FORM 2
THE PATENTS ACT 1970
(39 OF 1970)


COMPLETE SPECIFICATION
(SECTION 10)
AN IMPROVED PROCESS FOR THE SYNTHESIS OF DIBENZO[B,F][1,4]THIAZEPINE-11-(10H)-ONE.
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
MAHALAXMI CHAMBERS, 2nd FLOOR,
22, BHULABHAI DESAI ROAD, MUMBAI-400 026.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE SYNTHESIS OF DIBENZO[B,F][1,4]THIAZEPINE-11-(10H)-ONE.
TECHNICAL FIELD
The present invention relates to an improved, environment friendly and economic process for the synthesis of dibenzo[b,f][l,4]thiazepine-ll-(10H)-one of formula (I), a key intermediate for the synthesis of Quetiapine.

BACKGROUND OF THE INVENTION
Quetiapine is chemically known as 2-(2-(4-dibenzo[b,f][l,4]thiazepin-11-yl-l-piperazinyl)ethoxy)ethanol. Quetiapine is a psychoactive organic compound that acts as an antagonist for multiple neurotransmitter receptors in the brain and acts as an antipsychotic agent reportedly useful for treating, among other things, schizophrenia. This drug has been approved by USFDA as Seroquel.


US 4879288 (March, 1987; ICI America inc) discloses various methods for the synthesis of Quetiapine starting from dibenzo[b,f][l,4]thiazepine-l l-(10H)-one of the formula (I).

(I)
Dibenzo[b,f][l,4]thiazepine-11-(10H)-one of formula (I) is the key intermediate in the
synthesis of antipsychotic agent Quetiapine and pharmaceutically active salts thereof,
hence an improved method for synthesizing it will be highly desired.
Several methods are known in the art for the synthesis of dibenzo[b,f][l,4]thiazepine-11-
(l0H)-one(I).
Helv. Chim. Acta 42,1265, (Jaques, R et al, 1959) describes a process for preparing
dibenzo thiazepine derivatives comprising the steps of heating thiosalicylic acid esters
with o-halogenated nitrobenzene in presence of sodium metal to give 2-nitro-2'-
carbomethoxy-diphenylsulphide compound; reducing the diphenylsulfide compound
obtained with Raney Ni to form 2-amino-2'-carboxy diphenylsulphide; and finally
heating it to give dibenzo thiazepine derivative. However the process suffers from
disadvantages such as not commercially viable due to use of expensive thiosalicylic acid
ester.
Helv. Chim. Acta 48,336, (1965) (Schmutz, J.) discloses a method for the preparation of
dibenzo thiazepine derivatives involving the steps of reacting o-chloronitrobenzene with
thiophenol to form 2-nitrodiphenylsulphide; reducing the nitro group to form
corresponding amino compound; treating the amino compound with phosgene and then
cyclizing using AICI3 to give the dibenzo thiazepine derivatives. The above process uses
hazardous phosgene gas, thus making the process commercially not feasible.


As per the process disclosed in WO 92/19607 (NICOL, R et al, 1992) dibenzothiazepine derivatives can be prepared by treating 2-aminothiophenol with 2-fluorobenzonitrile to give 2-(2-aminophenylthio) benzonitrile, hydrolyzing the resulting compound to give 2-(2-carboxyphenylthio)aniline and cyclizing to give the desired product. The fluoro compounds like 2-fluorobenzonitrile used in the process are expensive.
J. Med. Chem. 44, 372, (2001) (Edward J. Warawa) discloses a method for synthesizing dibenzo thiazepine derivatives, which utilizes 2-bromonitrobenzene and thiosalicylic acid, but the process employs hazardous tin chloride, making commercially non-viable.
EP 0282236 Al (Barker, Alan Charles, 1988) teaches a method for the preparation of dibenzothiazepine derivatives comprising the step of cyclization of phenyl 2-(phenylthio)phenylcarbamate in polyphosphoric acid as solvent. As the polyphosphoric acid is highly viscous, the reaction mass is difficult to stir at commercial scale. Also the Work up of the reaction involves addition of water in polyphosphric acid since it can't be transferred. Thus effluent generation is also high due to requirement of lot of water for precipitating the product and makes the process not amenable on large scale.
All the processes described above for the preparation of dibezothiazepine derivatives are suffering from various disadvantages such as use of hazardous and expensive raw materials, generation of lot of acidic waste, poor yields, commercially not viable etc.
In view of lack of process, which is avoiding all the shortcomings of the prior art method, an alternative improved process for the preparation of dibenzothiazepine derivatives is highly desired.
The present invention provides an improved method for the preparation of dibenzothiazepine derivative of formula (I). This method is cost effective, environmentally friendly, high yielding, and commercially viable as avoids use of

