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WO2006027789A1 - Procede de production de 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine et d'un sel acceptable sur le plan pharmaceutique associe - Google Patents

Procede de production de 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine et d'un sel acceptable sur le plan pharmaceutique associe Download PDF

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Publication number
WO2006027789A1
WO2006027789A1 PCT/IN2004/000281 IN2004000281W WO2006027789A1 WO 2006027789 A1 WO2006027789 A1 WO 2006027789A1 IN 2004000281 W IN2004000281 W IN 2004000281W WO 2006027789 A1 WO2006027789 A1 WO 2006027789A1
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Prior art keywords
thiazepine
dibenzo
process according
hydroxyethoxy
piperazinyl
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Ceased
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PCT/IN2004/000281
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English (en)
Inventor
Shailendra Pathak
Jitendra Sharma
Geetesh Kaushik
Rajesh Kumar Thaper
Sushil Kumar Dubey
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Jubilant Organosys Ltd
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Jubilant Organosys Ltd
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Priority to PCT/IN2004/000281 priority Critical patent/WO2006027789A1/fr
Publication of WO2006027789A1 publication Critical patent/WO2006027789A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16—[b, f]-condensed

Definitions

  • This invention in general relates to a process for producing an atypical neuroleptic or anti-psychotic and its pharmaceutically acceptable salt. More particularly, this invention provides an improved, concise and industrially favorable process for producing 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4]thiazepine (Quetiapine) and its fumarate salt.
  • the compound of Formula [I] and its pharmaceutically acceptable salts are prepared from dibenzo[b,fJ[l,4]thiazepine-l l-(10H)one [II] which is prepared by a variety of methods; for example as described in the literature e.g. J. Scmutz et al. HeIv. Chim. Acta, 48: 336 (1965), by cyclizing a compound selected from compounds of the Formula [III], [IV] and [V] in acidic conditions preferably in the presence of concentrated sulfuric acid or polyphosphoric acid at high temperature.
  • the compound iminohalide [VI] is prepared from lactam [II] using a dehydrating agent e.g. phosphorous pentahalide or oxyhalide in the presence of N,N-dimethylaniline at reflux temperature.
  • the iminohalide [VI] thus prepared reacts with 1- hydroxyethoxyethylpiperazine to give the title compound [I].
  • Another preferred method to prepare the title compound [I] is by reacting compound [V ⁇ ] with 2-substituted ethoxyethanol whereby the substituting group Z is an atom or a group removable as anion e.g. mesyloxy, tosyloxy or halogen in polar organic solvent or aprotic solvent e.g. n-propanol, N-methyl pyrrolidone in the presence of alkali metal halide e.g. NaI and alkali metal carbonate e.g. Na 2 CO 3 .
  • alkali metal halide e.g. NaI
  • alkali metal carbonate e.g. Na 2 CO 3
  • the compound [VII] is prepared by reacting iminohalide [VI] with piperazine in an inert organic solvent e.g. toluene or xylene under reflux for 5 hours.
  • an inert organic solvent e.g. toluene or xylene under reflux for 5 hours.
  • the lactam [II] may convert into a thiolactam of Formula [VIII] by reacting with a polysulfur compound e.g. P 2 S 5 , which on alkylation gives thioether of the Formula [IX] wherein R 3 is chosen such that S-R 3 is a leaving group.
  • a polysulfur compound e.g. P 2 S 5
  • R 3 is chosen such that S-R 3 is a leaving group.
  • the thioether on reaction with 1-hydroxyethoxyethylpiperazine gives title compound [I].
  • the said patent discloses preparing quetiapine from iminohalide [VI] via dibenzothiazepine [H].
  • Iminohalide [VI] disclosed in the above patent is an unstable intermediate and hydrolyzes during work up by addition of water and part of it is converted back into * dibenzothiazepine [H].
  • this side- reaction reduces the yield and the product of the hydrolysis contaminates the end product. This affects the overall yield and cost in the quetiapine preparation and thus is disadvantageous on a commercial manufacturing scale.
