WO2007020011A1 - Procedes de preparation de thiazepines - Google Patents

Procedes de preparation de thiazepines Download PDF

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Publication number
WO2007020011A1
WO2007020011A1 PCT/EP2006/007925 EP2006007925W WO2007020011A1 WO 2007020011 A1 WO2007020011 A1 WO 2007020011A1 EP 2006007925 W EP2006007925 W EP 2006007925W WO 2007020011 A1 WO2007020011 A1 WO 2007020011A1
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compound
formula
preparation
group
bck
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PCT/EP2006/007925
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English (en)
Inventor
Anil Ganpat Holkar
Abhinay Chandrakant Pise
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Sandoz Ag
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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

  • the present invention relates to new processes for the preparation of thiazepines and salts thereof, in particular thiazepines like quetiapine.
  • the present invention provides simple one-pot nrfu-pcciw: f ⁇ r tUp nf thi «7 ⁇ »ninf>c
  • Thp invention further rplatpQ tn the nip of esientiallv the same inert solvent or of a mixture of inert solvents for the preparation of thiazepines and salts thereof, to the use of an about equimolar amount of a starting material and a halogenating agent in the preparation of thiazepines and to compositions useful for the process of the invention.
  • Quetiapine was described in USP 4,879,288 (EP 240228) as an antipsychotic agent useful for treating, among other things, schizophrenia. It is chemically known as 2-[2-(4-dibenzo[b,f] [1,4] thiazepin-1 1- yl-l-piperazinyl)ethoxy]-ethanol and can be represented by Formula VII
  • quetiapine can be obtained by reacting 1 1-piperazinyl dibenzo[b,f]-[l,4]thiazepine hydrochloride with 2-(2-chloroethoxy)ethanol for about 24 hours.
  • quetiapine can also be prepared by the reaction between 11-chloro dibenzo[b,fj-[l,4]thiazepine (an iminochloride) and 1- (2-hydroxyethoxy) ethylpiperazine.
  • the oily crude product that forms is then subjected to purification by chromatography using a silica gel column to obtain a yield of 77.7 % on a scale of about 0.5 moles.
  • EP 282236 describes a process for the preparation of the compound of Formula VII by reaction of the said iminochloride with piperazine, followed by the reaction of the product so obtained with chloroethoxyethanol.
  • WOO 1/55125 describes a method for the preparation of quetiapine, which method comprises the condensation of phenyl-2-(phenylthio)phenylcarbamate with 2-( 1 -piperazinyl)ethanol, followed by the cychzation of the intermediate and then substitution of the hydroxy group with a chlorine atom by reaction with phosphorous oxychlo ⁇ de
  • the ll-[4-(2-chloroethyl)-l-piperazinyl]dibenzothiazepine formed is then reacted with ethylene glycol to afford Quetiapine base
  • the main drawback of this method is the use of intermediates which are substituted by hydroxyl groups or chlorine atoms which favor undesirable side reactions such as elimination, substitution and dimensation reactions thereby affecting the yield and quality of the final product
  • the present invention provides simple one-pot processes for the synthesis of thiazepines, and in particular of quetiapine, which process overcomes the shortcomings of the prior-art processes
  • the present inventors have surprisingly found that starting from a compound of formula II,
  • the present invention therefore relates to new processes for the preparation of a compound of formula I comprising, in the given order, the steps of: a) reacting a compound of formula II with a halogenating agent in an inert solvent or mixture of inert solvents to form a compound of formula III,
  • Hal is Cl, Br or I, to give the compound of formula I; wherein R 1 and R 1 - independently from one another denote a halogen atom selected from F, Cl and Br or a hydrogen atom or a methyl-, trihalogenmethyl-, dihalogenmethyl- or monohalogenmethyl-group wherein the halogen substituent is F or Cl, wherein R 2 is a C r C 6 alkylgroup, a C 1 -C 6 hydroxyalkylgroup, a (Ci. 6 -alkoxy)-C,.
  • and A 2 represent an atom selected from C and N
  • a 3 represents an atom selected from C, N, S and O
  • n represents an integer equal to 0 or 1 , provided that when n is equal to 0,
  • a 3 represents an atom selected from N, O and S
  • a 2 is bonded to the carbon atom bearing R t • by a single bond.
  • the substituted right aromatic ring - the one bearing R 1 - preferably represents a benzyl ring (being an example where n is 1 and Ai and A 2 and A 3 all denote C), but may also represent an aromatic 5-membered or 6-membered heterocyle bearing a substituent or R 1 -.