hazardous chemicals, generates less effluent and provides dibenzothiazepine derivative of formula (I).
OBJECT OF THE INVENTION
Object of the present invention is to provide an improved and environmentally friendly process for the synthesis of dibenzo[b,f][l,4]thiazepine-ll-(10H)-one derivatives by limiting the use of various solvents
Another object of the present invention is to provide an improved method for the synthesis of dibenzo[b,f][l,4]thiazepine-ll-(10H)-one derivatives, which eliminates the use of hazardous chemicals.
Still another object of the present invention is to provide an easy to implement and cost effective process for the commercial preparation of dibenzo[b,f][l,4]thiazepine-ll-(lOH)-one derivatives.
Further object of the present invention is to provide an improved process for the synthesis of dibenzo[b,f][l,4]thiazepine-l l-(10H)-one derivatives in good yield and purity.
SUMMARY OF THE INVENTION
According to the present invention there is provided of process for the preparation of dibenzo [b,f][l,4]-thiazepine-l l-(10H)-one of formula (I), which comprises

(I) a. condensation of o-halo nitrobenzene of formula (II) with thiophenol to form nitro compound of formula (III),

NO.

(II)
wherein, X is halo group; b. in-situ reduction of the said nitro compound of formula (III) to form an amino compound of formula (IV),

(IV)
c. optionally isolating and converting the said amino compound of formula (IV) into
its salt;
d. reacting the said amino compound of formula (IV) or its salt with phenyl
chloroformate to form phenyl 2-(phenylthio)phenylcarbamate of formula (V);

e. cyclizing the said phenyl 2-(phenylthio)phenylcarbamate of formula (V) with or without isolating it to form the dibenzo[b,f][l,4]thiazepine-ll-(10H)-one of formula (I).


DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved and environmental friendly process for the synthesis of dibenzo[b,f][l,4]thiazepin-11-(10H)-one using less hazardous chemicals. Also, it involves limiting use of various solvents and by avoiding the use of polyphosphoric acid for cyclisation which is a strong acid and generates highly acidic wastes thereby posing problems in disposal. The present invention involves the comparatively less reaction time as reactions carried out in situ without isolating intermediate stages. In the present invention cyclisation of phenyl 2-(phenylthio)phenylcarbamate into Dibenzo[b,f][l,4] thiazepine-11-(10H)-one carried out in methane sulphonic acid which acts as an acid catalyst as well as a solvent, generates lesser acidic waste , keeps reaction mass stirrable in less amount as against the use of polyphosphoric acid reported in the prior art
The said process for the preparation of dibenzo[b,f][l,4]thiazepine according to present invention comprises the steps of
a) condensation of o-halo nitrobenzene with thiophenol to form nitro compound of formula (III);
NO„
X

(II) (III)
wherein X is halo group selected from the group consisting of chloro, bromo or iodo, preferably chloro;
b) in-situ reduction of the said nitro compound of formula (III) to form an amino compound of formula (IV);



(IV)
c) optionally converting the said amino compound of formula (IV) into its salt;
d) reacting the said amino compound of formula (IV) with phenyl chloroformate to form phenyl 2-(phenylthio)phenylcarbamate of formula (V);

(V)
e) cyclizing the said phenyl 2-(phenylthio)phenylcarbamate of formula (V) with or without isolating it to form the dibenzo[b,f][l,4]thiazepine-11-(10H)-one of formula (I).

