MXPA01003741A - Method for the preparation of citalopram - Google Patents

Abstract

The present invention relates to a method for the preparation of citalopram or any of its enantiomers and acid addition salts thereof comprising treatment of a compound of formula (IV), wherein X is O or S;R1 - R2 are each independently selected from hydrogen and C1-6 alkyl, or R1 and R2 together form a C2-5 alkylene chain thereby forming a spiro-ring;R3 is selected from hydrogen and C1-6 alkyl, R4 is selected from hydrogen, C1-6 alkyl, a carboxy group or a precursor group therefore, or R3 and R4 together form a C2-5 alkylene chain thereby forming a spiro-ring, with a dehydration agent or alternatively where X is S, thermally cleavage of the thiazoline ring, or treatment in presence of a radical initiator, to form citalopram. The invention also relates to intermediates used in the new process for the preparation of citalopram, as well as citalopram prepared according to the new process.

Description

* (»*».

METHOD FOR THE PREPARATION OF CITALOPRAM The present invention relates to a method for the preparation of the well-known anti-tumor drug citalopram, 1 - [3 - (dime ti 1 ami no) propyl] -1- (4-f luorof enyl) -1,3-d? hydro-5-isobenzofurancarbonitrile.

BACKGROUND OF THE INVENTION Citalopram is an antipyretic drug known that it is currently on the market a few years ago and has the following structure: Formula I It is a reuptake inhibitor of serotonin (5-hydroxytryptamine; 5-HT) that acts centrally, selectively, that has activities at nt i dep r e s i s s. The antigenic activity of the compound has been reported in various publications, for example, J. Hyttel, Prog. Neuro-20 P s and Ch opha rma c o 1. & Biol. Psychiat, 1982, ~ ^ * ^ ^ iiFí-i 6,277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. The compound has also been described to show effects in the treatment of dementia and cerebrovascular disorders, EP-A 474580. Citalopram was first described in DE 2,657,271 which corresponds to US Patent 4,136,193. This patent publication describes the preparation of citalopram by one method and outlines an additional method that can be used to prepare citalopram. According to the process described, the corresponding 1- (4-f luorofenyl) -l, 3-dihydro-5-i s ob in z or f u r an c a r boni t r i 1 o is reacted with 3 -. { N, N -dime t i 1 ami no) p r op i 1 - c 1 or ur in the presence of me t i 1 s u 1 f i n i lme t i da as a condensing agent. The starting material was prepared from the corresponding 5-bromo derivative by reaction with cuprous cyanide. According to the second method, which is only delineated in general terms, citalopram can be obtained by ring closure of the compound: in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cyano using cuprous cyanide. The starting material of formula II is obtained from 5-boron phthalic acid by means of two successive Grignard reactions, that is to say with magnesium chloride of 4-f 1 or rofeni 1 o and magnesium chloride of N, N - Tell me 1 ami n op r op 11 o, respectively. A new and surprising method and an intermediary for the preparation of citalopram were described in U.S. Patent No. 4,650,884 according to which an intermediate of the formula III is subjected to a ring closure reaction by dehydration with strong sulfuric acid in order to obtain citalopram. The intermediate of formula III was prepared from 5-cyanophtha1 ida 5 by two successive Grignard reactions, ie, with magnesium halide of 4-f 1 or rof in 11 o and magnesium halide of N, N-dimethylaminopropyl , respectively. Additional processes are described in international patent applications Nos. WO 98/019511, WO 98/019512 and WO 98/019513. WO 98/019512 and WO 98/019513 relate to methods in which a 5-amino, 5-carboxy or 5- (aminocarbonyl sec.) Phthalide is subjected to two Grignard reactions. successive, ring closure and conversion of derivative 1, 3-d i h i dr or i s ob e n z o f u r a n o resulting to the corresponding compound 5-c? An, that is, citalopram. International patent application No. 98/019511 describes a process for the manufacture of citalopram in which a compound (4-substituted-2-hydroxymethylphenol- (4-f luorofenyl) -methanol is subjected to ring closure and the l- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-substituted acid converted to corresponding 5-cyano derivative and alkylated with a (3-dime ti 1 ami no) pr op i 1 ha 1 ogenuoa to obtain citalopram Finally, the methods of preparation of the individual enantiomers of citalopram are described in the Patent of the States No. 4,943,590 from which it also appears that the ring closure of the intermediate of formula III can be carried out via a labile ester with a base.It has now been discovered that citalopram can be obtained with a high performance as a very pure product through a new process in which a 2- [1- [3- (dimethylamino) propyl] -l- (4-f luorofenil) -1Optionally substituted 3-dihydroisobenzofuran-5? L] oxazoline or -thiazoline is converted to a step to citalopram substantially without appearance of undesired side reactions. It has also been found that it is possible to prepare 2 - [1 - [3 - (dime ti 1 ami no) pr op i 1] - 1 - (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-yl] oxazoline or -thiazoline optionally substituted intermediary directly starting from 5-car box ifta 1 i da, by forming its amide with a 2-hi dr ox i -eti 1 ami na or 2 -me rc ap to - eti 1 ami na optionally replaced and closure. The oxazolmas and intermediary thiazolms are stable under the Grignard reaction conditions.

