FIELD OF THE INVENTION
The present invention relates to an eco-friendly and cost effective process for preparation of phenyl carbamate derivative of formula 1, a key intermediate in the preparation of quetiapine and pharmaceutically acceptable salt thereof.
(Formula Removed)

BACKGROUND OF THE INVENTION
Quetiapine, chemically known as 2-[2-(4-dibenzo[b,f][l,4]thiazepine-l l-yl)ethoxy ethanol, is an antipsychotic drug belonging to the class of dibenzothiazepine derivatives and has following structure formula,
(Formula Removed)

It has antidopaminergic and /or serotonin receptor antagonist activity, therefore used in treating symptoms associated with psychiatric disorders and other psychoses such as delusions, hallucinations, disorganized thinking and speech and bizarre behavior.
Quetiapine and pharmaceutically acceptable salts were first disclosed in US patent 4,879,288 (herein referred as '288). In general, the synthetic approach reported in '288 for preparation of quetiapine or salts involves phenyl-2-(phenylthio) phenyl carbamate of formula 1, a key intermediate in synthesis of quetiapine. This
intermediate is prepared by reaction of 2-amino diphenyl sulfide with phenyl chloroformate in the presence of a base and an organic solvent such as toluene. After completion of reaction, organic layer is washed with dilute hydrochloric acid and product is isolated by removal of toluene under vacuum. Patent is completely silent about purity of intermediate, thus obtained.
PCT publication WO 2001/055125 exemplifies process for preparation of phenyl-2-(phenylthio) phenyl carbamate of formula I by reaction of 2-amino diphenyl sulfide with phenyl chloroformate in the presence of a base and dichloromethane as a solvent. After the completion of reaction, organic layer is washed three times with hydrochloric acid followed by solvent evaporation to give desired material. Major disadvantage of the process is use of dichloromethane, which is a low boiling solvent so recovery losses are very high which adds cost to the process.
PCT publication WO 2005/012274 exemplifies process for preparation of phenyl-2-(phenylthio) phenyl carbamate of formula I starting from hydrochloride salt of 2-amino diphenyl sulfide. Process involves generation of 2-amino diphenyl sulfide, by neutralization of its hydrochloride salt using 10 % sodium hydroxide, which in situ react with phenyl chloroformate in the presence of a base such as combination of sodium hydroxide and sodium carbonate and toluene as a solvent.
European Patent EP0282236 B1 discloses process for preparation of phenyl-2-(phenylthio) phenyl carbamate of formula 1 by reaction of 2-amino diphenyl sulfide and phenyl chloroformate in the presence of base and using toluene as a solvent.
Indian patent application 821/MUM/2008 discloses process for preparation of phenyl-2-(phenylthio) phenyl carbamate of formula 1 by condensation of 2-amino diphenyl sulfide and phenyl chloroformate in the presence of a base using chlorinated hydrocarbons and hydrocarbons like dichloromethane, dichloroethane, toluene,
xylene as a solvent. After the completion of reaction, phenyl-2-(phenylthio) phenyl carbamate is isolated by evaporation of the solvent.
Most of prior art processes, involve use of organic solvent during condensation of 2-amino diphenyl sulfide and phenyl chloroformate for preparation of phenyl-2-(phenylthio) phenyl carbamate of formula I which is isolated by solvent removal under vacuum and evaporation. We have not found any reference wherein organic solvent is not used during said condensation.
Usually, organic solvents are used in much larger quantities than the solutes they carry and have a tendency to escape into the environment through evaporation and leakage. Use of solvent also adds cost to the process. In addition to this, use of organic solvent in synthetic reactions also requires the control of the solvent to be shown in the final API like quetiapine.
In view of the above, present invention provides a process for synthesis of compound of formula I by condensation of 2-amino diphenyl sulfide and phenyl chloroformate in the absence of organic solvent, which makes the process eco-friendly, cost effective and economically viable. The process of present invention also involves easy isolation, without using vacuum distillation of organic solvent, during the synthesis of phenyl carbamate derivative of formula I.
OBJECTIVES OF THE INVENTION
It is the foremost objective of the present invention to provide an eco-friendly, and cost-effective process for preparation of phenyl carbamate derivative of formula I, a key intermediate for quetiapine.
Another objective of the invention is to provide a process for preparation of phenyl carbamate derivative of formula 1 in the absence of organic solvent during condensation.
Another objective of the invention is to provide a process for preparation of phenyl carbamate derivative of formula I that replaces hazardous organic solvent with an environment friendly solvent.
Still another objective of the invention is to provide a process for the preparation of phenyl carbamate derivative of formula 1 using water as solvent during condensation.
Yet another objective of the present invention is to provide a process for preparation of phenyl carbamate of formula I which involves easy isolation without vacuum distillation.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an eco-friendly and cost-effective process for preparation phenyl carbamate derivative of formula I, a key intermediate for quetiapine,
(Formula Removed)