(I)
The process according to the present invention, wherein the condensation reaction (a) is carried out in presence of an alcoholic solvent and base. The condensation reaction is carried out at a temperature 25°C to 100°C. Preferably at reflux temperature of the solvent used.


The said alcoholic solvent used in the condensation step is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol and mixture thereof; preferably the solvent used in the condensation step is methanol.
The process according to present invention, wherein the base is selected from the group consisting of alkali metal hydroxide and alkaline metal hydroxide particularly lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide or mixture thereof, preferably the base used is sodium hydroxide.
The nitro compound of formula (III) formed in the condensation step was subjected to the reduction without isolating it to form the amino compound of formula (IV). The said reduction of the nitro compound of formula (IV) is carried out in the presence of catalyst under pressure at the temperature of 25-90°C, preferably at 50-60°C and the catalyst used in the reduction of the nitro compound of formula (IV) is Raney Nickel and hydrogen gas as reducing agent. The hydrogen pressure can be in the range of 3-15 kg preferable 5-8 kg. The said amine of formula (IV) is optionally converted into its salt, The acid which is used for salt formation are hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid preferably hydrochloride salt by treating the said amine with an aqueous hydrochloric acid in an alcoholic solvent like , methanol, ethanol, n-propanol, iso-propanol and mixture thereof, preferably methanol.
The process according to the present invention further involves the step of reacting the amine or its salt so formed with phenyl chloroformate in presence of base and a solvent at the temperature of 0 to 60°C preferably at 25-30°C, to form corresponding phenyl 2-(phenylthio)phenylcarbamate of formula (V).
The said reaction with phenyl chloroformate is carried out in the presence of base and solvent, wherein the base is selected from the group consisting of sodium hydroxide, potassium hydroxide , potassium carbonate , sodium carbonate or mixture thereof. The said reaction is preferably carried out in a mixture of sodium hydroxide and sodium carbonate. The solvent which can be used are chlorinated hydrocarbon and hydrocarbons like dichloromethane, dichloroethane, toluene, xylene , preferably the reaction is carried out in toluene.


The carbamate of formula (V) so formed can be isolated after evaporation of the solvent or it can directly be subjected to cychzation to form the desired compounds of formula (I).
The said cychzation of the carbamate compound of formula (V) is carried out in presence of an acid catalyst and solvent to form compound of formula (I).
The said acid catalyst used is methane sulphonic acid, and the said hydrocarbon solvent is selected from the group consisting of toluene, xylene and benzene, preferably toluene. However, in the said cychzation methane sulphonic acid is optionally itself used as a solvent as well as catalyst, or it can be used in combination with phosphorus pentoxide to fasten the reaction. The said cychzation reaction is carried out at 25-100°C, preferably at 75-85°C.
In the said methane sulphonic acid is used in the range of 1 - 5 volume of phenyl 2-(phenythio)phenylcarbamate; preferably 3 volume of phenyl 2-(phenythio)phenylcarbamate, and in case of combination with phosphrous pentaoxide wherein the said phosphorus pentoxide is used in the range of 5 - 20%, preferably 5%. The dibenzo[b,fj[l,4]thiazepine-l l-(10H)-one is obtained by pouring the reaction mass in water and filtration of the resulting product.
The process according to present invention thus provides an improved method for the synthesis of dibenzo[b,fj[l,4]thiazepine-ll-(10H)-one having advantages such as cost effective, easy to implement, avoids use of hazardous chemicals and provides the product with good yield and purity.
The synthetic course of the present invention can be illustrated with the following scheme-



CI
^V*£^ NaOH + NajCOj
NO,

i) nitration
*■
ii) reduction
RaneyNi

PhOCOCl -Toluene

Thiophenol

2-chloro nitrobenzene

o-Amino diphenyl sulfide



^^

MSA

(I)

phenyl 2-(phenylthio)phenylcarbamate
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.

