Title of Invention	"PROCESS FOR THE PRODUCTION OF CITALOPRAM"
Abstract	The invention relates to a process for the manufacture of salts of citalopram in high purity, y the careful selection of solvents and the careful manipulation of the pH value, citalopram salts may be isolated in the absence of 5-chlorocitalopram, 5-bromocitalo-pram, desmethyl-citalopram and 5-carboxyamide citalopram.

Full Text

Since the publication of the above mentioned US Patent, a nu mber of further processes for the preparation of citalopram have been devised and in many of diese, as weii as in be above US Patent, the last step of the process invoives the conversion of a group different from the cyano in the 5 position of the phthalane ring into the 5-cyano group Preferably the conversion takes place from a bromine analogue. AS is well-known however, impurities are inevitably formed during the cyanation reaction and these impurities are difficult to separate from the desired end product, impurities also remain from early synthesis stages and accordingly, extensive purification procedures are required. "Where the final stage of citaloprain manufacture involves cyanation of 5-bromine analogue to the corresponding nimlie, the main impurities encountered are: (Formula Removed) "Various purificaiicn procedures are already blown in the art for purifying a crudb citalopram mixture produced. a.fi:er such a cyanation reaction. For example, GB 2356199 teaches that the impurities may be removed using a conventional film distillation technique. The crude ba.se is simply distilled using, for example, a thin film distillation apparatus yielding a purer citalopram material. The base product may then be formed into the salt. GB 23577162, describes an alternative procedure in which the crude free base is simply crystallised prior to conversion to the salt. There still remains the need however, to devise efficient and more economic purify-cation procedures especially for use on industrial scale where, for example, the use of film distillation apparatus maybe prohibitively expensive. The present inventors have now found an altemative and rapid way of isolating purer citalopram salts substantially in the absence of the above-mentioned impurities without using potentially time consuming crystallisation techniques or expensive film distillation apparatus. Rather, the present inventors have found that by the careful selection of solvents and the careful manipulation of pH, citalopram salts may be isolated, in very high purity in the absence of the major impurities 5-chlorocitalopram, 5-bromocitalopram, desmethyl-citalopram and 5-carboxyamide citalopram. Thus, viewed from one aspect the invention provides a process for the preparation of ~, salt of citalopram comprising: (A) dissolving citalopram in a. solvent, selected from acetone, alcohol, or toluens on mixtures thereof and adding oxalic acid: (B) separating the precipitated citaloprarn oalate, e.g. by filtration: ( C) suspending..said cialopram exalate in water and adding a base in. an. aunoment sufficient to llberate. citalopram,e.g. to a pH. 9 to 10; (D) extracting the liberated citalopram with an organic scivent, isolating the organic phase and evaporating said solvent; optionally repeating steps (A) to (D)y repeating steps (A) and (B) and aubsequently; (E) suspending said citalopram oxalate in water and adding base to a pH 6 to 7; (F) adding a solvent selected from toluene, cyclohexane, n-hexane, u-heptane, isopropyl ether or xyiene or mixtures thereof and isolating the aqueous phase; (G) adding base to said aqueous phase in an amount sufficient to liberate citaloprain and extracting the liberated citalopram with an organic solvent, isolating the organic phase and evaporating said solvent; (H) dissolving said citalopram in an alcohol solvent, adding an acid and separating the precipitated citalopram salt, Viewed from another aspect the invention comprises a process icr the separation of desmethyl citaiopram from a vrude mixture thereof with citalopram base comprising: (A.) dissolving citalopram in a solvent selected from acetone, alcohol, or toluene or .