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1. WO2010001407 - SYNTHESIS OF 11-(4-[2-(2-HYDROXYETHOXY)ETHYL]- PIPERAZINYL)DIBENZO[B,F][1,4]THIAZEPINE AND ITS FUMARATE SALT

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[ EN ]

SYNTHESIS OF ll-(4-[2-(2-HYDROXYETHOXY)ETHYL]- PIPERAZINYL)-DIBENZO[B,F][1,4]THIAZEPINE AND ITS

FUMARATE SALT

BACKGROUND OF THE INVENTION Field of the Invention

This invention broadly relates to a method for synthesizing ll-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,fj [l,4]thiazepine hemifumarate salt (Quetiapine hemifumarate) of formula I


Formula I

Quetiapine and its pharmaceutically acceptable salts, especially Quetiapine hemifumarate (sold by AstraZeneca under the trade name SEROQUEL®), possess antidopaminergic activity, especially antipsychotic activity. Quetiapine is thought to exhibit a lower incidence of the variety of side effects, such as acute dystonia, acute dyskinesia, pseudo-Parkinsonism and tardive dyskinesia, which commonly plague antipsychotic agents. A considerable body of literature describes how to make and use Quetiapine and particularly Quetiapine hemifumarate. Specific references for the preparation and use of these agents include EP 240228 and EP 282236; U.S. Pat. Nos. 4,879,288 and 6,372,734; U.S. Pat. Pubs. 2003/0216376, 2004/0220400, 2004/0242562 and 2005/0080072, and International published applications WO 97/45124 and WO 01/55125.

Since Quetiapine constitutes an important therapeutic agent, additional and improved ways of preparing Quetiapine and its salts are of value to the pharmaceutical arts.

SUMMARY OF THE INVENTION

The present invention is directed to a method of producing l l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)dibenzo[b,fj[l,4]thiazepine(Quetiapine) from 11-piperazinyldibenzo[b,fj[l,4]thiazepine dihydrochloride of formula IV.


Formula IV

The present invention also relates to a method for producing 11-piperazinyldibenzo [b,fj[l,4]thiazepine dihydochloride of formula IV from 11-chloro-dibenzo[b,fj[l,4]thiazepine of formula III


Formula III In yet another aspect, the present invention pertains to a method for producing l l-chlorodibenzo[b,f][l,4]thiazepine of formula III from dibenzo[b,f][l,4]thiazepine-1 l(10H)one (DBTO) of formula II


Formula II

In further aspect, the present invention relates to a method for recovering the hemifumarate salt of l l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,fj[l,4]thiazepine (Quetiapine) of high purity without isolating free base.

DETAILED DESCRIPTION OF THE INVENTION

Methods of preparing dibenzo[b,fj[l,4]thiazepine-l l(10H)one (DBTO) of formula II, used as a starting material in accordance with the present invention, are well known. See for example- 1 of EP 0282236, which is incorporated herein by reference and the process is as follows:



Formula Ir

The present invention is not to be limited in any particular way for obtaining Formula II.

The present invention thus provides for the following reaction scheme to produce 1 1 -(4- [2-(2-hydroxyethoxy)ethyl] -piperazinyl)-dibenzo [b,fj [l,4]thiazepine (Quetiapine) starting with dibenzo[b,fj[l,4]thiazepine-l l(10H)one (DBTO),


Chlorocthoxyethanol Step-3 nlkylalion


Qucliupiπu According to the present method, in Step (1), compound of formula II is dissolved in non-aromatic organic solvent, preferably acetonitrile, sulfolane and is chlorinated in the presence of an amine base using excess of phosphorous oxychloride (POCl3). The. reaction is preferably conducted at atmospheric pressure in the presence of phase transfer catalyst (PTC) and non-aromatic organic solvent under reflux conditions.

Applicants have discovered that excess of the chlorinating agent being used in the prior art is not necessary. In particular, while U.S. 4,879,288 illustrates (in its Example 1) using almost 14 mole excess of phosphorous oxychloride relative to DBTO in the absence of any other solvent; using hazardous chemical of chlorinating agent in excess quantity in the reaction is very difficult to remove under distillation, which will cause severe environmental problems

To overcome these problems, applicants of WO2006/135544 have discovered the use of solvent during the reaction with bit excess quantity of phosphorous oxychloride. Unfortunately, their invention was restricted to aromatic solvents, preferably toluene. The disadvantage of this process is that it requires higher temperature (toluene, reflux temperature is 110 0C), which leads to more evaporation of chlorinating agent and takes more time for reaction completion.