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 :
2-Amino diphenyl sulphide:
50.0 gm (0.3173 mole) o-chloronitrobenzene and 75 ml methanol were charged into a round bottom flask fitted with overhead stirrer and condenser at 25-30°C. Dissolved 15.23 gm (0.3807 mole) of sodium hydroxide in 35 ml water in a separate round bottom flask and add 35.67 ml (0.3490 mole) of thiophenol in a single lot to it, stirred for 15-20 min to prepare sodium salt of thiophenol. This thiophenol salt solution was added to reaction mass in 3-4 lots at 27-30°C, stirred for 15-20 min. The reaction mass was heated to reflux at 72-75°C and stirred at reflux temperature till completion of reaction, monitored on TLC (mobile phase Hex : Ethyl acetate 9.9:0.1) After o-chloronitrobenzene was consumed the reaction mass was charged into autoclave as such, then was charged 7.5 gm Raney Ni and 500 ml MeOH at 27-30°C. Applied 6-8 kg hydrogen pressure at 50-55°C and maintain till completion of reaction. The reaction was monitored on TLC (mobile phase Hex : Ethyl acetate 9.8:0.2). After completion of reduction, filtered reaction mass through hyflow bed, washed it with 50 ml methanol. Methanol filtrate and washing were evaporated to dryness to get 80 gm oil of 2-amino diphenyl sulphide. This 2- amino diphenyl sulphide can be converted into its hydrochloride salt to obtain as a solid.
Example 2 :
2-Amino diphenyl sulphide hydrochloride:
50 gm oil obtained in example 1 was dissolved in 100 ml methanol and charged into reaction assembly at room temperature. 27 ml of aq hydrochloric acid (35 %) was added to it at 0-5°C and raise the temperature to 25-30°C, stirred at 25-30°C till salt precipitated

out. Filtered and washed with 25 ml chilled methanol. Dried in an air oven at 100°C. The 2-amino diphenyl sulphide hydrochloride obtained is 44 gm with 75 % yield .
Example 3 :
Phenyl 2-(phenylthio)phenylcarbamate:
30 gm (0.1492 mole) oil of 2-amino diphenyl sulphide obtained in example-1 was dissolved in 240 ml toluene and charged in a round bottom flask fitted with overhead stirrer. To this 10.36 ml (0.0820 mole) of phenyl chloroformate in 60 ml toluene was added over a period of 30 - 40 min at 0-5°C, stirred for 15-20 min, again second lot of 10.36 ml (0.0820 mole) of phenyl chloroformate in 60 ml toluene was added simultaneously with the addition of solution of 4.47gm (0.1119 mole) of sodium hydroxide and 11.86 gm (0.1119 mole) of sodium carbonate in 120 ml water at 0-5°C. Stirred reaction mass at 27-30°C till its completion, monitored on TLC (mobile phase Hex : Ethyl acetate 9.9:0.1). After completion of reaction separated layers, toluene layer of reaction mass washed with 2x300 ml water, separated layer, dried over sodium sulphate. The toluene layer was evaporated to dryness to get crude 50 gm phenyl 2-(phenylthio)phenylcarbamate. The toluene layer can be subjected to cyclisation as such without isolating product phenyl 2-(phenylthio)phenylcarbamate.
Example 4 :
Phenyl 2-(phenylthio)phenylcarbamate:
30 gm (0.1263 mole) of 2-Amino diphenyl sulphide hydrochloride salt of example 2, dissolved in 90 ml water, 7.57 gm (0.1894mole) NaOH dissolved in 10 ml water and this solution was added to reaction mass with stirring, stirred for 15-20 min and then added 200 ml toluene to extract free amino compound. Separated layer, toluene layer washed with 2 x 150 ml water. 200 ml toluene layer of amino compound was charged in reaction assembly. To this added 8.64 ml (0.0684 mole) phenylchloroformate in 50 ml toluene over a period of 30-40 min at 0-5°C , stirred for 15-20 min ,then added another lot of 8.64 ml (0.0684 mole) phenyl chloroformate in 50 ml toluene simultaneously with the addition of a solution of 3.73 gm (0.0932 mole) sodium hydroxide and 9.89gm (0.0932 mole)

