WO2004094399A1 - Procede ameliore de preparation de bromhydrate de citalopram - Google Patents

Procede ameliore de preparation de bromhydrate de citalopram Download PDF

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Publication number
WO2004094399A1
WO2004094399A1 PCT/IN2003/000165 IN0300165W WO2004094399A1 WO 2004094399 A1 WO2004094399 A1 WO 2004094399A1 IN 0300165 W IN0300165 W IN 0300165W WO 2004094399 A1 WO2004094399 A1 WO 2004094399A1
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WO
WIPO (PCT)
Prior art keywords
citalopram
base
formula
hydrobromide
acid
Prior art date
Application number
PCT/IN2003/000165
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English (en)
Inventor
Nannapaneni Venkaiah Chowdary
Muddasani Pulla Reddy
Donthineni Lingarao
Podile Khadgapathi
Original Assignee
Natco Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Natco Pharma Ltd filed Critical Natco Pharma Ltd
Priority to AU2003238676A priority Critical patent/AU2003238676A1/en
Priority to PCT/IN2003/000165 priority patent/WO2004094399A1/fr
Publication of WO2004094399A1 publication Critical patent/WO2004094399A1/fr

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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

Definitions

  • the present invention relates to an improved process for the preparation of citalopram hydrobromide.
  • Citalopram hydrobromide [l-(3-dimethylaminopropyl)-l-(4 1 -fluoro- phenyl)-l,3-dihydro-isobenzofuran-5-carbonitrile] is having the formula-I given below is prepared from citalopram base of formula-Ill without isolating and crystallizing the latter. Organic layer containing citalopram base is directly converted into its hydrobromide salt by treating with hydrobromic acid.
  • Citalopram base of formula-Ill is prepared from the isobenzofuran derivative of formula-II by earlier known method.
  • Citalopram hydrobromide is a well-known antidepressant drug available in the market. It is a selective, centrally active serotonine (5-hydroxytrypamine, 5-HT) re-uptake inhibitor, accordingly having antidepressant activity.
  • Bogeso (EP patent no 171, 943, corresponding to US patent no 4, 650, 884) has indicated that the methods described in the above patents for the preparation of citalopram hydrobromide possess some problems in the scale-up to commercial production.
  • Bogeso started with 5-cyanophthalide of formula-IX and surprisingly found that cyano group survived the cyclization step where 70% sulfuric acid was used at 80°C temperature (Scheme-3).
  • citalopram base thus obtained was converted to its HBr salt in acetone medium by passing molar quantity of HBr gas.
  • WO 98/019512 and WO 98/019513 relate to methods wherein a 5-amino-, 5-carboxy-, or 5-(sec-aminocarbonyl)phthalide is subjected to two successive Grignard reactions, ring closure and conversion of the resulting 1,3-dihydroisobenzofuran derivative to the corresponding 5-cyano compound, i.e. citalopram base.
  • hydrobromide have very high boiling point ( ⁇ 200°C at ⁇ 0.1mm Hg) and are sensitive to overheating. This is also a major drawback in developing this process for commercial production.
  • Second route of the original patent for preparation of citalopram hydrobromide involves purification of intermediate compounds of the formulae-I and II by high vacuum distillation (180-200°C at ⁇ 0.1mm Hg). This process is also practically difficult for a commercial production. Also, this route involves handling of a costly and hazardous reagent, lithium aluminum hydride.
  • Third and simplified route for the preparation of citalopram hydrobromide involves the introduction of 5 -cyano group present in citalopram hydrobromide at the beginning itself.
  • the citalopram base prepared by this method is extracted into toluene at pH 10.0 and the extracted product was twice passed through a bed of silica gel (weight equal to product).
  • hydrogen bromide gas is introduced into the acetone - toluene solution of citalopram base and made acidic until pH 3.0. pH is raised to 7.0 by adding some of the above citalopram base containing solution.
  • the crude citalopram hydrobromide thus obtained was recrystallized from water after charcoal treatment.
  • the crystals from the first recrystallization were dissolved in methanol/sopropyl alcohol medium and recrystallized after charcoal treatment.
  • the material from this 2 nd recrystallization is dissolved in a mixture of methanol and acetone and filtered with charcoal and recrystallized to get the