To overcome the difficulties faced in the prior art, the present applicants have developed an improved process for the preparation of compound of formula III. Applicants have found that by using non-aromatic organic solvents such as acetonitrile, sulfolane, only a slight mole excess of the phosphorous oxychloride (POCI3) is needed. In particular, not more than a 1.0 mole excess and preferably only about 0.1 mole excess of phosphorous oxychloride, relative to DBTO needed.

These modifications facilitate the in-situ preparation of the 11 -chloro-dibenzo[b,fj [l,4]thiazepine intermediate (formula III), its purity and thus simplify the overall procedure for scale-up, particularly the need to strip excess phosphorous oxychloride from this intermediate product.

DBTO, N,N-dimethylaniline and phosphorous oxychloride can be added along with tetra butyl ammonium bromide (PTC) in acetonitrile and refluxed. There is no need to add slow addition of POCl3 to the refluxing solution of DBTO. Applicants have found that there is no loss in yield by adding the above compounds at once, in fact there is significant improvement in the yield and quality. The chlorination progresses as the DBTO solid dissolve. This reaction is usually completed in about 4-8 hours, e.g., about 6 hours. The completion of the reaction is monitored by conventional technique that is TLC/HPLC.

Once the step (1) reaction is completed, the reaction mixture is cooled and distilled completely under vacuum below 60 °C. The addition of toluene to the reaction residue is followed by quenching the mixture in pre-cooled water at below 25 °C and the unreacted DBTO is filtered, the recovered BDTO can be reused.

The chlorinated DBTO (i.e., 1 l-chloro-dibenzo[b,f][l,4]thiazepine) in toluene is reacted with piperazine. The reaction is conducted with a molar excess of anhydrous piperazine under reflux conditions at atmospheric pressure (about 1 to 4 moles of piperazine per mole of chlorinated DBTO typically is used, preferably about 2 to 3 moles). Typically, the conversion of the chlorinated DBTO to 11-piperazinyldibenzo[b,fj[l,4]thiazepine is completed in about 4-8 hours. The completion of the reaction is monitored by TLC. The reaction mass is cooled.

While the piperazine dihydrochloride salt, which forms a by-product of this reaction, tends to form an easily filterable cake, when the reaction mixture cools, excess piperazine is not as easily removed. Piperazine removal is necessary to avoid the undesired alkylation reaction between piperazine and chloroethoxyethanol in further step.

The organic phase is washed with water and the solvent is distilled out below 60 °C. The residue is dissolved in chlorinated solvent, water is added and pH adjusted to 0-2 with dil HCl. The organic layer is separated, which contains bis impurity of the below compound, BBTO (formula-II) and chloro compound of formula-Ill.

One predominant alkylation by-product that is not removed by aqueous washing is dialkylated piperazinyl compound believed to have the structure:


Which, remains with the toluene solution of 11 -piperazinyldibenzo[b,f] [1,4] thiazepine. To remove this material, applicants have found that following the aqueous wash step, the toluene solution should be mixed with sufficient alcoholic acid which will result in the formation of a water-soluble salt of the desired H--piperazinyldibenzo[b,fj[l,4] thiazepine. In this way, it becomes possible to partition the desired product separately from the impurity. Common acids should be sufficient for accomplishing salt formation and alcoholic hydrochloric acid, more preferably ethanolic or methanolic hydrochloric acid used. The purity of the hydrochloride salt of l l-piperazinyldibenzo[b,fj[l,4]thiazepine is at least 95%, preferably at least 99% and typically at least 99.8% pure.

The alkylation is preferably conducted at a temperature above about 60 °C and preferably below about 70 °C. Following complete addition of the 2-(2-chloroethoxy)ethanol to the reaction mixture,.