  • Preferred examples of 5-membered aromatic heterocyclic rings are pyrrole, furan, thiophene, imidazole, oxazole and thiazole.
  • Preferred examples of 6-membered aromatic heterocyclic rings are pyridine and pyrimidine.
  • the right ring is a thiophen ring substituted with
  • the present invention provides simple one-pot processes for the synthesis of compounds of formula IIIV, wherein starting from a compound of formula IX,
  • the present invention in particular relates to one pot processes for the preparation of a compound of formula IIIV comprisingrin the given orderrthe steps of: — - - - - a) reacting a compound of formula IX with a halogenating agent in an inert solvent or mixture of inert solvents to form a compound of formula X,
  • R 2 is a Ci-C 6 alkylgroup, a Ci-C 6 hydroxyalkylgroup, a alkyl-group or a (C
  • a "one-pot” or “one-pot reaction” within the meaning of this invention means that in a multi-step process-with-defined-isolatablejntermediates ⁇ the product-of-a-previous-synthetic step is-used-in-the- subsequent synthetic step without isolation of the product of said previous synthetic step from the solvent in which said previous synthetic step had been carried out.
  • the iminohalogen- derivative of compound of formula I is not separated from the inert solvent used in step a) before the addition of compound of formula IV in step bl) or the addition of compound of formula V in step b2- I).
  • the starting compound used according to the present invention is a compound of formula II, preferably a compound of formula IX, in particular a substituted or unsubstituted dibenzo[b,f][l,4]thiazepine-l l(10H)-one, wherein the substiruents are R 1 and Rp wherein Ri and Rr are as defined above.
  • These starting materials can be obtained according to methods known in the art, for example substituted or unsubstituted dibenzo[b,f][l,4]thiazepine-l l(10H)-one by the method described in J. Schmutze et al., HeIv. Chim. Acta 48, 336 (1965).
  • Examples of compounds of formula I are quetiapine, which is particularly preferred, but also Clothiapine.
  • examples of compounds of formula IIIV are Quetiapine, G-34448FF-BCK-9989 and Clothiapine. The invention, thus, also relates to the respective processes for the production of Clothiapine.
  • - are independently from one another selected from a hydrogen atom, a chlorine atom and a trifluoroniethyl group.
  • is a hydrogen atom and R 1 - is selected from the list consisting of a hydrogen atom, a chlorine atom, a methyl group, a trichloromethyl group and a trifluoromethyl group, with most preferably R 1 ' being a methyl group or a hydrogen atom.
  • R 1 • is a hydrogen atom and R
  • is a hydrogen atom.
  • R 1 is a chlorine atom.
  • R 2 is a C ⁇ -C 6 alkylgroup, in particular a Ci-C 4 alkylgroup with a methyl-, ethyl-, propyl- or isopropyl group being particularly preferred. In a very preferred embodiment R 2 is a methyl group.
  • R 2 is a Ci-C 6 hydroxyalkylgroup, in particular a Ci-C 4 alkylgroup with a hydroxymethyl-, hydroxyethyl-, hydroxypropyl- or hydro xyisopropylgroup being particularly preferred.
  • R 2 is a (Ci_ 6 -alkoxy)-Ci_ 6 -alkyl-group, in particular a (C r4 -alkoxy)- a — methoxymethyl-, — methoxyethyl-, — ethoxymethyl — or— ethoxyethylgroup .
  • R 2 is a (Hydroxy-Ci. 6 -alkoxy)-Ci ⁇ -alkyl-group, in particular a
  • the halogenating agent used in step a) of the process of the invention is a phosphorous oxyhalide or a phosphorous pentahalide, in particular POCl 3 or PBr 5 , in particular POCl 3 .
  • the compound of formula II or IX is dibenzo[b,f][l,4]thiazepine-l 1(10H)- one.
  • the compound of formula IV is l-[2-(2-Hydroxyethoxy)ethyl]piperazine.
  • the compound of formula VI is 2-chloroethoxyethanol.
  • the process of the invention does not comprise the use of ethers or halogenated organic compounds as solvents or extracting agents between step a) and step b 1 ) or step b2-I).
  • the inert solvent or mixture of inert solvents is an unsaturated or aromatic hydrocarbon or mixture of unsaturated and/or aromatic hydrocarbon, in particular it is selected from the list consisting of toluene, m-, o-, and p-xylene, ethylbenzene, cumene, mesitylene and benzene or mixtures thereof, more particularly it is selected from the group consisting of benzene, toluene or xylene or mixtures thereof. It is particularly preferred that the aromatic hydrocarbon solvent be toluene.
  • step a) is carried out in the presence of a base.
