GB2387596A - Separation of 5-carboxyamide analogs of citalopram from a mixture containing citalopram - Google Patents
Separation of 5-carboxyamide analogs of citalopram from a mixture containing citalopram Download PDFInfo
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- GB2387596A GB2387596A GB0315853A GB0315853A GB2387596A GB 2387596 A GB2387596 A GB 2387596A GB 0315853 A GB0315853 A GB 0315853A GB 0315853 A GB0315853 A GB 0315853A GB 2387596 A GB2387596 A GB 2387596A
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- Prior art keywords
- citalopram
- solvent
- carboxyamide
- salt
- oxalate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the separation of the 5-carboxyamide analog of citalopram from a crude mixture containing citalopram comprises dissolving citalopram in an alcohol solvent, adding and acid, and separating the precipitated salt. The exemplified alcoholic solvent is isopropyl alcohol, and the exemplified acid is hydrobromic acid to yield citalopram hydrobromide salt.
Description
- - 1 - >o376j:) 77697/003.621
Process This invention relates to citalopram, in particular 5 salts of Citalopram and a process for the manufacture of said salts in very high purity.
Citalopram is a well-known anti-depressant drug which has been on the market for a number of years. It has 10 the structure shown below.
N C,, 1\
Citalopram is a selective, centrally acting serotonin (5hydroxytryptamine:5-HT) re-uptake inhibitor and accordingly possesses anti-depressant activity. The anti-depressant activity of the compound has been 25 reported in a number of publications and Citalopram has further been disclosed as showing potential in the treatment of dementia and cerebrovascular disorders.
Citalopram was first disclosed in US 4136193 which 30 describes a number of processes for its preparation.
Once manufactured, the Citalopram base is generally converted to a salt using conventional procedures although it can be used as a free base. Hydrobromide salts are especially preferred since they are orally 35 available.
Since the publication of the above mentioned US Patent,
l a number of further processes for the preparation of citalopram have been devised and in many of these, as well as in the above US Patent, the last step of the process involves the conversion of a group different 5 from the cyano in the 5 position of the phthalane ring into che 5-cyano group. Preferably the conversion takes place from a bromine analogue.
As is well-known however, impurities are inevitably 10 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 rewired.
Where the final stage of citalopram manufacture involves cyanation of 5bromine analogue to the corresponding nitrite, the main impurities encountered are: B r_, -,/ C I,-,: 5-Br/CI-analog of h citalopram O F - \o I H2N/ l NH "_ /-, N.
F F desmethvl citaloDram 5-carboxamide analog of ci taloPram
- 3 - Various purification procedures are already known in the art for purifying a crude citalpram mixture produced after such a cyanation reaction. For example, GB 2356199 teaches that the impurities may be removed using 5 a conventional film distillation technique. The crude base 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 2357762 describes an alternative procedure in 10 which the crude free base is simply crystallized prior to conversion to the salt.
There still remains the need however, to devise efficient and more economic purification procedures 15 especially for use an industrial scale where, for example, the use of film distillation apparatus may be prohibitively expensive.
The present inventors have now found an alternative and 20 rapid way of isolating purer citalopram salts substantially in the absence of or with low levels of the above-mentioned impurities without using a potentially time consuming crystallization techniques or expensive film distillation apparatus. Rather, the 25 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 with low levels, e.g. less than 0.1%, of the major impurities 5-chloro analog of citalopram, 5- bromo analog 30 of citalopram, des-methyl-citalopram and 5-carboxyamide analog of citalopram.
Thus, viewed from one aspect the invention provides a process for the preparation of a salt of citalopram 35 comprising: (A) dissolving citalopram in a solvent selected from
- 4 - acetone, methanol, ethanol, isopropyl alcohol, or toluene or mixture thereof and adding oxalic acid; (B) separating the precipitated citalopram oxalate, e.g. 5 by filtration; (C) suspending said citalopram oxalate in water and adding a base in an amount sufficient to 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; 15 optionally repeating steps (A) to (D), repeating steps (A) and (B) and subsequently; (E) suspending said citalopram oxalate in water and 20 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 mixture thereof and isolating the aqueous phase; (G) adding base to said aqueous phase in an amount sufficient 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.
35 Viewed from another aspect the invention comprises a process for the separation of desmethyl citalopram from
À 5 a crude mixture thereof with citalopram base comprising: (A) dissolving citalopram in a solvent selected from acetone, alcohol, or toluene or mixture thereof and 5 adding oxalic acid; (B) separating the precipitated citalopram oxalate; (C) suspending said citalopram oxalate in water and lo adding a base in an amount sufficient to 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 15 said solvent; optionally repeating steps (A) to (D).
Viewed from a still further aspect the invention 20 provides a process for the separation of 5-chloro analog of citalopram and/or 5-bromo analog of citalopram from a crude mixture of citalopram oxalate comprising: (E) suspending citalopram oxalate in water and adding 25 base to a pH 6 to 7; (F) adding a solvent selected from toluene, cyclohexane, n-hexane, nheptane, 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 analog of citalopram 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 5 processes of the invention as well as their use in medicine and pharmaceutical salts comprising the same.
