# US 2010/0168151 A1 · Novel processes for preparing 6-(difluoromethoxy)[1]benzofuro[3,2-c]pyridine-9-carbaldehyde, a novel intermediate for the synthesis of pde iv inhibitors

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- Number: US 2010/0168151 A1
- Document ID: US20100168151A1
- Status: Published application
- Kind: A1
- Application number: 12/601,245
- Filed: 2008-05-21
- Published: 2010-07-01
- Earliest claimed: 2007-05-22
- Assignees: Glenmark Pharmaceuticals S.A.
- Inventors: Laxmikant Atmaram Gharat; Jitendra Maganbhai Gajera; Sandip Damodar Patil; Suresh M. Kadam
- Web page: https://patentgrep.com/patent/US20100168151A1

## CPC

- C07D 491/048: the oxygen-containing ring being five-membered
- A61P 11/06: Antiasthmatics
- C07D 213/89: with hetero atoms directly attached to the ring nitrogen atom
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel processes for preparing 6-(difluoromethoxy)[1] benzofuro[3,2-c]pyridine-9-carbaldehyde, which is a novel and useful intermediate for preparing compounds with PDE4 inhibitory activity, such as 3,5-dichloro-4-(6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-1-pyridiniumolate.

## Claims

### Claim 1

A process for preparing a compound of formula (10):
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl, or R1 and R2 together, with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclyl optionally containing one or more heteroatoms selected from O, S and N; and
P is selected from an optionally substituted benzyl, alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxyalkyl, the method comprising the steps of:
(a) converting a compound of formula (5) to a compound of formula (6)
and
(b) converting a compound of formula (6) to a compound of formula (10) or an N-oxide or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The process of claim 1, wherein compound of formula (5) is prepared by cyclizing a compound of formula (4):
wherein P is as defined above.

### Claim 3 (depends on 2)

The process of claim 2, wherein compound (4) is prepared by reacting a compound of formula (2) with a compound of formula (3)
wherein P is as defined above.

### Claim 4 (depends on 3)

The process of claim 3, wherein the reaction of the compound of formula (2) with the compound of formula (3) is performed in the presence of one or more metal halides, metal hydrides, metal alkoxides or a mixture thereof.

### Claim 5 (depends on 1)

The process of claim 1, wherein step (a) comprises reacting the compound of formula (5) with a metal powder and optionally one or more organic acids.

### Claim 6 (depends on 5)

The process of claim 5, wherein the metal powder is iron powder, zinc powder, or any mixture thereof, and the organic acid is acetic acid, trifluoroacetic acid, propionic acid, or any mixture thereof.

### Claim 7 (depends on 1)

The process of claim 1, wherein step (a) comprises (i) deprotecting the compound of formula (5) to form a compound of formula (7)
and
(ii) reacting the compound of formula (7) with a difluoromethylating agent.

### Claim 8 (depends on 1)

The process of claim 1, wherein step (b) comprises:
(i) oxidizing the compound of formula (6) to form a compound of formula (8)
(ii) reacting the compound of formula (8) with 4-nitro phenol to form a compound of formula (9)
(iii) reacting the compound of formula (9) with an amine of the formula NHR1R2 to form a compound of formula (10); and
(iv) optionally converting the compound of formula (10) to an N-oxide or a pharmaceutically acceptable salt thereof.

### Claim 9

A process for preparing a compound of formula (7)
comprising deprotecting a compound of formula (5)
wherein P is selected from an optionally substituted benzyl, alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxyalkyl.

### Claim 10 (depends on 9)

The process of claim 9, further comprising converting the compound of formula (7) to a compound of formula (10):
or an N-oxide or a pharmaceutically acceptable salt thereof, wherein:
R1 and R2 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl, or R1 and R2 together, with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclyl optionally containing one or more heteroatoms selected from O, S and N; and
P is as defined above.

### Claim 11

A process for preparing a compound of formula (6),
wherein P is selected from an optionally substituted benzyl, alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxyalkyl, wherein the process comprises the step of converting a compound of the formula (5) to form the compound of formula (6)

### Claim 12 (depends on 11)

The process of claim 11, wherein the compound of formula (5) is prepared by
(i) reacting a compound of formula (2) with a compound of formula (3)
to form a compound of formula (4)
and
(ii) cyclizing the compound of formula (4) to form a compound of formula (5)

### Claim 13 (depends on 11)

The process of claim 11, wherein the compound of formula (5) is reduced to form the compound of formula (6).

### Claim 14 (depends on 11)

The process of claim 11, wherein the compound of formula (6) is formed by:
(A) deprotecting a compound of formula (5), where P is not CHF2, to form a compound of formula (7)
and
(B) reacting the compound of formula (7) with one or more difluoromethylating agents to form a compound of formula (6), where P is CHF2.

### Claim 15 (depends on 11)

The process of claim 11, further comprising converting a compound of formula (6) to a compound of formula (10), an N-oxide thereof, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The process of claim 1, wherein the compound of formula (10) or N-oxide thereof is 3,5-dichloro-4-(6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-1-pyridiniumolate.

### Claim 17 (depends on 1)

The process of claim 1, wherein the compound of formula (10) or N-oxide thereof or pharmaceutically acceptable salt thereof is 3,5-dichloro-4-(6-difluoromethoxybenzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-1-pyridiniumolate sodium.

### Claim 18

A pharmaceutical composition comprising:
(a) a compound of the formula (10)
an N-oxide or pharmaceutically acceptable salt thereof, wherein:
P is selected from an optionally substituted benzyl, alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl and silyloxyalkyl; and
R1 and R2 are independently hydrogen, alkyl, aryl, heteroaryl or heterocyclyl, or R1 and R2 together, with the nitrogen atom to which they are attached, form a 3-7 membered heterocyclyl optionally containing one or more heteroatom(s) selected from O, S and N; and
(b) a compound selected from
or a salt thereof, wherein P is as defined above.

### Claim 19 (depends on 18)

The pharmaceutical composition of claim 18, wherein the compound in component (a) is present in an amount greater than 98% by weight and the compound in component (b) is present in an amount up to 0.1% by weight, based upon 100% total weight of component (a) and (b).

### Claim 20

A compound selected from:
or salts thereof,
wherein:
P is selected from an optionally substituted benzyl, alkyl, halogenated alkyl, cycloalkyl, cycloalkylalkyl, silyl, allyl, propargyl, tetrahydropyran, alkoxyalkyl or silyloxyalkyl.