ITMI20002674A1 - CITALOPRAM PREPARATION PROCEDURE - Google Patents

Description

Description of the industrial invention entitled:

"CITALOPRAM PREPARATION PROCESS"

The present invention relates to a process for the preparation of citalopram, 1- [3- (dimethylamino) propyl] -1- (4) -fluorophenyl) -1, 3-dihydro-5-isobenzofurancarbonitrile, a well known antidepressant drug.

Background of the invention

Citalopram and other 1-dimethylaminopropyl-1-phenylphthalane derivatives (or 1- (3-dimethylaminopropyl) -1-phenyl-1,3-dihydroisobenzofurans) have been described in US 4,136,193. Citalopram has antidepressant properties (J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486) .

EP-A-474580 also describes the use of citalopram in the treatment of dementia and cerebral vascular disease.

US 4,136,193 describes a process for the preparation of Citalopram by cyclization of the compound of formula (a)

in the presence of dehydrating agent and subsequent exchange of the 5-bromine group with copper cyanide.

The starting material of formula (a) is obtained from 5-bromophthalide by two successive Grignard reactions with 4-fluorophenylmagnesium chloride and Ν, Ν-dimethylaminopropyl magnesium chloride, respectively.

A different process for the preparation of Citalopram is described in US 4,650,884 according to which an intermediate of formula (b)

it undergoes a cyclization reaction by dehydration with sulfuric acid.

The intermediate of formula (b) is prepared from 5-cyanophthalide by two successive Grignard reactions with 4-fluorophenylmagnesium halide and Ν, Ν-dimethylamino propyl magnesium halide, respectively.

Methods for the preparation of the single enantiomers of Citalopram have been described in US 4,943,590, which further describes the cyclization of the intermediate of formula (b) under basic conditions.

Subsequently WO 99/30548 describes a new synthetic process in which a compound of formula (c)

where R is a Ν, Ν-disubstituted amido-group or a 4,5-dihydro-1,3-oxazol-2-yl group, is subjected to reduction with the reducing agent DIBAL-H (diisobutylaluminium hydride) to obtain intermediate 5 -formiIe. The subsequent transformation to 5-cyan-group yields the citalopram product.

In this process, the difficulty of operating on an industrial scale with a chemical reduction reaction that involves the use of metal hydrides such as DIBAL-H is obvious, both for problems relating to the costs of this reaction and for safety problems. This reaction is generally used only on a laboratory scale.

Summary of the invention

It has now been found that citalopram can be obtained with good yields by means of the process according to claim 1, starting from a 5-formyl-phthalide (VII) acetal, according to the following scheme in which the preparation of the compound of departure (VII).

V.

The 5-carboxyphthalide (X) used as starting material is known and commercially available (Tirouflet, J .; Bull. Soc. Sci. Bretagne, 26, 35 (1951).

This compound is transformed by reaction with thionyl chloride into the corresponding chloride (IX) which is then converted into the new 5-formyl-phthalide compound of formula (VIII), with high transformation yields and excellent purity.

This reduction reaction can be obtained either by catalytic techniques (ROSENMUND reaction with H2 and Pd catalyst on carbon in an inert solvent such as cyclohexane, toluene or xylene) or by chemical reductions using lithium or sodium and aluminum hydrides (lithium triterbutoxy aluminum hydride or RcD -To the).

After preparation of the formyl group in the form of acetal (compound VII, R = methyl or ethyl), two Grignard reactions are carried out in sequence: a first reaction with 4-fluorobenzene magnesium chloride, bromide or iodide (preferably bromide)

and a second reaction with Ν,-dimethylpropylamine 3-magnesium chloride, bromide or iodide (preferably chloride).

The new intermediate of formula (VI) may not be isolated: in this case two Grignard reactions are carried out in succession obtaining directly the intermediate of formula (V).

Similarly, the new intermediates of formula (IV) and (III) obtained by hydrolysis of the intermediate of formula (V) and transformation of the 5-formiIe group (formula IV) into an oxime group (formula III) can also not be isolated. and purified.

