ITMI20091838A1 - ASYMMETRIC SYNTHESIS PROCESS OF ESOMEPRAZOLE AND ITS SALTS - Google Patents

Description

Applicant: FIS FABBRICA ITALIANA SINTETICI

Title: "PROCESS OF ASYMMETRIC SYNTHESIS OF ESOMEPRAZOLE AND ITS SALTS"

Description

The object of the present invention is a synthesis process of Esomeprazole or of (S) - (-) - Omeprazole and its salts.

State of the art

Esomeprazole is a pharmaceutical active ingredient classified as an acid pump inhibitor. Other active ingredients also belonging to the Prazoli family, such as Omeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole, Rabeprazole, Picoprazole and Iraprazole, belong to the same therapeutic category. These active ingredients act by limiting gastric acid secretion.

Esomeprazole is marketed by AstraZeneca and its licensees as a magnesium trihydrate salt under the name of Nexium <®> and, to a limited extent, as a sodium salt under the name of Nexium IV <®>.

Esomeprazole is formulated in delayed release capsules of 20 mg or 40 mg equivalent base and the recommended daily dose is 20 mg / day.

Esomeprazole of formula (I)

it is characterized by a heterocyclic 1H-benzimidazole system, by a (pyridin-2-yl) methyl group and by an optically active sulfoxide group, in particular of S configuration and with negative optical rotation.

The aforementioned groups constitute the skeleton of all the active ingredients belonging to the Prazoli family which therefore differ in the substituents of both aromatic systems and from the sulfoxide group which may or may not be optically active.

The corresponding racemate of Esomperazole is in fact the active ingredient Omeprazole, hence that Esomeprazole is also called (S) - (-) - Omeprazole or (S) -Omeprazole.

Names that chemically define Esomeprazole are 1H-Benzimidazole, 5-methoxy-2 - [(S) - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] - or 5-methoxy-2 - [(S) - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-Benzimidazole.

A process of synthesis of Esomeprazole of the known art described in EP652872 includes the optical resolution of diasteromeric derivatives of Omeprazole, separated by chromatography or fractional crystallization. The efficiency of the process is inherently very limited.

The process described in WO9602535 provides for an enantioselective oxidation process of prochiral heterocyclic sulphides mediated by chiral complexes of Titanium and in the presence of a base. The typical conditions of the process involve the use of Titanium isopropoxide, L-Diethyltartrate and Cumene hydroperoxide, a reactive classified as Toxic.

The oxidation reaction, in addition to having to be enanti-specific, must be carried out in conditions such that the product can be recovered since the instability of the class of products resulting from the oxidation reaction reported here is well known:

Summary of the invention

The problem addressed by the present invention is therefore that of providing a different and efficient process for the preparation of Esomeprazole and its salts which allows to at least partially obviate the drawbacks mentioned above with reference to the known art.

This problem is solved by a process of synthesis and isolation of Esomeprazole as outlined in the attached claims, the definitions of which form an integral part of the present description.

Further features and advantages of the process according to the invention will result from the following description of preferred embodiment examples, given for indicative and non-limiting purposes.

Detailed description of the invention

The present invention relates to a synthesis process of Esomeprazole of formula (I) and its salts:

(THE)

through the following procedure, which involves the asymmetric oxidation of the intermediate Pyrmetazole of formula (II)

()

carried out by means of a peroxide and in the presence of a complex of Vanadium (IV) with a chiral ligand.

It was surprisingly found that the use of chiral ligands such as the Schiff bases of formula (III) of Salicylaldehyde and its derivatives with chiral β-Aminoalcohols

where X1 and X2 can be independently H, F, Cl, Br, I, NO2, C1-C4 linear or branched alkyls and R1 and R2 can be independently H, C1-C4 linear or branched alkyls, linear C1-C4 carboxylic esters or branched, phenyl, benzyl, naphthyl or the union of R1 with R2 gives rise to a cyclopentane or a cyclohexane or a chiral cycloindane, allow to carry out the oxidation reaction of the Pyrmetazole of formula (II), by means of a complex of Vanadium (IV) and a peroxide to give Esomeprazole avoiding the use of toxic reagents.