SUMMARY OF THE INVENTION Accordingly, the present invention relates to a novel method for the preparation of citalopram, its enantiomers and its acid addition salts comprising the treatment of a compound of formula IV Formula IV where X is O u S; R1-R2 are each independently selected from hydrogen and Ci-g alkyl or R1 and R2 together form an alkylene chain of C2-s thereby forming a spiro ring; R is selected from hydrogen and C? -6 alkyl, R4 is selected from hydrogen, C? -6 alkyl a carboxy group or a precursor group thereto, or R and R together form an alkylene chain of C2-5 forming in that way a spiro ring; with a dehydrating agent or alternatively where X is S, thermal dissociation of the thiazoline ring or treatment with a radical initiator, such as peroxide or with light, to form citalopram having the f or rmu 1 a Formula I as the base or an acid addition salt thereof, and then optionally converting said base or acid addition salt thereof to its pharmaceutically acceptable salt. The dehydrating agent can be any suitable dehydrating agent conventionally used in the art, such as phosphoroxitrichloride, thionylchloride, f or s p or n t a c o r r, PPA (acidic acid) and P O10. The reaction can be carried out in the presence of an organic base, such as pyridine.

Alternatively, the dehydrating agent can be a Vilsmeier reagent, that is, a compound which is formed by reaction of a chlorinating agent, preferably an acid chloride, for example, phosgene, oxalyl chloride, thionyl chloride, phosphorus, oxo-1 oruro, phosphorpentachloride, trichloromethylchloroformate, also briefly termed "diphosgene", bis (tric 1 or orne 111) carbonate, also termed briefly triphosgene, with a tertiary amide such as N, N-dimethoxylated or an N, N-di to 1 qu and 1 to 1 c anami da, for example N, N-dimethylacetamide. A classic Vilsmeyer reagent is chloride 1 or r orne t i 1 e n dime t i 1 imi n i o. The Vilsmeier reagent is preferably prepared by adding the chlorinating agent to a mixture containing the initial oxazoline or thiazoline derivative of the formula IV and the tertiary amide. When X is S and the conversion of the thiazoline group to the cyano group is carried out by thermal transfer, the thermal decomposition of compound IV is preferably carried out in an anhydrous organic solvent, more preferably a polar aprotic solvent, such as N, N - Tell me 1 fo rmami da, N, N - d ime ti 1 acet ami da, dimethyl sulfoxide or acetonitrile. The temperature at which the thermal decomposition transforms the 2-thiazolyl group to a cyano group is between 60 ° C and 140 ° C. The thermal decomposition can be carried out, conveniently, by refluxing in a suitable solvent, preferably acetonityl. The thermal dissociation can be conveniently carried out in the presence of oxygen or an oxidation agent. The compounds of formula IV Wherein X is S and R4 is a carboxy group or a precursor for a carboxy group can also be converted to citalopram by treatment with a radical initiator such as light or peroxides. In a further aspect, the invention is refers to the aforementioned process in which the compound of formula IV is in the S-enantiomer form. In another aspect, the present invention relates to citalopram and S-citalopram manufactures by the process of the invention and a pharmaceutical composition ant i dep re s i va comprising citalopram or S-citalopram manufactured by the process of the invention. In accordance with the present invention, it has been It has surprisingly been discovered that the oxazoline or thiazoline group can be introduced into the 5-position of phthalide and that it remains stable during subsequent reactions. Additionally, it has been found that the group is oben zofur an ca rb oni 1 or 1, 1 - di stituted in the intermediate of formula IV is surprisingly stable and that the reaction of 2- [l- [3- (dimethylamino ) propyl] -1- (4-p-fluorophenyl) -1,3-dihydro-1s obe nzofuran-5-y1] oxa zo 1 i na or -thiazoline with a dehydration reagent, in particular by a Vilsmeier reagent, to give the corresponding nitrile, ie citalopram, can be carried out at higher temperatures than those described in relation to said dehydration reactions in the literature. It has also been found that, due to the combined stability of the optionally substituted 2-oxa zo 1 ini 1o or 2-thiazolinyl group and the is or isoflavone 1 or 1, 1-disubstituted group, it is possible to prepare intermediary IV 2- [ l- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydro-i s or enzofur an-5-i 1] ox azo 1 i na or -thiazoline and, therefore, , citalopram and its salts in pure form, starting directly from 5 - ca r box ifta 1 i da.

