# US 7,612,219 B2 · 11—[ (Z) -3- (dimethylamino) propylidene]—6, 11-dihydro-dibenz [B,E] oxepin-2-YI ]—acetic acid

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- Number: US 7,612,219 B2
- Document ID: US7612219B2
- Status: Granted
- Kind: B2
- Application number: 11/658,600
- Filed: 2005-07-11
- Published: 2009-01-01
- Granted: 2009-11-03
- Earliest claimed: 2004-07-28
- Assignees: Urquima, S.A.
- Inventors: Joan Bosch Cartés; Jordi Bachs Roca; Antonia Ma Gomez Gomez; Yolanda Alonso Marin; Mercè Bessa Sanchez
- Web page: https://patentgrep.com/patent/US7612219B2

## CPC

- C07C 69/734: Ethers
- C07C 69/738: Esters of keto-carboxylic acids {or aldehydo-carboxylic acids}
- C07C 217/48: the carbon skeleton being unsaturated and containing rings
- C07C 229/34: the carbon skeleton containing six-membered aromatic rings
- C07D 313/12: [b,e]-condensed
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Process for the preparation of olopatadine (I), which comprises reacting a compound of formula (V) in the presence of a palladium catalyst to provide a compound of formula (VI), wherein the acid protecting group is removed to provide the compound of formula (I) and if desired, transformation into its salts.

## Claims

### Claim 1

A process for the preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydro-dibenz-[b,e]oxepin-2-yl acetic acid of formula 1 or a pharmaceutically acceptable salt thereof:
comprising reacting a compound of formula V,
wherein one of R1 and R2 is halogen and the other is CH═CH—CH2—CH2—N(CH3)2 and R3 is an acid protecting group, in the presence of a palladium catalyst, to obtain a compound of formula VI,
and removing the acid protecting group R3 of said compound of formula VI to obtain the compound of formula I; and if desired, converting the compound of formula I into a pharmaceutically acceptable salt.

### Claim 2 (depends on 1)

A process for the preparation of 11-[(Z)-3-(dimethylamino)propylidene]-6,11-dihydro-dibenz-[b,e]oxepin-2-yl acetic acid of formula I or a pharmaceutically acceptable salt thereof:
comprising reacting a compound of formula IX
with a compound of formula X,
wherein R6 is a leaving group, one of R4 and R5 is halogen and the other is CHO and R3 is as defined in claim 1, in the presence of a base to obtain a compound of formula VII,
wherein R4 is as defined for formula IX and R5 and R3 are as defined for formula X, reacting said compound of formula VII with a compound of formula VIII or a salt thereof,
wherein X is iodine, chlorine or bromine, in the presence of base to obtain a compound of formula V
wherein R1, R2 and R3 are as defined in claim 1, reacting said compound of formula V in the presence of palladium catalyst to obtain a compound of formula VI
and removing the acid protecting group R3 of said compound of formula VI to obtain the compound of formula I; and if desired, converting the compound of formula I into a pharmaceutically acceptable salt.

### Claim 3 (depends on 1, 2)

A process according to claim 1 or 2, wherein R3 is C1-C4 alkyl.

### Claim 4 (depends on 1, 2)

A process according to claim 1 or 2, wherein the palladium catalyst is palladium acetate.

### Claim 5 (depends on 1, 2)

A process according to claim 1 or 2, wherein R1 is halogen and R2 is (E)-CH═CH—CH2—CH2—N(CH3)2.

### Claim 6 (depends on 1, 2)

A process according to claim 1 or 2, wherein R1 is (Z)-CH═CH—CH2—CH2—N(CH3)2 and R2 is halogen.

### Claim 7 (depends on 1)

A process according to claim 1, wherein said compound of formula V is prepared from a compound of formula VII,
wherein one of R4 and R5 is halogen and the other is CHO and R3 is an acid protecting group by reaction with a compound of formula VIII or a salt thereof.
wherein X is iodine, chlorine or bromine, in the presence of a base.

### Claim 8 (depends on 7)

A process according to claim 7, wherein X is iodine.

### Claim 9 (depends on 7)

A process according to claim 7 wherein one of R4 and R5 is iodine and the other is CHO.

### Claim 10 (depends on 9)

A process according to claim 9, wherein R4 is iodine and R5 is CHO and the reaction is carried out in the presence of a lithium base.

### Claim 11 (depends on 10)

A process according to claim 10, wherein lithium base is lithium bis(trimethylmethylsilyl)amide.

### Claim 12 (depends on 9)

A process according to claim 9, wherein R4 is CHO and R5 is iodine and the reaction is carried out in the presence of a sodium base.

### Claim 13 (depends on 12)

A process according to claim 12, wherein the sodium base is sodium bis(trimethylsilyl)amide.

### Claim 14 (depends on 7)

A process according to claim 7 wherein said compound of formula VII is prepared from a compound of formula IX
by reaction with a compound of formula X
wherein R6 is a leaving group, R3 is an acid protecting group and one of R4 and R5 is a halogen and the other is CHO in the presence of a base.

### Claim 15 (depends on 14)

Process according to claim 14, wherein R3 is C1-C4 alkyl.

### Claim 16 (depends on 14)

A process according to claim 14, wherein R6 is halogen.

### Claim 17 (depends on 7)

Process according to claim 7, wherein R3 is C1-C4 alkyl.

### Claim 18 (depends on 14, 15)

A process according to claim 14 or 15, wherein the base for the preparation of said compound of formula VII from said compound of formula IX is potassium carbonate.

### Claim 19 (depends on 14)

Process according to claim 14, wherein the halogen is iodine.

### Claim 20 (depends on 18)

Process according to claim 18, wherein the halogen is iodine.