  • the base is preferably an organic base such as such as N,N-Dimethyl amino pyridine, Triethyl amine, Pyridine, N-methyl morpholine, diethyl amine, DBU (2,3,4,6,7,8,9, 10-Octahydropyrimido[l,2-a]azepine, CAS Nr. 6674- 22-2), DBN (2,3,4,6,7,8-Hexahydropyrrolo[l ,2-a]pyrimidine, CAS Nr. 3001-72-7) or a teriary amine.
  • the base may also be an alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide , potassium hydroxide, or magnesium hydroxide, or an alkali metal or alkaline earth metal carbonate, such as sodium carbonate or potassium carbonate.
  • an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide , potassium hydroxide, or magnesium hydroxide
  • an alkali metal or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
  • the process can, for example, be carried out by reacting the compound of formula II, and in particular the compound of formula IX, for example dibenzo[b,f][l,4]thiazepine-l l(10H)one, with the halogenating agent, for example phosphorous oxychloride, preferably in the presence of a base, in aromatic hydrocarbon solvent at reflux temperature, for example for from about 5 to about 24 hours, more preferably about 12 hours, and then adding water to the reaction solution at 3O-35°C under stirring.
  • the organic layer so obtained can then be separated from the aqueous layer. It may be washed with water, or with a weak basic solution, for example a bicarbonate solution, followed by a wash with water, and the organic layer can be dried by conventional methods, such as Dean Stark azetropic distillation.
  • Piperazine is added to the organic layer obtained from the previous step, preferably in an amount of from about 1 to about 4 molar equivalents, like about 3 molar equivalents, compared to the compound of formula II, as it was observed that a slightly above equimolar amount of piperazine improves the overall purity of the final product.
  • the resulting mixture is stirred at reflux temperature until completion of the reaction, for example for about 4-30 hours, more preferably about 10 hours, at about 100 to 130 degrees C.
  • the organic layer comprising the compound of formula V, and in particular the compound of formula XI can be obtained by filtration of the organic layer after having cooled the reaction mixture to ambient temperature and then washing of the organic layer with water.
  • the organic layer can further be dried, for example by way of Dean stark azeotropic distillation. Then, chloroethoxyethanol and a base, like an alkali metal carbonate, or an alkaline earth metal carbonate, preferably sodium or potassium carbonate, can be added to the so obtained organic layer comprising compound V, and in particular G-34448FF-BCK-9989 the compound of formula XI.
  • the solution can then be stirred at reflux temperature, preferably in the presence of a catalyst like an iodide salt, for example selected from NaI, KJ, LiI and AgI, until the reaction is essentially brought to completion, for example about 4-30 hours, more preferably about 10 hours, at about 100 to 130 degrees C.
  • a catalyst like an iodide salt, for example selected from NaI, KJ, LiI and AgI
  • the resulting reaction solution can then be washed with water, the organic layer can then be separated from the wash solution and the solvent can then be evaporated to give the compound of formula I, and in particular the compound of formula IIIV, for example quetiapine, which is in the form of its free base. Further preferred features of the process of the invention are given in the examples.
  • a compound of formula IV like 1 -[2-(2-Hydroxyethoxy) ethyl] piperazine, can be added to the organic layer obtained from step a), preferably in an amount of from about 1 to about 4 molar equivalents, like about 3 molar equivalents, compared to the compound of formula II, and in particular the compound of formula IX, as it was observed that slightly above equimolar amounts of a compound of formula IV improve the overall purity of the final product.
  • the resulting mixture can then be stirred at reflux temperature until the reaction is essentially brought to completion, for example from about 4 to about 30 hours, more preferably about 10 hours, at about 100 to about 130 degrees C.
  • the compound of formula I, and in particular the compound of formula IITV, for example quetiapine, which is in the form of its free base can be obtained, for example, by washing the resulting reaction solution with water, separating the organicjayer from the_aqueousjayer_and_then evaporating the organic solvent-to afford the compound- of formula I, and in particular the compound of formula IIIV, for example quetiapine, which is in the form of its free base.
