FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
AN IMPROVED PROCESS FOR THE PREPARATION OF QUETIAPINE AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF.
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, S. V. ROAD, JOGESHWARI (W), MUMBAI 400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.
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AN IMPROVED PROCESS FOR THE PREPARATION OF QUETIAPINE AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
TECHNICAL FIELD
The present invention relates to an improved and industrially favorable process for the preparation of 1 l-[4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl]dibenzo[b,f][l,4]thiazepine (Quetiapine) and its fumarate salt.
BACKGROUND OF THE INVENTION
Quetiapine of Formula I is a novel psychotropic agent belonging to the chemical class of dibenzothiazepine derivatives that acts as an antagonist for multiple neurotransmitter receptor in the brain and is useful in treating mental disorders, psychosis, schizophrenia.
O^X^-OH

(I)
Several approaches are described in the literature for the synthesis of Quetiapine and its pharmaceutically active hemifumarate salt.
Quetiapine and its preparation is disclosed in US4879288 (Warawa et al, 1989). More specifically, this patent discloses a process for preparing Quetiapine by converting dibenzo[b,f][l,4] thiazepine-11-(10H)-one, formula II, to ll-chloro-dibenzo[b,f][l,4]-thiazepine, formula III, by using excess of phosphorous oxychloride, followed by treating
2

the obtained 11-chloro-dibenzo[b,f][l,4]-thiazepine dissolved in xylene with an excess of l-(2-hydroxyethoxy)ethylpiperazine, to yield the crude quetiapine free base as a viscous amber-colored oil, which is converted to quetiapine hemi-fumarate. The oily crude product is purified by column chromatography to yield pure quetiapine free base. The free base product is converted to its hemi-fumarate salt by reacting it with fumaric acid in ethanol.
This process of preparing quetiapine in '288 involves the use of large excess of phosphorous oxychloride which is hazardous at industrial scale. Also '288 involves column chromatography as an essential purification step for obtaining quetiapine as a pure free base, which is a complicated, expensive, inconvenient and environmentally unfriendly technique.
EP 0282236 Al (Barker et al, 1991), describes a process in which 11-chloro-dibenzo[b,f][l,4] thiazepine of formula III was obtained by chlorination of Dibenzo[b,f][l,4]thiazepine-11-[10H]-one of formula II with excess of phosphorous oxychloride and N,N-dimethyl aniline as a base. The chloro derivative thus obtained was first condensed with piperazine followed by alkylation with 2-(2-chloroethoxy) ethanol to obtain Quetiapine free base.
A major disadvantage of both the above processes is excessive use of POCl3 as a chlorinating agent and use of N,N-dimethyl aniline which is very toxic and hazardous in nature and also creates environmental problems.
WO 2006/117700 A2 (Bosch L J, et al) discloses a process wherein the chlorination of Dibenzo[b,f][l,4] thiazepine-ll-[10H]-one of formula II was done with slight molar excess of POCl3 in xylene and triethylamine was used as a base. But addition of triethylamine causes exothermic reaction and generates a dense fumes which creates problems in large scale operation.
WO 2004/076431 Al (Diller D, et al) describes a process of N-alkylation of 11-piperazinyl-dibenzo[b,f][l,4] thiazepine, with slight excess of 2-(2-chloroethoxy)ethanol,
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n-butanol as a solvent in presence of Na2CO3, PTC and Nal. It takes 24 hours of refluxing to complete the reaction. Also the fumarate salt formed in the subsequent stage needs further crystallization to enhance purity resulting in poor yield.
WO 2006/077602 Al (Kumar, et al) describes a N-alkylation of 11-piperazinyl-dibenzo[b,f][l,4] thiazepine in water as a solvent, and in presence of Na2CO3, NaI and a optionally PTC was used in reaction medium. The '602 highlights the use of water as a solvent medium with to reduce the reaction time but still the reported yields are on lower side.
Therefore there exist a need in order to improve the efficiency of the process which eliminates the disadvantages of the prior art reported process for the synthesis of Quitiapine in shorter reaction time with high yield and purity
OBJECT OF THE INVENTION
The object of the invention is to provide an improved and environment friendly process for the synthesis of Quetiapine of formula (I) and its hemifumarate salt
Another object of the present invention is to avoid the use of hazardous reagents like N,N-dimethyl aniline during the synthesis of Quitiapine
Another object of the invention is to provide an easy to implement and cost effective process for commercial preparation of Quetiapine of formula (I) with good yield and high purity.
SUMMARY OF THE INVENTION
According to the present invention there is provided a process for the preparation of Quetiapine of formula (I) and its hemifumarate salt,
4