Toluene, sodium carbonate, sodium iodide, N-methyl pyrrolidinone is charged to the above compound and stirred at 20-40 °C. 2-(2-chloroethoxy)ethanol is added to it, heated to reflux and maintained for 4-5 hours. The reaction is allowed to continue until over 99% completion and preferably over 99.5% of the 1 1-piperazinyldibenzo[b,f][l,4]thiazepine dihydrochloride is consumed. The reaction typically takes about 8-12 hours for completion. The reaction/product conversion can be monitored by conventional methods like HPLC/TLC. The reaction mass is cooled to room temperature, water is added and stirred for 1 hour. The aqueous layer is extracted with toluene. The organic phase is washed with water and concentrated to give a residue. Methanol was added to it, stirred to dissolve and heated to reflux. Fumaric acid is added to it at reflux temperature to give a clear solution and refluxed for 1 hour. The reaction mass is allowed to cool to room temperature and filtered to obtain salt of Quetiapine fumarate.

Using the noted isolation and purification techniques, the recovery of quetiapine fumarate that is permitted is more than 99% pure and preferably at least 99.5% pure. The following prophetic Examples are presented to illustrate the detailed various aspects of the present invention.

EXAMPLES

Example 1 Preparation of ll-piperazinyldibenzo[b,f|[l,41thiazepine dihydrochloride using acetonitrile

300 g of DBTO and 600 mL of acetonitrile are introduced into a reaction vessel under nitrogen atmosphere. Under stirring, 96.0 g (0.60 eq.) of N,N-dimethyl aniline, 212.6 g (0.5 eq.)of tetrabutylammonium bromide and 912.0 g (4.5 eq.) of phosphorus oxychloride are added at 25-35 °C temperature. The temperature is raised to reflux (about 70 °C) over a one hour period and refluxed for about 6-8 hours. After completion of the reaction, it is cooled to 50 °C. The solvent is distilled out completely under vacuum at below 55 °C to give a residue. 1500 mL of toluene is added to it and stirred to dissolve and cooled to 25-35 °C. 3600 mL of pre-cooled water was added to fresh RB flask slowly at 25 0C, cooled to 0 0C, added the above toluene layer and with stirring maintained at 25-30 °C for 30 min. The unreacted starting material DBTO is filtered. The toluene layer is separated, washed with water, dried on anhydrous sodium sulphate and filtered. ( ll-chloro-dibenzo[b,fj[l,4]thiazepine solution is charged in toluene in another dry RB flask and heated to 45-50 °C. Piperazine is added slowly portion wise at the same temperature and heated to 70-80 °C and maintained for 3-4 hours. The completion of the reaction was checked by TLC. The obtained piperazine hydrochloride salt was cooled to room temperature and washed with toluene. The toluene layer is washed with water. The separated toluene layer is washed to remove starting material DBTO, bis impurity and ll-chloro-dibenzo[b,fj[l,4]thiazepine.

Toluene is taken in fresh RB flask and 600 mL of ethanol is added to it. Ethanolic HCl is added (804 mL; assay: not less than 15%) at 25-35 °C and the reaction is maintained at the 70-80 °C for 1 hour. It is cooled to 25-35 0C, stirred for 2-3 hours and filtered 1 lpiperazinyldibenzo[b,f][l,4]thiazepine as dihydrochloride salt, washed with 900 mL of ethanol and dried at 70-75 °C to get a constant weight, (wt: 447.5 g; yield: 92.0%; HPLC purity:99.62% and Dimer impurity: 0.27%)

Example 2 Preparation of ll-piperazinyldibenzo[b,f|[l,41thiazepine dihydrochloride using sulfolane

20 g of DBTO and 40 mL of sulfolane are introduced into a reaction vessel under a nitrogen atmosphere. Under stirring, 6.7 mL (0.60 eq.) of N,N-dimethyl aniline, 14.2g (0.5 eq.)of tetrabutylammonium bromide and 20.4 g (2.5 eq.) of phosphorus oxychloride are added at 25-35 0C temperature. The temperature is raised to reflux (about 70 °C) over a one hour period and refluxed for about 6 hours. After completion of the reaction, it is cooled to 50 0C. The solvent is distilled out completely under vacuum at below 60 0C to give a residue. 160 mL of toluene is added to the residue and this solution is added to 80 mL of pre-cooled water slowly at 25 °C with stirring maintained for 30 min. The unreacted starting material DBTO is filtered. The toluene layer is separated, washed with water, dried on anhydrous sodium sulphate and filtered.