  • step a) is carried out in such a way that the compound of formula II, preferably being a compound of formula EX, and the halogenating agent are present in about equimolar amounts. It is preferred that the halogenating agent be present in an amount of from about 0.5 to about 2, preferably from about 0.6 to about 1.5, more preferably from about 0.7 to about 1.2 molar equivalents and even G-34448FF-BCK-9989 more preferably from about 0.8 to about 1.0 molar equivalents with respect to the compound of formula II, preferably being a compound of formula IX.
  • the process of the invention in contrast, allows water to be quickly added to the reaction mixture resulting from step a), speeding up the overall process and making the process easier to be carried out on an industrial scale, for example when the desired product is to be obtained in an amount of from about 0.1kg to about 1000kg per production batch, preferably in an amount of from about lkg to about 500kg per production batch, more preferably in an amount of from about 5kg to about 300kg per production batch.
  • a halogenating agent and a compound of formula II By using about equimolar amounts of a halogenating agent and a compound of formula II, the convenient inactivation of the halogenating agent by hydrolysis or alcoholysis becomes possible.
  • the amount of halogenating agent is chosen such that by the end of step a) all of the halogenating agent has reacted, even the quenching step with water or alcohol can be omitted.
  • Preferred halogenating agents are phosphorous pentahalides or phosphorous oxyhalides.
  • the compound of formula III, in particular the compound of formula X is intended to be an iminochloride, then POCl 3 is advantageously used, while if the compound of formula III, in particular the compound of formula X, is intended to be an iminobromide, then phosphorous pentabromide is advantageously used.
  • step a) followed by step bl) or step a) followed by step b2-I) followed by step b2-II) can take place without the need to remove the solvent in which step a) had been carried out. It is particularly advantageous that the solvent in which the reaction steps are carried out need not be changed. That is, essentially the same solvent can be used for step a) and step bl) or for step a) and step b2-I) and step b2-II).
  • the process of the invention does not comprise a chromatographic purification step. It has surprisingly been found that in the one-pot process of the invention such a purification step is not necessary in order to obtain the desired product of formula I, in particular the compound of formula IIIV, with the desired purity. G-34448FF-BCK-9989
  • the process of the invention does not comprise an acidic or alkaline extraction step between step a) and step bl) or step b2-I).
  • the invention relates to a process for the preparation of a salt of the compound of formula I, in particular the compound of formula IHV, like quetiapine, wherein, after a process as described above has been carried out to produce the compound of formula I, the compound of formula I, which is obtained in the form of its base, is then reacted with a suitable acid to give a salt of the compound of formula I.
  • suitable acids are those that give pharmaceutically acceptable salts, but other salts may also be prepared. Suitable acids include, for example, hydrochloric acid, maleic acid, fumaric acid, citric acid, phosphoric acid, methane sulfonic acid and hemi-fumaric acid, with hemi-fumaric acid being preferred.
  • the pharmaceutically acceptable acid addition salt of the compound of formula I, and in particular the pharmaceutically acceptable acid addition salt of the compound of formula IIIV, for example of quetiapine can then be formulated into a pharmaceutically acceptable dosage form, for example a tablet, pill, capsule or injectable dosage form.
  • the most preferred compound of formula I is quetiapine.
  • the invention relates to a process for the preparation of a salt of quetiapine, in particular wherein this salt is quetiapine hemifumarate.
  • the invention relates to a process for the preparation of a salt of Clothiapine, in particular a pharmaceutically acceptable salt thereof.
  • the invention further relates to the use of essentially the same inert solvent or the same mixture of inert solvents for a) the preparation of a compound of formula III from a compound of formula II, and b) the subsequent preparation of a compound of formula I from said compound of formula III.
  • the invention relates to the use of essentially the same inert solvent or the same mixture of inert solvents for a) the preparation of a compound of formula X from a compound of formula IX, and b) the subsequent preparation of a compound of formula IIIV from said compound of formula X. It is an advantageous finding of the present invention that this simplification can indeed be carried out without loss of yield or a decrease in purity.