The transformation of the 5-oxime group to the 5-cyano group is a known reaction that involves the formation of acetyloxime and the subsequent loss of acetic acid at a high temperature.

The closure of the benzofuran ring of the compound of formula (III) can be carried out both in inorganic acids such as sulfuric or phosphoric and through the formation of labile esters such as methanesulfonyl, p-toluenesulfonyl, trifluoromethanesulfonyl ester and subsequent reaction with bases such as triethylamine, dimethylamine, pyridine in non-alcoholic solvents, such as methylene chloride or tetrahydrofuran.

Surprisingly, the closure of the benzofuran ring by esterification and addition of bases simultaneously leads to the transformation of the 5-oxime group into a 5-cyano group, thus allowing the transformation of the compound of formula (III) into citalopram to be carried out directly in a single step.

In all stages of the process of the present invention, good purity of the intermediates and good yields are obtained; furthermore, the reaction conditions allow production on a large industrial scale, making the entire process economically competitive.

The compound of formula (I) can be used as a free base or preferably as a salt with a pharmacologically acceptable acid (organic or inorganic).

The process of the invention can also be used to prepare the (S) enantiomer of Citalopram.

In this case the compound of formula (III) is separated into the optically active enantiomers by means of a procedure similar to that described in US 4,943,590 in such a way as to obtain the enantiomer (S) of compound (III) which is then used in the closure of the benzofuran ring according to the methods described above.

The following examples illustrate the invention in greater detail.

Example 1

5-Chlorocarboxy-phthalide

5-carboxyphthalide (100 g, 0.56 mole) is suspended in toluene (600 ml). DMF (0.2 ml) is added and immediately thereafter thionyl chloride (106.3 g, 0.89 mol). The mixture is heated slowly under reflux of the solvent for 3 hours.

300 ml of solvent are distilled at atmospheric pressure and cooled under good stirring at a temperature of 25 ° C for one night. The crystallized product is filtered and washed with toluene.

It dries to constant weight.

Yield: 90 g (82%).

Example 2

5-Formyl-phthalide

In a nitrogen atmosphere, a solution of lithium triterbutoxy aluminum hydride (4.25 g, 0.0167 moles) in THF (15 ml) in a solution of 5-chlorocarboxphthalide (3 g, 0.0152 moles) is dropped at -78 ° C in THF (15 mi), in 30 minutes. It is kept under stirring at -70 ° C for 90 minutes. Ethyl acetate (30 ml) is added and it is slowly poured into a mixture composed of H20 (5 ml), conc. (5 ml), saturated NaCl solution (10 ml), pre-cooled to 5 ° C.

At the end of the addition, the T. int. is 15 ° C. The phases are separated and the upper organic phase is washed with acidulous water (50 ml), anhydrified and concentrated to a dry residue of 2.8 g.

It is chromatographed on Si02 eluting with a mixture of methylene chloride 98: methanol 2.

0.5 g of chromatographically pure product are obtained after chromatography.

Example 3

5-Formyl-phthalide

The 5-chlorocarbophthalide (75 g, 0.38 moles) in toluene (750 ml) is dissolved under stirring at 100 ° C and loaded into a hydrogenation reactor. Anhydrous sodium acetate (100 g; 1.14 moles), 10% anhydrous palladium on carbon catalyst (0.9 g), quinoline-S (0.5 ml) is added (J.W. Williams, Org. Syn, Cali. Vol. 3, 629,1955).

The reactor is washed with nitrogen and then pressurized to 4 bar with hydrogen. The mixture is heated under stirring at 70 ° C for 4 hours.

It is cooled to rt. and the reaction mass is discharged and heated again to 100 ° C, filtered with the pump washing the isolated salts with hot toluene (200 ml).

The filtered organic phase is concentrated to 500 ml residues and cooled at 10 ° C for 2 hours. The crystallized product is filtered and washed with a little cold toluene. It is dried under vacuum at constant weight.

