WO2008059514A2 - Process for preparing escitalopram - Google Patents
Process for preparing escitalopram Download PDFInfo
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- WO2008059514A2 WO2008059514A2 PCT/IN2007/000323 IN2007000323W WO2008059514A2 WO 2008059514 A2 WO2008059514 A2 WO 2008059514A2 IN 2007000323 W IN2007000323 W IN 2007000323W WO 2008059514 A2 WO2008059514 A2 WO 2008059514A2
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- WIPO (PCT)
- Prior art keywords
- formula
- fluorophenyl
- dimethylamino
- hydroxybutyl
- hydroxymethyl
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- UQSJIUYABKWWRP-UHFFFAOYSA-N CN(C)CCCC(c(cc1)ccc1F)(c(cc1)c(CO)cc1[BrH+])O Chemical compound CN(C)CCCC(c(cc1)ccc1F)(c(cc1)c(CO)cc1[BrH+])O UQSJIUYABKWWRP-UHFFFAOYSA-N 0.000 description 1
- WSEQXVZVJXJVFP-UHFFFAOYSA-N CN(C)CCCC1(c(cc2)ccc2F)OCc2cc(C#N)ccc12 Chemical compound CN(C)CCCC1(c(cc2)ccc2F)OCc2cc(C#N)ccc12 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N CN(C)CCC[C@@]1(c(cc2)ccc2F)OCc2cc(C#N)ccc12 Chemical compound CN(C)CCC[C@@]1(c(cc2)ccc2F)OCc2cc(C#N)ccc12 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
Classifications
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides an improved process for preparation of Escitalopram of formula (I) or its pharmaceutically acceptable salt, solvates or hydrates thereof formula (I), (III): via formation of hydrobromide salt of 4-(4-(dimethylamino)-l-(4-fluorophenyl)-l- hydroxybutyl)-3-(hydroxymethyl) benzonitrile of formula (III) to purify the compound of formula (III).
Description
PROCESS FOR PREPARING ESCITALOPRAM Field of the invention
The present invention relates to an improved process for preparing Escitalopram of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof. The present invention further provides the process for preparing Citalopram of formula (II) or its pharmaceutically acceptable salts, solvates, hydrates thereof. More, particularly the present invention relates to the process for preparing 4-(4-(dimethylamino)-l-(4- fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl) benzo- nitrile of formula (III).
Escitalopram is chemically known as (S)-l-(3-(dimethylamino)propyl)-l-(4- fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile or and represented by below mentioned formula (I). Escitalopram is a (S) enantiomer of Citalopram of formula (II), which is chemically known as (±)-l-(3-(dimethylamino)propyl)-l-(4-fluorophenyl)-
(H)
(III)
Background of the invention
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
The preparation and properties of antidepressant substituted 1- dimethylaminopropyl- 1 -phenylphthalans or 1 -(3 -dimethylaminopropyl)- 1 -phenyl- 1,3-
dihydroisobenzofurans) have been described in U.S. Pat. No. 4,136,193. The most interesting of these compounds contain a cyano-group, and one of these, l-(3- dimethylaminopropyl)-l-(4'-fluorophenyl)-l,3-dihydroiso benzo furan-5-c arbonitrile, has shown great promise as a valuable antidepressant drag with few side effects. It has been found, however, that the methods described in U.S. Pat. No.
4,136,193 for the preparation of this compound possesses some problems in the scale- up to commercial production, and this has necessitated further research in an attempt to discover a shorter route to this compound and to avoid the risk involved in the metalation step used previously. Citalopram was first disclosed in DE 2, 657, 271, corresponding to US 4, 136,
193. This patent publication describes the preparation of citalopram by one method and outlines a further method, which may be used for preparing citalopram.