In one embodiment, the peroxides that can be used are, by way of example but not limiting the invention, hydrogen peroxide, tert-butyl hydroperoxide (t-BuOOH), 3-Chloroperbenzoic acid (m-CPBA), etc.

In one embodiment, the oxidation reaction is carried out in an organic solvent, preferably in Ethanol, in Chloroform or in Methylene chloride.

In one embodiment, the oxidation reaction is carried out in an organic solvent, preferably in Ethanol, in Chloroform or in Methylene chloride.

The reaction temperature is maintained between 0 ° C and 30 ° C, and preferably between 15 ° C and 20 ° C.

Vanadium (IV) is used as a salt of Vanadium (IV), in particular, Vanadium (IV) oxyacetylacetonate (i.e. Vanadyl acetylacetonate) of formula VO (C5H7O2) 2 can be used.

The amount of Vanadium (IV) used is comprised between 0.001 and 0.1 molar equivalents with respect to the pyrmetazole substrate to be oxidized.

In particular, the oxidation can be carried out using between 0.005 and 0.01 molar equivalents of Vanadium (IV).

The Schiff-based chiral ligand of formula (III) of Salicylaldehyde and its derivatives with chiral β-Aminoalcohols is prepared separately by reaction of Salicylaldehyde or its derivatives with a suitable chiral β-Aminoalcohol by means of known organic synthesis techniques.

The amount of chiral ligand used is between 0.5 and 5 molar equivalents with respect to Vanadium (IV), more preferably between 1.0 and 3.0 equiv. molars, and preferably it can be about 1.5 equiv. molars. The preparation of the chiral Vanadium (IV) -Legant complex can be performed separately or, alternatively, in situ, in the presence of Pyrmetazole.

The preparation of the Vanadium (IV) -chiral binder complex can be carried out by mixing the Vanadium (IV) salt with the Schiff-based chiral binder, adding the solvent and stirring at room temperature for a time between 15 minutes and 10 hours. .

Once the preparation of the chiral Vanadiolegante complex is finished, the solution containing it is added to a solution containing Pyrmetazole, then the oxidant peroxide is added.

If hydrogen peroxide is used as peroxide, it must have a titer of less than 40% and preferably about 35%.

The amount of peroxide used to conduct oxidation is between 1 and 3 eq. molars with respect to pyrmetazole and preferably can be about 2.0 molar equivalents.

The addition of the oxidant to the mixture containing the Vanadium (IV) catalyst complex-chiral binder and the Pyrmetazole substrate can be carried out one-pot or it can be dosed in portions or dropped in a time ranging from 5 minutes to 5 hours, more preferably between 10 minutes and an hour.

The reaction normally comes to completion within 1-5 hours from the end of the addition and can be quenched by adding an aqueous solution of sodium thiosulfate.

In one embodiment, the product can then be extracted by simple phase separation or after adding Isopropylacetate depending on the solvent used to conduct the reaction and its relative miscibility with water.

The organic extracts are combined, washed with water and concentrated to a small volume. The residue is taken up with 2 volumes of Ethanol, it is cooled to 0/5 ° C for 2 hours then the suspension is filtered.

The solid is washed with cold ethanol and dried under vacuum.

The following examples illustrate the surprising effect of the Schiff-based chiral ligand of Salicylaldehyde of formula (III) on the enantioselectivity of the oxidation reaction of Pyrmatazole to Esomeprazole by means of a peroxide and in the presence of the relative complex with Vanadium (IV).

The optical purity of the Esomeprazole obtained can be conveniently increased by the crystallization processes described in WO9702261 or the chromatographic ones described in WO2003051867.

EXPERIMENTAL PART

Example 1 - Synthesis of Esompraozole (I) - exemplary of the invention

S h of i t i

They are loaded into a 250 mL flask

5 g of Pyrmetazole and 30 mL of Ethanol.