Yield = 43 g (70%); HPLC purity = 99%; m.p. = 160 ÷ 162 ° C

Example 4

5-Formyl-phthalide-dimethylacetal

The 5-formyl-phthalide (22 g; 0.1 mol) is suspended in methanol (220 ml). P-toluenesulfonic acid (2.2 g; 0.0115 moles) is added and the mixture is heated to an internal temperature of 35 ° C for 3 hours. The obtained solution is filtered and concentrated to residue. Water (300 ml) is added and the pH corrected to 8 with a saturated bicarbonate solution. It is extracted with ethyl acetate (300 ml) and the phases are separated. The organic phase is washed with water and a saturated NaCl solution and anhydrified.

The residue is concentrated and isopropyl alcohol (150 ml) is added. It is kept under stirring at 15 ° C for 3 hours and the crystallized product is filtered.

It dries s.v. at constant weight.

Example 5

4 [4- (Dimethylamino,) - 1 - (4 'fluoro phenyl- 1-hydroxybutyl-3- (hydroxymethylH-5-formylbenzene (formula 1VÌ.

A solution of 4-fluorophenylmagnesium bromide, prepared from 4-fluorobromobenzene (30 g, 0.1 mol) and magnesium shavings (4.26 g, 0.177 mol) in anhydrous THF (150 ml) is slowly dripped into a solution of

5-formylphthalide dimethylacetal (20 g, 0.096 moles)) in THF (130 ml) at a maximum temperature of 0 ° C.

When the addition is complete, it is left under stirring at 0 ÷ 5 ° C for 1 hour. A second solution of Grignard prepared from 3-dimethylaminopropyl chloride (18.6 g, 0.153 mol) and magnesium shavings (3.67 g, 0.153 mol) in anhydrous THF (70 ml) is poured in 1 hour in the same reaction mixture. The temperature is kept below 10 ° C during the addition.

When the addition is complete, it is left under stirring overnight at room temperature. The reaction mixture is poured into saturated ammonium chloride solution (200 ml). The phases are separated and extracted from the aqueous phase with ethyl acetate (150 ml). Methanol (100 ml), water (100 ml) and 6N HCl (300 ml) are added to the organic phase.

After 30 'under stirring at a temperature of 25 ÷ 30 ° C it is concentrated under vacuum at half volume and diluted with water (200 ml). It is extracted from the aqueous phase with ethyl acetate (300 ml).

The pH of the aqueous phase is corrected to the value of 10-10.5 with 25% NH4OH and it is extracted again with ethyl acetate (twice with 200 ml each). It is dried with sodium sulphate and concentrated to a dry residue.

Yield = 28 g (60%); HPLC purity = 98%.

A sample is chromatographed on Si02 eluting with ethyl acetate 90: methanol 10, obtaining a standard for analysis with HPLC purity higher than 99%.

Example 6

4 [4-fDimethylaminoV I -f4-fluorophenin- 1-hydroxybutin-3-fidroxymethyl-5-formylbenzene-oxime (formula IIP.

Compound (IV) (40 g, 0.116 moles) is dissolved in 95% ethanol (150 ml). Hydroxylamine HCl (15 g, 0.214 mol) in water (30 ml) is added. It is kept under agitation for 30 'at an internal temperature of 30 ° C. It is diluted with water (300 ml) and the pH is corrected to 9.5 with 25% NH4OH (30 ml). It is extracted with ethyl acetate (2x 50 ml). The organic phase is dried and concentrated to residue.

Example 7

1 -3-Dimethylaminopropill- 1 -f4-fluorophenin- 1.3-dihydroisobenzofuran-5-carbonitrile hydrobromide.

To a solution of 4- [4- (dimethylamino) -1- (4'-fluorophenyl) -lhydroxybutyl] -3- (hydroxymethyl) -5-formylbenzene-oxime (formula III), (20 g,

0.055 mol)] in methylene chloride (200 ml) are added triethylamine (22.3 g,

0.22 mol) and, at 0 ° C, methanesulfonyl chloride (14.7 g, 0.123

moles) in 30 minutes.