^NN

NM'

^
S~\ /
(I)

which comprises
a. Chlorination of Dibenzo- [b,fj[l,4] thiazepine-ll-(10H)-one of formula II with phosphorous oxy chloride in presence of a base and a solvent
H

•V1
N^
us^h

b. Condensation of the resultant intermediate 11-chloro-dibenzo [b,f][l,4]-thiazepine of formula III with piperazine
CI

c. N-alkylation of resultant intermediate of step b of formula IV with 2-(2-chloroethoxy)ethanol in presence of a phase transfer catalyst, base and a solvent
5

N—'
IV x—/ ,
d. Salt formation of free base of formula I with fumaric acid
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved and environment friendly process for synthesis of Quetiapine base by avoiding the use of large excess of phosphorous oxychloride which creates problems in disposal and is hazardous in nature. In the present invention overall reaction times is reduced and the developed a environment friendly process.
In the N-alkylation with 2-(2-chloroethoxy)-ethanol the reaction was completed in 10 hrs
when performed in a biphasic solvent system in presence of a phase transfer catalyst.
According to the present invention the Quetiapine base of the formula I can be
synthesized by the chlorination of Dibenzo[b,f][l,4] thiazepine-11-[10H]-one of formula
II with phosphorous oxychloride in presence of solvent and a base .The quantity of
phosphorous oxychloride used was in the range of 1.0 to 2.5 mole preferably in the range
of 1.20 to 1.50 mole with respect to 1 mole equivalent of Dibenzo[b,f][l,4] thiazepine-
11-[10H]-one .The solvent which can be used for chlorination is from hydrocarbons like
toluene, xylene, chlorinated hydrocarbons like dichloromethane , dichloroethane ,esters
like ethyl acetate or ethers like tetrahydrofuran, preferably in toluene and the various
base which can be used are pyridine or substituted pyridines like lutidine , collidine,
preferably pyridine was used as a base. The reaction can be carried out at 40°C -150°C ,
preferably at 70°C -110°C and most preferably at reflux temperature of the solvent used
for chlorination. After reaction was over the toluene layer was separated and washed
with water and dried The toluene layer containing 11-chloro dibenzo
[b,f][l,4]thiazepine of formula III was taken as such for next step without isolating it.
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The condensation of 11-chloro dibenzo [b,f][l,4]thiazepine of formula III with
piperazine can be done in the same solvent as used for chlorination at the reflux
temperature of the solvent to give 11-piperazinyl dibenzo [b,f][l,4]thiazepine of the
formula IV. The amount of piperazine used is the range of 2-4 mole preferably 2.5 mole
at reflux temp of the solvent used.
After reaction was over the piperazine hydrochloride which was separated out during
reaction filtered and the layer was washed with water . The organic layer was
concentrated to obtain 11-piperazinyl dibenzo [b,f][l,4]thiazepine of the formula IV as a
thick oil.
The oil thus obtained can be treated with hydrogen chloride to obtain a crystalline
dihydrochloride as a 11-Piperazinyl-dibenzo [b,f]l,4] thiazepine dihydrochloride, which
optionally can be used as a starting material for the subsequent step.
The N-alkylation of the 11-piperazinyl dibenzo [b,f][l,4]thiazepine of formula IV was
done by using 2- (2- chloroethoxy) ethanol in solvent system comprising water and n-
butanol in presence of a phase transfer catalyst like tetra butyl ammonium iodide and
base like Na2CO3, K2CO3 preferably Na2CO3 at a temperature 96-100°C preferably at
reflux temperature. After reaction was over the aqueous layer was separated and the
organic layer was washed with water to remove inorganic salts and dried over sodium
sulphate to obtain Quetiapine free base of formula (I). The organic layer containing
Quetiapine free base was taken as such for next step and to this fumaric acid was added
and stirred at room temperature i.e. at 25-30°C. The precipitated Quetiapine
hemifumarate was filtered and dried.
The synthetic mode of the present invention can be illustrated with the following scheme.
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M

