# US 9,040,711 B2 · Processes for the preparation of 3,5-disubstituted-1,2,4-oxadiazoles

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- Number: US 9,040,711 B2
- Document ID: US9040711B2
- Status: Granted
- Kind: B2
- Application number: 13/933,616
- Filed: 2013-07-02
- Published: 2014-02-06
- Granted: 2015-05-26
- Earliest claimed: 2012-07-02
- Assignees: Monsanto Technology LLC
- Applicants: Monsanto Technology LLC
- Inventors: William Harold Miller; Charles Richard Graham; David Louis Brown
- Web page: https://patentgrep.com/patent/US9040711B2

## CPC

- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein are processes for the preparation of 3,5-disubstituted-1,2,4-oxadiazoles and salts thereof comprising reacting a N-hydroxyamidine with an acyl chloride in a reaction mixture comprising a water-immiscible organic solvent and an aqueous base at relatively low reaction temperatures.

## Claims

### Claim 1

A process for preparing a 3,5-disubstituted 1,2,4-oxadiazole of Formula (Ia) or (Ib), or a salt thereof,
the process comprising reacting an N-hydroxyamidine of Formula (IIa) or (IIb), respectively, or a tautomeric form thereof,
with an acyl chloride of Formula (IIIa) or (IIIb), respectively,
in a reaction mixture comprising an organic phase and an aqueous phase,
wherein the reaction mixture comprises a water-immiscible organic solvent and an aqueous base,
wherein the temperature of the reaction mixture is no greater than about 85° C.;
and wherein Ar1 is selected from the group consisting of phenyl, pyridyl, pyrazyl, oxazolyl or isoxazolyl, each of which can be optionally independently substituted with one or more substituents selected from the group consisting of halogen, CF3, CH3, OCF3, OCH3, CN and C(H)O; and
Ar2 is selected from the group consisting of is thienyl, furanyl, oxazolyl or isoxazolyl, each of which can be optionally independently substituted with one or more substituents selected from the group consisting of fluorine, chlorine, CH3, and OCF3.

### Claim 2 (depends on 1)

The process of claim 1 wherein the process comprises reacting an N-hydroxyamidine of Formula (IIa), or a tautomeric form thereof, with an acyl chloride of Formula (IIIa) to form a 3,5-disubstituted 1,2,4-oxadiazole of Formula (Ia), or a salt thereof.

### Claim 3 (depends on 1)

The process of claim 1 wherein the process comprises reacting an N-hydroxyamidine of Formula (IIb), or a tautomeric form thereof, with an acyl chloride of Formula (IIb) to form a 3,5-disubstituted 1,2,4-oxadiazole of Formula (Ib), or a salt thereof.

### Claim 4 (depends on 1)

The process of claim 1 wherein the reaction mixture further comprises a phase transfer catalyst.

### Claim 5 (depends on 4)

The process of claim 4 wherein the phase transfer catalyst is selected from the group consisting of quaternary ammonium salts, phosphonium salts, and crown ethers.

### Claim 6 (depends on 4)

The process of claim 4 wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydroxide, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylphosphonium bromide, tetrabutylphosphonium chloride, and benzyltrimethylammonium hydroxide.

### Claim 7 (depends on 6)

The process of claim 6 wherein the phase transfer catalyst is tetrabutylammonium hydroxide.

### Claim 8 (depends on 1)

The process of claim 1 wherein the water-immiscible organic solvent solubilizes the N-hydroxyamidine and the 3,5-disubstituted-1,2,4-oxadiazole.

### Claim 9 (depends on 1)

The process claim 1 wherein the water-immiscible organic solvent forms an azeotrope with water.

### Claim 10 (depends on 1)

The process of claim 1 wherein the water-immiscible organic solvent is selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

### Claim 11 (depends on 10)

The process of claim 10 wherein the water-immiscible organic solvent is 2-methyltetrahydrofuran.

### Claim 12 (depends on 1)

The process of claim 1 wherein the aqueous base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, and calcium hydroxide.

### Claim 13 (depends on 12)

The process of claim 12 wherein the aqueous base is selected from the group consisting of sodium hydroxide and potassium hydroxide.

### Claim 14 (depends on 1)

The process of claim 1 wherein the pH of the aqueous phase is greater than about 8.

### Claim 15 (depends on 1)

The process of claim 1 wherein the pH of the aqueous phase is greater than about 10.

### Claim 16 (depends on 1)

The process of claim 1 wherein the pH of the aqueous phase is increased or maintained by adding additional aqueous base to the reaction mixture.

### Claim 17 (depends on 1)

The process of claim 1 wherein the temperature of the reaction mixture is maintained at from about 55° C. to about 75° C.

### Claim 18 (depends on 1)

The process of claim 1 wherein the N-hydroxyamidine is dissolved in the water-immiscible organic solvent prior to adding the acyl chloride to form the reaction mixture.

### Claim 19 (depends on 1)

The process of claim 1 further comprising recovering the 3,5-disubstituted-1,2,4-oxadiazole from the reaction mixture as a precipitate from an aqueous layer after removal of at least a portion of the water-immiscible organic solvent from the reaction mixture.