  • the piperazine derivative [VII] reacts with 2-haloethoxyethanol e.g. 2-chloroethoxyethanol to give compound of the Formula [I].
  • the compound of formula [VII] is obtained from iminohalide [VI] by reaction with piperazine in the presence of an inert organic solvent e.g. xylene or toluene.
  • the compound of formula [VII] is obtained from dibenzothiazepine [II] in the presence of dehydrating agent e.g. phosphorous oxychloride.
  • lactam [II] a key intermediate for quetiapine is prepared from 2-amino-2'-carboxydiphenylsulphide [X] under reflux temperature optionally in the presence of an organic solvent e.g. toluene or xylene in 20 hours.
  • the 2-amino-2'- carboxydiphenylsulphide [X] is prepared by the reduction of the 2-nitro-2'- carboxydiphenylsulphide [XI].
  • the 2-nitro-2'-carboxydiphenylsulphide [XI] is prepared from thiosalicylic acid [XVI] and o-halonitrobenzene [XVII] with a suitable base e.g. potassium carbonate or sodium carbonate or sodium hydroxide in the presence of solvents like water or amides or alcohol at O 0 C to 15O 0 C within 20 hours.
  • a suitable base e.g. potassium carbonate or sodium carbonate or sodium hydroxide in the presence of solvents like water or amides or alcohol at O 0 C to 15O 0 C within 20 hours.
  • compound of the Formula [I] is prepared by reacting haloethylpiperazinylthiazepine derivative [XV] with sodium and ethylene glycol following Williamson's synthesis.
  • the haloethylpiperazinylthiazepine derivative [XV] is prepared by the cyclization of haloethylpiperazine derivative [XIV] using a dehydrating agent e.g. phosphorous pentaoxide or phosphorous oxychloride, which itself is prepared from halogenation of hydroxyethylpiperazine derivative [XIII].
  • a dehydrating agent e.g. phosphorous pentaoxide or phosphorous oxychloride
  • hydroxyethylpiperazine derivative [XIII] a novel piperazine derivative is prepared by reaction of l-(2-hydroxyethyl) piperazine with urethane derivative [XII] in the presence of solvent e.g. toluene under reflux.
  • the urethane derivative [XII] can be prepared by a method known in the prior art by reacting 2-aminodiphenylsulfide with phenyl chloroformate.
  • dibenzothiazepine [II] The main intermediate for the preparation of quetiapine is dibenzothiazepine [II], which was first described in the United Kingdom Patent GB802901, assigned to CIBA Ltd.
  • the process for preparation of dibenzothiazepine [II] is described in many patents such as EP1201663, US 5,607,929, EP419861, US 4,728,735 and US 3,367,930.
  • a process for preparing 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,fJ[l,4] thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof wherein the process is performed in a manner to avoid multi-steps, longer reaction period and provide an industrially feasible and economical viable process.
  • an improved and industrially feasible process for producing l l-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,fj[l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt which comprises reacting thiosalicylic acid with o-halonitrobenzene using phase transfer catalyst to obtain 2-nitro-2'-carboxydiphenylsulphide, reducing 2-nitro- 2'-carboxydiphenylsulphide in the presence of a noble metal catalyst to obtain 2- amino-2'-carboxydiphenyl sulphide, reacting 2-amino-2'-carboxydiphenylsulphide with a halide or an oxyhalide of phosphorous to obtain in situ iminohalide [VI], reacting said iminohalide with 1-hydroxyethoxyethylpiperazine to produce l l-[4-[2-(2-(2-(2-(2-(2-(2-(
  • an improved and industrially feasible process for producing ll-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,fj[l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt wherein the process comprises further reacting said iminohalide [VI] which is obtained in situ by the process mentioned above, with piperazine to obtain 11- piperazinyldibenzo[b,f][l,4]thiazepine, followed by reacting with 2- chloroethoxyethanol to produce l l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl] dibenzo[b,fj[l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof.