In the process of the invention, citalopram is obtained as a pure product with a good yield, thus reducing costly purification processes In accordance with the present invention, the Formula IV can be prepared from 5-car boxy phta 11 da and transformed into citalopram and its salts by a process, which comprises: a) reacting a functional 5-carboxyphthalate 11 of the formula V with a 2-h? Drox? - or 2 -me rc ap toet an ami na of the formula VI where X, R -R4 are as defined above, b subjecting the amide of formula VII thus obtained ifc ~ * ^ * »« '- wherein X, RX-R4 are con nect s defined above, to a ring closure by dehydration; (c) subjecting the 2- (1-oxo-l, 3-d i h i dr or i s ob e n z or f ur an- 5 - i 1) ox z or 11 na or -thiazoline of the formula VIII thus obtained wherein X, R -R are as defined above, to two subsequent Grignard reactions, the first with a halide of f 1 uorofeni lma gnesio and the second insitu with a halide of [3- (dimethylamino) propyl] magnesium?; ZBb £ £? -2 ... ¿-13 (d) subject to 2 - [3 - hi odr ox íme ti 1 - 4 - [(1 (4-fluorofenyl) -1 -hydroxy- [4- (dimethylamine) butyl] -f in 11] ox azo 1 i na of formula IX thus obtained wherein X, R ^ R4 are as defined above, to a ring closure by dehydration; (e) reacting 2- [1- [3- (dimethylamino) propyl] -1- [4-f-fluorophenyl] -1,3-dihydric acid or n-nofur-an-5-11] oxa z ol inao- thiazolin thus obtained from formula IV wherein X, R1-R4 are as defined above, with a dehydrating reagent or alternatively if X is S subjecting the compound of formula IV to a thermal decomposition reaction, or to treatment with a radical initiator; and isolating the citalopram thus obtained in the form of the free base or as its acid addition salt; and (f) optionally converting said free base or said acid addition salt to its pharmaceutically acceptable salt. The total synthesis of citalopram as described above, comprises the use of novel mediaries for the preparation of the oxazolines or the intermediary thiazolines by reaction of a 5-caboxylate with an ethanolamine or optionally substituted amine and ring closure of the amide thus obtained. The functional derivative of 5 - c to r box i f t a 1 i da used in step (a) is an acid halide thereof, the anhydride, a mixed anhydride, an active ester, for example 4-nitropheni-1-ester, or the free acid, suitably activated for example with di-cyc. ohe xi 1 car bodi imi da. A functional derivative Preferred is the acid chloride, which can be obtained by reaction of the free acid with thionyl chloride and prepared directly to react in situ with the 2-hydroxy-1,1-amino or 2-mercapto-ethylamine of the formula VI. The 5-c a r b ox i f t a 11 da can be prepared from 5-cyanophthalide. Another advantageous functional derivative is mixed anhydride with a monoester of carbonic acid, preferably with monoether carbonic acid ester, which can be obtained from 5-carb ox-ifta 11 da and ethyl chloroformate and prepared directly to react in situ with 2-hydroxy-e 111 amine nao 2-mercapto ethylamine from fo rmul a VI. In the starting material of formula VI, R1-R4 are preferably selected from methyl or ethyl or hydrogen or one of the pairs of R1 and R2 or R3 and R, specifically, they are linked in order to form a 1,4-butylene group or a 1, 5 -pe nti 1 eno More preferably, R1 and R2 and R3 and R4, respectively, are identical. The preferred reagents are 2-amino-2-met-11-propanol, 2-ammo-2-metho-propantol, 2-ami no-3-hi-dr ox i -pr op i on i co (R, S-serma, R-serine and S-sepna) and R, S-c i s t e i n a, R-cysteine and S-cistern. The compounds of formula VI are commercially available or can be prepared from commercially available compounds using conventional methods. The reaction of the functional derivative of 5-ca rb ox ifta 1 i da (V) with ethanolamine or me rc ap toeti 1 amine VI is carried out at a temperature of 10-40 ° C, preferably at 15-25 ° C. C, in an aprotic organic solvent such as an ether, for example methyl t-butyl ether, tetahi dr ofur an or dioxane, a ketone, for example acetone or me ti 11 s obu 111 ce tone, a hydrocarbon, for example toluene , or a chlorinated solvent, for example, dichloromethane, 1,2-di-c-1-naetatic acid or 1,1-tric-1-oethane. Preferably, a hydrocarbon, suitably toluene, is used when the functional derivative is the chloride, while a ketone, conveniently acetone, is used when the functional derivative is a mixed anhydride. The reaction occurs in the usual form of amide formation. However, when the activated acid derivative is the 5-carboxyphide 1-ida chloride, the reaction is conveniently carried out in the presence of an inorganic base such as sodium or potassium carbonate, while an organic base such as triethylamine can be used when, by Éfei. For example, the mixed anhydride with carbon dioxide and carbon dioxide is used as a functional derivative. In step (b), the amide of formula VII is subjected to a ring closure reaction by dehydration, preferably by treatment with thionyl chloride. The amide of formula V is added to the dehydration agent at a low temperature, basically at less than 10 ° C, preferably less than 5 ° C, more preferred between -10 ° C and 3 ° C. When the thionyl chloride is used, the temperature is advantageously lower than 0 ° C, approximately preferable -10 ° C. Then, the temperature is allowed to rise to 20 ° C and the reaction is completed at a temperature of 20-40 ° C, to 25-35 ° C, more preferably 28 to 30 ° C. When thionyl chloride is used as the dehydrating agent, the 2-1-oxo-l, 3-dihydride is either n-1 or n-thiazoline.

Formula VIII is obtained in the form of a hydrochloride which can be isolated by dilution with an ether solvent, preferably t e t r a h i dr or f u an. The corresponding base can be isolated by precipitation of a solution aqueous alkaline hydrochloride.

