Form 2 THE PATENTS ACT, 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See section 10 and rule 13]
1. TITLE OF THE INVENTION
"An improved process for the preparation of 2-[2-(4-Dibenzo[b,f][l,4] thiazepin-ll-yl-l-piperazinyl)ethoxy] ethanol fumarate"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the Companies ACT, 1956
(c) ADDRESS: B.S.D. Marg, Station Road Govandi, Mumbai 400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
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 2-[2-(4-Dibenzo[b,f][l,4]
thiazepin-ll-yl-l-piperazinyl)ethoxy] ethanol fumarate
Technical Field of Invention:
The present invention relates to an improved process for the preparation of 2-[2-(4-Dibenzo[b,f][l,4] thiazepin-ll-yl-l-piperazinyl)ethoxy] ethanol hemifumarate (Quetiapine hemifumarate) of Formula I.

Background & Prior Art:
Quetiapine fumarate is described in US 4879288 as being useful in treating psychosis and hyperactivity. Several approaches have been described in the literature to make Quetiapine hemifumarate. Broadly, they fall in two categories:
1. The first approach, uses Dibenzo[b,f][l,4] thiazepin-1 l-[10H]one as an intermediate to which the side chain is then attached
2. More recently many patents have described cyclization of urea or amide intermediate to build the thiazepine moiety
US 4879288 (EP 0240228), EP 0282236 and WO 2005014590 describe preparation of Quetiapine hemifumarate starting from Dibenzo[b,f][l,4] thiazepin-1 l-[10H]one
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whereas PCT applications WO 0155125, WO 005012274, WO 2005028458 and WO 2005028459 describe the latter approach.
Two routes have been disclosed in EP 0240228, In the first convergent route Dibenzo[b,f][l,4] thiazepin-1 l-[10H]one is reacted with phosphorus oxychloride in the presence of a N,N-dimethyl aniline to isolate imino chloride which is then condensed with l-(2-hydroxyethoxy) ethyl piperazine to get ll-(4-[2-(2- hydroxyethoxy) ethyl]-1-piperazine dibenzo[b,f][l,4] thiazepine (Scheme 1). The piperazine base is then converted to its corresponding hemifumarate salt (Quetiapine hemifumarate).
Scheme 1

In the second linear route Dibenzo[b,f][l,4] thiazepin-1 l-[10H]one is reacted with
phosphorus oxychloride in the presence of a N,N-dimethyl aniline to isolate imino
chloride which is then condensed with piperazine followed by side chain attachment
to give the Quetiapine hemifumarate (Scheme 2).
The overall yield reported for Quetiapine hemifumarate through linear route is about
72.54%.
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Scheme 2

EP 0282236 describes an improved process, which overcomes the need to use carboxyethyl-1-piperazine. The yield reported is 78%.
WO 0155125 discloses that the cyclization of N-[4-(2-chloroethyl) piperazine-1-carbonyl]-2-aminodiphenyl sulfide afforded ll-[4-(2-chloroethyl) piperazinyl]-dibenzo[b,f]-l,4-thiazepine. The chloro derivative is further condensed with ethylene glycol to get the corresponding Quetiapine base, which is converted to its corresponding hemifumarate salt (Scheme 3). The overall yield reported for Quetiapine hemifumarate is 56.9 %.
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Scheme 3

It is disclosed in WO 2005012274, that reaction of phenyl carbamate derivative with piperazine afforded urea derivative which then cyclized with POCI3/P2O5 to afford 11-(l0-piperazinyl)-dibenzo [b,f][l,4]thiazepine (Scheme 4) which is the key intermediate of Quetiapine hemifumarte. The overall yield, for ll-(10-piperazinyl)-dibenzo [b,f][l,4] thiazepine is 65%.
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Scheme 4

-K, ^N.

WO 2005014590 describes the reaction of 2-(4-dibenzo[b,f][l,4] thiazepine-11-yl-piperazine-1-yl) ethanol with 2-(2-chloroethoxy)-tetrahydro-2H-pyran in presence of aqueous alkaline solution and phase transfer catalsyt to afford Quetiapine base (Scheme 5).