which comprises the steps of:
a), providing 2-amino diphenyl sulfide of formula II,
(Formula Removed)

or salts thereof;
b). reacting the same with phenyl chloroformate in presence of a suitable base in water;
c). isolating phenyl carbamate derivative of formula I from the reaction mixture; and
d). optionally, purifying phenyl carbamate derivative of formula I using a suitable solvent.
According to another embodiment, present invention provides a process for preparation of phenyl carbamate derivative of formula I, which comprises the steps of:
a), reducing 2-nitro diphenyl sulfide of formula III,
(Formula Removed)

using a suitable reducing agent to form 2-amino diphenyl sulfide of formula II,
(Formula Removed)

or salts thereof;
b). optionally, isolating 2-amino diphenyl sulfide of formula II or salt thereof,
c). reacting 2-amino diphenyl sulfide of formula II or salt thereof with phenyl chloroformate in presence of a base in water;
d). isolating phenyl carbamate derivative of formula 1 from the reaction mixture; and
e). optionally, purifying phenyl carbamate derivative of formula I using a suitable solvent.
According to still another embodiment, present invention provides a process for preparation of quetiapine, which comprises the steps of:
a), providing 2-amino diphenyl sulfide of formula II,
(Formula Removed)

or salts thereof; b). reacting the same with phenyl chloroformate in the presence of base in water;
c). isolating phenyl carbamate derivative of formula I from the reaction mixture;
d). optionally, purifying phenyl carbamate derivative of formula I using a suitable solvent; and
e). converting phenyl carbamate derivative of formula I to quetiapine and pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the process of present invention is cost effective, eco-friendly and industrially advantageous for the preparation of phenyl carbamate derivative of formula I, a key intermediate in the preparation of quetiapine and pharmaceutically acceptable salts thereof.
According to one embodiment, present invention provides a process for preparation of phenyl carbamate derivative of formula I by reacting 2-amino diphenyl sulfide of formula II or salt thereof with phenyl chloroformate in presence of a base in water as solvent which forms a novel part of the invention.
Generally, process involves reaction of amino intermediate of formula II or salt therefore with phenyl chloroformate in presence of a suitable base in water as solvent. Base employed for the reaction is inorganic base. Inorganic base can be selected from alkali or alkaline metal hydroxides, carbonate, bicarbonate such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like or combination thereof. Intermediate of formula II employed for the reaction can be provided as solid, oil or directly from the reaction mixture where it is prepared or in form of acid addition salt. Salt of intermediate of formula II used for the reaction can be salt with inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid or organic acid such as oxalic acid, citric acid, acetic acid, tartaric acid, formic acid, methanesulphonoc acid and the like or combination thereof.
The reaction can be carried out at a temperature of 5 to 30 °C for sufficient time till condensation takes place. Generally completion of reaction is accomplished within 1 to 6 hours. Preferably, reaction is carried out at 10 to 15°C till the completion of the reaction. Reaction completion can be monitored by suitable techniques such as high-pressure liquid chromatography (HPLC), thin layer chromatography (TLC), gas chromatography (GC), ultra pressure liquid chromatography (UPLC) and the like. After the completion of the reaction, compound of formula I can be isolated from the reaction mixture using suitable techniques such as filtration, centrifugation and the like.
It is highly advantageous to use water as solvent for the reaction as it circumvents the need of solvent removal by cumbersome techniques such as evaporation and the like. Use of water as solvent for condensation reaction also provides advantage of environment friendly and cost effective process. Phenyl carbamate derivative of formula 1, prepared by the process of present invention can be isolated very easily just by filtration or centrifugation.
Phenyl carbamate derivative of formula I, thus obtained, can be optionally purified using any suitable purification procedure to enhance the purity of the compound or to reduce the presence of undesired impurities in the compound. Any suitable purification method can be used for purification of compound of formula I such as slurry wash, crystallization and the like. Preferably, compound of formula I can be purified by crystallization using a suitable solvent. Solvent used for the crystallization can be selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof or aqueous alcohols. Aqueous alcohols can be prepared by mixing alcohols with water in suitable proportion.