Steps (a) and (b) above can be carried out as a container process, that is, without isolating the amide of formula VII. In step (c), the compound of the formula VIII thus obtained is subjected to two subsequent Grignard reactions. In particular, it is reacted under customary conditions with a halide of 4-phenyl or 1, preferably the chloride or the bromide, preferably the bromide, and preferably using tetrahydrofuran as the solvent. The reaction mixture is then treated with a halogenide of [3 - (dimethyldiamine) pr opy] g, preferably the chloride or bromide, preferably the chloride, dissolved in the same solvent used for the reaction of Prior grignard, preferably tetrahydrofuran, using the usual conditions of a Grignard reaction. 2- [3-hydroxymethyl4 - [(1- (4-fluorophenyl) -1-hydroxy} - [4 - (dimethy1 ami no) bu ti 1] pheny1] oxazoline or -thiazoline of the formula IX thus obtained it can be isolated according to conventional techniques In step (d), the ring closure of compound IX is carried out through elimination of one molecule of water.This elimination can be carried out by an acid or by medium of a labile ester with a base The acidic ring closure was carried out with an inorganic acid, such as a sulfuric or phosphoric acid, or an organic acid, such as 5-methyl-1-amino acid, toluenesulfonic or trifluoroacetic The basic ring closure is carried out by means of a labile ester, such as methane sulphonyl, p -to 1 uensu 1 f on i 1, 10- c amf orsu 1 f on i 1 or, trif 1 uoroaceti 1 oo t r i f 1 u or r o n t a n t i n t i t i n t in the presence of a base, such as triethylamine, dime t i 1 a i i na, pyridine, etc. The reaction is carried out in an inert solvent, preferably with cooling, in particular about 0 ° C and carried out preferably by means of a one-pot process, ie with esterification in the presence of a base. Step (e), the treatment of the IV compound with the dehydrating reagent is carried out as described above. The reaction of the compound of the formula IV, as the free base or as a salt thereof, with the Vilsmeier reagent is carried out in anhydrous organic solvent. The anhydrous organic solvent can be a solvent apolar such as a hydrocarbon, for example It is either toluene or xylene, or Ctn., Polar solvent, or it can be N, N-dime 111 fo rmami da or N, N-dime ti 1 acet ami da that form the Vilsmeier reagent, where the tertiary amide it is present in at least the amount which is organic with respect to the acid chloride, preferably in an excess thereof, for example, in an amount twice the amount of the latter. The addition of the chlorinating agent is generally carried out at low temperatures, although the reaction itself occurs at a temperature between 80-150 ° C, preferably 90-130 ° C, or more preferably 100-120 ° C. These temperature ranges allow the reaction to be completed within 4 hours, particularly within 30-60 minutes. The ring closure in step d) and the subsequent dehydration in order to convert the oxazolm or thiazoline to CN in step e) can be carried out, in a preferred embodiment, in a step without isolation of the intermediate of formula IV, for example using thionyl chloride as an agent of dehydration. As stated above, the citalopram thus obtained can be isolated in the form of the free base or its salt and can be converted to the selected final product, preferably Citalopram hydrobromide. The process of the present invention it allows the preparation of citalopram and its salts starting from the compounds bearing an oxazoline or thiazoline group which represents valuable and direct precursors of the g upo cyan that are stable under the conditions of a Grignard reaction. oxazoline or thiazoline in the compound of formula IV can be very simple and convenient.Furthermore, the process of the present invention allows the preparation of two of the enantiomers of citalopram and their salts starting from the corresponding enantiomers of the compound of the formula IV, or, when the total synthesis is used starting from 5-carb ox ifta 1 i da, by resolution of the Item of formula IX. The compounds of the formula IV or IX, wherein R3 and R4 represent methyl and R1 and R2 are hydrogen, are particularly indicated. The intermediates of formula IV and IX in the form of enantiomers, can be obtained using separation techniques with encionales or as described in U S - - 4,943,590.

