WO1998015516A1 - Process for the preparation of a pharmaceutical intermediate - Google Patents

Process for the preparation of a pharmaceutical intermediate Download PDF

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Publication number
WO1998015516A1
WO1998015516A1 PCT/HU1997/000058 HU9700058W WO9815516A1 WO 1998015516 A1 WO1998015516 A1 WO 1998015516A1 HU 9700058 W HU9700058 W HU 9700058W WO 9815516 A1 WO9815516 A1 WO 9815516A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
solvent
dichloro
phenyl
naphthalene
Prior art date
Application number
PCT/HU1997/000058
Other languages
English (en)
French (fr)
Inventor
Peter KÓTAY NAGY
József Barkóczy
Gyula Simig
Ilona SZTUHÁR
László BALÁZS
Imre Domán
Zoltán Greff
Zoltán RÁTKAI
Péter SERES
György CLEMENTIS
Tamás KARANCSI
László LADÁNYI
Original Assignee
EGIS Gyógyszergyár Rt.
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 HU9602762A external-priority patent/HUP9602762A2/hu
Application filed by EGIS Gyógyszergyár Rt. filed Critical EGIS Gyógyszergyár Rt.
Priority to PL332779A priority Critical patent/PL192111B1/pl
Priority to AU48788/97A priority patent/AU4878897A/en
Priority to RO99-00294A priority patent/RO120194B1/ro
Priority to SK341-99A priority patent/SK284671B6/sk
Publication of WO1998015516A1 publication Critical patent/WO1998015516A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/512—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being a free hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation

