# US 9,751,835 B2 · Processes and intermediates for preparing indole pharmaceuticals

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- Number: US 9,751,835 B2
- Document ID: US9751835B2
- Status: Granted
- Kind: B2
- Application number: 14/890,514
- Filed: 2014-05-13
- Published: 2016-04-21
- Granted: 2017-09-05
- Earliest claimed: 2013-05-15
- Assignees: Indiana University Research and Technology Corporation
- Applicants: Indiana University Research and Technology Corporation
- Inventors: James R. McCarthy
- Web page: https://patentgrep.com/patent/US9751835B2

## CPC

- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- B01J 23/44: Palladium
- C07C 249/16: of hydrazones
- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The invention described herein pertains to processes and intermediates for preparing indole containing pharmaceuticals, particularly to processes and intermediates for preparing selective estrogen receptor modulators, such as bazedoxifene.

## Claims

### Claim 1

A process for preparing a compound of the formula
or a pharmaceutically acceptable salt thereof,
comprising:
(d) contacting a compound of the formula
with an acid; or
(c) contacting a first compound of the formula
with a second compound of the formula
or a salt thereof, and a base; or
(b) contacting a first compound of the formula
or a salt thereof, with a reagent capable of converting the hydroxyl group into a leaving group to form a second compound of the formula
or a salt thereof, where L is the leaving group; or
(a) contacting a first compound of the formula
with a second compound of the formula
Ar2—NHNH2
or a salt thereof; or
a combination of any of the foregoing steps; wherein
Ar1 and Ar2 are each aryl, each of which is independently optionally substituted;
Ar3 is a group of the formula
wherein n is 2, 3, 4, or 5; and each RN is independently selected from hydrogen, alkyl, heteroalkyl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted, or both RN and the attached nitrogen are taken together to form a cycloheteroalkyl;
RA is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl;
RB is hydrogen, or optionally substituted alkyl or optionally substituted arylalkyl; and
R2 is hydrogen, or represents one or more optional substituents.

### Claim 2 (depends on 1)

The process of claim 1, wherein the second compound in step (a) is a salt; and step (a) is performed in the presence of less than about 1 equivalent of a base.

### Claim 3 (depends on 2)

The process of claim 2, wherein the base is an inorganic base.

### Claim 4 (depends on 1)

The process of claim 1, wherein the reagent in step (b) capable of converting the hydroxyl group into a leaving group is a halogenating agent.

### Claim 5 (depends on 1)

The process of claim 1,
wherein the base in step (c) is a hydride base.

### Claim 6 (depends on 1)

The process of claim 1, wherein the acid in step (d) is a carboxylic acid.

### Claim 7 (depends on 1)

The process claim 1, wherein Ar1 and Ar2 are each independently a protected phenol.

### Claim 8 (depends on 7)

The process of claim 7, wherein Ar1 and Ar2 are 4-benzyloxyphenyl.

### Claim 9 (depends on 8)

The process of claim 8 further comprising, contacting the compound of the formula
with a reducing agent.

### Claim 10 (depends on 9)

The process of claim 9, wherein the reducing agent is hydrogen gas in the presence of a metal catalyst, and the metal catalyst is palladium on carbon, to provide a deprotected phenol compound of the formula

### Claim 11 (depends on 1)

The process of claim 1, wherein the compound of the formula
or a pharmaceutically acceptable salt thereof, has the formula
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 10)

The process of claim 10, further comprising crystallizing the deprotected phenol compound in the presence of an acid, or a carboxylic acid, or acetic acid to form an acid addition salt thereof.

### Claim 13 (depends on 1)

The process of claim 1, wherein RA is methyl.

### Claim 14 (depends on 1)

The process of claim 1, wherein RB is hydrogen.

### Claim 15 (depends on 1)

The process of claim 1, wherein Ar3 is a radical of the formula

### Claim 16 (depends on 1)

The process of claim 1, wherein the first compound of step (c) is of the formula
or a salt thereof.

### Claim 17 (depends on 1)

The process of claim 1, wherein the second compound of step (c) is of the formula
or a salt thereof.

### Claim 18 (depends on 1)

The process of claim 1,
wherein the compound of step (d) is of the formula
or a salt thereof.

### Claim 19 (depends on 3)

The process of claim 3, wherein the inorganic base in step (a) is NaHCO3.

### Claim 20 (depends on 4)

The process of claim 4, wherein the halogenating agent of step (b) is PBr3.

### Claim 21 (depends on 5)

The process of claim 5, wherein the hydride base of step (c) is NaH.

### Claim 22 (depends on 6)

The process of claim 6, wherein the carboxylic acid of step (d) is acetic acid.