EP1397342A1 - Procede de preparation d'intermediaires de sertraline - Google Patents

Procede de preparation d'intermediaires de sertraline

Info

Publication number
EP1397342A1
EP1397342A1 EP02727626A EP02727626A EP1397342A1 EP 1397342 A1 EP1397342 A1 EP 1397342A1 EP 02727626 A EP02727626 A EP 02727626A EP 02727626 A EP02727626 A EP 02727626A EP 1397342 A1 EP1397342 A1 EP 1397342A1
Authority
EP
European Patent Office
Prior art keywords
dichlorophenyl
dihydro
sertraline
cis
formula
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02727626A
Other languages
German (de)
English (en)
Inventor
Ilpo Laitinen
Pekka PIETIKÄINEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fermion Oy
Original Assignee
Orion Yhtyma Fermion Oy
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
Priority claimed from FI20011146A external-priority patent/FI20011146A0/fi
Application filed by Orion Yhtyma Fermion Oy filed Critical Orion Yhtyma Fermion Oy
Publication of EP1397342A1 publication Critical patent/EP1397342A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation
    • C07C209/88—Separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a novel method for the production of sertraline.
  • the present invention also relates to a novel process for the preparation of a pharmaceutical intermediate, N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphtalenylidene]methanamine.
  • Sertraline is marketed in the form of its hydrochloride for the treatment of depression, obsessive-compulsive disorder and panic disorder.
  • reaction is an equilibrium reaction, where the equilibrium has to be shifted. This can be done e.g. by using titanium tetrachloride to remove water from the reaction mixture. Titanium tetrachloride, however, is extremely reactive with water and side products formed are hazardous, and therefore other dehydrating agents have been considered.
  • (+) enantiomer of sertraline is prepared by either of the processes described above using (+) enantiomer of 4-(3,4- dichlorophenyl)-3,4-dihydro-l(2H)-naphtalenone as a starting material, so that no resolution of the final product is needed.
  • Still another route to to N-4-[3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphtalenylidene]methanamine is described in the patent application WO 99/36394.
  • Sertraline hydrochloride is produced by further hydrogenating the N-4-[3,4- dichlorophenyl)-3,4-dihydro-l(2H)-naphtalenylidene]methanamine resulted from processes above and resolving the racemic mixture and finally crystallizing sertraline hydrochloride.
  • the reaction can be performed in atmospheric pressure and ambient temperature. Also the amount of the solvent needed is low, impurities are not formed and the yield is good. Water removal agents like titanium tetrachloride or molecular sieves are not needed.
  • Another aspect of this invention relates to the process wherein the imine product formed in the process of the invention is hydrogenated to form sertraline which is further resolved by e.g. mandelic acid and finally crystallized as (lS-cis)-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine hydrochloride or some other pharmaceutically suitable salt.
  • Still another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising ( 1 S-cis)-4-(3,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 - naphthalenamine or its hydrochloride or some other pharmaceutically suitable salt prepared by the process of the invention.
  • the present invention provides a process for producing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine, by reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone with monomethylamine in a solvent selected from the a group consisting of amide solvents of general formula IV:
  • Rl and R3 are independently hydrogen or C 1-6 alkyl, which can be substituted, and R2 is hydrogen.
  • the present invention provides a process wherein the N-[4-(3,4-dichlorophenyl)-3,4-dihydro- 1 (2H)-naphthalenylidene]methanamine so formed in the process of the invention is hydrogenated to form sertraline which may be further resolved by the use of, e.g., mandelic acid and finally crystallized as (1S- cis)-4-(3,4-dichlorophenyl)-l ,2,3,4-tetrahydro-N-methyl-l -naphthalenamine hydrochloride or some other pharmaceutically suitable salt.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising (lS-cis)-4-(3,4-dichlorophenyl)-l ,2,3,4-tetrahydro-N- methyl-l -naphthalenamine or its hydrochloride or some other pharmaceutically suitable salt prepared by the process of the invention.
  • the solvent used in the imination step is dimethylformamide or methylformamide, most preferably, the solvent is dimethylformamide.
  • the imination of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone with monomethylamine may be performed in the presence of acid catalyst, which can be any suitable organic or inorganic acid, e.g., formic acid, acetic acid, sulfonic acid, or hydrochloric acid. In a preferred embodiment of the invention, formic acid or acetic acid is used as the acid catalyst.
  • the solubility of the product in the solvent of the invention is low, so that the product is slowly crystallizing out of the reaction mixture and it can be isolated easily by, e.g., filtration.
  • the process has also considerable purification capacity.
  • the reaction can be performed under atmospheric pressure and is typically carried out at a temperature in the range of from about 0 °C to about 50 °C, preferably at ambient temperature, i.e., from about 15 °C to about 25 °C.
  • the imination may also be carried out under a slight positive pressure of an inert atmosphere, such as nitrogen gas or argon gas.
  • the 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone is added to the solvent in an amount of about 300 g to about 400 g per liter of solvent, preferably about 320 g to about 350 g per liter of solvent.
  • the methylamine is added in an amount of about 4 mole to about 6 mole per mole of 4-(3,4-dichlorophenyl)- 3,4-dihydro-l-(2H)-naphthalenone, preferably about 4.8 mole to about 5.2 mole per mole of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone.
  • the acid catalyst is typically added to the mixture in an amount of about 0.1 mole to about 2.0 mole per mole of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)- naphthalenone, preferably about 0.4 mole to about 0.6 mole per mole of 4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone.
  • the present method is not constrained to any particular order of addition, and the reaction may be conveniently performed by charging all of the components into a suitable-size vessel at 0 °C and then allowing the reaction mixture to rise to ambient temperature. The reaction mixture is then stirred at ambient temperature for a time of about 10 to about 30 hours, preferably about 20 to about 24 hours. If desired, the progress of the reaction may be monitored by any suitable technique, including chromatography, especially high-pressure liquid chromatography (HPLC) or thin- layer chromatography (TLC).
  • HPLC high-pressure liquid chromatography
  • TLC thin- layer chromatography
  • the resulting imine compound, N-[4-(3,4-dichlorophenyl)-3,4-dihydro- l(2H)-naphthalenylidene]methanamine is insoluble in the reaction solvent and exists as a solid precipitate in the reaction mixture at the completion of the reaction.
  • the resulting imine compound, N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)- naphthalenylidene]methanamine may then be isolated from the reaction mixture by any suitable solid-liquid separation technique, such as filtration, centrifugation, or decantation.
  • the resulting imine compound, N-[4-(3,4-dichlorophenyl)-3,4-dihydro- l(2H)-naphthalenylidene]methanamine may be further hydrogenated to form cis- ( 1 S)( 1 R)- 4-(3 ,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 -naphthalenamine which may then be optically resolved with, e.g., mandelic acid and finally crystallized to afford (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- naphthalenamine hydrochloride or some other pharmaceutically suitable salt.
  • compositions comprising (lS-cis)-4-(3,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 -naphthalenamine or its pharmaceutically suitable salt prepared by the method of the invention can be prepared by methods well-known in the art.
  • N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]- methanamine 50 g is hydrogenated over palladium on charcoal to yield cis- (lS)(lR)- 4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.
  • the rasemic compound is resolved by mandelic acid and finally crystallized as sertraline hydrochloride.
  • the total yield from 4-(3,4-dichlorophenyl)-3,4-dihydro-l- (2H)-naphtalenone is 67 % (of the theoretical (+)-enantiomer).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un intermédiaire pharmaceutique, N-[4-(3,4-dichlorophényl)-3,4-dihydro-1(2H)-naphtalénylidène]méthanamine, pouvant être utilisé dans la production d'hydrochlorure de sertraline, et préparé de manière adéquate par réaction de 4-(3,4-dichlorophényl)-3,4-dihydro-1-(2H)-naphtalénone avec de la monométylamine dans un solvant qui est un solvant amide avec une structure de formule générale (IV). Dans cette formule, R1, R3 représentent indépendamment un atome d'hydrogène ou un alkyle en C1-C6, qui peut être substitué, et R2 représente un atome d'hydrogène.
EP02727626A 2001-05-31 2002-05-30 Procede de preparation d'intermediaires de sertraline Withdrawn EP1397342A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US29426601P 2001-05-31 2001-05-31
US294266P 2001-05-31
FI20011146A FI20011146A0 (fi) 2001-05-31 2001-05-31 Uusi valmistusmenetelmä
FI20011146 2001-05-31
PCT/FI2002/000466 WO2002096860A1 (fr) 2001-05-31 2002-05-30 Procede de preparation d'intermediaires de sertraline

