# US 2013/0281702 A1 · Methods For Preparing Fentanyl And Fentanyl Intermediates

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- Number: US 2013/0281702 A1
- Document ID: US20130281702A1
- Status: Published application
- Kind: A1
- Application number: 13/868,729
- Filed: 2013-04-23
- Published: 2013-10-24
- Earliest claimed: 2012-04-24
- Inventors: Jonathan P. Pease; Anthony J. LePine; Catherine M. Smith
- Web page: https://patentgrep.com/patent/US20130281702A1

## CPC

- C07D 211/58: attached in position 4
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A method and an intermediate are provided for preparing fentanyl. Aniline and 1-phenylethyl-4-piperidone are reacted with a borane complex, in a lower C1-C4 alcoholic solvent, in the presence of an alkanoic acid. The reaction mixture is then treated with a hydrohalic acid to precipitate 4-anilino-N-phenethyl-4-piperidine (ANPP) as the bis-hydrohalide salt in high yield and purity. This ANPP salt may be directly treated with propionyl halide to produce fentanyl, or the ANPP salt may be converted to the free base of ANPP and similarly treated with propionyl halide to produce fentanyl.

## Claims

### Claim 1

A method for preparing a compound of formula (II) or a salt thereof:
the method comprising:
(a) reacting aniline with a compound of formula (IV)
and
(b) adding a complex of formula D→A to produce the compound of formula (II), wherein D is a group of atoms having an electron donor atom, and A has formula (III):
wherein R1, R2, and R3 are independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, aryloxy, and wherein at least one of R1, R2, and R3 is hydrogen.

### Claim 2 (depends on 1)

The method of claim 1 wherein:
D is heterocyclic.

### Claim 3 (depends on 2)

The method of claim 2 wherein:
the electron donor atom is selected from nitrogen, oxygen, or sulfur.

### Claim 4 (depends on 2)

The method of claim 2 wherein:
the electron donor atom is nitrogen.

### Claim 5 (depends on 1)

The method of claim 1 wherein R1, R2, and R3 are hydrogen.

### Claim 6 (depends on 1)

The method of claim 1 wherein:
D is selected from substituted or unsubstituted pyridine, substituted or unsubstituted aniline, or substituted or unsubstituted amine.

### Claim 7 (depends on 1)

The method of claim 1 wherein:
D is 5-ethyl-2-methylpyridine, and
R1, R2, and R3 are hydrogen.

### Claim 8 (depends on 1)

The method of claim 1 further comprising:
adding a C1-C4 alcoholic solvent in step (b).

### Claim 9 (depends on 1)

The method of claim 1 further comprising:
adding an organic acid in step (b).

### Claim 10 (depends on 8)

The method of claim 8 wherein:
the organic acid is an alkanoic acid of C1-C8.

### Claim 11 (depends on 8)

The method of claim 8 wherein:
the organic acid is acetic acid.

### Claim 12 (depends on 1)

The method of claim 1 further comprising:
(c) adding a mineral acid at completion of reaction thereby crystallizing out a salt of the compound of formula (II).

### Claim 13 (depends on 12)

The method of claim 12 wherein:
the mineral acid is a hydrohalic acid.

### Claim 14 (depends on 12)

The method of claim 12 wherein:
the mineral acid is hydrochloric acid.

### Claim 15

A method for preparing a compound of formula (I):
the method comprising:
(a) reacting aniline with a compound of formula (IV)
and
(b) adding a complex of formula D→A, wherein D is a group of atoms having an electron donor atom, and A has formula (III):
wherein R1, R2, and R3 are independently selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, aryloxy, and wherein at least one of R1, R2, and R3 is hydrogen; and
(c) adding a propionyl halide or propionic anhydride to produce the compound of formula (I).

### Claim 16 (depends on 15)

The method of claim 15 wherein:
step (b) further comprises adding a mineral acid thereby crystallizing out a salt of a compound of formula (II):

### Claim 17 (depends on 16)

The method of claim 16 wherein the mineral acid is a hydrohalic acid.

### Claim 18 (depends on 15)

The method of claim 15 wherein:
the propionyl halide is propionyl chloride.

### Claim 19 (depends on 15)

The method of claim 15 wherein:
D is heterocyclic, and the electron donor atom is nitrogen.

### Claim 20 (depends on 15)

The method of claim 15 wherein:
D is selected from substituted or unsubstituted pyridine, substituted or unsubstituted aniline, substituted or unsubstituted amine.

### Claim 21 (depends on 15)

The method of claim 15 wherein:
D is 5-ethyl-2-methylpyridine, and
R1, R2, and R3 are hydrogen.