As used herein "citalopram" refers to the free base thereof. In part (A) of the process of the invention, the crude citalopram base should preferably be dissolved in acetone. Without wishing to be limited by theorv, it is believed that desmethyl citalopram is removed in the 15 solvent washings in step (B) when the citalopram oxalate salt is isolated. It has been found that the most efficient elimination of desmethyl citalopram occurs when the solvent employed is acetone.
20 Isolation of the precipitated citalopram oxalate in step (B) may be achieved by, for example, filtration or centrifugation or by any other conventional technique for separating a solid from a liquid. The citalopram oxalate is precipitated (it being insoluble in the 25 organic solvent employed) and isolation should not be effected by evaporating off the organic phase since the desmethyl citalopram would, of course, not be removed in such a procedure.
30 The base used to liberate citalopram from its oxalate in step (C) may be any conventional base which is compatible with citalopram. Suitable bases include NaOH, KOH and various organic bases however, it is preferred if ammonia is used as the base. The pH of the 35 solution in step (C) needs to be increased to a value sufficient to ensure citalopram base is liberated and the required pH will be readily determined by the
7 - skilled chemist. It is preferred however if 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 5 measuring apparatus.
The liberated citalopram free base may be extracted from the aqueous solution by using a standard organic solvent (Step D). Most suitable in this regard is toluene 10 although other hydrocarbon solvents such as xylene, hexane, heptane eta 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 15 distillation or under reduced pressure. Conveniently however, the solvent is removed under atmospheric pressure conditions so as to maintain the liberated citalopram as an oil. By using atmospheric pressure evaporation, it is likely that some traces of solvent 20 will remain (perhaps up to 10%) hence maintaining the liberated citalopram in an oil form.
In order to remove any remaining traces of desmethyl citalopram it may be necessary to repeat the oxalate 25 formation and subsequent base liberation steps (A to D).
Without wishing to be limited by theory, it is believed that the further main impurities, bromo/chloro analogs of citalopram can be removed by careful manipulation of 30 pH and then by washing in particular solvents.
In order to remove these impurities according to the invention, it is necessary to add citalopram oxalate to water and adjust the pH of the solution to 6 to 7, 35 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
8 - preferred. The inventors have surprising found that at this pH citalopram oxalate remains substantially in its salt 5 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 10 aqueous phase. The organic washing solvent is conveniently toluene, cyclohexane, nhexane, 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 can then be fully basified and the citalopram free base extracted into an organic solvent for subsequent conversion to the desired 20 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).
25 Most suitable in this regard is again toluene although other hydrocarbon solvents such as xylene, hexane, heptane etc could be employed equally successfully. The solvent may then be evaporated off by simple distillation or under reduced pressure. Conveniently 30 however, the solvent is removed under atmospheric pressure conditions so as to maintain the liberated citalopram 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 35 liberated citalopram in an oil form.
It is during the final stage, i.e. conversion to the
- 9 - desired salt, that the inventors believe that the 5 carboxyamide analog of citalopram impurity may be removed. 5 This is achieved by dissolving the citalopram in an alcohol solvent, especially isopropyl alcohol or methanol. The aqueous salt forming agent, i.e. acid, is then added to form the citalopram salt (Step H). The citalopram salt crystals may be isolated conventionally 10 by filtration or centrifugation but the 5-carboxyamide analog of citalopram impurity remains in the organic phase and is hence easily and surprisingly removed with the organic phase.
15 The salt to be manufactured is preferably the hydrobromide, hydrochloride or oxalate salt.
The purification technique of the present invention is particularly suitable for preparing citalopram 20 hydrobromide where the initial citalopram mixture has been prepared via a cyanation of 5-bromocitalopram.
However, the process is equally suitable for the purification of the crude citalopram made by any other process. Other such processes are described in, for 25 example, EP-A-171943.
The cyanation of bromo analog of citalopram is easily carried out using, for example, sodium cyanide or preferably copper cyanide. Bromocitalopram itself can 30 be manufactured in a number of ways, for example, as described in US Patent No. 4136193.
Depending on the nature of the impurities present it may be possible to omit some of the purification stages of 35 the process of the invention. Thus, if no desmethyl citalopram is present in a crude citalopram mixture, it may be possible to omit stages (A) to (D) and simply
- 10 remove the other impurities following the teaching of steps (E) to (H). This forms a further aspect of the invention. Similarly, if a 5carboxyamide analog of citalopram impurity is not present then conversion to 5 the desired salt may be effected without following the explicit teachings of step (H). Hence the present invention also provides a process as described in steps (A) to (G) and steps (A) to (D) followed by step (H).