- At the end of the addition, a mixture of H2O (200 ml) and NaOH ~ IN (20 ml) is poured. The phases are separated and the organic phase is washed three times with water

(100 mi each).

The washed and anhydrified organic phase is concentrated to a residue

dry. Acetone (200 ml) and 48% hydrobromic acid (5 ml) are added. The pH

of the resulting solution is 3.8.

It is concentrated under vacuum to dry residue and alcohol is added

isopropyl (80 ml).

It is left under stirring at 0 ÷ 5 ° C for 2 hours and the product is filtered

crystallized. It is washed with cold isopropanol and dried at constant weight.

Example 8 for comparison with example 71

5-Formyl- [1 - (3-dimethylaminopropyl) 1 -f4-fluorophenes) - 1.3-dihydroisobenzofuran Voxime (formula III.

A mixture of 96% H2SO4 (1ml) and H2O4 (0.7ml) is added to the solution of the compound of Example 6 (2g, 5.55mmol) in toluene (20ml). The mixture is heated to 80 ° C. After 1 hour it is poured into water and ice and the phases are separated. The aqueous phase is brought to basic pH with NaOH I N and extracted with toluene. It is anhydrified and concentrated to dry residue.

Example 9 for comparison with example 7)

I - (3-Dimethylaminopropyl) 1 -f4'-fluorophenyl- 1.3-dihydroisobenzofuran-5-carbonitrile.

The compound of Example 7 (0.7 g, 2.04 mmoles) is dissolved in acetic anhydride (4 ml). The mixture is refluxed for 30 minutes, distilling the solvent away until a dense residue is formed. Ice (30 g) and 25% NH4OH is added up to pH 9. It is extracted with ethyl acetate, washed with water and dried.

It is concentrated to a dry residue and chromatographed on Si02 eluting with methylene chloride 90: methanol 10.

Claims (13)

CLAIMS 1. A process for the preparation of citalopram, comprising: a) reaction of a compound of formula (VII): where R is CrC4 alkyl; with a fluorobenzene magnesium halide, to give a compound of formula (VI): where R is defined above; b) reaction of compound (VI) with a 3-halogenomagnesium-N, N-dimethylpropylamine to give a compound of formula (V) where R is defined above; c) acid hydrolysis of the compound of formula (V) to give a compound of formula (IV) d) reaction with hydroxylamine to give the compound of formula (III): e) transformation of the compound of formula (III) into the compound of formula (I), isolated as a base or as a pharmacologically acceptable salt. 2. Process according to claim 1 wherein in step a) 4-fluorobenzene magnesium bromide is used. 3. Process according to claim 1 wherein Ν, Ν-dimethylpropylamine magnesium chloride is used in step b). 4. Process according to claims 1-3 in which the hydrolysis of the intermediate of formula (V) is carried out in a hydroalcoholic environment by using inorganic acids. 5. Process according to claims 1-4 in which the intermediate of formula (IV) is transformed into the compound of formula (III) through reaction with hydroxylamine salts (preferably hydrochloride or sulfate) in a hydroalcoholic environment (preferably methanol or ethanol). 6. Process according to claims 1-5 wherein the closure of the benzofuran ring and the simultaneous transformation of the 5-oxime group to 5-cyano is carried out on the compound of formula (III), by using methanesulfonyl chloride and organic bases (preferably triethylamine, dimethylamine, pyridine). 7. Process according to claims 1-6 characterized in that step e) is carried out on the enantiomer (S) of the product of formula (III). 8. An intermediate having formula (III) 9. An intermediate having formula (IV) 10. An intermediate having formula (V) where R = C1-C4 alkyl. 11. An intermediate having formula (VI) where R = C1-C4 alkyl. 12. An intermediate having formula (VII) where R = C1-C4 alkyl. 13. An intermediate having formula (VIII)