According to the process described, the corresponding l-(4-fluorophenyl)-l,3- dihydro-5-iso benzofurancarbonitrile is reacted with 3-(N,N-dimethylamino) propyl- chloride in the presence of methylsulfinylmethide as condensing agent. The starting material was prepared from the corresponding 5-bromo derivatives by reaction with cuprous cyanide. According to the method,, which is only outlined in general terms, citalopram may be obtained by the ring closure of the compound below
in the presence of a dehydrating agent and subsequent exchange of the 5-bromo group with cuprous cyanide. The starting material of Formula - (A) is obtained from 5- bromophthalide by two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium chloride and N,N-di methylaminopropyl magnesium chloride, respectively. A new and surprising method and an intermediate for the preparation of citalopram were described in US 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-cyanophthalide by two successive Grignard reactions, i.e. with 4- fluorophenyl-magnesium halogenide and N5N- dimethylaminopropyl magnesium halogenide, respectively.
The process for preparation of citalopram is outlined below.
Scheme-1
EP1414435 Bl claims the crystalline particles of Escitalopram oxalate, characterized in that median particle size is of crystals is at least 40 μm which is further claimed in the range of 50-200 μm. EP1522539 Bl claims the method of manufacturing crystalline particles of Escitalopram oxalate.
However, there is a need to have a process for preparing 4-(4-(dimethylamino)- l-(4-fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl) benzonitrile of foπnula (III), which yields substantially purer form.
Objects of the Invention
It is an important object of the present invention to provide a process for preparing Escitalopram of formula (I) and its pharmaceutically acceptable salts, solvates and hydrates thereof.
Another object of the present invention is to provide the process for preparing Citalopram of formula (II) and its pharmaceutically acceptable salts, solvates and hydrates thereof.
Yet another object of the present invention is provide a process for purifying A- (4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl) benzonitrile of formula (III), which is one of the key intermediate of Escitalopram and Citalopram.
Still another object of the present invention is to provide a substantially pure A- (4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl) benzonitrile Description of the invention:
According to the embodiment of the present invention, the present invention provides an improved process for preparation of Escitalopram of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof
(I) which comprises:
(a) reacting 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III) with hydrobromic acid to form 4-(4- (dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 - (hydroxymethyl)benzonitrile hydrobromide salt of formula (IV);
(III) (IV)
(b) reacting 4-(4-(dimethylaniino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 - (hydroxymethyl) benzonitrile hydrobromide salt of formula (IV) with base to obtain 4-(4- (dimethylamino)- 1 -
(4-fluorophenyl)- l-hydroxybutyl)-3 -(hydroxymethyl) benzonitrile;
(c) resolving 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 - (hydroxymethyl) benzonitrile to obtain (S)- 4-(4τ(dimethylamino)-l-(4- fluorophenyl)-l- hydroxybutyl)-3 -(hydroxymethyl) benzonitrile of formula (Ilia); and
(Ilia)
(id) converting said compound of formula (Ilia) to Escitalopram of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof.
The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting hydrobromide salt.. In the process, a mixture, slurry, or solution of 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III) and a solvent may be contacted with a hydrobromic acid, or conversely, a mixture, slurry, or solution of hydrobromic acid and a solvent may be contacted with 4-(4-(dimemylamino)-l -(4-fluorophenyl)- 1- hydroxybutyl)-3 -(hydroxymethyl) benzonitrile of formula (III). The solvent system can be comprised of a single solvent or a mixture of solvents. Suitable solvents for slat formation reaction includes water, a lower alcohol (C1- C6) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisopropyl ether, dioxane and the like.
The temperature of contact of 4-(4-(dimethylamino)-l -(4-fluorophenyl)- 1- hydroxybutyl)-3 -(hydroxymethyl) benzonitrile of formula (III) and hydrobromic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two-phase solution are also possible, though a single solution is generally preferred.
Base used in the step (b) can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium carbonate, potassium tert-butoxide and the like. The reaction is preferably carried out in water or with mixture of water and water miscible solvent such as alcohol, acetonitrile and the like.
Thus, obtained 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 - (hydroxymethyl) benzonitrile of formula (III) is further undergoes resolution with with (+)Di-tolyl-D-tartric acid, reacting with base selected from group consisting of sodium carbonate, potsssium carbonate in suitable solvent to give (S)-4-(4-(dimethylamino)-l- (4-fluorophenyl)- l-hydroxybutyl)-3 -(hydroxymethyl) benzo- nitrile of formula (Ilia), which is converted to Escitalopram of formula (I) or its pharmaceutically acceptable salt, solvates or hydrates thereof.
