WO2006135544A1

WO2006135544A1 - SYNTHESIS OF 11-(4[-(2-HYDROXYETHOXY)ETHYL]-PIPERAZINYL)-DIBENZO[b,f][1,4]THIAZEPINE AND ITS FUMARATE SALT

Info

Publication number: WO2006135544A1
Application number: PCT/US2006/020143
Authority: WO
Inventors: Greg Steven Buenger; Anatoly Alexander
Original assignee: Cambrex Charles City, Inc.
Priority date: 2005-06-10
Filing date: 2006-05-25
Publication date: 2006-12-21

Abstract

The invention is directed a method for synthesizing l l-(4-[2-(2- hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,f] [l,4]thiazepine (quetiapine) and for recovering quetiapine as its fumarate salt in which dibenzo[b,f][l,4]thiazepine- l l(10H)one is chlorinated in the presence of a trialkyl amine base using a slight molar excess of phosphorous oxychloride to produce l l-chloro-dibenzo[b,f] [l,4]thiazepine which then is alkylated with piperazine to l l-piperazinyldibenzo[b,f] [l,4]thiazepine, which finally is alkylated with 2-(2-chloroethoxy)ethanol.

Description

Synthesis of ll-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,f][l,4]thiazepine and its Fumarate Salt

BACKGROUND OF THE INVENTION

Field of the Invention

[0001] This invention broadly relates to a method for synthesizing 1 l-(4-[2-(2- hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,fj[l,4]thiazepine (quetiapine) and for recovering quetiapine as its fumarate salt.

Description of Related Art

[0002] Quetiapine and its pharmaceutically acceptable salts, especially quetiapine hemifumarate (sold under the tradename 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 dyskinesa, which commonly plague antipsychotic agents.

[0003] A considerable body of literature describes how to make and use quetiapine and particularly quetiapine fumarate. 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 (all of which are incorporated herein by reference).

[0004] 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

[0005] The present invention is directed to a method of producing ll-(4-[2-(2- hydroxyethoxy)ethyl]-piperazinyl)dibenzo[b,f][l,4]thiazepine (also known as quetiapine) from 1 l-piperazinyldibenzo[b,fj[l,4]thiazepine.

[0006] The present invention also relates to a method for producing 11- piperazinyldibenzo[b,fj[l,4]thiazepine from 1 l-chloro-dibenzo[b,fj[l,4]thiazepine.

[0007] In yet another aspect, the present invention pertains to a method for producing l l-chloro-dibenzo[b,f][l,4]thiazepine from dibenzo[b,f][l,4]thiazepine- ll(10H)one (DBTO).

[0008] In a 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,f][l,4]thiazepine (quetiapine) of high purity.

DETAILED DESCRIPTION OF THE INVENTION

[0009] Methods of preparing dibenzo[b,f][l,4]thiazepine-l l(10H)one (DBTO), used as a starting material in accordance with the present invention, are well known. See for example U.S. Pat. 4,879,288, which is incorporated herein by reference. The present invention is not to be limited to any particular way for obtaining DBTO.

[0010] The present invention thus provides for the following reaction scheme to produce l l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,f][l,4]thiazepine

(quetiapine) starting with dibenzo[b,f][l,4]thiazepine-l l(10H)one (DBTO):

[0011] According to the method, in Step (1), DBTO is dissolved in an aromatic solvent, preferably toluene, and is chlorinated in the presence of an amine base using an excess of phosphorous oxychloride (POCl₃). The reaction is preferably conducted at atmospheric pressure in the presence of the aromatic solvent under a reflux condition.

[0012] While the prior art {e.g., U.S. 4,879,288) conducted this chlorination reaction in the presence of an N,N-disubstituted aniline, such as N,N-dimethylaniline, applicants have found that such toxic and potentially carcinogenic amines can be replaced with a trialkylamine, especially triethylarnine (TEA). The TEA is typically used in a slight molar excess relative to DBTO.

[0013] Furthermore, applicants have also discovered that the large excess of the chlorinating agent used by the prior art is not necessary. In particular, while U.S. 4,879,288 illustrates (in its Example 1) using almost a 14 mole excess of phosphorous oxychloride relative to DBTO in the absence of any other solvent; applicants have found that by using an aromatic solvent such as toluene (having a reflux temperature of about 110 ⁰C), only a slight mole excess of the phosphorous oxychloride (POCl₃) is needed. In particular, no more than a 1 mole excess, and preferably only about a 0.1 mole excess of phosphorous oxychloride relative to DBTO (and to TEA) is needed.