sodium carbonate in 100 ml water at 0-5°C. Stirred reaction mass at 27-30°C till its completion which was monitored on TLC (mobile phase Hex : Ethyl acetate 9.9:0. l)After completion of reaction separated layers, toluene layer of reaction mass washed with 2x250 ml water, separated layer ,dried over sodium sulphate. The toluene layer was evaporated to dryness to get 40 gm crude phenyl 2-(phenylthio)phenylcarbamate .
Example 5 : Dibenzo-[b,f][l,4]-thiazepine-11-(10H)-one:
75 ml toluene layer of pheny2-(phenylthio)phenylcarbamate of example 3 without evaporating charged into reaction assembly ,to it was added 10 ml methane sulphonic acid, heated reaction mass at 90°C till completion of reaction monitored on TLC (mobile phase Hex : Ethyl acetate 8:2). Cooled reaction mass to RT first and then to 15-20°C in an ice-water bath, added 50ml water, product precipitated out, filtered product, washed with 20 ml water and then with 10 ml methanol. Dried in an oven at 100°C. Weight of the product obtained is 5.0 gm with 70 % yield and 99.5 % purity by HPLC.
Example 6 :
Dibenzo-[b,f] [l,4]-thiazepine-l l-(10H)-one:
30 ml methane sulphonic acid was charged into reaction assembly, 10 gm (0.0312 mole) phenyl 2-(phenylthio)phenylcarbamate as obtained in example 4 was charged in lots with stirring at room temperature, Raise the temperature of reaction mass to 80-85°C and maintain for 32-36 hrs. After completion of reaction, monitored on TLC (mobile phase Hex : Ethyl acetate 8:2) cooled reaction mass at 15-20°C and poured slowly over 150 ml chilled water with stirring. Stirred for an hour at RT, product precipitated out, filtered product washed with 10 ml water and then with 10 ml methanol. Dried in an oven at 100°C. Wt of the product obtained is 5.7 gm with 80 % yield and 99.4 % purity by HPLC.

Example 7 :
Dibenzo [b,f][l,4]-thiazepine-11-(10H)-one:
30 ml methane sulphonic acid was charged into reaction assembly 0.5 gm phosphorous pentoxide was charged in a single lot at 20°C with stirring. Then was added 10 gm (0.0312 mole) phenyl 2-(phenylthio)phenylcarbamate as obtained in example 4 in 3-4 lots. Raise temperature of reaction mass to 80-85°C and maintain for 10-12 hrs. After completion of reaction monitored on TLC (mobile phase Hex : Ethyl acetate 8:2). Cooled reaction mass at 15-20°C and poured slowly over 150 ml chilled water with stirring. Stirred for an hour at RT, product precipitated out, filtered product washed with 10 ml water and then crystallized from dimethylformamide. Dried in an oven at 100°C. Wt of the product obtained is 4.98 gm with 70 % yield and 99.94 % purity by HPLC Mass confirmation was done, m/z =228.7.
1H NMR (DMSO). 7.10(lH,m), 7.22 (1H, d), 7.32 (lH,m), 7.55 (4H,m), 7.67 (1H, dd ), 10.70 (lH,s)

We Claim:
1. A process for the preparation of dibenzo [b,f][l,4]-thiazepine-ll-(10H)-one of formula (I ), which comprises,

a. condensation of o-halo nitrobenzene of formula (II) with thiophenol to form nitro compound of formula (III), NO„


NO.
■v^
'2 (III)
(II)
wherein, X is halo group; b. in-situ reduction of the said nitro compound of formula (III) to form an amino compound of formula (IV),

'NH
^r
2
(IV)

c. optionally isolating and converting the said amino compound of formula (IV) into its salt;
d. reacting the said amino compound of formula (IV) or its salt with phenyl chloroformate to form phenyl 2-(phenylthio)phenylcarbamate of formula (V);

e. cyclizing the said phenyl 2-(phenylthio)phenylcarbamate of formula (V) with or without isolating it to form the dibenzo[b,f][l,4]thiazepine-ll-(10H)-one of formula (I).
2. A process of claim 1 (a), wherein X is chloro, bromo or iodo, preferably chloro.
3. A process of claim 1 (a), wherein the said condensation reaction is in presence of an alcoholic solvent and a base.