H
POCI,
/%S
H.-
KASJ \\Pyridine
\—■/ Toluene

CI N-
//%/^==\ Piperazine ./^/-^
S-IV
NAS^/ \ Toluene k^s.^f^

N-Butanol Water

N-Alkylation
TBAI &Na2C03


Salt formation
Fumaric acic
Quetiapine fumarate

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
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EXAMPLES
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example 1:
11-Chloro-dibenzo [b,f][l,4] thiazepine
25.0 gm of Dibenzo-[b,f][l,4]-thiazepine-ll-(10H)-one (0.11 mole) and 125 ml of dry toluene was charged into dry and nitrogen flushed reaction assembly at 27-30°C. 12.11 ml phosphorus oxychloride (0.13 mole) was added slowly to the reaction mass with stirring and to this 9.7 ml pyridine ( 0.12 mole) was added drop wise at 27°C-30°C. The reaction mass was stirred at refluxing temperature for 4-5 hrs . The reaction was monitored by HPLC. After completion of reaction the reaction mass was cooled and quenched in a mixture of 50 ml toluene and 100 ml ice cold water. The reaction mass was stirred for 15 min and organic layer was separated . The separated organic layer was washed with water (100 ml twice) and finally with 100 ml saturated NaHC03 solution. The separated organic layer was dried over Na2SC«4 and taken as such for condensation with piperazine without isolating the product. The HPLC purity of toluene layer 99.70 % by area.
Example 2:
11-Piperazinyl -dibenzo[b,f][l,4] thiazepine
30.0 gm anhydrous piperazine (0.34 mole) and 60 ml toluene was charged into reaction assembly with stirring at 27°C-30°C and heated to 75°C-80°C to form a clear solution. To the clear solution toluene layer of 11- Chloro-dibenzo [b,f][l,4]- thiazepine obtained from Example 1 was charged and the reaction mass thus obtained was refluxed for 3 hours under stirring. The reaction was monitored by HPLC. After completion of reaction it was cooled to 27°C-30°C and filtered to remove piperazine dihydrochloride, washed the residue with 10 ml toluene. Filtrate and toluene washing were combined together and washed with 3x100 ml water to remove excess piperazine. The separated toluene layers
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was evaporated to dryness to obtained 11-Piperazinyl [b,f][l,4] thiazepine as thick oil (30.0 gm) having purity 99.87 % by HPLC and overall yield is 92.0% .
Example 3:
11-Piperazinyl-dibenzo [b,f][l,4] thiazepine dihydrochloride
The crude oil obtained in Example 2 can be converted into its hydrochloride salt.
30.0 ml cone. Hydrochloric acid was added to the crude oil (30.0 gm) obtained from
example-2 and stirred for 1.0 hr. To the mixture toluene (150 ml) was added and water
was removed azeotropically. After total water was removed , the mass was cooled and
filtered. It was dried in an air oven to get 30.0 gm dry salt. Purity by HPLC = 99.57% and
yield 75.0% (overall yield with respect to Dibenzo-[b,f]l,4]-thiazepine-ll-(10H)-one
used)
Example 4 :
ll-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine
To the solution of 50 gm 1 l-Piperazinyl-dibenzo[b,f][l,4] thiazepine (0.169mole) in 250 ml n- butanol at 27°C-30°C, 200 ml water, 53.89 gm Na2CO3 (0.508mole) and 2.5gm tetrabutyl ammonium iodide was added in a single lot .Then 23.19 gm 2-(2-chloroethoxy) ethanol (0.186mole) was also added slowly at 27°C-30°C with stirring. The reaction mass was heated at reflux temperature for 8 hours and monitored by HPLC. After reaction was over it was cooled to 27°C-30°C, two layers were separated and n-butanol layer was washed with 2 ><150 ml water . The n -butanol layer was dried over Na2SC«4 and carried forward as such for hemifumarate salt formation. Purity of n-butanol layer of Quetiapine free base by HPLC=98.8 %
Example 5 :
ll-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine hemifumarate salt.
250 ml n-butanol layer from Example-4 was charged into reaction assembly and to this
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9.25 gm Fumaric acid ( 0.0797 mole) was charged under stirring at 25°C to 30°C. The reaction mixture thus obtained was stirred at same temperature ,hemifumarate salt precipitated out and it was furtherer stirred for another one hour, filtered and washed with 50 ml n-butanol . The salt thus obtained was dried in an air oven at 120°C to get 60.0 gm hemifumarate salt. The overall % yield with respect to 11-Piperazinyl-dibenzo[b,f][l,4]thiazepine is 80 % and purity 99.70% by HPLC.
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We Claim:
1. A process for the preparation of Quetiapine free base of formula I and its hemifumarate salt