-.uixtures thereof and adding oxalic acid; (B) separating the precipitated .citalopram oxalate; (C) suspending said citaiopram. oxalare in water and adding a base in an amount sufficient co liberate citalopram e.g. to a pH 9 to 10; (D) extracting the liberated citalopram 'with an organic solvent, isolating the organic phase and evaporating said solvent; optionally repeating steps (A) to (D). Viewed from 3. still further aspect the invention provides a process for the separation of 5-chlorocitalopram and 5-bromocitalopram from a crude mixture of citalopram oxalate comprising: (E) suspending citalopram oxalate in water and adding base to a pH 6 to 7; (F) adding a solvent selected from toluene, cyclohexane, n-hexane, n-heptane, isopropyl ether or xylene or mixtures thereof and isolating the aqueous phase. Viewed from another aspect the invention provides a process for the separation of 5-carboxyamide from a crude mixture of citalopram comprising: (H) dissolving citalopram in an alcohol solvent, .adding an acid and separating the precipitated salt. e.g. by filtration. Viewed from a still yet further aspect, the invention provides citalopram or salts thereof obtained by the processes of the invention as well as their use in medicine and pharmaceutical salts comprising the same. As used herein "citalopram" refers to the :5:e« base -"hereof rr; part (A) of tb.-? vr::)cass of the i\T/en*ion. th^ c;~:;d" citalopram base should preferably be dissolved m acetone. Without cashing to bs liraifed by theory, it is believed "hot iesroethyi ci.^.lo":ra.Tri is removed in "the sc^/^ir' ^asbings in step (B) when 'fee :rty o-•jrarn ox? late r^ar k isolated. Tt har; been fo-.r.n. v?;.?t the most e-irficierit e'irmii^r'.rr}. ::: •lesmetb.y' cit;?.lc'V-v^.:ri :)ccui3 wher the 3olr/:;.n';: ^rauloed is acetone. Isolation of the precipitated citaiopram oxalate in step (B) may be achieved by, for example, filtration or centrifugation or by any oilier conventional technique for separating a solid from a liquid. The citaiopram oxalate is precipitated (it being insoluble in the organic solvent employed) and isolation should not be effected by-evaporating off the organic phase since the desrne.tihyl citaloprarn would, of course.non BE removed in such a procedure. The base used to liberate cimlopram from its oxaiate in step (C) may be any conventional base which is compatible with citaloprarn. Suitable bases include NaOHs KOH and various organic bases however, It is preferred if ammonia is used as the base. The pH of the solution in step (C) needs to be increased to a value sufficient to ensure citaloprarn base is liberated and the requked pH will be readily determined by the skilled chemist. It is preferred however if the pH is adjusted to between 8.5 to 10, especially, 9.0 to 9.5, most preferably 9.0 to 9.2. The pH can of course be monitored using standard indicators or other pH measuring apparatus. The liberated citaloprarn free base may be extracted from the aqueous solution by using a standard organic solvent (Step D). Most suitable in this regard is toluene although other hydrocarbon solvents such as xylene, hexane, heptane etc, could be employed equally successfully. The organic phase formed should be separated by a simple layer separation procedure and the solvent may then be evaporated off by simple distillation or under reduced pressure. Conveniently however, the solvent is removed under atmospheric pressure conditions so as to maintain the liberated citaloprarn as an oil. By using atmospheric pressure evaporation, it is likely that some traces of solvent will remain (perhaps up to 10%) hence maintaining the liberated citaloprarn in an oil form Without wishing to be limited, by theory, it be believed that the further maim irnpurities, bromo/chloro citalopram can be removed by careful manipulation of pH and then by washing in particular solvents. in order to remove these impurities according to the invention, it is necessary to add citalopram. oxalat.e to water and adjust the pF. of the solution to 6 to 7, preferably 6.2 to 7 (Step E). Again the base may be any base suitable for this task. e.g. as described, above in relation to step (C), however, ammonia is again preferred. The inventors have surprisingly found that at this pH citalopram oxalate remains substantially in its salt form but the salts of the chloro and bromo intermediates tend, to convert back to their corresponding bases. On organic washing therefore (Step F), it has surprisingly proved possible to remove the impurities in the organic washings whilst maintaining the desired