  • an improved and industrially feasible process for producing ll-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo[b,f][l,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt wherein the process comprises further reacting said iminohalide [VI] which is obtained in situ by the process mentioned above, with l-(2-hydroxyethyl) piperazine to obtain ll-[4-(2-hydroxyethyl)piperazine-l-yl]dibenzo[b,fJ[l,4]thiazepine [XXXI], converting said ll-[4-(2-hydroxyethyl)piperazine-l-yl]dibenzo[b,f][l,4] thiazepine [XXXI] to an intermediate l l-[4-(2-substitutedethyl)piperazin-l-
  • a catalytic amount of phase transfer catalyst is added while condensing thiosalicyclic acid with o-halonitrobenzene to obtain 2-nitro-2'-carboxydiphenylsulphide, which increases the rate of reaction and reduces the reaction time cycle.
  • in situ formation of iminohalide [VI] by reacting 2-amino-2'-carboxydiphenylsulphide [X] with a halide or an oxyhalide of phosphorous is provided, wherein the isolation or purification step of intermediate (lactam) [II] is avoided, which reduces the number of operations involved in quetiapine preparation and thereby increasing the operational efficiency and convenience on large-scale manufacturing.
  • the present invention provides an improved and industrially feasible process for producing 11 -[4-[2-(2-hydroxyethoxy)ethyl] - 1 -piperazinyl]dibenzo[b,f] [ 1 ,4]thiazepine [I] and a pharmaceutically acceptable acid addition salt thereof.
  • R is good leaving group nal is halo atom quetiapine hemifumarate
  • the process involves reacting thiosalicylic acid with o-halonitrobenzene using phase transfer catalyst to obtain 2-nitro-2'-carboxydiphenylsulphide, reducing 2-nitro-2'- carboxydiphenylsulphide in the presence of a noble metal catalyst to obtain 2-amino- 2'-carboxydiphenylsulphide, reacting 2-amino-2'-carboxydiphenylsulphide with a halide or an oxyhalide of phosphorous to obtain in situ iminohalide [VFj and reacting iminohalide with 1-hydroxyethoxyethylpiperazine to produce ll-[4-[2-(2- hydroxyethoxy)ethyl]-l-piperazinyl] dibenzo[b,f][l,4]thiazepme [I].
  • the invention also discloses the process where iminohalide [VI] is obtained in situ and reacts with piperazine to obtain ll-piperazinyldibenzo[b,f][l,4]thiazepine followed by reaction with 2-chloroethoxyethanol to produce ll-[4-[2-(2-hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo [b,fj[l,4]thiazepine [I].
  • the process also involves reaction of iminohalide [VI] which is obtained in situ with 1- (2-hydroxyethyl)piperazine to obtain l l-[4-(2-hydroxyethyl)piperazine-l-yl]dibenzo [b,f][l,4]thiazepine [XXXI], which' converts to an intermediate l l-[4-(2- substitutedethyl)piperazm-l-yl)dibenzo[b,f][l,4]thiazepine [XXXII] wherein the substituent at the 2-position is selected from mesyloxy or tosyloxy or halo group followed by reaction with ethylene glycol to produce l l-[4-[2-(2-hydroxyethoxy) ethyl] - 1 -piper azinyl] dibenzo [b , f] [ 1 ,4] thiazepine [I] .
  • thiosalicylic acid [XVI] condenses with o-halonitrobenzene [XVII] using phase transfer catalyst to obtain 2-nitro-2'- carboxydiphenylsulphide [XI].
  • the phase transfer catalyst acts as a shuttling agent between the anion and the organic substrate, and thereby increases the rate of the reaction and reduces the reaction cycle time.
  • phase transfer catalyst can be used and is not limited to the examples incorporated herein.
  • the phase transfer catalyst used in the process herein can be from a group comprising ammonium based phase transfer catalyst, phosphonium based phase transfer catalyst, PEG based phase transfer catalyst, crown ethers etc.
  • phase transfer catalyst examples include tetrabutylammonium bromide, tetrabutyl ammonium iodide, tetrabutylammonium hydrogen sulfate, benzyl tributylamrhonium chloride, benzyl triethylammonium chloride, tetramethylammonium chloride, tetrabutylphosphonium chloride, Polyethylene glycol 200, Polyethylene glycol 400, Polyethylene glycol 600, dibenzo- 18-crown-6 and the like.
