WO2007020011A1

WO2007020011A1 - Processes for the preparation of thiazepines

Info

Publication number: WO2007020011A1
Application number: PCT/EP2006/007925
Authority: WO
Inventors: Anil Ganpat Holkar; Abhinay Chandrakant Pise
Original assignee: Sandoz Ag
Priority date: 2005-08-12
Filing date: 2006-08-10
Publication date: 2007-02-22
Also published as: GB0516603D0

Abstract

The present invention relates to new processes for the preparation of thiazepines and of salts thereof. Specifically the present invention provides simple one-pot processes for the preparation of thiazepines. The invention further relates to the use of essentially 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 for the preparation of thiazepines and to compositions useful in the process of the invention.

Description

PROCESSES FOR THE PREPARATION OF THIAZEPINES

The present invention relates to new processes for the preparation of thiazepines and salts thereof, in particular thiazepines like quetiapine. Specifically the present invention provides simple one-pot nrfu-pcciw: fΛr 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

According to the said patent (from hereon referred to as the '288 patent) 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. According to the '288 patent, 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.

However, according to the prior art references cited above, the process for the preparation of quetiapine employs a large molar excess, e.g. more than 10 molar equivalents, of the hazardous and corrosive chemical phosphorousoxychloride (POCl₃). After completion of the chlorinating reaction G-34448FF-BCK-9989 phosphorousoxychloπde is subsequently removed by distillation in order to isolate the lminochloπde- intermediate as a prerequisite for the following steps This is environmentally unsound on an industrial scale, as phosphorousoxychloπde is a very aggressive compound Also, the isolation of certain unstable intermediates such as 1 1-Chloro-dibenzo [b, f] [1, 4] thiazepine, is undesirable, as this intermediate is sensitive to hydrolysis by the humidity of the air to give the starting compound

Further, in the above-mentioned prior art the obtained Quetiapine base is purified by silica gel column chromatography, an expensive and somewhat cumbersome step to be carried out on an industrial scale

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 oxychloπde 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

All of the above mentioned prior art methods for the preparation of quetiapine or its salts involve the isolation of intermediates and repeated exchange of solvents This is a disadvantage both from an ecologicalund economical poinfof View ^{" "} It is thus an object of the present invention to provide an improved process for the preparation of thiazepines, and in particular of quetiapine, which allows to carry out synthesis, preparation, purification and isolation of these compounds on an industrial scale while avoiding disadvantages of the prior art

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,

all the steps of a process leading to a compound of formula I G-34448FF-BCK-9989

can be carried out in a one-pot format.

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,

wherein Hal is Cl, Br or I (this compound of formula III is herein below sometimes referred to as "an iminohalogen-derivative of the compound of formula II"); and b 1 ) reacting the compound of formula III obtained from step a) with a compound of formula IV

HN N-R₀

IV

to give the compound of formula I; or b2-I) reacting the compound of formula III obtained from step a) with piperazin to give a compound of formula V G-34448FF-BCK-9989

followed by b2-II) reacting the compound of formula V with the compound of formula VI

HaI-R₂ VI

wherein Hal is Cl, Br or I, to give the compound of formula I; wherein R₁ and R₁- 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 R₂ is a C_rC₆ alkylgroup, a C₁-C₆ hydroxyalkylgroup, a (Ci.₆-alkoxy)-C,.₆-alkyl- group or a (Hydroxy-Ci_₆-alkoxy)-Ci_-6-alk:yl-group, wherein A| and A₂ represent an atom selected from C and N, A₃ 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, A₃ represents an atom selected from N, O and S, and A₂ is bonded to the carbon atom bearing R_t • by a single bond.

In the compounds of formulas I, II, III and V, the substituted right aromatic ring - the one bearing R₁- preferably represents a benzyl ring (being an example where n is 1 and Ai and A₂ and A₃ all denote C), but may also represent an aromatic 5-membered or 6-membered heterocyle bearing a substituent or R₁-. 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. In preferred embodiments, the right ring is a thiophen ring substituted with

R₁, G-34448FF-BCK-9989

In particular, the present invention provides simple one-pot processes for the synthesis of compounds of formula IIIV, wherein starting from a compound of formula IX,

all the steps of a process leading to a compound of formula IIIV

can be carried out in a one-pot format.

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,

wherein Hal is Cl, Br or I (this compound of formula X is herein below sometimes referred to as "an iminohalogen-derivative of the compound of formula IX"); and bl) reacting the compound of formula X obtained from step a) with a compound of formula IV to give the compound of formula IHV; or b2-I) reacting the compound of formula X obtained from step a) with piperazin to give a compound of formula XI G-34448FF-BCK-9989

followed by b2-II) reacting the compound of formula XI with the compound of formula VI wherein Hal is Cl, Br or I, to give the compound of formula IIIV; wherein R_t and R_r 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, and wherein R₂ is a Ci-C₆ alkylgroup, a Ci-C₆ hydroxyalkylgroup, a

alkyl-group or a (C|.₆-Hydroxyalkoxy)-Ci.₆-alkyl-group, like a (2-Hydroxyethoxy)ethyl- group, which process is carried out as a one-pot process.

