FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section l0 and rule 13]
1. Title of the invention: "Novel process for the preparation of Quetiapine Hemifumarate"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

20 NOV 2008

NOVEL PROCESS FOR THE PREPARATION OF QUETIAP1NE
HEMIFUMARATE
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of quetiapine hemifumarate of structural formula I. The process comprising the steps of a) condensing silyl protecting dibenzo[b ,f [l:4]thiazepine of structural formula VII with piperazine to give a condensed product I l-piperizinyldibenzo[b,ƒ] [1, 4]thiazepine of structural formula VIII; b) reacting ll-piperizinyldibenzo[6,f] [1, 4]thiazepine of structural formula VIII with 2-(2-chloroethoxy)ethanol of structural formula IX to afford quetiapine of structural formula IV and c) optionally converting quetiapine of structural formula IV into quetiapine hemifumarate of structural formula I.
BACKGROUND OF THE INVENTION
Quetiapine hemifumarate is chemically 2-[2-(4-dibenzo [b,f ] [1, 4] thiazepin-11-yl-l-piperazinyl) ethoxy]-ethanol fumarate (2:1) (salt) and is represented by structural formula I.

Formula I

The Proprietary name of quetiapine hemifumarate is seroquel. Seroquel is an atypical antipsychotic agent indicated for bipolar disorder including bipolar depression, bipolar mania, bipolar maintenance and schizophrenia.
Quetiapine hemifumarate and a process for its preparation are disclosed in U.S. Patent. No. 4,879,288. The process disclosed therein involves condensation of imino chloride of structural formula II with l-(2-hydroxyethoxy) ethylpiperazine of structural formula III in xylene at reflux temperature for 30 hours to get quetiapine of structural formula IV. This process is not suitable at commercial level production as it involves the use of imino chloride of structural formula II, which is highly unstable and leads to the formation of several impurities, which are being removed by the commercially non feasible and tedious processes like flash chromatography.


U.S. Patent. No. 7,071,331 describes a process for the preparation of quetiapine comprising the step of reacting 11 -piperazinyl dibenzo [b, f]-[l, 4] thiazepine hydrochloride and 2-(2-chloroethoxy) ethanol in a solvent in the presence of a base and a phase transfer catalyst.
U.S. Patent Publication No. 2005/0080072 describes a process for the preparation of quetiapine comprising cycling the compound of structural formula V using cyclising agent in the presence of a solvent to produce compound of structural formula VI, and deprotecting the compound of structural formula VI using basic reagent in the presence of solvent to produce quetiapine of structural formula IV.

Where R is alcohol protecting group such as acyl, alkyl, trityl or benzyl.

U.S. Patent Publication No. 2006/0063927 describes a process for the preparation of quetiapine comprising reacting 11-chloro-dibenzo [b,ƒ]-[ 1,4] thiazepine of structural formula II with 1-(2-hydroxyethoxy) ethylpiperazine of structural formula III, or its salt, in the presence of inorganic or organic base in an organic solvent or in a two-phase solvent system.
U.S. Patent Publication No. 2006/0276641 describes a process for the preparation of quetiapine comprising the steps of: combining 11-chloro-dibenzo [b,ƒ]-[l,4] thiazepine of structural formula II, about 1 to about 1.5 molar equivalents with respect to l-(2-hydroxyethoxy) ethylpiperazine of structural formula III, a base, and a halide that is either an alkali metal halide or a silylhalide in a reaction solvent to obtain a reaction mixture, and heating the reaction mixture at a reaction temperature from about room temperature to reflux temperature for a reaction time.
The processes hitherto reported for the preparation of quetiapine hemifumarate involve high temperature of reaction, long reaction hours and chromatographic purifications, which all are not advisable at commercial scale production of quetiapine hemifumarate.
Accordingly, there is a need to develop an alternate process for preparing quetiapine hemifumarate at industrial large scale production.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to develop an alternate process for preparing quetiapine hemifumarate at industrial large scale production.
A second aspect of the present invention to develop a process for preparing quetiapine hemifumarate, which overcomes the shortcomings of prior-art methods.
A third aspect of the present invention is to develop an alternate process for preparing quetiapine hemifumarate which avoids the use of chromatographic purification step.
A fourth aspect of the present invention to develop a process for preparing quetiapine hemifumarate of formula I comprising the steps of:
a. condensing silyl protecting dibenzo[bƒ][l,4]thiazepine of structural formula VII with piperazine to give a condensed product 11 -piperizinyldibenzo[b,ƒ] [l,4]thiazepine of structural formula VIII.