[0014] These modifications facilitate the preparation of the 11 -chloro- dibenzo[b,f][l,4]thiazepine intermediate at a higher purity and thus simplify the overall procedure for scale-up, particularly the need to strip excess phosphorous oxychloride from this intermediate product.

[0015] While the triethylamine and phosphorous oxychloride reagents can be added slowly to the refluxing toluene solution of DBTO, applicants have found that there is no significant loss in yield by adding them at once. The chlorination progresses as the DBTO solids dissolve. The chlorination reaction is usually complete (at reflux) in about 2-6 hours, e.g., about 3 hours. The completion of the reaction is typically accompanied by the clarification of the reaction system.

[0016] Once the step (1) reaction is complete, the reaction mixture is cooled and quenched by mixing it into cold water. The addition of the reaction mixture into the water is controlled so that the temperature of the reaction mixture in the presence of water does not exceed about 40 ⁰C. Applicants have found that it is best to conduct the quenching in a way to arrive at a temperature between about 20 and 40 ⁰C. Undesired degredation of the 1 l-chloro-dibenzo[b,f][l,4]thiazepine occurs in the presence of water at temperatures above 40 ⁰C. Further, the separation of the organic phase containing the desired 1 l-chloro-dibenzo[b,f][l,4]thiazepine from the aqueous phase occurs extremely slowly at a temperature below 20 ⁰C. The separation is preferably conducted at a temperature in the range of about 30 to 40 ⁰C. It also is preferred to pass the two-phase mixture first through a clarifying filter to remove the rag layer before completing the separation. [0017] The organic (toluene) phase may be washed with water and then is azeotropically dried, preferably under a vacuum to minimize the exposure of the 11- chloro-dibenzo[b,fj[l,4]thiazepine to elevated temperatures.

[0018] The chlorinated DBTO (i.e., 1 l-chloro-dibenzo[b,f|[l,4]thiazepine) in toluene then is reacted (alkylated) with piperazine in step (2) of the process. The reaction is conducted with a molar excess of anhydrous piperazine under reflux conditions at atmospheric pressure (about 2 to 5 moles of piperazine per mole of chlorinated DBTO typically is used, preferably about 3 to 4 moles). Typically, the conversion of the chlorinated DBTO to 1 l-piperazinyldibenzo[b,f][l,4]thiazepine is completed in about 1-3 hours.

[0019] While the piperazine dihydrochloride salt, which forms as a by-product of this reaction, tends to form an easily filterable cake when the reaction mixture cools, the excess piperazine is not as easily removed. Piperazine removal is necessary to avoid the undesired alkylation reaction between piperazine and the chloroethoxyethanol in Step (3) of the process. Unfortunately, the toluene solution of 11 -piperazinyldibenzo[b,fj [1 ,4]- thiazepine forms a fairly stable emulsion when one attempts to wash the water-soluble piperazine directly from the aromatic solvent solution with water, thus significantly prolonging, if not preventing, the phase separation needed to recover the 11-piperazinyl- dibenzo[b,f] [1 ,4]thiazepine.

[0020] Applicants discovered that by conducting the washing with a mixture of water and methyl-fert-butyl ether (MTBE), one is able to avoid emulsion formation and readily accomplish the removal of excess piperazine. Generally, the MTBE and water are used in a relative amount, by volume in the range of 1 : 1 < MTBE: water < 1 :5. In some cases, a combination of MTBE and methanol in the aqueous wash step is needed to obtain a complete phase separation. In that case MTBE and methanol are used in a relative amount, by volume, in the range of 1 :0.1 < MTBE:methanol < 1 :2. Multiple washings (for example as many as three) may be appropriate to maximize impurity, especially piperazine, removal. [0021] To maximize recovery, the piperazine hydrochloride salts are washed with toluene and the washings are added to the toluene solution before the aqueous wash.

[0022] One predominant alkylation by-product that is not removed by the aqueous washing is a 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 aqueous acid to result in the formation of a water-soluble salt of the desired 1 l-piperazinyldibenzo[b,f][l,4]thiazepine. In this way, it becomes possible to partition the desired product separately from the impurity. Common inorganic acids should be sufficient for accomplishing salt formation and aqueous hydrochloric acid is preferred. Establishing a pH of about 3.0 in the water phase has proven to be sufficient.