According to another aspect of the present invention, there is provided a process for preparation of Citalopram of formula (II),
(H) which comprises:
(a) reacting 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III) with hydrobromic acid to form 4-(4- (dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl) benzonitrile hydrobromide salt of formula (IV);
(b) reacting 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile hydrobromide salt of formula (IV) with base to obtain 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl) benzonitrile of formula (III);
(c) converting said compound of formula (III) to Citalopram of formula (II) or its pharmaceutically acceptable salts, solvates, hydrates thereof.
According to another aspect of the present invention, there is provided a process for purifying 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III) comprising treating 4-(4- (dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl)benzonitrile of formula (III) with hydrobromic acid to form 4-(4-(dimethylamino)-l-(4- fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl)benzonitrile hydro- bromide salt of formula (IV), reacting said hydrobromide salt of formula (IV) with base to obtain substantially pure 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3- (hydroxy methyl) benzonitrile of formula (III). The reaction is preferably carried out in suitable solvent. The solvent system is preferably selected so as to facilitate the salt reaction and to allow subsequent separation of the resulting hydrobromide salt.. In the process, a mixture, slurry, or solution of 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III) and a solvent may be contacted with a hydrobromic acid, or .conversely, a mixture, slurry, or solution of hydrobromic acid and a solvent may be contacted with 4-(4-(dimethylamino)-l -(4-fluorophenyl)- 1- hydroxybutyl)-3 -(hydroxymethyl) benzonitrile of formula (III). The solvent system can be comprised of a single solvent or a mixture of solvents. Suitable solvents for slat formation reaction includes water, a lower alcohol (C1-C6) such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; ester such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketone such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ether such as tetrahydrofuran, di ethyl ether, diisopropyl ether, dioxane and the like.
The temperature of contact of 4-(4-(dimethylamino)-l -(4-fluorophenyl)- 1- hydroxybutyl)-3-(hydroxyrnethyl) benzonitrile of formula (III) and hydrobromic acid in the solvent system is from ambient to the boiling point of the solvent system, with elevated temperatures, but generally less than the boiling point, being preferred. It is not required that a complete solution is formed in this step, i.e. a slurry or two-phase solution are also possible, though a single solution is generally preferred. Base used in the step (b) can be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium carbonate, potassium tert-butoxide and the like. The reaction is preferably carried out in water or with mixture of water and water miscible solvent such as alcohol, acetonitrile and the like.
The present invention further provides substantially pure 4-(4-(dimethylamino)- l-(4-fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl) benzonitrile of formula (III).
The present invention further provides an improved process for preparing Escitalopram of formula (I) or its pharmaceutically acceptable salt, solvates or hydrates thereof which comprises treating 4-(4-(dimethylamino)-l-(4-fluorophenyl)-l- hydroxybutyl)-3-(hydroxymethyl) benzo- nitrile of formula (III) with (+) Di-tolyl-D- tartric acid, reacting with base selected from group consisting of sodium carbonate, potsssium carbonate in suitable solvent to give (S)-4-(4-(dimethylamino)-l-(4- fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl) benzonitrile of formula (Ilia), which is converted to Escitalopram of formula (I) or its pharmaceutically acceptable salt,
(Ha) solvates or hydrates thereof.
The present invention further provides a process for preparing substantially pure Escitalopram formula (I), which comprises treating Escitalopram of formula (I) with aliphatic hydrocarbon solvent selected from hexane, n-heptane, to obtain substantially pure Escitalopram formula (I)
According to the preferred embodiment of the present invention, there is provided a process for Escitalopram Oxalate (Ia),
which comprises the steps of (a) dissolving Escitalopram in aliphatic hydrocarbon solvent;
(b) optionally filtering the said solution;
(c) distilling aliphatic hydrocarbon solvent to obtains Escitalopram residue;
(d) dissolving the Escitalopram residue in ketonic solvent; and
(e) treating the said solution with oxalic acid to obtain Escitalopram oxalate.
Aliphatic hydrocarbon solvent as described in above process can be selected from n-hexane, n-heptane, cyclohexane and the like, preferably n-heptane. Ketonic solvent as described in above process can be selected from can be selected from acetone, methyl isobutyl ketone, methyl ethyl ketone and the like, preferably acetone.