  • halogen atom is selected from fluorine, chlorine, bromine or iodine takes place in the presence of a solvent selected from alcohol, ester, ketone, amides or mixture thereof.
  • the solvent is selected from a group comprising methanol, ethanol, n- propanol, isopropanol, n-butanol, ethyl acetate, isobutyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethyl formamide, N,N-dimethylacetamide, N- methylpyrrolidone or mixture thereof.
  • Reaction of thiosalicylic acid [XVI] with o-halonitrobenzene [XVII] optionally takes place in the presence of a base selected from carbonates, bicarbonates, hydroxides, alkoxides or hydrides of alkali metal or alkaline earth metal in an amount corresponding to 0.5-3 moles and most preferably 0.7-2.0 moles.
  • the reaction is performed at a temperature of 50 to 100 0 C and most preferably at 60 to 7O 0 C under inert atmosphere.
  • Reduction of 2-nitro-2'-carboxydiphenylsulphide [XI] to 2-amino-2'-carboxydiphenyl sulphide [X] is carried out in the presence of a noble metal catalyst.
  • the noble metal catalyst is selected from a group comprising palladium, platinum or its compounds, Raney-nickel, ferrous sulfate heptahydrate in aqueous ammonia and the like.
  • the reaction is preferably carried out in the presence of an alcoholic solvent e.g. methanol or ethanol.
  • the reaction is conveniently performed at a temperature of 25-4O 0 C using hydrogen gas.
  • the iminohalide [VI] disclosed in the present invention is formed in situ and is taken as such without any isolation or purification, for further reaction, thus avoiding its decomposition. This reduces the number of operations involved in quetiapine preparation and thereby increases the operational efficiency and convenience on large- scale manufacturing.
  • the base used in the reaction is selected from triethylamine, N,N-dimethylaniline or heterocyclic amines such as pyridine, N-methyl morpholine, dimethyl amino pyridine more preferably triethylamine.
  • the reaction is carried out at the reflux temperature of the reaction mixture for a period of preferably 5-8 hours and most preferably 5-6 hours.
  • the resulting iminohalide [VI] which is formed in situ, condenses with 1- hydroxyethoxyethylpiperazine, without the isolation of lactam [II], in the presence of a solvent, preferably non-polar solvents such as toluene or xylene and optionally in the presence of a co-solvent selected from the group comprising dimethylsulphoxide, N 5 N- dimethylformamide, N,N-dimetylacetamide, N-methylpyrrolidone, dimethylimidazolidone or a mixture thereof.
  • a solvent preferably non-polar solvents such as toluene or xylene and optionally in the presence of a co-solvent selected from the group comprising dimethylsulphoxide, N 5 N- dimethylformamide, N,N-dimetylacetamide, N-methylpyrrolidone, dimethylimidazolidone or a mixture thereof.
  • the resulting iminohalide [VI] which is formed in situ without the isolation of lactam [II], condenses with piperazine to obtain ll-piperazinyldibenzo[b,f][l,4]thiazepine [XI] which reacts with 2- haloethoxyethanol to give quetiapine [I].
  • the resulting iminohalide [VI] which is formed in situ condenses with piperazine in the presence of a solvent preferably non polar solvent such as toluene, xylene, anisole or its mixture thereof to obtain l l-piperazinyldibenzo[b,f][l,4]thiazepine [XIX].
  • a solvent preferably non polar solvent such as toluene, xylene, anisole or its mixture thereof to obtain l l-piperazinyldibenzo[b,f][l,4]thiazepine [XIX].
  • Reaction of ll-piperazinyldibenzo[b,fj[l,4]thiazepine [XIX] with 2-haloethoxyethanol where halogen is most preferably a chlorine atom takes place in the presence of polar or non polar solvents such as n-butanol or toluene.
  • the reaction takes place optionally in the presence of a base selected from alkali metal or alkaline earth metal carbonates or bicarbonates wherein the alkali metal and alkaline earth metal is selected from lithium, sodium, potassium, calcium or magnesium etc, in an amount corresponding to 1 to 5 moles, preferably 2-4 moles.