4. A process of claim 3, wherein the said alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol and mixture thereof, preferably methanol.
5. A process of claim 3, wherein the said base is preferably sodium hydroxide.
6. A process as claimed in claim 1 (a), wherein the said condensation of o-halo nitrobenzene with thiophenol is carried out at 25-100°C, preferably at reflux temperature of the solvent used.

7. A process of claim 1 (b), wherein the in situ reduction is carried out by using Raney Nickel and hydrogen gas at 25-90°c preferably at 50-60°c and 3-15 kg hydrogen pressure preferably at 5-8 kg hydrogen pressure.
8. A process of claim 1 (c), wherein the said amino compound of formula (IV) is preferably converted into its hydrochloric, hydrobromic acid, Hydroiodic acid , sulphuric acid salt preferably hydrochloride salt by using aqueous hydrochloric acid
9. A process of claim 1 (d), wherein the reaction with phenyl chloroformate is carried out in presence of base and a solvent to form the phenyl 2-(phenylthio)phenylcarbamate (V).

10. A process of claim 9, wherein the base is preferably a mixture of sodium hydroxide and sodium carbonate.
11. A process of claim 9, wherein the reaction with phenyl chloroformate is carried out at 0-60°c preferably at 25-30°C.

12. A process of claim 9, wherein the reaction with phenyl chloroformate is preferably carried out in toluene.
13. A process of claim 1 (e), wherein the insitu cyclization of the said phenyl 2-(phenylthio)phenylcarbamate (V) is carried out in the presence of an acid catalyst and a hydrocarbon solvent to form the dibenzo[b,f][l,4]thiazepine-11-(10H)-one of formula (I).
14. A process of claim 13, wherein the said acid catalyst is methane sulphonic acid.
15. A process of claim 13, wherein the said hydrocarbon solvent is selected from the group consisting of toluene, xylene and benzene, preferably toluene.

16. A process of claim 1(e), wherein, the cyclization of the isolated phenyl 2-(phenylthio)phenylcarbamate (V) is carried out in methane sulphonic acid to form the dibenzo[b,f][l,4]thiazepine-l l-(10H)-one of formula (I).
17. A process of claim 16 wherein, methane sulphonic acid is used as an acid catalyst as well as solvent.
18. A process as claimed in claim 16, wherein the said methane sulphonic acid is used in the range of 1 - 5 volume of phenyl 2-(phenythio)phenylcarbamate; preferably 3 volume of phenyl 2-(phenythio)phenylcarbamate.
19. A process of claim 16, wherein the cyclization of the isolated phenyl 2-
(phenylthio)phenylcarbamate (V) is carried out in methane sulphonic acid in presence
of phosphorous pentoxide to form the dibenzo[b,f][l,4]thiazepine-11-(10H)-one of
formula (I).
20. A process of claim 19, wherein the said phosphorus pentoxide is used in the range of 5 - 20%, preferably 5%.
21. A process as claimed in claims 1(e), wherein the said cyclization reaction is carried out at 25-100°C preferably at 75-85°C.
22. A process for the preparation of compound of formula (I) substantially as herein described and illustrated with reference to the accompanying examples.

Abstract:
The present invention relates to an improved process for the preparation of dibenzo[b,f][l,4]thiazepine-11-(10H)-one, a key intermediate in the synthesis of Quetiapine. The process of present invention comprises the steps of reaction of o-halonitrobenzene with thiophenol; followed by in-situ reduction; reaction of the amino compound so formed with phenyl chloroformate; and then cyclizing the carbamate formed in presence of an acid catalyst.