It is advantageous to treat the compounds of the formula IX, as racemates, with an optically active acid, for example with (-) - or (+) - tartaric acid or (-) - or (+) - camofor - 10 - sulfonic acid, in order to separate the salt mixture of asteeois orne rich and isolate the optically active compound of the formula IX, as a free base or as a salt thereof. The total synthesis of citalopram and its directly from 5-ca r box i f t a 1 i da, represents a preferred embodiment, and involves a series of intermediaries that are another objective of the present invention. Therefore, according to another of your For purposes of this invention, the invention relates to the compounds of the formula IV obtainable according to step (d) and the compounds of formula VIII and IX obtained according to step (b) and (c). The salts of compounds IV, VIII and IX can be any acid addition salt, including pharmaceutically acceptable acid addition salts, for example the hydrochloride, hydrobromide, hydrogen. Other reaction conditions, solvents, etc. they are conventional conditions for such reactions and can be readily determined by one skilled in the art. The compound of the general formula I can be used as the free base or as its pharmaceutically acceptable acid addition salt. As acid addition salts, such salts formed with organic or inorganic acids can be used. Examples of such organic salts are those with maleic, fumaric, benzoic, ascorbic acid, succinic, oxalic, bi sme ti 1 ensa 1 ic í 1 ico, me tansu 1 f ón ico, eta nd isu 1 f ón ico, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic , citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, be n cen s u 1 f ón i c o and the acetic acids of theophylline, as well as the 8 - ha 1 or t e or f i 1 a s, for example 8 - b r orno t e or f i 1 a. Examples of such inorganic salts are those with hydrochloric acids, hydrobromic, sulfuric, sulfamic, phosphoric and nitric. The acid addition salts of the compounds can be prepared by methods known in the art. The base is reacted with the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethyl ether, ethyl acetate or dichloromethane, with the salt separating spontaneously. The pharmaceutical compositions of the invention can be administered in any suitable manner and in any suitable form, for example, orally in the form of tablets, capsules, powders or syrups, or parenterally in the form of usual sterile solutions for injection. The pharmaceutical formulations of the invention can be prepared by conventional methods in the art. For example, tablets can be prepared by mixing the active ingredient with common adjuvants and / or diluents and subsequently compressing the mixture in a conventional tableting machine. Examples of adjuvants or diluents include: Corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Any other adjuvant or additive, colorants, aroma, preservatives etc. can be used. as long as they are compatible with the active ingredients. Solutions for injections can be prepared by dissolving the active ingredient and possible additives in a portion of the solvent for injection, preferably sterile water, adjusting the solution to the desired volume, sterilizing the solution and loading into suitable ampoules or flasks. Any suitable additive used conventionally in the art can be added, such as tonicity agents, preservatives, a n t i or x i d a n t e s, etc. The invention is further illustrated by the following examples: E xemployment 1 Preparation of citalopram hydrobromide To a mixture of 4 - 4 - dime ti 1 - 2 - [1 - [3 - (dimethylamino) propyl] -1- [4-f luorofenyl] -1,3-dihydro -isobenzofuran-5-yl] oxazoline (19 g, 0.0479 mol) in N, N-dimethylformamide (50 ml), cooled to -20 ° C, added, 8.93 ml of P0C13 (0.0958 m), without letting the temperature rise above -10 ° C. At the end of the addition, the temperature was allowed to rise to 10-15 ° C, then the mixture was heated to 110-115 ° C for 45-60 minutes and the mixture was immediately cooled to 20-25 ° C. The mixture is treated with 80 ml of deionized water and the pH is adjusted to 9 by the addition of a concentrated solution of ammonium hydroxide. The product is deeply extracted with toluene, carrying out the operation four times with 80, 60, 50 and, respectively, of toluene (40 ml), then the organic phases are collected and decolourised by treatment with charcoal for 30 minutes. The carbon is separated by filtration and the solvent is evaporated leaving 13.5 g of an oil. The oily residue is taken up in 80 ml of acetone and the solution obtained is treated with a solution of 48% HBr (4 ml). The mixture thus obtained is concentrated in vacuo, and the oily residue is taken up with acetone (40 ml) and the solution is left to stand overnight at 4-5 ° C. The solid is separated by filtration, washed first with toluene, then with acetone and dried. Therefore, 9.4 g of citalopram hydrobromide are obtained. The mother liquors are concentrated to dryness, the residue is taken up with 20 ml of acetone, the solution is kept for 4 hours at 4-5 ° C, then it is filtered, washed with a small amount of acetone and dried. Accordingly, additional 1.44 g of citalopram hydrobromide are obtained. ? j eg 2 Synthesis of citalopram hydrobromide starting from 5-car box ifta 1 i da (a) 2- [[(1-oxo-l, 3-d? hydroisobenzofuran-5-yl) carbonyl] amino] -2 -methyl-l-propanol To a stirred mixture of thionyl chloride (1850 ml) and N, N-dimethylformamide (5.5 ml), add 5-carb ox ifta 11 da (525 g, 2.95 mol). The stirred mixture is heated to reflux for 6 hours. The thionyl chloride is removed by distillation under reduced pressure to give the acid chloride as the residue. The residue is taken up in toluene (750 ml) and concentrated under reduced pressure. The residue is taken up in toluene (2 X 450 ml), concentrated under reduced pressure, then taken up in tetrahydrofuran (2500 ml). To a solution of 2-ami n o - 2 -me t i 1 - 1 -p ope n o 1 (800 g, 8.97 mol) in tetrahydrofuran (1300 ml) at 5 ° C, the acid chloride solution is added dropwise, maintaining the temperature between 5-10 ° C. Then, the mixture is stirred at about 20 ° C for 2 hours. The mixture is checked for alkalinity and then the solvent is evaporated at 50 ° C. The residue is absorbed in deionized water (2400 ml) and stirred for one hour. The solid product is isolated by filtration and washed with deionized water. The product is dried at 50 ° C m va c u o. Yield: 570 g (77%) having m.p. = 156-158 ° C and a purity (HPLC, peak area) > _ 90%. (b) 4,4-d? met? l-2- (l-oxo-l, 3-d? hydro? -sobenzofuran-5? l) oxazoline A stirred thionyl chloride (800 ml), a 0 ° C, 2- [[(1-oxo-l, 3-d? H? Dro? Sobenzofuran-5-? L) carbonyl] ami no] -2-met? Ll-propanol (560 g) was added portionwise. , 2.25 mol) maintaining the temperature below 10 ° C. The temperature is allowed to rise, and then the mixture is heated between 28-30 ° C for 5 hours. The thionyl chloride is removed by distillation or reduced pressure at 60 ° C. The residue is taken up in toluene (2 X 700 ml) and concentrated under reduced pressure at 0 ° C. The solid is separated by filtration, washed with toluene (2 X 100 ml) and dried m va c u o. The product is suspended in deionized water (3000 ml). The suspension is cooled and the pH is adjusted to basic pH by the addition of 28% aqueous ammonia (1000 ml). The product is separated by filtration, washed with deionized water, and dried at 50 ° C. Yield: 407 g (78%) having m.p. = 109-111 ° C and one purity (HPLC, peak area) >; 95% (c) 4,4-dimethyl-2- [3-hydroxymethyl-4- [4-fluoro-hydroxy-a- (dimethylamino) propyl] benzyl] -phenyl] oxazoline Under a nitrogen atmosphere, a solution of 4, 4-dime ti 1 - 2 - (1-oxo-1,3-dihydroisobenzofuran-5-yl) oxazoline 135 0.5 mol) (obtained from step (b)), in tetr ah i dr ofur ano (900 ml), stir at -15 ° C. Then, a solution to % bromide of p - f 1 uo r or f in i lma gn e s or in tetrahydrofuran (1130 g) is added slowly maintaining the temperature between -15 to -10 ° C. The temperature is allowed to rise to 5-10 ° C and is maintained at 5-10 ° C for 1 hour. A control is prepared by HPLC to verify that the amount of starting material is less than 1% (area). Then, the stirred solution is cooled to -5 ° C and a 30% solution of (3 - (dimethyl ti 1 ami) propyl) magnesium chloride in tetrahydrofuran (430 g) is added slowly maintaining the temperature between -5 ° C. C and -2 ° C. The temperature is allowed to rise to 5-10 ° C and is maintained at 5-10 ° C for 1 hour. After a control by HPLC, showing that the residue of the reaction intermediate is less than 5% (area), a 15% aqueous solution of ammonium chloride (ca 1000 g) is added slowly and the mixture is stirred for 30 minutes. The phases are separated and the lower phase is extracted with toluene (1000 + 700 ml). Then, the deionized water (1050 ml) is added to the upper phase and the pH is adjusted to 5-6 by the addition of acetic acid.