The particle size distribution of Escitalopram oxalate is carried out by using Malvern Light Scattering method with the following conditions.
Bulk density:
Determine the test on 25.0 g of the substance
Weigh accurately about 25.Og of the substance and transfer into a 100.0 mL of dry graduated cylinder. Note down the volume occupied by the substance. Weight of sample taken for the test
Bulk density = = g/mL
Volume occupied by the substance before tapping Tap density:
Stopper the cylinder and give 750 strokes. Note down the volume occupied by the substance.
Weight of sample taken for the test Tap density = • = g/ML • Volume occupied by the substance after tapping
Particle Size:
Take 2.0 g of sample for particle size analysis.
Measurement time : 12 seconds.
Background time : 12 seconds. Measurement snap : 12000
Background snap : 12000
Vibration feed rate : 40.0%
Dispersive Air Pressure : 1.6 Bar
Although the invention has been described with reference to a specific example, it will be appreciated by those skilled in the art that the invention can be embodied in many other forms. The process for the preparation of Escitalopram and its intermediate described in the present invention is demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of invention. Examples:
Example-1: 4-(4-(dimethyIamino)-l-(4-fluorophenyl)-l-hydroxybutyI)-3-
(hydroxymethyl) benzonitrile hydrobromide salt (IV) Dissolved 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III) (1.0 g) in ethyl alcohol (20 mL) at about 70 - 75°C and hydrobromic acid (10ml) was added. The reaction mixture was stirred at about 70 - 75°C temperature for 30 minutes. The reaction mass is cooled. The product started to precipitate at about 40°C. The reaction mass was stirred for one hour at about 25 - 30°C, filtered and washed with ethyl alcohol (5.0 mL) to obtain 4-(4- (dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl) benzonitrile hydrobromide salt (IV).
Example 2: Preparation of 4-(4-(dimethylammo)-l-(4-fluorophenyl)-l- hydroxybutyl)-3-(hydroxymethyl) benzonitrile salt with (+) Di-toIyl-D-tartric acid 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl) benzonitrile hydrobromide salt (lkg) was added in a mixture of 4L of dichloromethane and 3L of water at 250C to 4O0C. Potassium carbonate solution was added to the reaction mixture in about 1 hour and allowed to settle. The separated aqueous layer was treated with dichloromethane and was allowed to settle. The combined dichloromethane were washed with water and were separated. All the traces of dichloromethane were removed from the reaction mixture by vacuum followed by treatment with IL isopropanol. Isopropanol was removed under vacuum and the reaction mixture was cooled to 4O0C to 5O0C. Mixture of 0.456 Kg of (+) Di-tolyl-D- tartric acid and 8L isopropanol was added to the reaction mixture. The reaction mixture was heated at 600C to 650C and again cooled to 250C to 300C. The reaction mixture was filtered and washed with isopropanol. The wet cake thus obtained was purified by isopropanol.