Where R is trimethylsilyl, dimethylhexylsilyl, t-butyl dimethyl silyl, or t-butyldiphenylsilyl.

b. reacting 1 l-piperizinyldibenzo[b,ƒ] [l,4]thiazepine of structural formula VIII
with 2-(2-chloroethoxy)ethanol of structural formula IX to afford quetiapine of
structural formula IV and

c. optionally converting quetiapine of structural formula IV into quetiapine
hemifumarate of structural formula I.


DETAILED DESCRIPTION OF THE INVENTION
Silyl protecting dibenzo [b, ƒ] [1, 4] thiazepine of structural formula VII may be prepared by reacting dibenzo [b,ƒ] [1, 4] thiazepin-11(10H) one of structural formula X with silylating agent.

Where R is trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl.
Dibenzo [b,f] [1,4] thiazepin-11(10H) one of structural formula X may be prepared by any of the methods known in the art including those described in J.Schmutz et al. Helv.Chim. Acta., 48: 336 (1965); J. Med.Chem. 44, 372-389, 2001, and U.S. Patent Nos. 4,879,288 or 7,214,793, which are incorporated herein by reference only.
The silylating agent may be selected from the group comprising of hexamethyldisilazne, chlorotrimethylsilane, tert-butyldiphenylsilyl chloride or tert-butyldimethylsilyl chloride
The silylation of dibenzo [b,ƒ] [1, 4] thiazepin-11(10H) one of structural formula X may be carried out in the presence of organic acid.

Examples of organic acid include benzenesulfonic acid or p-toluenesulfonic acid monohydrate.
The silylation of dibenzo [b,ƒ] [1,4] thiazepin-ll(l0H) one of structural formula X may be carried out at a temperature in the range of 50°C to 130°C for 30 minutes to 10 hours.
The condensation of silyl protecting dibenzo [b,ƒ] [1, 4] thiazepine of structural formula VII with piperazine may be carried out at a temperature in the range of 50°C to 130°C for 30 minutes to 40 hours to afford condensed product 11-piperizinyldibenzo[b,ƒ] [1,4]thiazepine of structural formula VIII.
The condensed product 11-piperizinyibenzo [b,ƒ] [1, 4} thiazepine of structural formula VIII may be isolated by extraction with chlorinated solvents.
Examples of chlorinated solvents include dichloromethane or chloroform.
The condensed product ll-piperizinyldibenzo [b, f] [1, 4] thiazepine of structural formula VIII may be reacted with 2-(2-chloroethoxy) ethanol of structural formula IX in the presence of inorganic base in polar solvents to afford quetiapine of structural formula IV.
Examples of inorganic base include sodium carbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.
Examples of polar solvents include alcoholic solvents, dimethyl formamide, dimethyl sulphoxide, N-methylpyrrolidine or mixture(s) thereof.

Examples of alcoholic solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
The condensed product 11-piperizinyldibenzo [b, ƒ] [1, 4] thiazepine of structural formula VIII may be reacted with 2-(2-chloroethoxy) ethanol of structural formula IX in the presence of catalytic amount of sodium iodide to afford quetiapine of structural formula IV.
The 11-piperizinyldibenzo [b,ƒ] [1, 4] thiazepine of structural formula VIII may be reacted with 2-(2-chloroethoxy) ethanol of structural formula IX at a temperature in the range of 60°C to 130°C for 2 hours to 50 hours to afford quetiapine of structural formula IV.
The quetiapine of structural formula IV may be converted into quetiapine hemifumarate of structural formula I by any of the methods known in the art including those described in U.S. Patent Nos. 4,879,288; 7,238,686 or 7,071,331, which are incorporated herein by reference only.
The quetiapine of structural formula IV may be converted into quetiapine hemifumarate of structural formula I by reacting quetiapine of formula IV with fumaric acid in methanol solvent.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLE 1: PREPRATION OF QUETIAPINE HEMIFUMARATE
STEP-1: PREPARATION OF 11-PIPERIZINYLDIBENZO [b, ƒ] [1, 4] THIAZEPINE OF STRUCTURAL FORMULA VIII.
A suspension of dibenzo[b, ƒ][l,4] thiazepin-ll(10H)one of structural formula X (50 gm, 0.22 moles), in hexamethyldisilazane (HMDS, 213.3 g, 1.32 moles ), in presence of catalytic amount of p-toluenesulfonic acid monohydrate (PTSA, 8.3 gm, 0.043 moles) was heated up to 125-130°C and then refluxed for 3 hours with simultaneous distillation of hexamethyldisiloxane (HMDSO). The resulting clear solution was cooled to 100-110° C, piperazine (57 gm, 0.66 moles) was added and resulting reaction mixture was further refluxed at 125-130°C for 30 hours. The resulting reaction mixture was concentrated under reduced pressure to afford residue. The residue was dissolved in methylene chloride (200 ml) and washed with DM water (300ml) and then it was treated with IN aqueous hydrochloric acid (100 ml). The aqueous layer containing reaction product was neutralized with aqueous sodium carbonate solution to obtain a pH of 7.5-8 and then reaction product was back extracted with methylene chloride (250 ml) and its subsequent solvent distillation afforded 11-piperizinyldibenzo [b, ƒ] [1, 4] thiazepine. Yield: 43.4 gm
STEP-2: PREPARATION OF QUETIAPINE OF STRUCTURAL FORMULA IV
ll-Piperizinyldibenzo[b, ƒ] [l,4]thiazepine of structural formula VIII (47 gm, 0.16 moles), sodium carbonate (70 gm, 0.66 moles), 2-(2-chloroethoxy)ethanol (23.8 gm, 0.19 moles) and sodium iodide (0.95 gm, 0.006 moles were refluxed in a solvent mixture containing N-methylpyrrolidine (NMP, 95 ml) and n-propanol (700 ml) at 90-95°C for 48 hours. The resulting reaction mixture was extracted with ethyl acetate (400