[0023] The salt of 11 -piperazinyldibenzo[b,f] [1 ,4]thiazepine partitions into the aqueous phase, while the dialkylated impurity remains with the toluene phase, which is separated and discarded. A base is then added to the aqueous phase to neutralize the acid and establish a pH of about 13.0 in the aqueous phase. Then, the 11-piperazinyl- dibenzo[b,f][l,4]thiazepine is re-extracted into an organic phase using an organic solvent. Methyl ter t-buty\ ether (MTBE) has been used successfully for this purpose. Other suitable organic solvents would include toluene, ethers, esters, chlorinated solvents and the like. [0024] The organic solvent (MTBE) solution of 11-piperazinyl- dibenzo[b,f][l,4]thiazepine is then azeotropically dried. The 11-piperazinyl- dibenzo[b,f][l,4]thiazepine then can be isolated from the solvent as its hydrochloride salt by first diluting the solution -with a polar solvent, preferably isopropyl alcohol (IPA). Dilution to a solids content of about 7-10 wt % should be suitable. Then, hydrochloric acid is added in a stoichiometric amount. For convenience the acid is added as its 35% by weight aqueous solution. The addition of the acid causes salt formation (precipitation) and the precipitated solids can be isolated by any convenient solids recovery technique, such as by filtering. The solids can be washed with IPA and then are dried in a vacuum. The purity of the hydrochloride salt of 1 l-piperazinyldibenzo[b,fj[l,4]thiazepine is at least 95%, is preferably at least 99% and is typically at least 99.5% pure.

[0025] Alternatively, following the azeotropic drying of the solvent (MTBE) solution of 1 l-piperazmyldibenzotb^fl^Jthiazepine, its alkylation with 2-(2- chloroethoxy)ethanol according to Step (3) of the process can proceed directly. In the first operation, a solvent exchange is performed to introduce the 11-piperazinyl- dibenzo[b,f][l,4]thiazepine into the solvent of choice for the alkylation. While rø-butanol is the preferred solvent, wo-butanol and a mixture of toluene and N-methylpyrrolidone also have been shown to be suitable. Once the reaction solution is prepared, the reaction mixture is established by the addition of a base, potassium carbonate is preferred, and an activator, sodium iodide (in an amount of about 10-45% of the 11-piperazinyl- dibenzo[b,f][l,4]thiazepine by molar equivalent) is preferred.

[0026] The alkylation is preferably conducted at a temperature above about 90 ⁰C and preferably below about 105 ⁰C. Following complete addition of the 2-(2- chloroethoxy)ethanol to the reaction mixture, the reaction is allowed to continue until over 99% and preferably over 99.5% of the ll-piperazinyldibenzo[b,f][l,4]thiazepine has been consumed. The reaction typically takes about 12-18 hours to be complete. For example, the reaction mixture can be heated to 102 ⁰C for approximately 16 hours to complete the alkylation reaction. The conversion can be checked by HPLC. [0027] In order to convert the hydrochloride salt of 11 -piperazinyl- dibenzo[b,f][l,4]thiazepine to its free base for the alkylation reaction just described, the salt first is dissolved in a polar solvent, preferably water. Then, ;?-butanol is added to form a substantially homogeneous solution. Following the addition of an inorganic base, preferably sodium hydroxide, and thorough contacting, two phases form. The conversion of the salt to the free base is adequately performed using a 50% (by weight) solution of sodium hydroxide in a mixture of water and π-butanol. The organic phase comprises a mixture of n-butanol and l l-piperazinyldibenzo[b,fj[l,4]thiazepine. The aqueous phase contains sodium chloride and excess base (sodium hydroxide). The organic layer is recovered. It can be azeotropically dried by vacuum distillation to remove water as completely as possible. Additional rø-butanol can then be added to replace any π-butanol removed during the vacuum distillation. The n-butanol solution of 11-piperazinyl- dibenzo[b,f][l,4]thiazepme is ready for alkylation with 2-(2-chloroethoxy)ethanol as described above.

[0028] In accordance with this invention, the quetiapine is then recovered as its fumarate salt from the rø-butanol solution. The n-butanol solution of quetiapine first is contacted with water to cool and quench the reaction mixture and to remove a large portion of the water soluble impurities, such as mineral salts of chloride, iodide and carbonate. The phases separate best at 40 - 50 ⁰C. The aqueous phase is isolated at 40 - 50 °C and discarded. The organic phase can be washed again with water and, as above, the aqueous phase is isolated at 40 - 50 ⁰C and discarded. Since the presence of water adversely impacts ultimate product yield, the rø-butanol solution is next azeotropically dried by vacuum distillation to substantially remove all residual water.