Example 3: Preparation of 4-(4-(dimethylamino)-l-(4-fluorophenyl)-l- bydroxybutyl)-3-(hydroxymethyl) benzonitrile (Escitalopram)
IKg of 4-(4-(dimethylamino)-l-(4-fluorophenyl)-l-hydroxybutyl)-3- (hydroxymethyl) benzo- nitrile salt of (+) Di-tolyl-D-tartric acid was dissolved in mixture of 3L of dichloromethane and 3L of water at 250C to 4O0C. Potassium carbonate solution was added to the reaction mixture over a period of 1 hour at 2O0C to 250C. The reaction mixture was stirred and settled for 30 minutes. The separated aqueous layer was treated with IL of dichloromethane. The combined organic layer was treated with anhydrous sodium sulphate and stirred for 1 hour at 250C to 4O0C. The organic layer was treated with 3L of dichloromethane and cooled at 50C to 1O0C. 0.566 Kg of triethylamine was added to the reaction mixture and was further cooled to O0C to 70C. The reaction mixture was treated with methane sulphonyl chloride solution followed by stirring for 1 hour. The reaction mixture was poured in water, stirred and allowed to settle. The separated organic aqueous layer was again treated with dichloromethane followed by treatment of organic layer with solution of potassium carbonate. The separated organic layer was washed with water. The excess of dichloromethane was removed under vacuum. The product obtained was purified by n- heptane. Example 4: Preparation of Escitalopram oxalate IKg of Escitalopram was dissolved in 2L of acetone at 250C to 4O0C. The reaction was fine filtered to removed the traces of undissolved material. The freshly prepared oxalic acid solution in acetone was added to the above reaction mixture at 550C to 65°C over a period of 1 to 1.5 hour. After the completion of addition the reaction mass was stirred for 1 hour, cooled, filtered and dried to obtain Esctilopram oxalate (Yield = 85%)
Claims
1. An improved process, for preparation of Escitalopram of formula (I) or its pharmaceutically acceptable salt, solvates or hydrates thereof,
(i) reacting 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III)
(Ill)
with hydrobromic acid to form 4-(4-(dimethylamino)-l -(4-fluorophenyl)- 1- hydroxybutyl)-3-(hydroxymethyl) benzonitrile hydrobromide salt of formula (IV)
(ii) reacting 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile hydrobromide salt of formula (IV) with base to obtain 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 - (hydroxymethyl) benzonitrile
(iii) resolving 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 - (hydroxymethyl) benzonitrile to obtain (S)- 4-(4-(dimethylamino)-l-(4- fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl) benzonitrile of formula (HIa)
(iv) converting said compound of formula (Ilia) to Escitalopram of formula (I) or its pharmaceutically acceptable salts, solvates, hydrates thereof.
2. A process for preparation of Citalopram of formula (II)
(a) reacting 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -
(hydroxymethyl) benzonitrile of formula (III) with hydrobromic acid to form 4-(4- (dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 -(hydroxymethyl) benzonitrile hydrobromide salt of formula (IV); 
(b) reacting 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3- (hydroxymethyl) benzonitrile hydrobromide salt of formula (IV) with base to obtain 4-(4-(dimethylamino)- 1 -(4-fluorophenyl)- 1 -hydroxybutyl)-3 - (hydroxymethyl) benzonitrile of formula (III); and
(c) converting said compound of formula (III) to Citalopram of formula (II) or its pharmaceutically acceptable salts, solvates, hydrates thereof.
3. A process as claimed in claim 1 or 2, wherein step (i) or step (a) is carried out in solvent system selected from water, C1-C6 alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, iso-butanol, tert-butanol; esters such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ethers such as tetrahydrofuran, di ethyl ether, diisopropyl ether, dioxane and mixtures therof.
4. A process as claimed in claim 1 or 2, wherein base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium carbonate, potassium tert-butoxide and the like.
5. A process as claimed in claim I5 wherein resolution of 4-(4-(dimethylamino)-l-(4- fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl) benzonitrile of formula (III) is carried out with optically active acid selected from (+)- or (-)-p-di-tolyl-D-tartric acid, (+)- or (-)-di-benzoyl-D-tartaric acid, (+)- or (-)-camphor sulfonic acid and the like, preferably (+)-p-di-tolyl-D-tartric acid, in suitable organic solvent selected from water, C1-C6 alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol, iso-butanol, tert-butanol; esters such as ethyl acetate, isopropyl acetate, butyl acetate, iso-butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl tert-butyl ketone; ethers such as tetrahydrofuran, di ethyl ether, diisopropyl ether, dioxane; halogenated hydrocarbons like methylene dichloride and the like, preferably methylene dichloride to provide optically active acid salt of compound of formula (III).
6. A process as claimed in claim 5, wherein optically active salt of compound of formula (III) is further reacted with base selected from the group consisting of sodium carbonate, potassium carbonate to obtain (S)-4-(4-(dimethylamino)-l-(4- fluorophenyl)-l-hydroxybutyl)-3-(hydroxymethyl) benzonitrile of formula (Ilia).
7. A process for purification of Escitalopram of formula (I)
(I) which comprises treating Escitalopram of formula (I) with aliphatic hydrocarbon solvent selected from hexane, n-heptane, to obtain substantially pure Escitalopram formula (I).