The solvent is evaporated at 50 ° C and the toluene extracts are added to the residual aqueous phase. After cooling, the pH of the mixture is adjusted to 9-10 with 30% aqueous ammonia. The phases are separated and the aqueous phase is extracted with toluene (300 ml). The organic phases are combined and a mixture of acetic acid (660 ml) and deionized water (1050 ml) is added thereto (final pH of about 4.2). The phases are separated; The aqueous phase is recovered, treated with decolorizing carbon and filtered. To this filtered solution of toluene (1200 ml), the solution is cooled to 10-15 ° C and the pH of the suspension is adjusted to pH 10 by the addition of 30% aqueous ammonia. The phases are separated and the aqueous phase is extracted with toluene (300 ml). The toluene phases are combined and washed with deionized water (150 ml). The product is allowed to crystallize at room temperature for three hours and then at 5 ° C for 15 hours. The product is filtered and washed with anhydrous toluene. Yield: 154 g. An additional 18 g of the product is recovered from the mother liquors. Total yield: 154 + 18 g (71%) with a purity (HPLC, peak area) > 95% (d) 4,4-dimethyl-2 - [1- [3- (dimethylamino) -propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-yl] oxazoline To a stirred solution of 4 , 4-dimethyl-1 - 2 - [3-hydroxymethyl-4- [4-fluoro-α-hydroxy? -a- [3- (dimethylamino) propyl] benzyl]] oxazoline (141 g, 0.34 mol ), (obtained at the end of step (c)) in methylene chloride (2200 ml), triethylamine is added (200 ml). The stirred mixture is cooled to 5 ° C and a solution of methylene chloride (400 ml) (40 ml, 0.515 mol) in methylene chloride (400 ml) is added maintaining the temperature between 5-7 ° C. The temperature is brought to 25 ° C and the mixture is kept under these conditions for 2 hours. The mixture is cooled and a 0.1 N NaOH solution (1000 ml) is added. The phases are separated and the phase , ^ t-TA, 7Ay - * £ ^ £ A? 3t £ í = organic is washed in deionized water (3 x 1000 ml). The organic phase is concentrated under reduced pressure at 50 ° C resulting in an oily residue. Yield: 130 g (96%) with a purity (HPLC, peak area) > 85% (e) Citalopram Bromhydrate To a stirred solution of 4, 4-d, 111 - 2 - [1 - [3- (dimethylammo) propyl] -1- (4-fluorophen? l) -1, 3 -di hi dr dr After dissolving in pyridine (1000 ml), at 5 ° C, phosphorus oxychloride (135 ml, 1474 mol) was slowly added maintaining the temperature at 0 ° C (287 g, 0.724 mol) in pyridine (1000 ml). 5 to 10 ° C. The mixture is heated to reflux (115-116 ° C) for 3 to 4 hours. The mixture is cooled to approximately 10 ° C and treated with deionized water (3200 mL), and the pH is adjusted to approximately pH 9 by addition of 28% aqueous ammonia (800 ml). The product is extracted with toluene (1500 + 1000 + 500 + 500 ml) and the combined organic phases are decolorized with carbon. The organic phase is concentrated under reduced pressure at 60-70 ° C to give a residue or 1 to Q to which acetone (3000 ml) is added. The acetone solution is cooled to 10 ° C and treated with 60 ml of 48% HBr to a pH value of 4-5. The solvent is evaporated under reduced pressure and the residue is taken up in acetone (800 ml). The mixture is heated to 40-50 ° C and then cooled to 5 ° C. After 15 hours at 5 ° CThe product is separated by filtration, washed with cold acetone (500 ml) and dried at 50 ° C. 175-180 g of citalopram hydrobromide are obtained with a purity (HPLC, peak area) >; 90% An additional amount of 15 g is recovered with a purity (HPLC, peak area) > 90% of the mother liquors. Yield: 190-195 g (65-67%) with a purity (HPLC, peak area) > 90% (f) Crystallization of citalopram hydrobromide A mixture of citalopram hydrobromide (190 g) and deionized water (380 ml) is heated at 50-60 ° C until all the solid has dissolved. The solution is treated with charcoal (12 g), filtered and washed with deionized water (50 ml). The filtered solution is cooled to 20 ° C and stirred at room temperature for 5 hours and then at 5 ° C for 15 hours. The crystals are separated by filtration, washed with cold water (200 ml) and dried at 60 ° C for four hours.