  • Citalopram hydrobromide has become a well-known antidepressant drug that has been now in the market for a considerable amount of time and has proved to be a valuable antidepressant drug with few side effects. Therefore there is a need to develop an improved process for its production that can be employed commercially. Especially such an improved process would be welcome considering the difficulties associated with the commercial application of the above-mentioned processes for the preparation of citalopram hydrobromide. Keeping this aspect into consideration, we aimed to develop a simple and economical process for commercial production of citalopram hydrobromide.
  • citalopram base prepared according to the process described and claimed in our above said co-pending Indian patent application (where the organic layer containing citalopram base is concentrated to a certain volume by distillation of solvent at a particular temperature and pressure, cooling of this concentrated solution to particular temperature, isolation of citalopram base by filtration, and drying), is sufficiently pure enough to convert it directly into a pharmaceutical grade citalopram hydrobromide without further working up. Therefore, citalopram base containing organic solution can be directly used in the hydrobromide salt formation stage thereby making the process simpler.
  • citalopram base can be completely utilized in the hydrobromide salt formation (Normally we lose some (about 5-7%) material in the filtrate during filtration of citalopram base by our earlier process.).
  • the main objective of the present invention is to provide an improved process for the preparation of citalopram hydrobromide of formula-I, which is useful for commercial application.
  • Another objective of the present invention is to provide an improved process for the preparation of citalopram hydrobromide of formula-I, which is useful for commercial application which avoids the isolation of citalopram base of formula-Ill from the organic solvent in the process shown in scheme-II.
  • Yet another objective of the present invention is to provide an improved process for the preparation of citalopram hydrobromide of formula-I, which is useful for commercial application, which is simple and economical.
  • the present invention provides an improved process for the preparation of citalopram hydrobromide of the formula-I,
  • the strong base used in step (i) may be sodium hydride or potassium t-butoxide, preferably sodium hydride.
  • the aromatic solvent used in step (ii) may be selected from benzene, toluene, xylene, etc., preferably toluene.
  • the organic acid used in step (iii) may be selected from acetic acid, propionic acid, succinic acid, oxalic acid, etc., preferably acetic acid or oxalic acid.
  • the organic base used in step (iv) may be selected from ammonia, monomethyl amine, dimethylamine, triethylamine, etc., preferably ammonia.
  • the ether solvent used in step (v) may be selected from diethyl ether, di-isoporpyl ether, t-butyl methyl ether, etc.; preferably, diethyl ether or di-isopropyl ether and the aromatic solvent may be selected from, benzene, toluene, xylene, etc., preferably toluene.
  • the aqueous isopropanol used in step (viii) may have water in 5-50%, preferably 5-15%.
  • the combined organic layer containing crude citalopram base was extracted with 2 x 1000ml of 20% aqueous acetic acid.
  • the combined aqueous acetic acid layer was treated with 20gr of active carbon, filtered and the filtrate neutralized with aqueous ammonia (25%) to get the pH of 8.5-9.0.
  • 500ml of toluene was added and stirred for 15min.
  • Toluene layer was separated and the aqueous layer extracted with 2 x 200ml of toluene.
  • the combined toluene layer was treated with carbon (10gr) and filtered.
  • the toluene solution was treated with aqueous hydrobromic acid (60ml of cone.
  • the above toluene layer containing crude citalopram was ex cted with 2 x 1000ml of 20% aqueous acetic acid.
  • the combined aqueous acetic acid layer was treated with carbon (lOgr) and neutralized with aqueous ammonia (25% w/v) to get the pH of 8-8.5.
  • product was extracted into 3 x 500ml of toluene.
  • the combined toluene layer was treated with carbon (10gr) and filtered. The filtrate was taken into a 3L three-necked RB flask and added dilute hydrobromic acid (90ml of cone, hydrobromic acid dissolved in 250ml water) keeping the temperature 25-30°C.
  • citalopram base is not isolated & dried and is used directly thereby making the process simpler and economical.