8. A process for preparation of Escitalopram Oxalate of formula (Ia),
which comprises the steps of:
(a) dissolving Escitalopram in aliphatic hydrocarbon solvent;
(b) optionally filtering the said solution;
(c) distilling aliphatic hydrocarbon solvent to obtains Escitalopram residue; (d) dissolving the Escitalopram residue in ketonic solvent; and
(e) treating the said solution with oxalic acid to obtain Escitalopram oxalate.
9. A process as claimed in claim 7, wherein aliphatic hydrocarbon can be selected from n-hexane, n-heptane, cyclohexane and the like, preferably n-heptane and ketonic solvent can be selected from acetone, methyl isobutyl ketone, methyl ethyl ketone and the like, preferably acetone.
10. A process for preparation of Escitalopram of formula (I) or Citalopram of formula (II), its pharmaceutically acceptable salts, solvates or hydrates thereof substantially as herein described with reference to the foregoing examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1210/MUM/2006 | 2006-07-31 | ||
| IN1210MU2006 | 2006-07-31 |
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| WO2008059514A2 true WO2008059514A2 (en) | 2008-05-22 |
| WO2008059514A3 WO2008059514A3 (en) | 2009-04-02 |
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| PCT/IN2007/000323 WO2008059514A2 (en) | 2006-07-31 | 2007-07-31 | Process for preparing escitalopram |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7939680B2 (en) | 2005-07-27 | 2011-05-10 | Aurobindo Pharma Ltd. | Process for the preparation of Escitalopram |
| US8022232B2 (en) | 2007-09-11 | 2011-09-20 | H. Lundbeck A/S | Method for manufacture of escitalopram |
| CN104119248A (en) * | 2014-08-08 | 2014-10-29 | 广东东阳光药业有限公司 | Method for preparing S-citalopram |
| CN107074750A (en) * | 2014-11-14 | 2017-08-18 | 浙江华海药业股份有限公司 | A kind of method for splitting the cyanogen glycol of Citalopram intermediate 5 |
| CN109212045A (en) * | 2017-07-04 | 2019-01-15 | 万全万特制药（厦门）有限公司 | The method of separating and assaying of escitalopram oxalate residual solvent and impurity |
| WO2020060011A1 (en) * | 2018-09-17 | 2020-03-26 | (주)유케이케미팜 | Novel preparation method for citalopram and escitalopram using carbonates |
| CN115368327A (en) * | 2022-09-07 | 2022-11-22 | 无锡积大制药有限公司 | Escitalopram oxalate resolution process |
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| WO2003000672A1 (en) * | 2001-06-25 | 2003-01-03 | H. Lundbeck A/S | Process for the preparation of racemic citalopram and/or s- or r-citalopram by separation of a mixture of r- and s-citalopram |
| WO2003072565A1 (en) * | 2002-02-27 | 2003-09-04 | Matrix Laboratories Limited | Process for the production of citalopram |
| WO2004014821A1 (en) * | 2002-08-12 | 2004-02-19 | H. Lundbeck A/S | Method for the separation of intermediates which may be used for the preparation of escitalopram |
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| US7939680B2 (en) | 2005-07-27 | 2011-05-10 | Aurobindo Pharma Ltd. | Process for the preparation of Escitalopram |
| US8022232B2 (en) | 2007-09-11 | 2011-09-20 | H. Lundbeck A/S | Method for manufacture of escitalopram |
| CN104119248A (en) * | 2014-08-08 | 2014-10-29 | 广东东阳光药业有限公司 | Method for preparing S-citalopram |
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| EP3219702A4 (en) * | 2014-11-14 | 2018-05-30 | Zhejiang Huahai Pharmaceutical Co., Ltd. | Method for resolution of citalopram intermediate 5-cyanogen diol |
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| CN109212045A (en) * | 2017-07-04 | 2019-01-15 | 万全万特制药（厦门）有限公司 | The method of separating and assaying of escitalopram oxalate residual solvent and impurity |
| WO2020060011A1 (en) * | 2018-09-17 | 2020-03-26 | (주)유케이케미팜 | Novel preparation method for citalopram and escitalopram using carbonates |
| CN115368327A (en) * | 2022-09-07 | 2022-11-22 | 无锡积大制药有限公司 | Escitalopram oxalate resolution process |
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