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. In particular 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 R₁ 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, many of which are useful as serotonin 5HT₂ receptor antagonists with only moderate dopamine (D₂) receptor antagonism, 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.

In a preferred embodiment, R₁ and R|- are independently from one another selected from a hydrogen atom, a chlorine atom and a trifluoroniethyl group. In a moic picfcucd eiuuυdmieiύ R| is a hydrogen atom and R₁- 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 R₁' being a methyl group or a hydrogen atom. In another more preferred embodiment R₁ • is a hydrogen atom and R| is selected from the list consisting of a hydrogen atom, a chlorine atom, a methyl group, a trichloromethyl group and a trifluoromethyl group. In a very preferred embodiment R| is a hydrogen atom. In another very preferred embodiment R₁ is a chlorine atom.

In a preferred embodiment, R₂ is a C_{-C₆ alkylgroup, in particular a Ci-C₄ alkylgroup with a methyl-, ethyl-, propyl- or isopropyl group being particularly preferred. In a very preferred embodiment R₂ is a methyl group.

In a further preferred embodiment, R₂ is a Ci-C₆ hydroxyalkylgroup, in particular a Ci-C₄ alkylgroup with a hydroxymethyl-, hydroxyethyl-, hydroxypropyl- or hydro xyisopropylgroup being particularly preferred.

In a further preferred embodiment, R₂ is a (Ci_₆-alkoxy)-Ci_₆-alkyl-group, in particular a (C_r4-alkoxy)-

a — methoxymethyl-, — methoxyethyl-, — ethoxymethyl — or— ethoxyethylgroup . In a further preferred embodiment, R₂ is a (Hydroxy-Ci.₆-alkoxy)-Ci^-alkyl-group, in particular a

(Hydroxy-Ci-₄-alkoxy)-Ci.₄-alkyl-group, more particularly a hydroxymethoxymethyl- or a hydroxymethoxyethylgroup, in particular a (2-Hydroxyethoxy)ethyl-group.

In a preferred embodiment the halogenating agent used in step a) of the process of the invention is a phosphorous oxyhalide or a phosphorous pentahalide, in particular POCl₃ or PBr₅, in particular POCl₃.

In a preferred ambodiment, the compound of formula II or IX is dibenzo[b,f][l,4]thiazepine-l 1(10H)- one.

In a preferred embodiment the compound of formula IV is l-[2-(2-Hydroxyethoxy)ethyl]piperazine. In a preferred embodiment the compound of formula VI is 2-chloroethoxyethanol. In a preferred embodiment, 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). G-34448FF-BCK-9989

In a preferred embodiment, 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.

In a preferred embodiment, 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.

However, 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.

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.

If the process is then further carried out according to step b2-I, 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. 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.

If the process is, after step a), further carried out according to step bl), 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.

Further preferred features and combinations of features of the process of the invention can be taken from the examples. it is an advantage of the present invention that the compound of formula III, and in particular the compound of formula X, does not need to be isolated from the inert solvent of step a) before addition of compound IV in step bl) or compound VI in step b2-I). This is a great simplification allowing the compound of formula I, and in particular the compound of formula HIV, to be synthesized without cumbersome steps like distillation of solvents before step b 1 ) or step b2-I) or taking up an isolated intermediate in solvent again. Advantageously, 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. This is a great simplification allowing the compound of formula I, and in particular the compound of formula HIV, to be synthesized without cumbersome steps like distillation of the halogenating agent. In contrast, the '288 patent carried out the synthesis of the iminohalogen in the presence of a significant molar excess, e.g. more than 10 molar equivalents, of halogenating agent. As a consequence, inactivation of the halogenating agent by hydrolysis or alkoholysis is not easily achievable in the prior art process due to the violent and exothermic reaction of the halogenting agent with water or alcohols. 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. 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. Moreover, if 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. In particular, if the compound of formula III, in particular the compound of formula X, is intended to be an iminochloride, then POCl₃ 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.

In preferred embodiments, 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).

In a preferred embodiment, 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

In a preferred embodiment, the process of the invention does not comprise an acidic or alkaline extraction step between step a) and step bl) or step b2-I). This is a further advantage, as the overall amount of acidic or alkaline waste produced during the process is reduced compared to the cited prior art processes. In a further embodiment, 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. Preferred 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. Thus, in a preferred embodiment, the invention relates to a process for the preparation of a salt of quetiapine, in particular wherein this salt is quetiapine hemifumarate. In a further preferred embodiment, 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. In particular, 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. G-34448FF-BCK-9989

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. In particular 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.