[0029] The substantially anhydrous reaction mixture of the «-butanol solution of quetiapine is diluted with isopropyl alcohol (IPA). The addition of IPA helps to reduce the viscosity of the solution and prepares the solution for the subsequent addition of fumaric acid. Additional water-soluble impurities precipitate at this time and are filtered from the organic phase. To form the quetiapine fumarate, the M-butanol/IPA solution of quetiapine first is warmed to about 80-85 ⁰C and then a warm solution of fumaric acid in IPA is added. The solution of fumaric acid in isopropyl alcohol is also warmed to a temperature of 80 - 85 °C before it is charged to the hot quetiapine solution. The solution now containing the hemi-fumarate salt of quetiapine due to the added fumaric acid is held at a temperature of 75-85 ⁰C for at least one (1) hour and up to three (3) hours to allow proper nucleation and seed crystal formation. Following further cooling to below ambient temperature, crystallized quetiapine fumarate can be recovered via filtration as a wet cake. Preferably, the resulting mixture is stirred at 80 ⁰C for several hours. The mixture is then cooled slowly, at a rate of -20 °C per hour, to less than 15 °C (e.g., 5-15 ⁰C). The mixture is filtered after holding at a temperature of less than about 15 °C (e.g., 5-15 °C) for up to three (3) hours, such as for about 1 to 2 hours. The wet cake solids may be washed with cold isopropyl alcohol and dried.

[0030] Additional impurities can be removed by redissolving the quetiapine fumarate in a polar solvent, preferably water. Following dissolution at an elevated temperature (for example at a temperature of 85 - 95 ⁰C)₃ the solution, preferably aqueous, is cooled to about 55-60 ° C and held at that temperature for an extended time of about 2 or more, preferably at least about 3 hours, to allow proper nucleation and seed crystal formation. The solution may be filtered before the cooling of the warm solution is initiated. Then, the slurry is cooled to a below-ambient temperature and filtered. Preferably, the mixture is cooled slowly to less than about 15 °C (e.g., 5-15 ⁰C) and held for about 1 — 2 hours. The cake may be rinsed with cold water and is then dried, such as under vacuum at 70 — 80 °C. The recrystallization (preferably from water) may be repeated, as desired.

[0031] Some hard to remove impurities resist removal using the previous recrystallization procedure. In order to obtain a quetiapine fumarate product of the highest purity, it is preferred to subject the dried product recovered from the recrystallization to treatment with an absorbent. The isolated quetiapine fumarate is dissolved in a warm polar solvent. While isopropyl alcohol is preferred, use of water, methanol, ethanol, n-butanol can also be mentioned. The quetiapine fumarate is dissolved at a temperature of about 75 to 85 ⁰C. The solution then is contacted with an absorbent, such as an activated carbon. This contacting is easily accomplished by filtering the warm quetiapine fumarate solution, preferably an isopropyl alcohol solution, through a filter that is pre-loaded with the absorbent, e.g., active carbon and preferably an additional filter aid, such as Celatom®. Usually, about 1 part by weight carbon per 10 parts by weight of the quetiapine fumarate should be sufficient. This treatment can be repeated one or two additional times.

[0032] After the absorbent treatment, the quetiapine fumarate solution is heated again to about 75-85 ⁰C. With stirring, the solution is cooled to 55-60 ⁰C and stirred at that temperature for at least three hours to initiate nucleation and precipitation of quetiapine fumarate. The mixture then is cooled further to a temperature of less than about 15 ⁰C, such as to a temperature of 5-15 ⁰C, preferably at a rate of about 20 ⁰C per hour and held at that temperature for a period of about 30 minutes to two hours. The solids are recovered, for example by simple filtration and are vacuum dried (<20 in. Hg) at temperature of about 70-80 ⁰C.

[0033] Using the noted isolation and purification techniques permits the recovery of quetiapine fumarate that is more than 99% pure and preferably is at least 99.5% pure. The following prophetic Examples are presented to illustrate in more detail various aspects of the present invention.

EXAMPLE 1

Preparation of ll-chloro-dibenzo[b,f][l,4]thiazepine

[0034] 102 g (0.45 mole) of DBTO and 450 ml of toluene are introduced into a reaction vessel under a nitrogen atmosphere. With stirring, 47 g (0.465 mole) of triethylamine and 76 g (0.485 mole) of phosphorus oxychloride are added at room temperature (about 22 °C). The temperature is raised to reflux (about 110 ⁰C) over a one hour period and held at reflux for about 2 hours. After about 1.5 hours the reaction mixture clarifies. The reaction mixture then is quenched into chilled water with stirring such that the temperature does not exceed about 40 ⁰C. The reaction mixture is heated as needed to about 40 °C and then the aqueous and organic layers are separated. The organic layer is washed with water and then dewatered by vacuum distillation (maximum temperature about 60 ⁰C).