Definitions

  • This invention relates to a process for the preparation of a pharmaceutical intermediate.
  • the compound of the Formula I is a valuable intermediate which can be used in pharmaceutical industry for the preparation of pharmaceutical active ingredients.
  • the compound of the Formula I is useful in the preparation of sertraline, a known medicine which can be used against mental depression.
  • the chemical nomenclature of sertraline is cis-(1S,4S)-N-methyl-N-(3,3-dichloro-phenyl)-1 ,2,3,4-tetrahydro- -1 -naphthalene-amine.
  • the yield can be increased to 33 %
  • the contaminating isomer of the Formula II is a new compound not described in prior art.
  • the presence of this by-product is not desirable because if the amount of the 2,3-isomer of the Formula II in the desired 3,4-isomer of the Formula I exceeds 1 %, the corresponding contaminating 2,3-isomer appears also in the sertraline end product; in analoguous reactions this isomer cannot be removed to the desired extent.
  • the above object is achieved by subjecting the crude reaction product of the Formula I to a crystallization process to be described below and thereby reducing the amount of the isomer of the Formula II below a still tolerable limit.
  • the present invention is based on the recognition that the new 2,3-isomer of the Formula II not described in prior art has been isolated, identified by spectroscopical methods and a suitable process has been elaborated for the removal of this contamination A capillary GC and HPLC method has been elaborated for the qualitative side-by-side determination of the isomers of the Formulae I and II This process enables the control of isomer purity and served as basis for the elaboration of a purification method resulting highly pure compound of the Formula I
  • a C ⁇ -13 alkane methanol, ethanol, n-propanol or isopropanol
  • One may proceed preferably by using methanol for the crystallization
  • a C 6 10 alkane e g n-hexane, n-heptane, n- -octane
  • ether e g dioxane, diethyl ether, methyl tert butyl ether etc
  • One may proceed preferably by using as apolar solvent n-hexane or methyl-tert butyl ether
  • a solvent mixture containing an apolar solvent may also be used (e g a mixture of n-hexane and ethyl acetate or n-hexane and isopropanol)
  • the order of succession of the steps of the crystallization procedure are optional It is possible to crystallize the crude product at first from a polar solvent and thereafter from an apolar solvent or vica versa According to a preferred embodiment of the process one may proceed advantageously by crystallizing the crude product first from a polar solvent and thereafter from an apolar solvent or a solvent mixture containing an apolar solvent According to the process of the present invention, a 3,4- -isomer of the Formula I contaminated by less than 1 % - preferably less than 0.5 % - of the 2,3-isomer of the Formula II can be obtained.
  • the crude product of the Formula I used as starting material can be prepared by reacting o-dichloro-benzene and ⁇ -naphthol in a solvent as medium in the presence of a Friedel-Crafts catalyst.
  • an excess of the g-dichloro-benzene reagent plays the role of the solvent.
  • nitro-benzene, dichloro ethane, trichloro ethylene or carbon disulfide can be used.
  • the reaction is carried out in the presence of a Friedel- Crafts catalyst. It is preferred to use aluminium chloride, aluminium bromide, stannous (II) chloride or antimonic (V) pentafluoride, preferably aluminium chloride.
  • the reaction may be preferably carried out by using the ⁇ -naphthol : Friedel-Crafts catalyst : g-dichloro-benzene components in a molar ratio of 1:2:3 - 1:10:100.
  • the molar ratio of said components is particularly advantageously 1 :3:10.
  • the reaction may be performed at a temperature between 30°C and 200°C, preferably about 90°C.
  • the reaction takes place within some hours; the reaction time is generally 3-6 hours.
  • the reaction mixture may be worked up by known methods One may proceed preferably by pouring the reaction mixture in icecold water, extracting with an organic solvent (e g halogenated alkanes such as dichloro methane, chloroform, or other water-immiscible solvents, such as ethyl acetate) and washing, filtering and evaporating the organic layer
  • an organic solvent e g halogenated alkanes such as dichloro methane, chloroform, or other water-immiscible solvents, such as ethyl acetate
  • a HPLC method is used for the control of the standards.
  • TEAA buffer 10 ml triethyl amine, 10 ml glacial acetic acid, 1000 ml water
  • Injected volume 20 ml (about 4-5 mg/dissolved in 10 ml of acetonitrile, diluted with eluent)
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are heated to reflux in 188 ml of n-hexane until all the product goes into solution.
  • the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of n-hexane each.
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are stirred in 55 ml of a 9:1 mixture of n-hexane and ethyl acetate under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. In order to make crystallization complete the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of icecold n-hexane each.
  • the product thus obtained is stirred in 210 ml of n- hexane under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to render crystallization complete, the mixture is cooled to OX. The precipitated crystals are filtered and washed twice with 8 ml of icecold methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are heated in 50 ml of a 3:4 mixture of n-hexane and isopropanol to reflux until all the product is dissolved.
  • the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of ice-cold n-hexane each.
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.
  • the crystals thus obtained are dried under an infrared lamp for 24 hours.
  • the dry crystals are stirred in 40 ml of methyl-tert. butyl ether under heating to reflux until all the product goes into solution. Thereafter the solution is filtered and the mother-lye is slowly cooled under stirring. During cooling crystals slowly precipitate. In order to make crystallization complete, the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of ice-cold n-hexane each.
  • the substance thus obtained is dissolved in 84 ml of methanol under stirring and heating to reflux.
  • the solution is filtered, and the mother lye is slowly cooled under stirring. During cooling crystals slowly precipitate.
  • the mixture is cooled to OX.
  • the precipitated crystals are filtered and washed twice with 8 ml of methanol each.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
PCT/HU1997/000058 1996-10-09 1997-10-08 Process for the preparation of a pharmaceutical intermediate WO1998015516A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PL332779A PL192111B1 (pl) 1996-10-09 1997-10-08 Sposób otrzymywania wysokiej czystości 4-(3,4-dwuchloro-fenylo)-3,4-dwuwodoro-1(2H)-naftalen-1-onu
AU48788/97A AU4878897A (en) 1996-10-09 1997-10-08 Process for the preparation of a pharmaceutical intermediate
RO99-00294A RO120194B1 (ro) 1996-10-09 1997-10-08 Procedeu pentru prepararea 4-(3,4-diclorfenil)-3,4-dihidro-1(2h)-naftalen-1-onei de puritate înaltă
SK341-99A SK284671B6 (sk) 1996-10-09 1997-10-08 Spôsob prípravy vysoko čistého 4-(3,4-dichlórfenyl)-3,4-dihydro- 1(2H)-naftalén-1-ónu