  • a base selected from alkali metal or alkaline earth metal carbonates or bicarbonates wherein the alkali metal and alkaline earth metal is selected from lithium, sodium, potassium, calcium or magnesium etc, in an amount corresponding to 1 to 5 moles, preferably 2-4 moles.
  • the resulting iminohalide [VI] which is formed in situ without the isolation of lactam [II], reacts with l-(2- hydroxyethyl) piperazine in the presence of a non-polar solvent such as toluene or xylene to obtain ll-[4-(2-hydroxyethyl)piperazin-lyl]dibenzo[b,f][l 3 4]thiazepine
  • XXXI converts to an intermediate 1 l-[4-(2-substitutedethyl)piperazin-l-yl)dibenzo[b,f][l,4]thiazepine [XXXII] wherein the substituent at the 2-position is selected from mesyloxy or tosyloxy or halo group.
  • This intermediate ll-[4-(2-substitutedethyl)piperazin-l- yl)dibenzo[b,fj[l,4]thiazepine [XXXII] further reacts with ethylene glycol in the presence of a non polar solvent such as toluene or xylene and a base to obtain quetiapine [I].
  • the base is selected from alkali metal hydrides or alkoxide and the like.
  • the base used in the reaction is selected from sodium hydride, potassium hydride and potassium tertiary butoxide etc, more preferably sodium hydride.
  • the reaction is carried out at an elevated temperature preferably at the reflux temperature of the reaction mixture.
  • the salts of the compound of the Formula [I] are also prepared in the present invention, preferably the pharmaceutically acceptable salts. These may be obtained by reacting the quetiapine [I] in the presence of a suitable solvent e.g. acetone, ethyl acetate, isopropyl alcohol, methanol etc with a suitable acid such as hydrochloric acid, maleic acid, fumaric acid, citric acid, phosphoric acid, methane sulphonic acid or sulphuric acid most preferred salt is the hemifumarate.
  • a suitable solvent e.g. acetone, ethyl acetate, isopropyl alcohol, methanol etc
  • a suitable acid such as hydrochloric acid, maleic acid, fumaric acid, citric acid, phosphoric acid, methane sulphonic acid or sulphuric acid
  • a suitable acid such as hydrochloric acid, maleic acid, fumaric acid, citric acid, phosphoric acid
  • Potassium carbonate 134 g was taken in methanol (600 ml). To the resulting mixture thiosalicylic acid (100 g), o-chloronitrobenzene (123 g) and catalytic amount of terra butyl ammonium iodide was added. The reaction mixture was heated to 65-7O 0 C for 4-6 hours. Methanol was distilled off under vacuum, water (600 ml) and dichloromethane (200 ml) was added to the reaction mixture. The organic layer was separated off and the aqueous layer was acidified with concentrated hydrochloric acid. The precipitated product was collected by filtration, washed with water and dried to give the title compound as a yellow powder.
  • 2-Amino-2'-carboxydiphenylsulphide 100 g was taken in phosphorus oxychloride (500 ml). The reaction mixture was heated to reflux at 105-110 0 C for 5-6 hours. The reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride. The resulting mass was taken in toluene (800 ml) and 1- hydroxyethoxyethylpiperazine (213 g) and N-methyl pyrrolidone (100 ml) was added. To the above reaction mixture, sodium carbonate (260 g) was added. The reaction mixture was heated to reflux for 6-8 hours.
  • reaction mixture was subjected to vacuum distillation to remove unreacted phosphorous oxychloride along with toluene: The resulting mass was taken in toluene (800 ml) and 1-hydroxyethoxyethylpiperazine (213 g) and N- methyl pyrrolidone (100 ml) was added. To the above reaction mixture, sodium carbonate (260 g) was added. The reaction mixture was heated to reflux for 6-8 hours. After completion of reaction, toluene was distilled off under vacuum and a mixture of ethyl acetate and water was added.