EXAMPLE 2

Preparation of ll-piperazinyldibenzo[b,f][l,4]thiazepine

[0035] To the organic fraction recovered according to Example 1, 140 g (1.6 moles) of anhydrous piperazine is added in a reaction vessel. The temperature of the mixture is gradually increased to reflux (about 110 ⁰C) over a period of about one hour and is kept at that temperature for about 1 to 2 hours. The heat-up is aided by the exothermic reaction that occurs. The extent of the reaction can be monitored by HPLC, but is typically completed within three hours. The reaction mixture then is cooled to ambient temperature and precipitated piperazine dihydrochloride is filtered from the product solution. An aqueous solution of MTBE and methanol (water:MTBE:methanol having a volume ratio of 2.5:1:0.6) is used to wash excess piperazine from the solution, which is removed with the aqueous phase that separates from the organic phase on standing. The organic layer can be washed one to two additional times with water.

[0036] In order to remove a dialkylated piperazinyl by-product that forms during the alkylation reaction, following the aqueous wash step, the toluene solution is mixed with aqueous hydrochloric acid (mixture of 250 ml distilled water and 65 ml of concentrated HCl is suitable) to establish a pH of about 3 in the aqueous phase. The acid treatment results in the formation of a water-soluble salt of the desired 11 -piperazinyl- dibenzo[b,fj [1 ,4]thiazepine, which is recovered with the aqueous phase. The desired free base, 1 l-piperazinyldibenzo[b,f][l,4]thiazepine, then is obtained by contacting the aqueous phase with a combination of MTBE (400 ml) and a 30% by weight solution of sodium hydroxide (85 ml - 0.85 mole NaOH) to produce a pH of at least 13 in the aqueous phase. Formation of the free base causes it to partition into the organic phase which is recovered separately from the aqueous phase. The aqueous phase is discarded while the organic phase is dewatered.

[0037] A solvent exchange can then be conducted to prepare the 11-piperazinyl- dibenzo [b,f] [ 1 ,4]thiazepine for alkylation with 2-(2-chloroethoxy)ethanol. Following the dewatering, the MTBE solution of 1 l-piperazinyldibenzo[b,fj[l,4]thiazepine is concentrated. Both the dewatering and concentrating is accomplished by the removal of about 450 ml of liquid from the organic phase (about 100 ml of a MTBE- water heteroazeotrope and about 350 ml of MTBE). Then, 500 ml of R-butanol is added and the distillation is continued to a bottoms temperature of about 110 ⁰C. The resulting n- butanol solution of 1 l-piperazinyldibenzo[b,f][l,4]thiazepine is then ready for quetiapine synthesis. Alternatively, before the solvent exchange, the 11-piperazinyl- dibenzo[b,fj[l,4]thiazepine first could be isolated from the MTBE solution as it dihydrochloride salt (see Example 3 below).

EXAMPLE 3

Preparation of the dihydrochloride salt of ll-piperazinyldibenzo[b,f][l,4]thiazepme

[0038] The dewatered MTBE solution of 11 -ρiρerazinyldibenzo[b,f] [1 ,4]- thiazepine recovered in accordance with Example 2 is cooled to ambient temperature. 1200 ml of isopropanol are added, followed by 72 ml of concentrated hydrochloric acid. The mixture is stirred at ambient temperature for about 4 hours during which time the dihydrochloride salt of 1 l-piperazinyldibenzo[b,f][l,4]thiazepine begins to crystallize. The mixture is cooled to a temperature below 15 ⁰C {e.g., to 10 ⁰C), and filtered. The solids can be washed with cold isopropyl alcohol. Solvent-free solids can be recovered by vacuuming drying at 60-70 ⁰C.

EXAMPLE 4

Preparation of ll-piperazinyldibenzo[b,f][l,4]thiazepine from its dihydrochloride

[0039] 90 g of the dihydochloride salt of 1 l-piρerazinyldibenzo[b,fj[l,4]- thiazepine, such as produced in accordance with Example 3, is charged to an Erlenmeyer flask equipped with a stir-bar. 30O g of water is added to the flask and the mixture is stirred at a temperature of 15 - 25 °C to dissolve the salt slowly. 343 g of n-butanol is then charged to the flask and the biphasic mixture that forms is stirred at a temperature of 15 — 25 °C. Thereafter, 41.4 g of a 50% aqueous sodium hydroxide solution is added to the mixture. The dihydrochloride salt should be completely dissolved before charging the sodium hydroxide. The mixture is stirred at a temperature of 20 - 30 °C for at least 30 minutes. The temperature of the solution will increase with the charging of the sodium hydroxide. The stirring is then stopped and the biphasic mixture is transferred to a separatory funnel and the phases are allowed to separate. The lower aqueous phase is isolated and discarded. The upper organic phase (solution) contains the 11-piperazinyl- dibenzo[b,f][l,4]thiazepine. The organic solution is transferred to a flask equipped with a distillation setup suitable for vacuum distillation to azeotropically remove water. Vacuum is applied to the distillation setup and the solution is heated. It may be necessary to heat the solution to a temperature in the range of 55 — 65 °C by the end of the distillation. The distillation is continued until there is no more water observed accumulating in the collection trap. The still bottoms may be checked by KF moisture analysis. The amount of water by this analysis should be less than 0.5% by weight. Then, the solution is cooled to less than 35 °C. At least 95% of the amount of any n- butanol which has determined to have been lost in the distillate is added back into the 11- piperazinyldibenzo[b,fj[l,4]thiazepine solution. An additional 135 g of «-butanol also is added at this time to the solution and the mixture is stirred under a nitrogen atmosphere. EXAMPLE 5