Publications (1)

Publication Number Publication Date
EP1397342A1 true EP1397342A1 (fr) 2004-03-17

Family

ID=26161179

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02727626A Withdrawn EP1397342A1 (fr) 2001-05-31 2002-05-30 Procede de preparation d'intermediaires de sertraline

Country Status (3)

Country Link
EP (1) EP1397342A1 (fr)
CA (1) CA2448300A1 (fr)
WO (1) WO2002096860A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TR200808115T1 (tr) * 2006-04-28 2009-03-23 Sandoz Ag 4(S,R)-(3,4-diklorofenil)-3,4-dihidro-l(2H)-naftalin-l-ilid n]metilamin'ın Hazırlanması için Proses.@

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HU222341B1 (hu) * 1996-12-18 2003-06-28 Richter Gedeon Vegyészeti Gyár Rt. Eljárás sertralin előállítására és az eljárásban alkalmazott intermedier
IN191358B (fr) * 1998-01-16 2003-11-29 Pfizer Prod Inc
US6593496B1 (en) * 1999-06-09 2003-07-15 Pfizer Inc Process for preparing sertraline from chiral tetralone
IN185109B (fr) * 1999-09-01 2000-11-18 Torrent Pharmaceuticals Ltd
AU1998701A (en) * 1999-11-16 2001-05-30 Ciba Specialty Chemicals Holding Inc. Process for the preparation of ketimines
DE60020153T2 (de) * 1999-11-16 2006-01-26 Ciba Speciality Chemicals Holding Inc. Verfahren zur herstellung von ketiminen
EP1797875A3 (fr) * 1999-12-21 2007-08-29 Teva Pharmaceutical Industries Ltd Nouveaux polymorphes d'hydrochlorure de Sertraline, leurs processus de préparation, leurs compositions et leurs procédés d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02096860A1 *

Also Published As

Publication number Publication date
WO2002096860A1 (fr) 2002-12-05
CA2448300A1 (fr) 2002-12-05

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