  • reaction mixture was heated to reflux for 6-8 hours. After completion of reaction, toluene was distilled off under vacuum and a mixture of ethyl acetate and water was added. After separation, the ethyl acetate layer was extracted with dilute hydrochloric acid and the solution was made alkaline with aqueous ammonia solution, extracted with ethyl acetate (800 ml) and organic layer was combined and distilled off under vacuum to yield the title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de production de 11-[4-[2-(2-hydroxyéthoxy)éthyl]-l-pipérazinyl]dibenzo [b,f][1,4]thiazépine [I] et d'un sel d'addition acide acceptable sur le plan pharmaceutique associé. A cet effet, on fait réagir un acide thiosalicylique [XVI] avec un o-halonitrobenzène [XVII] au moyen d'un catalyseur par transfert de phase afin d'obtenir du 2-nitro-2'-carboxydiphénylsulfure [XI]. Le produit obtenu est hydrogéné en présence d'un catalyseur en métal noble afin d'obtenir du 2-amino-2' carboxydiphénylsulfure [X]. On fait réagir le 2-amino-2'-carboxydiphénylsulfure [X] avec de l'halogénure ou de l'oxyhalogénure du phosphore afin d'obtenir in situ de l'iminohalogénure [VI], que l'on fait réagir ensuite tel quel avec de la 1-hydroxyéthoxyéthylpipérazine ou que l'on condense avec de la pipérazine afin d'obtenir de la 11-pipérazinyldibenzo[b,f][1,4]thiazépine [XIX]. On fait réagir cette dernière avec du 2-chloroéthoxyéthanol ou avec de la 1-(2-hydroxyéthyl)pipérazine afin d'obtenir de la 11-[4-(2-hydroxyéthyl)pipérazine-1-yl]dibenzo[b,f][ 1,4]thiazépine [XXXI] qui est ensuite convertie en une 11-[4-(2-éthyl substitué)pipérazin-1-yl)dibenzo[b,f][1,4]thiazépine intermédiaire, l'élément de substitution en position 2 étant sélectionné à partir de mesyloxy ou de tosyloxy ou d'un groupe halo [XXXII], cette opération étant suivie d'une réaction avec de l'éthylèneglycol afin d'obtenir de la quétiapine [1].
PCT/IN2004/000281 2004-09-08 2004-09-08 Procede de production de 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine et d'un sel acceptable sur le plan pharmaceutique associe Ceased WO2006027789A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7687622B2 (en) 2005-04-14 2010-03-30 Teva Pharmaceutical Industries, Ltd Process for preparing quetiapine fumarate
WO2010100623A1 (fr) 2009-03-04 2010-09-10 Ranbaxy Laboratories Limited Procede de preparation de fumarate de quetiapine
US8034805B2 (en) 2006-07-03 2011-10-11 Farmak, A.S. Methods for the preparation of salts of 2-[2-(4-dibenzo[B,F][1,4]thiazepin-11-yl-1-piperazinyl)ethoxyl]ethanol (quetiapine) and for the purification thereof
CN103664822A (zh) * 2012-09-18 2014-03-26 四川大学华西医院 一种可用作麻醉剂的化合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0240228A1 (fr) * 1986-03-27 1987-10-07 Ici Americas Inc. Dérivés de thiazépine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0240228A1 (fr) * 1986-03-27 1987-10-07 Ici Americas Inc. Dérivés de thiazépine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7687622B2 (en) 2005-04-14 2010-03-30 Teva Pharmaceutical Industries, Ltd Process for preparing quetiapine fumarate
US8034805B2 (en) 2006-07-03 2011-10-11 Farmak, A.S. Methods for the preparation of salts of 2-[2-(4-dibenzo[B,F][1,4]thiazepin-11-yl-1-piperazinyl)ethoxyl]ethanol (quetiapine) and for the purification thereof
WO2010100623A1 (fr) 2009-03-04 2010-09-10 Ranbaxy Laboratories Limited Procede de preparation de fumarate de quetiapine
CN103664822A (zh) * 2012-09-18 2014-03-26 四川大学华西医院 一种可用作麻醉剂的化合物

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