Process for obtaining olopatadine and intermediates

1. A process for obtaining a compound of general formula (II)

wherein

Y is

OR 1 , wherein R 1 is C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, aryl, or heterocycle; or

NR 2 R 3 , wherein R 2 and R 3 , independently from each other, are C 1 -C 7 alkyl, aryl, or R 2 and R 3 together with the nitrogen atom to which they are bound form a heterocycle of 3 to 7 members,

or a solvate or a salt thereof,

comprising

a) reacting a compound of general formula (III)

wherein Y has the previously mentioned meaning,

 with a Wittig reagent selected from the group consisting of a (3-dimethylaminopropyl)triphenylphosphonium halide and salts thereof, under Wittig reaction conditions, in the presence of a base in a reaction medium comprising an organic solvent, for obtaining a compound of general formula (II); and

b) optionally, converting the compound of general formula (II) into a solvate or into a salt thereof.

2. Process according to claim 1 , wherein said Wittig reagent is (3-dimethylaminopropyl)triphenylphosphonium bromide or a salt thereof.

3. Process according to claim 1 , wherein the ratio between said Wittig reagent and said compound of general formula (III) is comprised between 1 and 2 equivalents of Wittig reagent per equivalent of compound of general formula (III).

4. Process according to claim 1 , wherein said base is selected from the group consisting of a metal hydride, a metal alkoxide, a metal amide, an amide with great steric volume, and mixtures thereof.

5. Process according to claim 4 , wherein said base is selected from the group consisting of lithium hydride, sodium hydride, potassium hydride, calcium hydride, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide and mixtures thereof.

6. Process according to claim 1 , wherein said organic solvent is selected from the group consisting of an aromatic solvent, a halogenated solvent, an ether, a polar aprotic solvent, and mixtures thereof.

7. Process according to claim 6 , wherein said organic solvent is selected from the group consisting of toluene, xylene, methylene chloride, diisopropyl ether, di-tert-butyl ether, tetrahydrofuran (THF), methyl-tetrahydrofuran (Me-THF), dioxane, dimethylformamide (DMF), dimethylacetamide (DMA), and mixtures thereof.

8. Process according to claim 1 , wherein said Wittig reaction is carried out using as base a metal alkoxide in a reaction medium comprising THF as solvent or using as base a metal alkoxide in a reaction medium comprising toluene as solvent.

9. Process according to claim 8 , wherein said Wittig reaction is carried out using as base potassium tertbutoxide in a reaction medium comprising toluene as solvent.

10. Process according to claim 1 , wherein said reaction medium further comprises an organic polar aprotic cosolvent.

11. Process according to claim 10 , wherein said organic polar aprotic cosolvent is selected from the group consisting of dimethylacetamide (DMA), dimethylformamide (DMF), N-methylpyrrolidone (NMP), N-methylmorpholine (NMM), and mixtures thereof.

12. Process according to claim 1 , wherein said base is sodium hydride and said medium comprises a solvent and an organic polar aprotic cosolvent.

13. Process according to claim 1 , wherein said Wittig reaction is carried out using as base a metal hydride in a reaction medium comprising THF as solvent and DMA as organic polar aprotic cosolvent.

14. Process according to claim 1 , wherein the obtained compound of formula (II) is transformed into Olopatadine, of formula (I)

or a solvate or a salt thereof,

through a process comprising

a) subjecting to hydrolysis the compound of general formula (II)

wherein

Y is

OR 1 , wherein R 1 is C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, aryl, arylalkyl, or heterocycle; or

NR 2 R 3 , wherein R 2 and R 3 , independently from each other, are C 1 -C 7 alkyl, aryl, or R 2 and R 3 together with the nitrogen atom to which they are bound form a heterocycle of 3 to 7 members,

and, optionally,

b) converting the obtained compound of formula (I) into a salt or solvate thereof.

15. A process for obtaining (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid isopropyl ester of formula (IIa)

and salts thereof,

comprising

a) reacting a compound of formula (III):

with isopropyl alcohol in an acid reaction medium comprising at least an organic solvent for obtaining the compound of formula (IIIb)

b) subjecting said compound of formula (IIIb) to a Wittig reaction with a Wittig reagent selected from the group consisting of a (3-dimethyl-aminopropyl)-triphenylphosphonium halide and salts thereof, under Wittig reaction conditions, in the presence of a base, in a medium comprising an organic solvent, for obtaining said compound of formula (IIa); and, optionally

c) converting the compound of formula (IIa) into a salt thereof.

16. A compound selected from the group consisting of:

a) (11Z)-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid isopropyl ester of formula (IIa)

and

b) (11Z)-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid benzyl ester of formula (IIb)

17. Process according to claim 1 , wherein said Wittig reaction is carried out using as base a metal alkoxide in a reaction medium comprising THF as solvent.

18. Process according to claim 17 , wherein said Wittig reaction is carried out using as base potassium tertbutoxide.