Preparation of Quetiapine from ll-piperazinyldibenzo[b,f][l,4]thiazepine

[0040] 33.1 g of extra fine potassium carbonate is added to the rø-butanol solution of 1 l-piperazinyldibenzo[b,fj[l₅4]thiazepine with continuous stirring. Then, 16.48 g of sodium iodide and 35.97 g of 2-(2-chloroethoxy)ethanol are respectively added with stirring. With continued mixing, the reaction mixture is heated to a temperature of 102 °C and maintained at that temperature for 12 - 16 hours. The conversion of 11- piperazinyldibenzo[b,fj[l,4]thiazepine to quetiapine can be monitored by HPLC analysis. Once the conversion of is complete, the reaction mixture is cooled to a temperature of less than about 80 ⁰C and about 500 g of water is added to adjust the reaction mixture to a temperature of about 40 — 50 °C 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 lower aqueous phase is isolated and discarded. The upper organic phase containing crude quetiapine is transferred to a flask. Another 25O g of water is added to the quetiapine solution and the reaction mixture is stirred at a temperature of about 40 - 50 °C for at least 30 additional minutes. The biphasic mixture is again transferred to a separatory funnel and the aqueous and organic phases are allowed to separate. The lower aqueous phase is removed and discarded. The upper organic phase containing crude quetiapine is recovered and transferred to a flask and distillation setup suitable for vacuum distillation to azeotropically remove water. Vacuum is applied to the distillation setup as the solution is heated, possibly to a temperature as high as 55 - 65 °C at the end of the distillation, to remove water. The distillation is continued until no more water is observed collecting in the collection trap. The still bottoms may be checked by KF moisture analysis; the amount of KF water should be less than 0.5% by weight. Once the distillation is complete, the crude quetiapine solution is cooled to a temperature of less than 30 ⁰C. EXAMPLE 6

Preparation of Quetiapine Fumarate

[0041] 255.5 g of isopropyl alcohol is added to the crude quetiapine solution as prepared in accordance with Example 5, stirred under a nitrogen atmosphere. The crude quetiapine solution is cooled to a temperature of about 15 - 25 °C and stirring is continued for about one hour. The crude quetiapine solution is filtered and the filtrate is transferred to a suitable flask, while the solids are discarded. The crude quetiapine solution then is heated to a temperature of 80 - 85 ⁰C. In a separate Erlenmeyer flask, 14.5 g of fumaric acid and 180.5 g of isopropyl alcohol are combined and the mixture is heated to a temperature of 80 - 85 °C to dissolve the fumaric acid. The hot fumaric acid solution then is transferred to the hot crude quetiapine solution. The mixture is stirred at a temperature of about 80 °C for 1.5 hours. During this time, crude quetiapine fumarate should precipitate from the solution. The mixture is then gradually cooled to a temperature of 5 -10 °C at a rate of 20 °C per hour and held at a temperature of 5 °C for 0.5 - 2 hours. The slurry is filtered to collect the crude quetiapine fumarate solids and the filter cake is washed with 261 g of cold (0 - 10 ⁰C) isopropyl alcohol. The filtrate from both steps is discarded. The crude quetiapine fumarate wet cake is dried on the filter for 30 — 60 minutes with vacuum/nitrogen.