As explained above, 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.

In a preferred embodiment, 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.

In a preferred embodiment, the halogenating agent is a phosphorousoxychloride, such as POCl₃ or a phosphorousbromide, such as PBr₅.

In a preferred embodiment.Jhe compound of formula II is-dibenzo[b,f][l,4]thiazepine-l l(10H)-one.

It is further preferred that 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 POCl₃ or PBr₅, and 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 POCl₃ 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. Again, preferred halogenating agents for this composition are a phosphorousoxycloride, like POCl₃, or a phosphorousbromide, like PBr₅, 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. G-34448FF-BCK-9989

The invention further relates to 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.

Pharmaceuticals 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.

The process of the present invention is hereinafter described in more detail by means of the following examples. These examples are not to be construed to limit the scope of the invention as defined hereinabove or as claimed below in any way. These examples demonstrate further preferred features of the process(es) of the invention.

EXAMPLES

ΈXAMPLE-IT

PREPARATION OF 11 -CHLORO DIBENZO[b,fJ [1,4] THIAZEPINE. A mixture of 1000 ml of Toluene, 100 grams of dibenzo[b,fj[l,4]thiazepine-l l(10H)one (0.440 mol),

42 ml of phosphorous oxychloride (0.440 mol) and 35 ml of N,N-Dimethylaniline (DMA; 0.276 mol) is stirred at 110 tol20 degree C for about 8 hours. The reaction mass is cooled to 30-35 degree C, 1000 ml of distilled water is added slowly through dropping funnel and the resulting two phase reaction mixture is stirred for 15 min. The organic layer is separated and washed with 500 ml of 4% NaHCO₃ solution followed by water (500ml). Organic layer is dried using Dean stark by azeotropic distillation and taken for next step. Volume of Organic layer is about 1000 ml; Purity (HPLC area %) : 99.0 %

EXAMPLE 2:

PREPARATION OF 11 -PIPERAZINYL DIBENZO[b, f] [1,4] THIAZEPINE A mixture of 1000 ml of organic layer containing product (obtained from example 1) and 1 13.84 grams of Piperazine (1.32 mol) is stirred at 110-120 degree C for about 8 hours. The reaction mass is cooled to 30-35 degree C and washed with water (1x1000 ml and 2x500 ml) Organic layer is dried G-34448FF-BCK-9989 using Dean stark by azeotropic distillation and taken for next step. Volume of Organic layer is about 1000 ml; Purity (HPLC) : 99.0 %

EXAMPLE 3:

PREPARATION OF 1 1 -[4-(2-(2-HYDROXYETHOXY)-ETHYL)- I-PIPERAZINYL] DIBENZO[b,f][l,4]THIAZEPINE

To a mixture of 1000 ml of organic layer (obtained from example 2), 100 grams of sodium carbonate (0.944 mol) and 6.25 grams of sodium iodide (0.042 mol), 37.5 ml of chloroethoxyethanol (0.36 mol) and 187.5 ml of N-Methyl pyrrolidone (NMP; 1.95 mol) are added and the reaction mixture is stirred at 1 10-120 degree C for about 8 hours. 1000 ml of water is added to the reaction mass and stirred for 15 min. The organic layer is separated and washed with water (2x1000ml). Organic layer is dried using Dean stark by azeotropic distillation. This organic layer on distillation under reduced pressure yields the title compound (quetiapine free base) as a viscous oil. Yield : 135g (80 % ); Purity (HPLC area%) : 98.5 %.

EXAMPLE 4: PREPARATION OF 1 1-[4-(2-(2-HYDROXYETHOXY)-ETHYL)-I-PIPERAZINYL]

DIBENZO[b,f][ 1 ,4]THIAZEPINE

A mixture of 1000 ml of organic layer (obtained from example 1) and 150grams of l-[2-(2- hydroxyethoxy)ethyl]piperazine (HEEP) (0.860 mol) is stirred at 1 10-120 degree C for about 8 hours. 1000 ml of water is added to the reaction mass stirred for 15 min. The organic layer is separated washed with water (2x500 ml). Organic layer is dried using Dean stark by azeotropic distillation. This organic layer on distillation under reduced pressure yields the title compound (quetiapine base) as a viscous oil. Yield : 165.5 g ( 98 % ); Purity (HPLC area%) : 99.5%

EXAMPLE 5:

PROCESS FOR THE PREPARATION OF QUETIAPINE HEMIFUMARATE 100 grams of Quetiapine base (obtained as oil from example 3 or 4) is dissolved in 900 ml of ethanol under stirring. 18.17 grams of fumaric acid (0.15 mol) is added to the reaction solution under stirring. The reaction solution is stirred at 80-85 degree C for about 30 min, cooled to 30-35 degree C for about 2 hours. The separated crystalline solid is filtered and washed with 200 ml of ethanol. The obtained hemifumarate salt of quetiapine is dried under reduced pressure at 65 degree C for about 12 hours. Yield: 1 1 Ig (96.4 %); Purity: 99.50 % (HPLC, area %) G-34448FF-BCK-9989

Scheme-1 showing the preparation of quetiapine hemifumarate by the process steps as outlined in examples 1-3 and 5.