E xemployment 3 Preparation of citalopram oxalate A stirred solution of 4,4-dimethyl-2- [l- [3- (dimethylamino) propyl] -1- (4-f luorofenyl) -1,3-dihydro- i s or enzyof ur an -5-i 1] oxa zo 1 i na (2.3 g, 0.0058 mol) in thionyl chloride (20 ml) is heated at reflux for 3 hours. The organic phase is concentrated under reduced pressure and the residue is taken up in toluene (20 ml) and deionized water (20 ml) is added and the pH of the mixture is adjusted to approximately 9 by the addition of aqueous NaOH (2 N). . The phases are separated and the organic phase is collected and washed with deionized water (2 x 10 ml). T The organic phase is concentrated under reduced pressure to leave an oily residue. 1.8 g. The oxalate salt is precipitated from acetone.

Use 4 4, 4-dimethyl-2- (l-oxo-l, 3-dihydro-sobenzofuran-5-yl) oxazoline (one-pot method) To a thionyl chloride mixture (25 ml, 0.344 mol) and N, N-dimethylacetamide (0.2 ml), add 5-car box ifta 1 i da (5 g, 0.028 mol). The stirred mixture is heated 30 minutes at 60 ° C and taken The reaction is continued under reflux conditions (about 80 ° C) and is maintained under these conditions for 6 hours.The thionyl chloride is removed by in-vessel distillation to an internal temperature of approximately 90 ° C. The concentrated mixture is taken up in toluene (25 ml) and distilled in vacuo leaving a residue, which is taken up in toluene (10 ml) followed by concentration of the solution, the residual acid chloride is taken up with tetrahydrofuran (25 ml) and the mixture is heated to 60 ° C until a complete solution is obtained.The solution of the acid chloride in tetrahydrofuran is added dropwise to a mixture of micronized anhydrous potassium carbonate (5 g, 0.036 mol), 2-amino-2-methyl- l-propanol (3.06 ml, 0.032 mol) and tetrahydrofuran (15 ml), cooled to approximately 0 ° C, maintaining the temperature at 5-10 ° C. After approximately 30 minutes under these conditions, it is carried out an HPLC control to verify the complete amid formation The mixture is cooled to 0-3 ° C and thionyl chloride (2 ml, 0.027 mol) is added dropwise to the mixture. At the end of the addition, an HPLC control confirms that the ring closure of the amide is complete. To the mixture, 50 ml of deionized water is slowly added at 5-10 ° C. Solvents - < - * The organic compounds are separated by distillation and the pH is adjusted to 5 with 25% ammonia. The mixture is heated one hour at 50 ° C, then its - *% temperature is let down to about 20 ° C, it is kept at this value for 2 hours, then it is lowered to 10-15 ° C and the mixture is kept low these conditions for one hour. The mixture is dispersed by stirring, then it is filtered, washed with water and dried at 40 ° C. Yield: 3.87 g of the product. Total yield: 59.8%.

Use 5 4, 4-dimethyl-2- (1-oxo-l, 3-dihydro-sobenzofuran-5-yl) oxazoline (one-pot method). Acetone (40 ml) is stirred and 5-carb ox ifta 11 da (2 g, 0.011 mol) at approximately 20 ° C. The mixture is cooled to -10 ° C. The mixture is cooled to -10 ° C and ethyl chloroformate (1.18 ml, 0.012 mol) is added. At the end of the addition, a solution of triethylamine (1.56 ml, 0.011 mol) in acetone (3.50 ml) is added maintaining the temperature of the mixture at or below -10 ° C. The temperature of the mixture is allowed to rise to 10-13 ° C and, after 30 minutes, it is brought to -10 ° C and the mixture of 2-amin-2-me 111-1-pr is added quickly to the mixture. opa 1 (3.0 g, 0.034 mol) in acetone (5 ml). The temperature is raised to 15-20 ° C, whereby the reaction is completed as can be verified by HPLC. To the mixture thus obtained, cooled to -5 ° C, thionyl chloride (2.5 ml, 0.034 mol) is added, the temperature is allowed to rise to approximately 20 ° C and after 30 minutes, the ring closure is completed. The reaction mixture is concentrated to leave a residue, which is treated with water (20 ml). The mixture is concentrated again and an additional amount of water (10 ml) is added to the residue, the pH is made basic by the addition of 25% ammonia and the mixture is cooled to 5 ° C. The product is filtered, washed with water and dried m va c u o. Yield: 1.70 g. Total yield: 66.8%.

Claims (17)

1. Method for the preparation of citalopram or any of its enantiomers and their acid addition salts comprising the treatment of a compound of the formula IV where X is 0 u S; R1-R2 are each independently selected from hydrogen and C? -6 alkyl or R1 and R2 together form an alkylene chain of C2-5 thereby forming a spiro ring; R 3 is selected from hydrogen and C 1-6 alkyl, R 4 is selected from hydrogen, C 1-6 alkyl, a carboxy group or a precursor group therefor, or R 3 and R 4 together form an alkylene chain of C 2-5 forming that way a spiro ring, with a dehydrating agent or 'a **. alternatively where X *. * 's S, thermal dissociation of the thiazoline ring or treatment in the presence of a radical initiator, is used to form citalopram which has the formula (I) and then optionally converting the free base or its acid addition salt thereof thus obtained to its pharmaceutically acceptable salt thereof.