EXAMPLE 7

Purification of the Quetiapine Fumarate

[0042] The crude quetiapine fumarate wet cake as recovered according to

Example 6 is transferred to an Erlenmeyer flask and 694 g of water is added to the flask. The slurry, with stirring, is heated to a temperature of 85 - 95 ⁰C to dissolve the crude quetiapine fumarate solids and the hot solution is filtered into a suitable reaction flask. The filtered solids are discarded. With stirring, the solution then is cooled to a temperature of 55 - 60 °C and mixed at that temperature for at least three hours. Quetiapine fumarate should precipitate from the solution during this time. The mixture is gradually cooled to a temperature of 5 - 10 ⁰C at a rate of 20 °C per hour and then is held at that temperature for 0.5 - 2 hours. The slurry is filtered to collect the quetiapine fumarate and the filtrate is discarded. The filter cake is washed with 208 g of water chilled to 5 - 10 °C. The filtrate is discarded. Then, the quetiapine fumarate wet cake is dried on the filter for 30 - 60 minutes with vacuum/nitrogen and then is dried at a temperature of 70 - 80 °C under vacuum (<20 in. Hg). One should recover approximately 79-80 g of quetiapine fumarate.

[0043] If necessary, a further recrystallization can be done to remove additional impurities. In particular, 575 g of water is added to the flask of solids and heated with stirring to a temperature of 85 - 95 °C to dissolve the solids. Then, the mixture is cooled, with stirring to a temperature of 55 - 60 °C and stirred at that temperature for at least 3 hours. The mixture is gradually cooled to a temperature of 5 - 10 °C at a rate of 20 ⁰C per hour and is held at that temperature for 0.5 — 2 hours. The slurry is filtered to collect the quetiapine fumarate, while the filtrate is discarded. The filter cake is washed with an additional 95 g of water chilled to 5 — 10 °C. Again, the filtrate is discarded. The quetiapine fumarate wet cake is dried on the filter for 30 - 60 minutes with vacuum/nitrogen and then the wet cake is dried further at a temperature of 70 — 80 °C under vacuum (<20 in. Hg). About 75 g of quetiapine fumarate should be recovered.

[0044] 46.6 g of the dried quetiapine fumarate is dissolved in 1223 g of warm

(75-85 ⁰C) isopropyl alcohol. The solution is filtered through a filter provided with 15 g of a filter aid (Celatom®) and 5 g active carbon (Nuchar S-A). The filtrate is collected; heated again (as necessary) to a temperature of 75-85 ⁰C, and passed through the filter a second time. The filtrate is reheated to 75-85 ⁰C and then cooled with stirring to a temperature of 55-60 ⁰C. Stirring at this temperature is continued for about 3 hours, during which time the quetiapine fumarate begins to crystallize. The mixture is then cooled to a temperature in the range of 5-15 ⁰C at a rate of 20 ⁰C per hour and held at that temperature for a period of 30 minutes to 2 hours. The slurry is filtered to isolate the solids, which are washed with 100 g of chilled (5-15 ⁰C) isopropyl alcohol. The quetiapine fumarate wet cake is dried on the filter for 15 to 30 minutes using dry nitrogen and vacuum and then is heated (70-80 ⁰C) under vacuum (<20 in Hg) to complete the drying. About 40.8 g of quetiapine fumarate should be recovered.

[0045] 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 to context shows otherwise, the term "about" is intended to encompass + or - 5% throughout the specification.

Claims

Claims:We claim:

1. A process for making 11 -(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,f][l,4]thiazepine or a pharmaceutically acceptable salt thereof characterized by dissolving dibenzo[b,fj[l,4]thiazepine-l l(10H)one in an aromatic solvent and contacting dissolved dibenzo[b,f][l,4]thiazepine-

1 l(10H)one with phosphorous oxychloride, in the presence of a trialkylamine, to produce ll-chloro-dibenzo[b,fj[l,4]tliiazepine.

2. The process of claim 1 wherein the aromatic solvent is toluene.

3. The process of claim 2 wherein the trialkylamine is triethylamine.

4. The process of claim 3 wherein the phosphorous oxychloride is used in only a slight mole excess relative to the dibenzo[b,fj[l,4]thiazepine-l l(10H)one.

5. A process for making 11 -(4- [2-(2-hydroxyethoxy)ethyl] -piperazinyl)- dibenzo[b,fj[l,4]thiazepine or a pharmaceutically acceptable salt thereof characterized by alkylating ll-chloro-dibenzo[b,fj[l,4]thiazepine in an aromatic solvent with a molar excess of anhydrous piperazine under reflux conditions to produce l l-piperazinyldibenzo[b,f][l,4]thiazepine.

6. A process for making 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,f][l,4]thiazepine or a pharmaceutically acceptable salt thereof characterized by purifying 1 l-piperazinyldibenzo[b,fj[l,4]thiazepine from a solution in an aromatic solvent containing excess piperazine by contacting the solution with a mixture of water and methyl ført-butyl ether.