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HUP9602762 1996-10-09
HU9602762A HUP9602762A2 (en) 1996-10-09 1996-10-09 Process for producing naphtalene derivatives
HUP9701137 1997-07-02
HU9701137A HU218599B (hu) 1996-10-09 1997-07-02 Eljárás 4-(3,4-diklór-fenil)-3,4-dihidro-1-(2H)-naftalin-1-on előállítására

Publications (1)

Publication Number Publication Date
WO1998015516A1 true WO1998015516A1 (en) 1998-04-16

Family

ID=89995311

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU1997/000058 WO1998015516A1 (en) 1996-10-09 1997-10-08 Process for the preparation of a pharmaceutical intermediate

Country Status (7)

Country Link
AU (1) AU4878897A (cs)
CZ (1) CZ295766B6 (cs)
HU (1) HU218599B (cs)
PL (1) PL192111B1 (cs)
RO (1) RO120194B1 (cs)
SK (1) SK284671B6 (cs)
WO (1) WO1998015516A1 (cs)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506940B1 (en) 2000-01-04 2003-01-14 Sun Pharmaceuticals Industries Ltd. Process for converting stereoisomers of sertraline into sertraline
JP2003514794A (ja) * 1999-11-16 2003-04-22 チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド ケトイミンの調製方法
CN116041160A (zh) * 2021-10-28 2023-05-02 上虞京新药业有限公司 一种将异舍曲酮转化为舍曲酮的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346226A1 (fr) * 1988-06-08 1989-12-13 Synthelabo Procédé de préparation de 4-aryl disubstitué-1-tétralones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0346226A1 (fr) * 1988-06-08 1989-12-13 Synthelabo Procédé de préparation de 4-aryl disubstitué-1-tétralones

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 120, no. 9, 28 February 1994, Columbus, Ohio, US; abstract no. 106497, REPINSKAYA I B ET AL: "Condensation of 1-naphthol with ortho-dichlorobenzene in the presence of aluminum halides" XP000443777 *
SIB. KHIM. ZH. (SKZHEC);93; (3); PP.73-6, NOVOSIB. GOS. UNIV.;NOVOSIBIRSK; RUSSIA (RU) *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003514794A (ja) * 1999-11-16 2003-04-22 チバ スペシャルティ ケミカルズ ホールディング インコーポレーテッド ケトイミンの調製方法
EP1230212B1 (en) * 1999-11-16 2005-05-11 Ciba SC Holding AG Process for the preparation of ketimines
US6506940B1 (en) 2000-01-04 2003-01-14 Sun Pharmaceuticals Industries Ltd. Process for converting stereoisomers of sertraline into sertraline
CN116041160A (zh) * 2021-10-28 2023-05-02 上虞京新药业有限公司 一种将异舍曲酮转化为舍曲酮的方法

Also Published As

Publication number Publication date
HU218599B (hu) 2000-10-28
SK284671B6 (sk) 2005-08-04
SK34199A3 (en) 2000-03-13
HU9701137D0 (en) 1997-08-28
PL192111B1 (pl) 2006-08-31
AU4878897A (en) 1998-05-05
CZ120799A3 (cs) 1999-09-15
PL332779A1 (en) 1999-10-11
HUP9701137A2 (hu) 1999-04-28
HUP9701137A3 (en) 1999-05-28
CZ295766B6 (cs) 2005-10-12
RO120194B1 (ro) 2005-10-28

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