which comprises
a. Chlorination of Dibenzo- [b,f][l,4] thiazepine-ll-(10H)-one of formula II with phosphorous oxy chloride in presence of a base and a solvent
H
i P

b. Condensation of the resultant intermediate 11-chloro-dibenzo [b,f][l,4]-thiazepine of formula III with piperazine
CI
12

c. N-alkylation of resultant intermediate of step b of formula IV with 2-(2-chloroethoxy)ethanol in presence of a phase transfer catalyst and base in biphasic solvent

,H

d. Salt formation of free base of formula I with fumaric acid

2. The process of claim 1 -a) , wherein the phosphorus oxychloride used is in the range of 1.0 to 2.5 molar equivalent, preferably 1.2 molar equivalent.
3. The process of claim 1-a) wherein the base used for chlorination is
pyridine or substituted pyridines like lutidine ,collidine , preferably pyridine in the range 1.0 to 1.5 mole preferably 1.1 molar equivalent to that of Dibenzo-[b,f][l,4]thiazepine-11 (10H)-one.
4. The process of claim l-a) wherein the solvent used was selected from hydrocarbons like toluene ,xylene, chlorinated hydrocarbons like dichloromethane , 1,2- dichloroethane , esters like ethylacetate and ethers like tetrahydrofuran preferably toluene
5. The process of claim 1-a) wherein reaction is carried out at temperature 50°C -150°C preferably at reflux temperature of the solvent used for the reaction.
6. A process of claim 1-b), wherein the piperazine is used in the range of 2.25 to 4.0
mole preferably 2.5 mole at reflux temp of the solvent used.
7. The process of claim 1-c) wherein the phase transfer catalyst used for alkylation is
tetra butyl ammonium iodide in presence of base like Na2CO3, K2CO3 preferably Na2CO3.
8. The process of claim 1-c), wherein solvent used is n- butanol and water at a
temperature range 96-100°C preferably at reflux temperature.
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9. The process of claim 1-d), wherein reaction with fumaric acid is carried out at
room temperature.
10. A process for the preparation of compounds of formula (I) substantially as
herein described and illustrated with reference to the accompanying examples.
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Abstract:
An improved process for the preparation of 11-(4-[2-(2-hydroxyethoxy)ethyl]-l-piperazinyl)-dibenzo[b,f][l,4]thiazepine, known as Quetiapine and its hemifumarate salt, comprising chlorination of Dibenzo[b,f][l,4]thiazepine-11(10H)-one in presence of pyridine or substituted pyridine as a base to give 11-chloro-dibenzo[b,f][l,4]thiazepine which on condensation with piperazine followed by N-alkylation with 2-(2-chloroethoxy)ethanol gives Quetiapine free base which on treatment with fumaric acid gives hemifumarate salt.
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