  • the preferred solvents for this use are an unsaturated or aromatic hydrocarbon or mixtures thereof, in particular toluene, m-, o-, or p-xylene, ethylbenzene, cumene, mesitylene or benzene or mixtures thereof, more particularly benzene, toluene or xylene or mixtures thereof, like a mixture of toluene and xylene.
  • the most preferred compound of formula II for this use is dibenzo[b,f][l,4]thiazepine- l l(10H)-one and the most preferred compound of formula IH is an iminohalogen derivative of dibenzo[b,f] [ 1 ,4]thiazepine- 1 1(10H)-one.
  • the invention further relates to the use of an about equimolar amount of a compound of formula II and a halogenating agent in the preparation of a compound of formula III.
  • the invention relates to the use of an about equimolar amount of a compound of formula IX and a halogenating agent in the preparation of a compound of formula X. It is an insight of this invention that lowering the amount of the halogenating agent allows the further simplifications of the overall process as described above.
  • the most preferred compound of formula II for this use is dibenzo[b,f][l ,4]thiazepine-l l(10H)-one and the most preferred compound of formula III is an iminohalogen derivative of dibenzo[b,f][l,4]thiazepine-l l(10H)-one.
  • the one-pot process of the invention starts with the addition of a compound of formula II and halogenating agent to an inert solvent or a mixture of inert solvents.
  • the invention therefore also relates to a composition comprising a) an inert solvent or a mixture of inert solvents, b) a compound of formula II and c) a halogenating agent.
  • the inert solvent or the mixture of inert solvents is an aromatic hydrocarbon solvent selected from the group consisting of toluene, m-, o-, or p-xylene, ethylbenzene, cumene, mesitylene and benzene or mixtures thereof, like a mixture of toluene and xylene.
  • the halogenating agent is a phosphorousoxychloride, such as POCl 3 or a phosphorousbromide, such as PBr 5 .
  • Jhe compound of formula II is-dibenzo[b,f][l,4]thiazepine-l l(10H)-one.
  • the inert solvent is an aromatic hydrocarbon solvent selected from the group consisting of toluene, m-, o-, or p-xylene, ethylbenzene, cumene, mesitylene or benzene or mixtures therefrom, the halogenating agent is POCl 3 or PBr 5 , and the compound of formula II is dibenzo[b,f][l,4]thiazepine-l l(10H)-one.
  • aromatic hydrocarbon solvent selected from the group consisting of toluene, m-, o-, or p-xylene, ethylbenzene, cumene, mesitylene or benzene or mixtures therefrom
  • the halogenating agent is POCl 3 or PBr 5
  • the compound of formula II is dibenzo[b,f][l,4]thiazepine-l l(10H)-one.
  • a particularly preferred composition is wherein the aromatic hydrocarbon solvent is toluene, the halogenating agent is POCl 3 and the compound of formula II is dibenzo[b,f][l,4]thiazepine-l l(10H)-one. It is further preferred that the compound of formula II, in particular the compound of formula IX, and the halogenating agent are present in about equimolar amounts, particularly that the halogenating agent is presenting an amount from about 0,5 to about 2, preferably from about 0,6 to about 1,5, more preferably from 0,7 to 1,2 molar equivalents and even more preferably 0,8 to 1,0 molar equivalents with respect to the compound of formula II.
  • preferred halogenating agents for this composition are a phosphorousoxycloride, like POCl 3 , or a phosphorousbromide, like PBr 5
  • preferred aromatic hydrocarbon solvents are toluene, benzene or xylene and the preferred compound of formula II is dibenzo[b,f] [ 1 ,4] thiazepine- 1 1(10H)-one.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, in particular a compound of formula IHV like quetiapine, or its pharmaceutically acceptable salt, wherein the compound of formula I, in particular the compound of formula HIV like quetiapine, or its pharmaceutically acceptable salt was prepared according to a process of the invention.
  • the compound of formula I, in particular a compound of formula IHV like quetiapine, or its pharmaceutically acceptable salts obtained according to the present invention can be used in pharmaceutical compositions which comprise the active pharmaceutical ingredient and a pharmaceutical acceptable carrier or other excipients.
  • compositions comprising quetiapine are useful for the treatment of the diseases and conditions listed on page 4, lines 15-18 of EP240288B1 and can be formulated and used as described on page 4, lines 18-31 of EP240288B1.