10 Citalopram 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 15 diluents 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 the like. Any other adjuvant or additive colourings, 20 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 25 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, sterilization of the solution and filling in suitable 30 ampoules or vials. Again, any 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 35 dependent on the nature of the patient and will be readily determined by the skilled physician. Tablets may however comprise, for example, 20 mg or 40 mg doses.
- 11 -
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 5 known in the art.
The invention will now be further described with reference to the following non-limiting examples.
10 EXAMPT.E 1
1-(3-Dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3-
dibydrobenzofuran-5-carbonitrile oxalate (Citalopram Oxalate). 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 desmethyl Citalopram content of up to 5.0\ was 20 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 ml) and the resulting mixture heated to 50-55 C. The mixture was cooled and the white 25 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 30 mol) 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 35 was concentrated under vacuum. Acetone (300 ml) is added to the residue and the mixture stirred for 15 min. at 40 C. To the above clear solution was added oxalic
- 12 acid (33 g, 0.26 mol), 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 5 pressure. Yield: 90 g (85%). Desmethyl citalopram content less than 0.1%.
10 EXAMPLE 2
1-(3-D;methylaminopropyl)-1-(4'-fluorophenyl)-1,3 dibydrobenzofuran-5carbonitrile hydrobromide (Citalopram hydrobromide).
1-(3-Dimethylaminopropyl)-1-(4'-fluorophenyl)-1,3 dihydrobenzofuran-5carbonitrile oxalate (90 g, 0.21 mol) prepared as per example 1 was suspended in water (500 ml) and aqueous ammonia (20-25%) was added to 20 adjust the pH of the solution to 6.2-7.0 (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 remaining aqueous phase was added ammonia (20-25%) to bring the pH to 9.0 25 9.2. The mixture was stirred for 15 min. and extracted with toluene (2 x 250 ml). The organic phases were washed with NaC1 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 30 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 20 C, the crystals are filtered and dried.
35 Yield: 75 g (85%) Purity: 99.7%
Claims (1)
- l L Claims1. A process for the separation of the 5-carboxyamide analog of citalopram from a crude mixture of citalopram 5 comprising: (H) dissolving citalopram in an alcohol solvent, adding an acid and separating the precipitated salt.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0204607.6A GB0204607D0 (en) | 2002-02-27 | 2002-02-27 | Process |
GB0210225A GB2375763B (en) | 2002-02-27 | 2002-05-03 | Process |
Publications (3)
Publication Number | Publication Date |
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GB0315853D0 GB0315853D0 (en) | 2003-08-13 |
GB2387596A true GB2387596A (en) | 2003-10-22 |
GB2387596B GB2387596B (en) | 2004-02-11 |
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Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
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GB0315852A Expired - Fee Related GB2387844B (en) | 2002-02-27 | 2002-05-03 | Separation of impurities from a crude mixture of citalopram |
GB0315853A Expired - Fee Related GB2387596B (en) | 2002-02-27 | 2002-05-03 | Process |
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Application Number | Title | Priority Date | Filing Date |
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GB0315852A Expired - Fee Related GB2387844B (en) | 2002-02-27 | 2002-05-03 | Separation of impurities from a crude mixture of citalopram |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7148364B2 (en) * | 2002-01-07 | 2006-12-12 | Sun Pharmaceutical Industries | Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998019513A2 (en) * | 1997-07-08 | 1998-05-14 | H. Lundbeck A/S | Method for the preparation of citalopram |
WO2003057132A2 (en) * | 2002-01-07 | 2003-07-17 | Sun Pharmaceutical Industries Limited | Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofuran carbonitrile |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1526331A (en) * | 1976-01-14 | 1978-09-27 | Kefalas As | Phthalanes |
GB2357762B (en) * | 2000-03-13 | 2002-01-30 | Lundbeck & Co As H | Crystalline base of citalopram |
GB2376945A (en) * | 2001-06-27 | 2002-12-31 | Cipla Ltd | Citalopram preparation |
-
2002
- 2002-05-03 GB GB0315852A patent/GB2387844B/en not_active Expired - Fee Related
- 2002-05-03 GB GB0315853A patent/GB2387596B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998019513A2 (en) * | 1997-07-08 | 1998-05-14 | H. Lundbeck A/S | Method for the preparation of citalopram |
WO2003057132A2 (en) * | 2002-01-07 | 2003-07-17 | Sun Pharmaceutical Industries Limited | Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)- 1,3-dihydro-5-isobenzofuran carbonitrile |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7148364B2 (en) * | 2002-01-07 | 2006-12-12 | Sun Pharmaceutical Industries | Process for the preparation of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-5-isobenzofuran carbonitrile |
Also Published As
Publication number | Publication date |
---|---|
GB0315852D0 (en) | 2003-08-13 |
GB2387844B (en) | 2005-05-11 |
GB0315853D0 (en) | 2003-08-13 |
GB2387596B (en) | 2004-02-11 |
GB2387844A (en) | 2003-10-29 |
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Effective date: 20100503 |