product in the aqueous phase. The organic washing solvent is conveniently toluene, cyclohexane, n-hexane, n-heptane, isopropyl ether or xylene or mixtures thereof. In a preferred embodiment the solvent is toluene, cyclohexane or a mixture thereof. After the impurities have been removed in the organic phase, the aqueous layer car? then be fully basified and the citalopram free base extracted into an organic solvent, for subsequent conversion to the desired citalopram salt (Step G). Again, the solvent used to extract the liberated citalopram can be any solvent suitable for the task, e.g. those described above with respect to step (D). Most suitable in rhj.3 regard, is again toluene although other hydrocarbon solvents step as xylene, hexane, heptane etc could be employerd equally successfully. The solvent may then be evacrated off by simple distillation. oxander reduced pressure. Convenlenthy' however, the solvent is removed under aunosphrlc pressure conditions so as to, maintain. the liberated citalopram as an oil, By using atmospheric pressure evaporation.. is likely that same, hraces of'solvent will remain (perhaps up to 10%) bencsCltalopram salts made by the process of the invention may be formulated into pharmaceutical compositions as is well known in the art. Such compositions may take the form of tablets which may be prepared by mixing the active ingredient with ordinary adjuvants and/or dilnents and subsequently compressing the mixture in. a conventional tableting machine. Examples of adjuvants or diluents comprise: corn starch, potato starch, talcum, magnesium stearate, gelatin, lactose, gums and is the like. Any other adjuvant or additive colourings, aroma, preservatives, taste masking agents etc. may be used provided that they are compatible with the active ingredient. The active ingredient may also be formulated as a solution for injection which may be prepared by solving the active ingredient and possible additives in a part of the solvent for injection, preferably sterile water, adjusting the solution to the desired, volume, sterilisation of the solution and filling in suitable ampoules or vials. Again, and suitable additive conventionally used in the art may be added such as tonicity agents, preservatives, antioxidants, etc. The amount of citalopram administered to a patient is dependent on the nature of the patient and will be readily determined by the skilled physician. Tablets may however comprise, for example, 20 m.g or 40 rag doses. Citalopram may be administered along with any other pharmaceutical with which it is compatible and additional active ingredients can of course be formulated into compositions with citalopram as is well known in the art. The invention, wiil.5 now be further described with reference to the following non.limiting examples,nirrile oxaiate (Citalopram Oxidate}. citalopram was prepared substantially as described, in Example 2 of US Patent No. 4136193 although toluene was used instead of benzene. 100 g of citalopram (0.30 mol) with a desrnethyl citalopram content of up to 5.0% was added to acetone (300 ml) and the resulting solution stirred for 15 min, at 40°C. To the above clear solution was added oxalic acid (40 g, 0.31 mol), dissolved in acetone (300 mi) and the resulting mixture heated to 50-55°C. The mixture was cooled and the white crystals of the title compound were filtered off at room temperature and dried at 60°C for 6 hrs at atmospheric pressure. Citalopram oxalate prepared as in Example 1 (105 g, 0.25 rnol) was suspended in water (525 ml) and the pH was adjusted to 9.0-9.2 by the addition of ammonia. The mixture was stirred for 30 minutes and extracted with toluene twice (250 ml). The organic phases were separated and washed with water (100 ml). Toluene layer was concentrated under vacuum. Acetone (300 mi) is added to the residue and the mixture stirred for 15 min, at 40°C. To the above clear solution was added oxalic acid (33 g, 0.26 tnol), dissolved in Acetone (300 ml) and the mixture was heated to 50-55°C. The white crystals of the title compound were filtered off at room temperature and dried at 60°C for 6 hrs at atmospheric pressure. Yield: 90 g (55%). Desmethyl cauiopram content less than 0. !yc EXAMPLE s i)-1,,3 dihydrobeuzofurasi" •ftltrile Iiydrobiro silde (Citalopramhydrobromide), oxalate (90 g, 0,2 ). moi) prepared as per example