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Scheme 5

PCT application WO 2005028457 describes the condensation of 2-[(2-benzyloxy-ethoxy) ethyl ]bis(2-chloroethyl)-amine with Dibenzo[b,f][l,4] thiazepin-11-yl amine, afforded 1 l-{4-[2-(2-benzyloxy-ethoxy)ethyl]-piperazin-l-yl} dibenzo[b,f]-l,4-thiazepine. The benzyloxy derivative on deprotection with borontrichloride gave Quetiapine base. Tetrahydropyran has also been used as -OH protective group (Scheme 6). The overall yield reported is 14.55 %.
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Scheme 6

WO 2005028458 discloses that the acetylation of 2-(2-amino-phenylsulfanyl)-phenyl-{4-[2-(2-hydroxy-ethoxy)ethyl-piperazin-l-yl}-methanone followed by the cyclization afforded ll-[4-[2-(2-acetyloxy ethoxy) ethyl]-l-piperazinyl)-dibenzo[b,f]-1,4-thiazepine. On deprotection the corresponding Quetiapine base was obtained (Scheme 7). The overall yield reported for Quetiapine base is 61.74 %.
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Scheme 7

WO 2005028459, describes a process wherein the cyclization of O-benzoyl protected phenylsulfanyl-piperazine derivative afforded O-benzoyl protected quetiapine base, which on deprotection afforded the corresponding Quetiapine base (Scheme 8). The overall yield reported is 32.39 %.
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Scheme 8

The process described in WO 9906381 is a process to obtain highly pure Quetiapine fumarate. The patent relates to improved purification method for obtaining greater than 90%, preferably greater than 99% pure Quetiapine fumarate.
It is disclosed in WO 2003080065 that Quetiapine hemifumarate forms solvates with Chloroform and Dichloromethane (Form II and Form III). It also discloses a process
for preparation of Form I involving two purifications of the crude Quetiapine hemifumarate.
Major drawbacks of the prior art processes are,
a. Use of large excess phosphorus oxychloride (w/v 1:6) for the chlorination
which causes recovery and disposal problems and is uneconomical;
b. Isolation of unstable Imino chloride derivative;
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c. Use of protecting group, which leads increase in number of steps;
d. Employ industrially unviable operations like column purification;
e. Employ commercially unviable steps like multiple purification.
Objects of the Invention
The primary object of the present invention is to provide an economical, commercially viable industrial process to make Quetiapine hemifumarate.
Another object of the present invention is to provide a process, which uses commercially and readily available starting materials.
A further object of the present invention is to provide a process, which obviates the drawbacks of the prior art processes.
Another object of present invention is to provide highly pure Quetiapine hemifumarate in a single purification step.
Another object of present invention is to provide a process, affording Quetiapine in high overall yield.
Summary of the Invention
The present invention comprises reacting Dibenzo[b,f][l,4] thiazepin-ll-[10H]one with a halogenating agent in an organic solvent in presence of an organic base to form imino chloride derivative. The unreacted halogenating agent and salts are removed from the organic layer. The iminochloride is then reacted with piperazine in situ. The
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resultant ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride is isolated from lower aliphatic alcohol and lower aliphatic alcoholic hydrogen chloride solution. 2-Chloro ethoxy ethanol is then condensed with 1 l-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride in a mixed solvent to afford Quetiapine base, which is then converted to Quetiapine hemifumarate in ethanol. Purification is achieved using methanol.
Detailed Description
The present invention relates to an improved process for preparation of Quetiapine hemifumarate of Formula I. The process comprises,
a. Reacting Dibenzo[b,f][l,4] thiazepin-1 l-[10H]one II with a halogenating agent
in an organic solvent in presence of an organic base to form imino chloride
derivative III (Scheme I);
Removing unreacted halogenating agent and salts from the organic layer; Reacting the imino chloride derivative III in situ with piperazine; Isolating ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride IV from lower aliphatic alcohol and lower aliphatic alcoholic hydrogen chloride solution.(Scheme I);
b. Condensing 2-chloro ethoxy ethanol with ll-piperazinyl-dibenzo[b,f][l,4]
thiazepine dihydrochloride in a mixed solvent to afford Quetiapine, base which
is then converted to Quetiapine hemifumarate in ethanol;
c. Purifying Quetiapine hemifumarate from a lower aliphatic alcohol.
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Scheme I