2. Method according to the rei indication 1 comprising: (a) reacting a functional derivative of 5-carboxy phthalate of the formula V with a 2-h? droxi 2 -me r c ap t o t ana m ana of the f ormu mi wherein X, R1-R4 are as defined above, (b) subjecting the amide of formula VII thus obtained wherein X, RX-R4 are as defined above, to a ring closure by dehydration; (c) subjecting the 2- (1-oxo-l, 3-dihydroisobenzofuran-5-yl) oxazoline or thiazoline of the formula VIII thus obtained wherein X, R1-R4 are as defined above, to two subsequent Grignard reactions, the first with a halide of f 1 u or r or f e n i lma g n e s i o and the second in situ with a halide of [3- (dimethylamino) propyl] magnesium; (d) subjecting 2- [3-hydroxymethyl-4- [(1- (4-fluorophenyl) -1-hydroxy- [4- (dimethylamino) butyl] phenyl] oxazoline or -thiazoline of the formula IX thus obtained wherein X, R -R4 are as defined above, to a ring closure by dehydration; (e) reacting 2 - [1 - [3 - (dimethylamino) propyl] -1- (4-f luorofenyl) -1,3-dihydro-i s or enzofuran-5-i 1] oxa zo 1 ina or -thiazoline thus obtained from formula IV St-ae-r • * •• - in which XR -R 'are as defined above, with a dehydration reagent or alternatively if X is S subjecting the compound of formula IV to a thermal decomposition reaction, or to treatment with a radical initiator; and isolating the citalopram thus obtained in the form of the free base or a salt thereof; and (f) optionally converting the obtained compound to a pharmaceutically acceptable salt thereof.

3. Method for the preparation of citalopram according to claims 1-2 wherein the compound of the formula IV is treated with a dehydrating agent selected from phosphoroxytrichloride, ti on i 1 c 1 oruo, phosphorus ntac 1 oruro, PPA ( po 1 ifosf ó rich acid) and P O10 or a Vilsmeier reagent.

4. Method according to claim 3 wherein the Vilsmeier reagent is formed by reaction of a chlorinating reagent with a tertiary amide.

5. Method according to the rei indication 4 in which the chlorinating agent is an acyl chloride selected from phosgene, oxalyl chloride, thionyl chloride, phosphoroxic 1 oruro, phosphorpentac 1 oruroytric 1 or ome 111 c 1 orofo rma toy tertiary amide it is selected from N, N-dimethyl-thiomide or a N, N-di to 1 qui 1 to 1 ca nami, for example N, N-dimetho 1 to ce t ami da.

6. Method according to claims 3 to 5 wherein the Vilsmeier reagent is prepared by adding the chlorinating agent to a mixture containing the initial oxazoline or thiazoline derivative of the formula IV and the tertiary amide.

7. Method for the preparation of citalopram according to claims 1 to 2 wherein the thermal dissociation of the thiazoline ring of a compound of the formula IV wherein X is S is carried out in the presence of oxygen or an oxidizing agent.

8. Method for the preparation of citalopram according to the rei indications 1 to 2 wherein the thiazoline ring of a compound of the formula IV wherein X is S and R is carboxy or a precursor for - ^ - * í *. ?? ^ * "^ carboxi is treated with a radical initiator, such as light or peroxides.

9. Method according to claim 2 wherein step b) is carried out by subjecting the amide of formula VII to a ring closure reaction by dehydration, preferably by treatment with thionyl chloride at low temperature, i.e. of 10 ° C, preferably less than 0 ° C, more preferably at -10 ° C after which the temperature is allowed to rise to 20 ° C and the reaction is completed at a temperature of 20-40 ° C, preferably at 25 ° C. -35 ° C, more preferably at 28 to 30 ° C.

10. Method according to any of claims 1-6 in which the compound of formula IV is in the form of S-e nan t i orme.

11. Method according to the claim 2 in which the compound of formula IX used is in the form of S-enan t i ome r o. ., 3c £ s &,

12. Compound of the general formula VIII or any of its enantiomers and their acid addition salts thereof having the formula wherein X, R1-R4 are as defined above in claim 1

13. Compound of the general formula IX or any of its enantiomers and acid addition salts thereof having the formula wherein X R -R 'are as defined in claim 1

JlGOí: "*** 14. Compound of general formula IV or any of its enantiomers and acid addition salts thereof which has the formula wherein X, R1-R4 are as defined in claim 1.

15. Citalopram prepared according to the method of claim 1.

16. S-citalopram prepared according to the method of claims 10-11.

17. Method according to claim 2 in which step a) and b) are carried out as a process of a container. SUMMARY The present invention relates to a method for the preparation of citalopram or any of its enantiomers and acid addition salts thereof which comprises the treatment of a compound of the formula IV where X is 0 u S; R1-R2 are each independently selected from hydrogen and C? -6 alkyl, or R1 and R2 together form an alkylene chain of C2-5 thereby forming a spiro ring; R3 is selected from hydrogen and C1-6 alkyl, R4 is selected from hydrogen, C? _6 alkyl, a carboxy group or a precursor group therefor, or R3 and R4 together form an alkylene chain of C2-5 forming that way a spiro ring, with an agent of sh 1 dr atac 1 on or alternatively where X is S, thermal dissociation of the thiazoline ring or rat. in the presence of a radical initiator, to form * seitalopram. The invention also relates to intermediates used in the new process for the preparation of citalopram, as well as citalopram prepared according to the new process.