I was suspended in water (500 mi) and aqueous ammonia (20-25%) was added to adjust the pH of the solution to 6:2 -7 C (approximately 20 ml). The solution, is stirred for 15 min. The above solution was washed with toluene (6 x 50 ml) and the organic phases are separated. To the rem.aini.ng aqueous phase was added ammonia (20-25%) to bring the pH to 9.0-9.2. The mixture, was stirred for 15 min, and extracted with toluene (2 x 250 ml). The organic phases were washed with NaCl solution (100 ml, 10%) and the toluene removed in vacuum to leave an oily residue. To the residue was added 350 ml isopropylalcohol and the clear solution filtered through Celite®. To the resulting clear solution is added 35 g of 48% aq. hydrobromic acid and the mixture is stirred for 1 hr at 50°C. After cooling to 2,0° C1 the crystals are filtered and dried. Yield: 75 g (85%) Purity: 99.7% 1. A process for the preparation of a salt of citalopram comprising: (A) dissolving citalopram in a solvent selected from acetone, alcohol, or toluene or mixtures thereof and adding oxalic acid; (B) separating the precipitated citalopram oxalate, e.g. by filtration; (C) suspending said citalopram oxalate in water and adding a base in an amount sufficient to liberate citalopram; (D) extracting the liberated citalopram with an organic solvent, isolating the organic phase and evaporating said solvent; optionally repeating steps (A) to (D), repeating steps (A) and (B) arid subsequently; (E) suspending said citalopram oxaiate in water and adding base to a pH 6 to 7; (r) adding a solvent selected from toluene., cyclohexane, n-hexane, n-heptane, isoproyyi ether or xylene or mixtures thereof and isolating the aqueous phase; (G) adding base to said aqueous phase in an arnouni surflcient to liberate citalopram and extracting the liberated citalopram with an organic solvent, isolating the organic phase and evaporating said solvent; (H) dissolving said citalopram in an alcohol solvent, adding an acid and separating the precipitated citalopram salt. 2. A. process for the separation, of desmethyl citalopram from a crude mixture thereof with, citalopram base comprising: (A) dissolving citalopram in a solvent selected from, acetone, alcohol, or toluene or mixtures thereof and adding oxalic acid; (B) separating the precipitated citalopram oxalate: (C) suspending said citalopram oxalate in water and adding a base in an amount sufficient to liberate citalopram; (D) extracting the liberated citalopram with an organic solvent, isolating the organic phase and evaporating said solvent; optionally repeating steps (A) to (D). 3. A process for the separation of S-chlorocitalopram and 5-bromocitalopram from a crude mixture of citalopram oxalate comprising: (E) suspending citalopram oxalate in water and adding base to a pH 6 to 7 (F) adding a solvent. selected from toluene, cyclohexane, n-hexane, n-heptane, isopropyl other or xylene or mixtures thereof and isolating the aqueous phase. 4. A process for the separation of 5--carboxyamide from a crude mixture of (H) dissolving citalopram in an airshol solvant adding an acid and separating the Citalopram. or salts thereof obtained by the process of any one of claims 1 to 4. 5. A pharmaceutical composition comprising citalopram or a salt thereof as claimed in claim 5. 6. A process for the preparation of a salt of citalopram, substantially as hereinbefore described with reference to the foregoing examples. 8. A pharmaceutical composition, substantially as hereinbefore described with reference to the foregoing examples.

Documents:

1674-delnp-2003-abstract.pdf

1674-delnp-2003-claims.pdf

1674-delnp-2003-Correspondence Others-(08-04-2011).pdf

1674-DELNP-2003-Correspondence-Others-(02-07-2010).pdf

1674-delnp-2003-correspondence-others.pdf

1674-delnp-2003-correspondence-po.pdf

1674-delnp-2003-description(complete).pdf

1674-delnp-2003-form-1.pdf

1674-delnp-2003-form-13.pdf

1674-delnp-2003-form-19.pdf

1674-delnp-2003-form-2.pdf

1674-delnp-2003-form-26.pdf

1674-delnp-2003-Form-27-(08-04-2011).pdf

1674-delnp-2003-form-3.pdf

1674-delnp-2003-form-5.pdf

1674-DELNP-2003-GPA-(02-07-2010).pdf

1674-delnp-2003-pct-105.pdf

1674-delnp-2003-pct-210.pdf

1674-delnp-2003-pct-301.pdf

1674-delnp-2003-pct-304.pdf

1674-delnp-2003-pct-308.pdf

1674-delnp-2003-Petition-137-(08-04-2011).pdf

1674-delnp-2003-petition-138.pdf