Abstract

L'invention concerne de nouveaux procédés de préparation de thiazépines et de leurs sels. Plus particulièrement, l'invention décrit des procédés monotopes de préparation de thiazépines. L'invention est également basée sur l'utilisation dudit solvant inerte ou d'un mélange de solvants inertes pour la préparation de thiazépines et de leurs sels, sur l'utilisation d'une quantité à peu près équimolaire d'une matière première et d'un agent d'halogénation pour la préparation de thiazépines et sur des compositions utiles dans le procédé de l'invention.
PCT/EP2006/007925 2005-08-12 2006-08-10 Procedes de preparation de thiazepines WO2007020011A1 (fr)

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GB0516603A GB0516603D0 (en) 2005-08-12 2005-08-12 Processes for the preparation of organic compounds useful as serotonin receptor antagonists

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008121415A2 (fr) * 2007-03-29 2008-10-09 Teva Pharmaceutical Industries Ltd. Procédé amélioré de préparation de fumarate de quétiapine
WO2008152434A1 (fr) * 2007-06-12 2008-12-18 Richter Gedeon Nyrt. Synthèse pour la préparation de quétiapine
JP2010053044A (ja) * 2008-08-26 2010-03-11 Sumitomo Chemical Co Ltd １１−クロロジベンゾ〔ｂ，ｆ〕〔１，４〕チアゼピンの製造方法
WO2010029458A2 (fr) * 2008-09-09 2010-03-18 Alembic Limited Procédé de préparation du fumarate de quétiapine
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
US8420807B2 (en) 2008-01-31 2013-04-16 Fermion Oy Process for the preparation of quetiapine
CN104447616A (zh) * 2014-12-23 2015-03-25 齐鲁天和惠世制药有限公司 一种富马酸喹硫平杂质d的制备方法
CN104710383A (zh) * 2013-12-11 2015-06-17 上海医药工业研究院 一种富马酸喹硫平有关物质及其制备方法和用途

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EP0282236A1 (fr) * 1987-03-10 1988-09-14 Imperial Chemical Industries Plc Procédé pour la préparation d'un dérive de thiazépine
US20060063927A1 (en) * 2004-09-22 2006-03-23 Olga Etlin Processes for preparing quetiapine and salts thereof

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GB1218045A (en) * 1967-02-27 1971-01-06 American Cyanamid Co Novel 11-(piperazinyl]dibenz[b,f] [1,4] oxazepines and analogous thiazepines
EP0240228A1 (fr) * 1986-03-27 1987-10-07 Ici Americas Inc. Dérivés de thiazépine
EP0282236A1 (fr) * 1987-03-10 1988-09-14 Imperial Chemical Industries Plc Procédé pour la préparation d'un dérive de thiazépine
US20060063927A1 (en) * 2004-09-22 2006-03-23 Olga Etlin Processes for preparing quetiapine and salts thereof

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Title
SCHMUTZ J: "ÜBER IN 11-STELLUNG AMINO-SUBSTITUIERTE DIBENZO(B,F)-1,4-THIAZAPINEUND OXAZEPINE", 2 December 1966, HELVETICA CHIMICA ACTA, VERLAG HELVETICA CHIMICA ACTA. BASEL, CH, PAGE(S) 245-254, ISSN: 0018-019X, XP000560267 *

Cited By (12)

* 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
WO2008121415A2 (fr) * 2007-03-29 2008-10-09 Teva Pharmaceutical Industries Ltd. Procédé amélioré de préparation de fumarate de quétiapine
WO2008121415A3 (fr) * 2007-03-29 2009-03-26 Teva Pharma Procédé amélioré de préparation de fumarate de quétiapine
JP2009529062A (ja) * 2007-03-29 2009-08-13 テバ ファーマシューティカル インダストリーズ リミティド フマル酸クエチアピンを調製するための改良法
WO2008152434A1 (fr) * 2007-06-12 2008-12-18 Richter Gedeon Nyrt. Synthèse pour la préparation de quétiapine
US8420807B2 (en) 2008-01-31 2013-04-16 Fermion Oy Process for the preparation of quetiapine
JP2010053044A (ja) * 2008-08-26 2010-03-11 Sumitomo Chemical Co Ltd １１−クロロジベンゾ〔ｂ，ｆ〕〔１，４〕チアゼピンの製造方法
WO2010029458A2 (fr) * 2008-09-09 2010-03-18 Alembic Limited Procédé de préparation du fumarate de quétiapine
WO2010029458A3 (fr) * 2008-09-09 2011-01-27 Alembic Limited Procédé de préparation du fumarate de quétiapine
WO2010100623A1 (fr) 2009-03-04 2010-09-10 Ranbaxy Laboratories Limited Procede de preparation de fumarate de quetiapine
CN104710383A (zh) * 2013-12-11 2015-06-17 上海医药工业研究院 一种富马酸喹硫平有关物质及其制备方法和用途
CN104447616A (zh) * 2014-12-23 2015-03-25 齐鲁天和惠世制药有限公司 一种富马酸喹硫平杂质d的制备方法

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