According to this method the overall yield of Quetiapine hemifumarate pure is 76.95%.
In another embodiment of the present invention the organic solvent used in the reaction (Stage I) may be an aromatic hydrocarbon, such as toluene, xylene, chloro benzene, nitro benzene and the like or different combinations of the said solvents.
In another embodiment of the present invention the imino chloride III is not isolated.
In another embodiment of the present invention ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride IV is isolated from alcohol and alcoholic HC1.
Halogenating agents like thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxybromide and phosphorus oxychloride may be used.
In another embodiment of the present invention halogenation is carried out at temperature ranging from 30 to 140° C, preferably 110° C.
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The weight-volume ratio of Dibenzo[b,f][l,4] thiazepin-ll-[10H]one II and phosphorus oxychloride is 1:0.5 to 3.0, preferably 1:2.5
In another embodiment of the present invention the mixed solvent used in the condensation (Stage II) may be a mixture of dipolar aprotic solvent and lower aliphatic alcohol. The dipolar aprotic solvent is preferably DMF and the lower aliphatic alcohol is preferably n-propanol.
In another embodiment of the present invention the organic solvent used in the purification of Quetiapine crude (Stage III) is an alcoholic solvent such as methanol, ethanol, isopropyl alcohol or mixtures thereof, preferably methanol.
The weight-volume ratio of Quetiapine crude and alcoholic solvent is 1:10 to 15, preferably 1:12.
Thus, the use of less quantity of chlorinating agent in the present process makes it more convenient and eco-friendly by eliminating any need for recovery and disposal of large excess of chlorinating agent.
The unstable imino chloride derivative III is not isolated in the present process and thus makes it economical and suitable for industrial production by reducing time cycle and eliminating any need for isolation and special drying of the unstable intermediate.
Purification of the crude Quetiapine hemifumarate with single crystallization from methanol in the present process makes it commercially viable by minimizing the yield loss due to multiple purification steps.
The product thus obtained has a high purity of > 99.8%.
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The process of the present invention is described herein below with reference to the following example, which are illustrative only and should not be construed to limit the scope of the present invention in any manner.
Examples:
Example 1
11-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride IV

Dibenzo[b,f][l,4] thiazepin-ll-[10H]one 100 gm, phosphorus oxychloride 125 ml, N,N-dimethyl aniline 33 ml in toluene 500 ml were refluxed for 4 h. Solvent distilled off under vacuum. Residue dissolved in 250 ml toluene and cooled to 10 C. Aqueous Potassium carbonate solution (100 g in 200 ml water) was added to the toluene layer below 15°C. The toluene layer separated and refluxed with piperazine 100 g for 24 h. Reaction mixture cooled and filtered to remove unreacted piperazine. Toluene was distilled off under vacuum. The residue was dissolved in isopropyl alcohol. Ethanolic HCl (33%), 100 ml was added to the reaction mixture at 25-35°C. White solid obtained was filtered, washed with 100 ml ethanol and dried at 60-70 C. Yield 138 g (90%).
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Example 2
2-[2-(4-Dibenzo[b,f] [ 1,4] thiazepin-11 -yl-1 -piperazinyl )ethoxy] ethanol
hemifumarate (Quetiapine hemifumarate Crude) I

ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride 138 gm, chloroethoxy ethanol 92.7 gm, Sodium carbonate 238 gm, Sodium iodide 2.83 gm, DMF 391 ml and n-propanol 552 ml were refluxed for 24 h. After the completion of the reaction, the reaction mixture was filtered off to remove the insolubles present. The filtrate was taken for distillation. Solvents were distilled off. The residue was dissolved in 2.31. MDC, the MDC layer was washed with 2.751 water. The MDC was then distilled off and the oily residue was dissolved in Ethanol 225 ml. To the resulting solution ethanolic solution of fumaric acid 22.9 gm dissolved in ethanol 312 ml was added slowly with stirring. The reaction mixture was cooled to 10-20 C. The solid obtained was filtered and dried at 60-70°C. Yield 149 g (95 %) mp 172-76°C.
Example 3
2-[2-(4-Dibenzo[b,f][l,4] thiazepin-ll-yl-l-piperazinyl)ethoxy] ethanol
hemifumarate (Quetiapine hemifumarate Pure)
2-[2-(4-Dibenzo[b,f][l,4]thiazepin-ll-yl-l-piperazinyl)ethoxy]ethanol hemifumarate (crude) 149 gm and methanol 1490 ml were refluxed for 1 h. Filtered hot and the filtrate gradually cooled to 10-15° C. Solid obtained was filtered and washed with cooled methanol (2x300ml) and dried at 60-70°C.
Yield 134 g (90 %) Percentage Purity 98.8%
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We Claim
1. A process for making Quetiapine hemifumarate (I) comprising,