DbeπzD[b,f][1,4]tHazEpine-11(1ClH)ane lrrinodicride Rperaane CHcroetracy

Qjstiapne bβse Clietiapine hemflmErεte

Scheme-2 showing the preparation of quetiapine hemifumarate by the process steps as outlined in examples 1, 4 and 5. _

G-34448FF-BCK-9989

DbeπzD [b,f][1,4]tHazEp^"ne-11(10H)crB Iπinodiαide HFFP

reflux

Claims

G-34448FF-BCK-9989We claim

1. A one-pot process 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,

wherein Hal is Cl, Br or I; and bl) reacting the compound of formula III obtained from step a) with a compound of formula IV

HN N-R,

IV -BCK-9989 to give the compound of formula I; or b2-I) reacting the compound of formula III obtained from step a) with piperazin to give a compound of formula V

followed by b2-H) reacting the compound of formula V with the compound of formula VI

HaI-R₂ VI

wherein Hal is Cl, Br or I, to give the compound of formula I; wherein Ri and R₁- 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 R₂ is a Q-C₆ alkylgroup, a Ci-C₆ hydroxyalkylgroup, a (C|^-alkoxy)-C|.₆-alkyl- group or a (Hydroxy-Cι_₆-alkoxy)-Ci.₆-alkyl-group, wherein A₁ and A₂ represent an atom selected from C and N, A₃ 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, A₃ represents an atom selected from N, O and S, and

A₂ is bonded to the carbon atom bearing Ri • by a single bond. G-34448FF-BCK-9989

2. The one-pot process of claim 1, wherein the compound of formula I is a compound of formula

IIIV

the compound of formula II is a compound of formula IX

the compound of formula III is a compound of formula X,

, and the compound of formula V in steps b2-I) and b2-II) is a compound of formula XI

and wherein R_x and R₁- 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(s) is (are) F or Cl, G-34448FF-BCK-9989 and wherein R₂ is a C_rC₆ alkylgroup, a Ci-C₆ hydroxyalkylgroup, a (C|.₆-alkoxy)-Ci.₆- alkyl-group or a (Hydroxy-Cι_6-alkoxy)-Cι_₆-alkyl-group.

3. The process of any one of claims 1 or 2, wherein Rj • is a hydrogen atom and Ri is a hydrogen atom or a frifliioromethyl group, in particular wherein R₁ is a hydrogen atom. 4. The process of claim 3, wherein the compound of formula II is dibenzo[b,f][l,

4]thiazepine- l l(10H)-one.

5. The process of claim 4, wherein the compound of formula IV is l-[2-(2- Hydroxyethoxy)ethyl]piperazine.

6. The process of claim 5, wherein the compound of formula VI is 2-chloroethoxyethanol.

7. The process according to any one of the preceding claims wherein the inert solvent is toluene.

8. The process according to any one of the preceding claims, wherein step a) is carried out in the presence of a base, in particular wherein the base is N,N-Dimethylaniline.

9. The process according to any one of the preceding claims, wherein in step a) the compound of formula II and the halogenating agent are present in about equimolar amounts.

10. The process according to any one of the preceding claims, wherein step a) and step bl) or step a) and step b2-I) and step b2-II) take place in essentially the same solvent.

1 1. A process for the preparation of a salt of the compound of formula I, comprising the steps of any one process according to the preceding claims, wherein, as an additional step, the compound of formula I in the form of its base is reacted with a suitable acid to give a salt of the compound of formula I.

12. The process of claim 11 , wherein in a further step the salt of the compound of formula I is formulated into a pharmaceutically acceptable dosage form, in particular wherein said dosage form is a tablet, pill, capsule or injectable.

13. The process of claim 12, wherein the compound of formula I is quetiapine and the salt of the compound of formula I is quetiapine hemifumarate.

14. Use of essentially the same inert solvent or of a mixture of inert solvents for i) the preparation of a compound of formula III from a compound of formula II and ii) the subsequent preparation of compound of formula I from said compound of formula III.

15. 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. G-34448FF-BCK-9989

16. Composition comprising a) an inert solvent or a mixture of inert solvents, b) a compound of formula Il and c) a halogenating agent.