### Claim 20 (depends on 19)

The process of claim 19 further comprising adding a surfactant to the reaction mixture.

### Claim 21 (depends on 20)

The process of claim 20 wherein the surfactant added to the reaction mixture stabilizes droplets of the 3,5-disubstituted-1,2,4-oxadiazole in an aqueous layer and allows the droplets to solidify without coalescing into larger droplets.

### Claim 22 (depends on 20)

The process of claim 20 wherein the surfactant is added to the reaction mixture prior to removal of at least a portion of the water-immiscible organic solvent from the reaction mixture.

### Claim 23 (depends on 20)

The process of claim 20 wherein the surfactant is added to the reaction mixture after the reaction is substantially complete.

### Claim 24 (depends on 20)

The process of claim 20 wherein the surfactant is selected from the group consisting of anionic or nonionic dispersants, anionic or nonionic detergents, anionic or nonionic surfactants, and combinations thereof.

### Claim 25 (depends on 1)

The process of claim 1 wherein the reaction of the N-hydroxyamidine and the acyl chloride produces an oxime ester intermediate of Formula (IVa) or (IVb), a salt thereof, or a tautomeric form thereof,
wherein Ar1 and Ar2 are defined as in claim 1.

### Claim 26 (depends on 25)

The process of claim 25 wherein the water-immiscible organic solvent solubilizes the N-hydroxyamidine, the oxime ester intermediate, and the 3,5-disubstituted 1,2,4-oxadiazole.

### Claim 27 (depends on 25)

The process of claim 25 wherein the oxime ester intermediate is isolated prior to formation of the 3,5-disubstituted 1,2,4-oxadiazole.

### Claim 28 (depends on 1)

The process of claim 1 wherein the N-hydroxyamidine is a benzamide oxime formed by reacting a substituted or unsubstituted benzonitrile and hydroxylamine hydrochloride in an alcoholic solvent with sodium hydroxide and the benzamide oxime is separated from the alcohol solvent and subsequently dissolved in a solvent selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

### Claim 29 (depends on 1)

The process of claim 1 wherein the N-hydroxyamidine is a benzamide oxime formed by reacting a substituted or unsubstituted benzonitrile and hydroxylamine and the formed benzamide oxime is dissolved in a solvent selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

### Claim 30 (depends on 29)

The process of claim 29 wherein the reaction to form the benzamide oxime is carried out at a temperature of from about 20° C. to about 65° C.

### Claim 31 (depends on 1)

The process of claim 1 wherein the N-hydroxyamidine is a benzamide oxime formed by combining and reacting a substituted or unsubstituted benzonitrile and aqueous hydroxylamine.

### Claim 32 (depends on 31)

The process of claim 31 wherein the substituted or unsubstituted benzonitrile and aqueous hydroxylamine are combined and reacted in the absence of a water-immiscible organic solvent.

### Claim 33 (depends on 31)

The process of claim 31 wherein the substituted or unsubstituted benzonitrile and aqueous hydroxylamine are combined and reacted in a water-immiscible organic solvent and the benzamide oxime is dissolved in the solvent.

### Claim 34 (depends on 33)

The process as set forth in claim 33 wherein the water-immiscible organic solvent is selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

### Claim 35 (depends on 1)

The process of claim 1 wherein the process comprises:
(1) introducing the N-hydroxyamidine into a reaction vessel as a solution dissolved in the water-immiscible organic solvent;
(2) adding a portion of the aqueous base, and optionally a phase transfer catalyst, to the reaction vessel;
(3) adding the acyl chloride to the reaction vessel to form the reaction mixture; and
(4) adding additional aqueous base to the reaction mixture in the reaction vessel.

### Claim 36 (depends on 35)

The process of claim 35 wherein the water-immiscible organic solvent is selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate.

### Claim 37 (depends on 35)

The process of claim 35 wherein the acyl chloride and the additional aqueous base are added to the reaction vessel simultaneously.

### Claim 38 (depends on 35)

The process of claim 35 wherein the acyl chloride and the additional aqueous base are added to the reaction vessel sequentially.

### Claim 39 (depends on 1)

The process of claim 1 wherein Ar1 is unsubstituted phenyl.

### Claim 40 (depends on 1)

The process of claim 1 wherein Ar1 is monosubstituted phenyl wherein the substituent is a halogen.

### Claim 41 (depends on 1)

The process of claim 1 wherein Ar1 is a disubstituted chloroalkylphenyl.

### Claim 42 (depends on 1)

The process of claim 1 wherein Ar2 is substituted or unsubstituted thiophene or furan.

### Claim 43 (depends on 42)

The process of claim 42 wherein Ar2 is unsubstituted thiophene.

### Claim 44 (depends on 1)

The process of claim 1 wherein the 3,5-disubstituted-1,2,4-oxadiazole is 3-phenyl-5-(2-thienyl)-1,2,4-oxadiazole, or a salt thereof.

### Claim 45 (depends on 28)

The process of claim 28 wherein the alcoholic solvent is methanol.