at least about 110° C.

### Claim 13 (depends on 11)

The method of claim 11, wherein the organic solvent is selected from xylenes, toluene, heptane, dimethyl acetamide, dimethyl formamide, methyl sulfoxide, isoparaffins, and any combination of any of the foregoing.

### Claim 14

A method of preparing an alkylated phenoxy containing compound from a dicarboxylated phenoxy containing compound comprising the step of decarboxylating and hydrolyzing the dicarboxylated phenoxy containing compound to form the alkylated phenoxy containing compound, wherein the dicarboxylated phenoxy containing compound has the formula
where
R1, R2, R3, and R4 are independently H, —OH, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, —C(O)R12, —NO2, —NR9R10, or —N+R9R10R13 (R14)−;
R5 is H, —OH, —NO2, halogen, —CF3, —R15R16, —N+R15R16R17 (R18)−, amide, C1-C12 alkoxy, C1-C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or —C(O)R19;
R7 is a linear or branched C1-C20 alkylene, C2-C20 alkenylene, or C2-C20 alkynylene;
R7 is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C1-C4 alkoxy, aryl, heteraryl, or vinyl;
R7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
R8 and R11 are independently C1-C4 alkyl or C1-C4 haloalkyl;
R9, R10, and R13 are independently H or C1-C10 alkyl;
R12 is H, C1-C4 alkyl, C2-C4 alkenyl, or —NH2;
R14 and R18 are independently a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;
R15, R16, and R17 are independently H, C1-C10 alkyl, C1-C10 alkyl substituted with —COOH, C2-C12 alkenyl, C2-C12 alkenyl substituted with —COOH, —C(O)R20;
R19 is —H, C1-C6 alkyl, or C2-C12 alkenyl; and
R20 is —OH, C1-C10 alkyl, or C2-C12 alkenyl,
wherein at least one of R1, R2, R3, R4 and R5 is —OH or alkoxy.

### Claim 15 (depends on 1)

The method of claim 1, wherein R7 is a linear or branched C7-C9 alkylene.

### Claim 16

A method of preparing an alkylated phenoxy containing compound from a phenoxy containing compound, the method comprises the steps of (a) alkylating the phenoxy containing compound with a dicarboxylate alkylating agent to form a dicarboxylated phenoxy containing compound, and (b) decarboxylating the dicarboxylated phenoxy containing compound to form the alkylated phenoxy containing compound,
wherein the phenoxy containing compound has the formula
wherein
R1, R2, R3, and R4 are independently H, —OH, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, —C(O)R12, —NO2, —NR9R10, or —N+R9R10R13 (R14)−;
R5 is H, —OH, —NO2, halogen, —CF3, —R15R16, —N+R15R16R17 (R18)−, amide, C1-C12 alkoxy, C1-C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or —C(O)R19;
R6 is a leaving group;
R9, R10, and R13 are independently H or C1-C10 alkyl;
R12 is H, C1-C4 alkyl, C2-C4 alkenyl, or —NH2;
R14 and R18 are independently a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;
R15, R16, and R17 are independently H, C1-C10alkyl, C1-C10 alkyl substituted with —COOH, C2-C12 alkenyl, C2-C12 alkenyl substituted with —COOH, —C(O)R20;
R19 is —H, C1-C6 alkyl, or C2-C12 alkenyl; and
R20 is —OH, C1-C10 alkyl, or C2-C12 alkenyl,
wherein at least one of R1, R2, R3, R4 and R5 is —OH or alkoxy.

### Claim 17 (depends on 16)

The method of claim 16, wherein the dicarboxylate phenoxy containing compound has the formula
where
R1, R2, R3, and R4 are independently H, —OH, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, —C(O)R12, —NO2, —NR9R10, or —N+R9R10R13 (R14)—;
R5 is H, —OH, —NO2, halogen, —CF3, —R15R16, —N+R15R16R17 (R18)−, amide, C1-C12 alkoxy, C1-C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or —C(O)R19;
R7 is a linear or branched, C1-C20 alkylene, C2-C20 alkenylene, or C2-C20 alkynylene;
R7 is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C1-C4 alkoxy, aryl, heteraryl, or vinyl;
R7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
R8 and R11 are independently C1-C4 alkyl or C1-C4 haloalkyl;
R9, R10, and R13 are independently H or C1-C10 alkyl;
R12 is H, C1-C4 alkyl, C2-C4 alkenyl, or —NH2;
R14 and R18 are independently a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;
R15, R16, and R17 are independently H, C1-C10 alkyl, C1-C10 alkyl substituted with —COOH, C2-C12 alkenyl, C2-C12 alkenyl substituted with —COOH, —C(O)R20;
R19 is —H, C1-C6 alkyl, or C2-C12 alkenyl; and
R20 is —OH, C1-C10 alkyl, or C2-C12 alkenyl,
wherein at least one of R1, R2, R3, R4 and R5 is —OH or alkoxy.

### Claim 18 (depends on 16)

The method of claim 16, wherein the alkylated phenoxy containing compound has the formula
where
R1, R2, R3, and R4 are independently H, —OH, halogen, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, —C(O)R12, —NO2, —NR9R10, or —N+R9R10R13 (R14)−;
R5 is H, —OH, —NO2, halogen, —CF3, —R15R16, —N+R15R16R17 (R18)−, amide, C1-C12 alkoxy, C1-C12 alkyl, C2-C12 alkenyl, carbamate, carbonate, urea, or —C(O)R19;
R7 is a linear or branched, C1-C20 alkylene, C2-C20 alkenylene, or C2-C20 alkynylene;
R7 is optionally substituted with C1-C4 alkyl, C1-C4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C1-C4 alkoxy, aryl, heteraryl, or vinyl;
R7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;
R9, R10, and R13 are independently H or C1-C10 alkyl;
R12 is H, C1-C4 alkyl, C2-C4 alkenyl, or —NH2;
R14 and R18 are independently a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate;
R15, R16, and R17 are independently H, C1-C10 alkyl, C1-C10 alkyl substituted with —COOH, C2-C12 alkenyl, C2-C12 alkenyl substituted with —COOH, —C(O)R20;
R19 is —H, C1-C6 alkyl, or C2-C12 alkenyl; and
R20 is —OH, C1-C10 alkyl, or C2-C12 alkenyl,
wherein at least one of R1, R2, R3, R4 and R5 is —OH or alkoxy.