1 l-chloro-dibenzo[b,f][l,4]thiazepine solution is charged in toluene in another dry RB flask and heated to 60-65 °C. Piperazine is added slowly portion wise at the same temperature and a clear dissolution is observed. The reaction mixture is heated to reflux and maintained for 6-7 hours. The completion of the reaction was checked by TLC. The obtained piperazine hydrochloride salt was cooled to room temperature and filtered. The toluene layer is washed with water and distilled off completely under vacuum below 60 °C to give a residue. The residue is dissolved in 120 mL of dichloromethane, 100 mL of water is added and pH adjusted to 0-1 by using dilute

HCl at room temperature. The separated dichloromethane layer is washed to remove starting material DBTO, bis impurity and ll-chloro-dibenzo[b,fj[l,4]thiazepine.

The aqueous layer is washed with dichloromethane and 100 mL of toluene is added to adjust pH to 12-14 using 20% sodium hydroxide solution. Toluene layer and water layer is separated. The toluene layer is taken in fresh RB flask and methanolic

HCl is added (60 mL; assay: not less than 10%) at 25-35 0C. The reaction is maintained at the same temperature for 45-60 min and heated to 65-75 °C. The solvent is distilled out slowly atmospherically at 65-75 °C. The solid separation is observed. It is cooled to 25-35 °C, stirred for 2 hours and filtered 1 1-piperazinyldibenzo[b,fj[l,4]thiazepine as dihydrochloride salt washed with 20 mL of toluene and dried at 70-75 °C to get a constant weight. (wt: 25.8g; yield: 80.0%; HPLC purity:98.45% and Dimer impurity: 1.42%)

Example 3

Preparation of Quetiapine hemifumarate

Charge 20.0 g of 1 l-piperazinyldibenzo[b,f][l,4]thiazepine dihydrochloride, 17.2 g (3.0 moles)of sodium carbonate, 1.3 g of sodium iodide (0.16 moles), 30 mL (1.5 volumes) of N-methyl pyrrolidine to 120 mL of toluene with continuous stirring. 6.3 mL (1.1 moles) of 2-(2-chloroethoxy)ethanol is added to it with stirring. With continued mixing, the reaction mixture is heated to reflux temperature and maintained at that temperature for 4-5 hours. The conversion of 11-piperazinyldibenzo[b,fj[l,4]thiazepine to quetiapine can be monitored by TLC analysis. Once the conversion is complete, the reaction mixture is cooled to a temperature less than about 35 °C, about 60 mL of water is added to adjust the reaction mixture to a temperature of about 25-350C and the mixing is continued for at least about 30 minutes. The biphasic mixture is transferred to a separatory funnel and the aqueous and organic phases are allowed to separate. The aqueous layer is extracted with toluene. The lower aqueous phase is isolated and discarded. The combined toluene layer containing crude Quetiapine is distilled off completely under vacuum at below 65 °C to get a residue. 160 mL of methanol is added to the residue and stirred to get a clear solution. It is heated to reflux and 3.46 g (0.55 moles) of fumaric acid is added at reflux temperature and clear dissolution is observed and the stirring is maintained at reflux for 1 hour. The hot solution is filtered to remove particles. The reaction mixture is allowed to cool to 25-35 °C and stirred for 2-3 hours to get solid separation. The obtained solid of Quetiapine hemifumarate is filtered, washed with cold methanol and dried at 60-70 °C.

(wt: 16.0 g, Yield:58.9%;HPLC purity: 98.8% and dimer impurity: 0.37%)

Example 4

Purification of Quetiapine hemifumarate Charge 14 g of crude Quetiapine hemifumarate in 196 mL of methanol at 25-30 °C and refluxed till dissolution. The reaction mixture is filtered under hot condition to remove particles and the filtrate was cooled to 25-30 °C for 2-3 h. The obtained solid was filtered and washed with 28 mL methanol and dried at 60-70 0C to get constant weight, (wt: 13.2 g, Yield:94.2%; HPLC purity: 99.5%) The present invention has been described with reference to specific embodiments. However, this application is intended to cover those changes and substitutions that may be made by those skilled in the art without departing from the spirit and the scope of the invention. Unless, otherwise specifically indicated, all percentages are by weight. Also, unless the context shows otherwise, the term "about" is intended to encompass + or -5% throughout the specification.