ml), washed with DM water (300 ml) and concentrated under reduced pressure to afford quetiapine of structural formula IV. Yield: 61 gm
STEP-3: PREPARATION OF QUETIAPINE HEMIFUMARATE OF STRUCTURAL FORMULA I
Fumaric acid (7.4 gm, 0.063 moles) was added into a solution of quetiapine (61 gm) in methanol (732 ml) and resulting reaction mixture water heated to obtain a clear solution. The clear solution was cooled up to 5°C and resulting solids were filtered and dried to afford quetiapine hemifumarate of structural formula I-Yield: 49 gm

WE CLAIM
1. A process for preparing quetiapine hemifumarate of formula I comprising the
steps of:
a. condensing silyl protecting dibenzo[b, ƒ][1,4]thiazepine of structural formula
VII with piperazine to give a condensed product ll-piperizinyldibenzo[b, ƒ]
[1,4] thiazepine of structural formula VIII;

Where R is trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, or t-butyldiphenylsilyl.
b. reacting 1 l-piperizinyldibenzo[b, ƒ] [l,4]thiazepine of structural formula VIII
with 2-(2-chloroethoxy)ethanol of structural formula IX to afford quetiapine
of structural formula IV and


c. optionally converting quetiapine of structural formula IV into quetiapine hemifumarate of structural formula I.

2. The process according to claim 1, wherein condensed product 11-
piperizinyldibenzo [b, ƒ] [1, 4] thiazepine of structural formula VIII is
reacted with 2-(2-chloroethoxy) ethanol of structural formula IX in the
presence of inorganic base in polar solvents to afford quetiapine of
structural formula IV,
3. The process according to claim 1, wherein condensed product 11-
piperizinyldibenzo [b, ƒ] [1, 4] thiazepine of structural formula VIII is
reacted with 2-(2-chloroethoxy) ethanol of structural formula IX in the
presence of catalytic amount of sodium iodide to afford quetiapine of
structural formula IV.
4. The process according to claim 2, wherein inorganic base is selected from
the group comprising of sodium carbonate, potassium carbonate, sodium
hydroxide or potassium hydroxide.

5. The process according to claim 2, wherein polar solvents is selected from the group comprising of alcoholic solvents, dimethyl formamide, dimethyl sulphoxide, N-methylpyrrolidine or mixture(s) thereof.
6. The process according to claim 5, wherein alcoholic solvents is selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
7. The process according to claim 1, wherein condensed product 11-piperizinyldibenzo [b, ƒ] [1, 4] thiazepine of structural formula VIII is reacted with 2-(2-chloroethoxy) ethanol of structural formula IX at a temperature in the range of 60°C to 130° to afford quetiapine of structural formula IV.
8. The process according to claim 1, wherein condensed product 11-piperizinyldibenzo [b, ƒ] [1, 4] thiazepine of structural formula VIII is reacted with 2-(2-chloroethoxy) ethanol of structural formula IX for 2 hours to 50 hours to afford quetiapine of structural formula IV.
9. The process according to claim 1, wherein quetiapine of formula IV is converted into quetiapine hemifumarate of formula I by reacting quetiapine of formula IV with fumaric acid in methanol solvent.
10. A process for preparing quetiapine hemifumarate of formula I as herein described in specification and example.

Dated this 10th day of November, 2009
Signature: Name: Dr. Rajendra Agarwal