Abstract

L'invention porte sur un procédé amélioré de préparation de bromhydrate de citalopram de formule (I) à partir d'une base de citalopram de formule (III) et sans devoir isoler ou cristalliser ce dernier. La base de citalopram de formule (III) se prépare selon les anciennes méthodes à partir d'isobenzofurane de formule (II). De ce fait, la couche organique contenant la base de citalopram, directement traitée par l'acide bromhydrique aqueux donne le bromhydrate de citalopram.
PCT/IN2003/000165 2003-04-21 2003-04-21 Procede ameliore de preparation de bromhydrate de citalopram WO2004094399A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003238676A AU2003238676A1 (en) 2003-04-21 2003-04-21 An improved process for the preparation of citalopram hydrobromide
PCT/IN2003/000165 WO2004094399A1 (fr) 2003-04-21 2003-04-21 Procede ameliore de preparation de bromhydrate de citalopram

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000165 WO2004094399A1 (fr) 2003-04-21 2003-04-21 Procede ameliore de preparation de bromhydrate de citalopram

Publications (1)

Publication Number Publication Date
WO2004094399A1 true WO2004094399A1 (fr) 2004-11-04

Family

ID=33307095

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000165 WO2004094399A1 (fr) 2003-04-21 2003-04-21 Procede ameliore de preparation de bromhydrate de citalopram

Country Status (2)

Country Link
AU (1) AU2003238676A1 (fr)
WO (1) WO2004094399A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008059514A2 (fr) * 2006-07-31 2008-05-22 Cadila Healthcare Limited Procédé de préparation d'escitalopram

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019511A2 (fr) * 1997-11-10 1998-05-14 H. Lundbeck A/S Procede de preparation du citaloprame
DE20007303U1 (de) * 2000-03-13 2000-07-27 Lundbeck A S Kopenhagen Koeben Kristalline Base von Citalopram
EP1125907A2 (fr) * 2000-02-17 2001-08-22 SUMIKA FINE CHEMICALS Co., Ltd. Intermédiaires pour la production de citalopram
EP1152000A1 (fr) * 2000-05-02 2001-11-07 SUMIKA FINE CHEMICALS Co., Ltd. Cristal de bromhydrate de citalopram et procédé de sa cristallisation
WO2002066453A1 (fr) * 2001-02-22 2002-08-29 Natco Pharma Limited Procede de preparation de citalopram
GB2375763A (en) * 2002-02-27 2002-11-27 Matrix Lab Ltd Preparation of highly pure salts of citalopram
WO2003029236A1 (fr) * 2001-09-24 2003-04-10 Pharmachem Technologies Limited Procede de preparation du citalopram
EP1346989A1 (fr) * 2002-03-21 2003-09-24 Jubilant Organosys Limited Procede ameliore de preparation de citalopram et de bromhydrate de citalopram

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998019511A2 (fr) * 1997-11-10 1998-05-14 H. Lundbeck A/S Procede de preparation du citaloprame
EP1125907A2 (fr) * 2000-02-17 2001-08-22 SUMIKA FINE CHEMICALS Co., Ltd. Intermédiaires pour la production de citalopram
DE20007303U1 (de) * 2000-03-13 2000-07-27 Lundbeck A S Kopenhagen Koeben Kristalline Base von Citalopram
EP1152000A1 (fr) * 2000-05-02 2001-11-07 SUMIKA FINE CHEMICALS Co., Ltd. Cristal de bromhydrate de citalopram et procédé de sa cristallisation
WO2002066453A1 (fr) * 2001-02-22 2002-08-29 Natco Pharma Limited Procede de preparation de citalopram
WO2003029236A1 (fr) * 2001-09-24 2003-04-10 Pharmachem Technologies Limited Procede de preparation du citalopram
GB2375763A (en) * 2002-02-27 2002-11-27 Matrix Lab Ltd Preparation of highly pure salts of citalopram
EP1346989A1 (fr) * 2002-03-21 2003-09-24 Jubilant Organosys Limited Procede ameliore de preparation de citalopram et de bromhydrate de citalopram

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIGLER A J ET AL: "QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS IN A SERIES OF SELECTIVE 5-HT UPTAKE INHIBITORS", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 12, no. 3, May 1977 (1977-05-01), pages 289 - 295, XP000944915, ISSN: 0223-5234 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008059514A2 (fr) * 2006-07-31 2008-05-22 Cadila Healthcare Limited Procédé de préparation d'escitalopram
WO2008059514A3 (fr) * 2006-07-31 2009-04-02 Cadila Healthcare Ltd Procédé de préparation d'escitalopram

Also Published As

Publication number Publication date
AU2003238676A1 (en) 2004-11-19

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