a. reacting Dibenzo[b,f][l,4] thiazepin-ll-[10H]one II with halogenating agent in an organic solvent in presence of an organic base, removing unreacted halogenating agent and salts, reacting with piperazine in situ and isolating 11-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride IV;

b. condensing chloro ethoxy ethanol with ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride in a solvent mixture, isolating Quetiapine hemifumarate I;
c. purifying Quetiapine hemifumarate from methanol.
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2. The process as claimed in claim 1, wherein halogenating agent is selected from thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxybromide or phosphorus oxychloride preferably phosphorus oxychloride.
3. The process as claimed in claim 1, wherein the organic solvent used in the reaction is selected from aromatic hydrocarbon including toluene, xylene, chloro benzene, nitro benzene or mixtures thereof preferably toluene.
4. The process as claimed in claim 1, wherein the organic base is selected from N,N-dimethyl aniline, N,N-diethyl aniline or triethylamine preferably N,N-dimethyl aniline.
5. The process as claimed in claim 1, wherein the halogenation is carried out at temperature between 30°C to 140°C preferably about 110°C.
6. The process as claimed in 1, wherein the weight / volume ratio of the Dibenzo[b,f][l,4] thiazepin-ll-[10H]one II and halogenating agent is 1:0.5 to 3.0.
7. The process as claimed in 6, wherein the ratio of the Dibenzo[b,f][l,4] thiazepin-ll-[10H]one II and halogenating agent is 1:1.25.
8. The process as claimed in 1, wherein the halogenation is carried out between 2.0 h to 5.0 h.
9. The process as claimed in 1, wherein the condensation of the imino chloride derivative III in situ with piperazine is carried out in organic solvent.
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10. The process as claimed in 9, wherein organic solvent is selected from aromatic
hydrocarbon including toluene, xylene, chloro benzene, nitro benzene or
mixtures thereof.
11. The process as claimed in claims 9 and 10, wherein the aromatic hydrocarbon is toluene.
12. The process as claimed in claim 1, wherein the condensation is carried out at temperature between 30 C and 140 C, preferably about 110°C.
13. The process as claimed in claim 1, wherein the condensation is carried out between 10 h to 30 h preferably 24 h.
14. The process as claimed in 1, wherein ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride IV is isolated from lower aliphatic alcohol and lower aliphatic alcoholic solution containing hydrogen chloride.
15. The process as claimed in claim 14, wherein the lower aliphatic alcohol is isopropanol and the lower aliphatic alcoholic solution containing hydrogen chloride is ethanolic HC1.
16. The process as claimed in claim 1, wherein the solvent mixture is selected from dipolar aprotic solvent or lower aliphatic alcohol.
17. The process as claimed in claim 16, wherein the dipolar aprotic solvent is DMF and the lower aliphatic alcohol is n-propanol.
18. The process as claimed in claim 1, wherein the purification is carried out at temperature 45°C to 90°C preferably at about 60°C -65°C.
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19. The process as claimed in claim 1, wherein ratio of the Quetiapine
hemifumarate and the alcohol is 1:5 to 15 preferably 1:10.
20. The process as claimed in claim 1, wherein the precipitation of Quetiapine hemifumarate is carried out between 0°C to 30°C preferably at about 10 C to 15°C.
Dated this the 4th day of July, 2005

Dr K G Rajendran
Head-Knowledge Cell
USV Limited
Applicant
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Abstract:
The present invention relates to an improved process for the preparation of 2-[2-(4-Dibenzo[b,f][l,4] thiazepin-ll-yl-l-piperazinyl)ethoxy] ethanol hemifumarate
(Quetiapine hemifumarate).
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