The mixture was stirred at T = 30/35 ° C until dissolution. Separately, a solution of 32 mg of Vanadium (IV) oxyacetyl acetonate (vanadyl acetylacetonate) of formula OV (C5H7O2) 2 and 45 mg of 2 - [(E) - {[(1R) -2-hydroxy-1-phenylethyl is prepared ] imino} methyl] phenol or Schiff Base chiral ligand of formula (III) of Salicylaldehyde with (2R) -2-amino-2-phenylethanol

where therefore R1 = phenyl, R2 = H, X1 = H, X2 = H (1.5 mol equiv. with respect to the catalyst OV (C5H7O2) 2) and 5 mL of Ethanol are added.

The mixture is kept under stirring at T = 25/30 ° C for 1 hour and then the two solutions are combined. It is cooled to T = 15/20 ° C and added, keeping the T below 20 ° C,

3 g of hydrogen peroxide at 35% w / w (2.0 molar equiv. With respect to the substrate Pyrmetazole)

The reaction is quenched after 3 hours by adding a solution of 25 mL of water and 3.5 g of sodium thiulphate at T = 15/20 ° C. Then 50 mL isopropyl acetate is added and the phases are separated. The aqueous phase is re-extracted with 20 mL of Isopropylacetate and the combined organic phases are washed with water. The phases are separated and the organic phase is concentrated to a residue which is taken up with 10 mL of ethanol. The suspension is cooled to T = 0/5 ° C, kept stirred for one hour, then it is filtered and the solid is washed with 10 mL of cold Ethanol.

The product is dried under vacuum at 45 ° C for 8 hours. 3.2 g of white solid are obtained.

Example 2 - Synthesis of Esomprazole (I)

The preparation described in example 1 was repeated under the same conditions but changing the chiral ligand Schiff Base of Formula (III).

Table 1 shows the e.e. percentages of the obtained configuration product (S).

Table 1

Example 3 - Synthesis of Esomeprazole (I) - comparative of the invention

The preparation described in example 1 was repeated under the same conditions but omitting the addition of the Schiff-based chiral ligand of Saliciladeide. The product obtained was isolated and the chiral HPLC analysis confirmed the absence of enantiometric excess confirming the absence of experimental errors and the actual chiral induction due to the ligand of the invention.

Example 4 - Synthesis of Esomeprazole Magnesium

86 g of Esomeprazole obtained as per the procedure reported in Example 1 on a larger scale and 400 mL of toluene are loaded into a flask. The solution is heated to 30 ° C and, keeping the T below 40 ° C, a solution of 23.0 g of Potassium Methoxide in 150 mL of Methanol is dropped in about 1 hour.

After 2 hours stirring at room temperature, the solution is filtered and the product is washed with 200 mL of Toluene and then with 100 mL of Methanol. 71 g of Esomeprazole Potassium are obtained (yield 68%). The product is taken up with 100 mL of methanol and 24.0 g of MgSO4 heptahydrate are added. The mixture is left under stirring at room temperature for two hours and is then filtered. The filtrate is concentrated to a small volume and 350 mL of acetone are dropped under stirring. The suspension is left under stirring for one night, then it is filtered, the product is washed with acetone. 60 g of Esomeprazole wet Magnesium salt are obtained.

Example 5 - Synthesis of Esomeprazole Magnesium dihydrate 20 g of Esomeprazole Magnesium obtained as per Example 4 are placed in an oven and dried under vacuum at 30 ° C up to a Karl Fischer value of 4.8%. 17 g of Esomeprazole Magnesium dihydrate of form l (IV) are obtained

(IV)

Example 6 - Synthesis of Esomeprazole Magnesium trihydrate

20 g of Esomeprazole Magnesium obtained as in Example 4 are placed in a flask and 60 mL of water are added. The suspension is left under stirring for 4 hours at 40 ° C. The suspension is filtered and the product is dried under vacuum to a Karl Fischer value equal to 7.6%. 18 g of Esomeprazole Magnesium trihydrate are obtained.

On the basis of what has been described above, the person skilled in the art will be able to appreciate the advantages offered by the process of the present invention.