7. The process of claim 6 wherein the mixture of water and methyl tert-butyl ether also contains methanol.

8. A process for making 11 -(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,fj[l,4]thiazepine or a pharmaceutically acceptable salt thereof characterized by adding an aqueous acid to a solution of 11-piperazinyl- dibenzo[b,fj[l,4]thiazepine in an aromatic solvent containing a dialkylated impurity and recovering a water soluble salt of 11-piperazinyl dibenzo[b,fj[l,4] thiazepine with a reduced level of the dialkylated impurity.

9. A process for obtaining 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,fj[l,4]thiazepine hemi-fumarate comprising adding a warm solution of fumaric acid to a warm solution of 1 l-(4-[2-(2-hydroxyethoxy)- ethyl]-piperazinyl)-dibenzo[b,fj[l,4]thiazepine to form a first mixture and maintaining the first mixture at a temperature of about 75 to 85 ⁰C for at least one hour for crystal formation to occur, cooling the first mixture to a temperature of less than about 15 ⁰C and holding the first mixture at the temperature of less than about 15 ⁰C for at least about 1 hour and then recovering ll-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)dibenzo[b,f][l,4]- thiazepine hemi-fumarate solids from the first mixture.

10. The process of claim 9 wherein the warm solution of fumaric acid is a warm isopropyl alcohol solution.

11. The process of claim 10 wherein the warm solution of 11 -(4-[2-(2-hydroxy- ethoxy)-ethyl]-piperazinyl)-dibenzo[b,fj[l,4]thiazepine is a warm M-butanol and isopropyl alcohol solution.

12. A process for obtaining 1 l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,fj[l,4]thiazepine hemi-fumarate of enriched purity comprising dissolving an impure l l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,fj[l,4]thiazepine hemi-fumarate in a polar solvent at an elevated temperature of about 85 to 95 ⁰C to form a solution, cooling the solution to a second temperature of about 55 to 60 ⁰C and holding at the second temperature for at least 2 hours for crystal formation to occur, further cooling the solution mixture to a temperature of less than about 15 ⁰C, holding at the temperature of less than about 15 ⁰C for at least about 1 hour and then recovering l l-(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)-dibenzo[b,fJ[l,4]- thiazepine hemi-fumarate solids of enriched purity from the solution.

13. The process of claim 12 wherein the polar solvent is water.

14. The process of claim 13 wherein the 1 l-(4-[2-(2-hydroxyethoxy)ethyl]- piperazinyl)-dibenzo[b,fj[l,4]thiazepine hemi-fumarate solids of enriched purity are dissolved in a polar solvent, contacted with an absorbent and then recovered by crystallization from the polar solvent.

15. The process of claim 14 wherein the polar solvent is selected from the group consisting of isopropyl alcohol, water, methanol, ethanol and «-butanol.

16. The process of claim 14 wherein the polar solvent is isopropyl alcohol.

17. A process for making 11 -(4-[2-(2-hydroxyethoxy)ethyl]-piperazinyl)- dibenzo[b,f][l,4]thiazepine or a pharmaceutically acceptable salt thereof comprising (1) dissolving dibenzo[b,fj[l,4]thiazepine-l l(10H)one in an aromatic solvent and contacting dissolved dibenzo[b,f][l,4]thiazepine-

11 (10H)one with phosphorous oxychloride, in the presence of a trialkylamine, to produce l l-chloro-dibenzo[b,fj[l,4]thiazepine; (2) alkylating the 11- chloro-dibenzo[b,fj[l,4]thiazepine in an aromatic solvent with a molar excess of anhydrous piperazine under reflux conditions to produce 11- piρerazinyldibenzo[b,fj[l,4]thiazepine; (3) purifying the 11- piperazinyldibenzo[b,f][l,4]thiazepine from a solution in an aromatic solvent containing excess piperazine by contacting the solution with a mixture of water and methyl fert-butyl ether; (4) adding an aqueous acid to a solution of 1 l-piperazmyl-dibenzo[b,f][l,4]thiazepine in an aromatic solvent containing a dialkylated impurity and recovering a water soluble salt of 11-piperazinyl dibenzo[b,fj[l,4] thiazepine with a reduced level of the dialkylated impurity; and (5) converting the water soluble salt of 11-piperazinyl dibenzo[b,fj[l,4] thiazepine to free 11-piperazinyl dibenzo[b,fj[l,4] thiazepine, and (6) alkylating ll-piperazinyl-dibenzo[b,f][l,4]thiazepine with 2-(2- chloroethoxy)ethanol in a solvent in the presence of a base and an activator.

18. The method of claim 17 wherein the activator is sodium iodide.

19. The method of claim 18 wherein the base is potassium carbonate.