In particular, it will be appreciated how the use of the conditions object of the present invention make it possible to obtain Esomeprazole with a different procedure than that described in the known art which does not provide for the use of toxic reagents such as Cumene hydroperoxide.

Claims (22)

CLAIMS L. Synthesis process of Esomeprazole of formula (I): comprising the asymmetric oxidation of the intermediate Pyrmetazole of formula (II) (II) carried out by means of a peroxide and in the presence of a Vanadium complex (IV) with a Schiff-based chiral ligand of formula (III) of Salicylaldehyde and its derivatives with chiral β Aminoalcohols where X1 and X2 can be independently H, F, Cl, Br, I, NO2, C1-C4 linear or branched alkyls and R1 and R2 can be independently H, C1-C4 linear or branched, linear or branched C1-C4 carboxylic esters, phenyl, benzyl or naphthyl or the union of R1 with R2 gives rise to a cyclopentane or a cyclohexane or a chiral cycloindane. 2. Process according to claim 1, wherein X1 and X2 can be independently linear or branched H, I, C1-C4 alkyls. 3. Process according to claims 1 or 2 wherein R1 and R2 can be independently H, C1-C4 linear or branched alkyls, linear or branched C1-C4 carboxylic esters, phenyl, benzyl or naphthyl or the union of R1 with R2 gives a cyclopentane or a cyclohexane or a chiral cycloindane. 4. Process according to claim 1 wherein R1 and R2 can be independently H, C1-C4 linear or branched alkyls, linear or branched C1-C4 carboxylic esters or phenyl. 5. Process according to claim 1 wherein R1 can be independently H, C1-C4 linear or branched alkyls, phenyl and R2 is H. 6. Process according to claim 4 or 5 wherein X1 and X2 can be independently H, F, Cl, Br, I, NO2, C1-C4 linear or branched alkyls. 7. Process according to claims 4 or 5 wherein X1 and X2 can be independently H, I. Process according to any one of claims 1 to 7, wherein the reaction is carried out in an organic solvent. 9. Process according to claim 8, wherein the reaction is carried out in Ethanol, in Chloroform or Methylene chloride. 10. Process according to any one of claims 1 to 9, wherein the reaction is carried out between 0 ° C and 30 ° C. 11. Process according to any one of claims 1 to 10, wherein Vanadium (IV) is used as a salt. 12. Process according to claim 11, wherein Vanadium (IV) is employed as Vanadium (IV) oxyacetylacetonate. 13. Process according to claim 11 or 12, wherein the amount of Vanadium (IV) used is comprised between 0.001 and 0.1 molar equivalents with respect to the pyrmetazole substrate. 14. Process according to claim 13, wherein the amount of Vanadium (IV) used is comprised between 0.005 and 0.01 molar equivalents. 15. Process according to any one of claims 1 to 14, wherein the amount of chiral ligand of formula (III) used is between 0.5 and 5 molar equivalents with respect to Vanadium (IV). 16. Process according to claim 15, wherein the amount of chiral ligand of formula (III) used is comprised between 1.0 and 3.0 equiv. molars compared to Vanadium (IV). 17. Process according to claim 16, wherein the amount of chiral ligand of formula (III) used is about 1.5 equiv. molars compared to Vanadium (IV). 18. Process according to any one of claims 1 to 17, wherein the preparation of the Vanadium (IV)-chiral ligand complex of formula (III) can be carried out separately. 19. Process according to any one of claims 1 to 17, wherein the preparation of the Vanadium (IV)-chiral ligand complex of formula (III) can be carried out in the presence of the pyrmetazole of formula (II). 20. Process according to any one of claims 1 to 19, wherein the peroxide used is selected from hydrogen peroxide, t-butyl hydroperoxide, 3-chloropebenzoic acid. 21. Process according to claim 20, wherein the amount of peroxide used is between 1 and 3 eq. molars compared to pyrmetazole. 22. Process according to any one of claims 1 to 21, in which the addition of the peroxide to the mixture containing the catalyst complex Vanadium (IV) -chiral binder and the Pyrmetazole substrate is carried out one-pot or dosed in portions.