Specifically, the compound of formula I in a suitable solvent is heated at temperature of 40 °C to reflux temperature of solvent used for 30 minutes to 2 hours. Preferably, reaction mixture is heated to a temperature of 60 to 70 °C for 45 minutes to 1 hour. Thereafter, reaction mixture is cooled to a temperature 0 to 15 °C, preferably 10 to 12 °C. The resulting product can be separated from the reaction mixture by known techniques such as decantation, filtration or centrifugation; any other suitable technique can be employed.
The compound of formula I, thus obtained by the process of present invention can be converted to the quetiapine by any of processes known in the art.
The starting compound of formula II or salts thereof can be procured from the market or prepared by prior art method or by the method described herein for reference.
2-Amino diphenyl sulfide of formula II or salt thereof can be prepared by reduction of 2-nitro diphenyl sulfide of formula III using a suitable reducing agent.
Generally, process involves reduction of 2-nitro diphenyl sulfide of formula III with a suitable reducing agent at a temperature of ambient temperature to 80°C for few minutes to several hours. Preferably, reaction is carried out at 50 to 75 °C for 2 to 5
hours, more preferably till the completion of the reaction. Reducing agent can be selected from any reagent known in the art that can effectively serve the purpose of reduction of nitro functionality to amine provided it may not affect other groups present in the molecule.
The reduction reaction can be carried out using a suitable catalyst under pressure. Catalyst employed for the reduction can be selected from iron dust in the presence of an acid, Raney nickel, palladium with or without support (carbon), platinum (IV) oxide and the like. The hydrogen pressure can be in the range of 4-8 kg/cm2 preferably 2-8 kg/cm2, most preferably 4-5 kg/cm2. The reaction can be carried out using a solvent which includes alcoholic solvent such as methanol, ethanol and the like or mixture thereof. Usually, reaction is carried out at ambient temperature to 80 °C till the completion of the reaction. After the completion of the reaction, catalyst used for the reaction can be filtered off and desired product can be isolated from the resulting filtrate. Amino intermediate of formula II can be isolated from the resulting reaction mixture by suitable techniques or can be preceded in situ for the further reaction with phenyl chloroformate.
Amino intermediate of formula II can be isolated from the reaction mixture in the form of acid addition salt. The acid employed for the salt formation can be inorganic acid or organic acid. Inorganic acid can be selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid; and the like or combination thereof. Organic acid can be selected from oxalic acid, citric acid, acetic acid, tartaric acid, formic acid, methanesulphonoc acid and the like or combination thereof.
The major advantage of the present invention resides in the use of nature's own solvent, water, for the reaction of 2-amino diphenyl sulfide of formula II with phenyl chloroformate. The use of water as a solvent has several added advantages for commercial synthesis of any pharmaceutically compound such as quetiapine or
intermediate thereof. One of the advantages is that it avoids use of organic solvent and special care for their handling. Water is ideally suited for the purpose of organic synthesis owing to its non-toxic character. Due to readily accessibility of water and enormous abundance, it is most lucrative alternative to replace organic solvent for the reaction from commercial point of view. The use of water as a solvent for organic reaction also offers several "green chemistry'' benefits, simple operation and significant rate enhancement is observed in water as compared to organic solvents. Moreover, present invention provides an environmentally benign as well as cost effective process for the synthesis of phenyl carbamate derivative of formula I.
The present invention is further illustrated by the following examples, which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. 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.
Examples
Example 1: Preparation of phenyI-2-(phenylthio)phenyl carbamate
2-Nitrodiphenyl sulphide (50 g) was added to ethanol (300 ml) at ambient temperature. Dehydrated Raney nickel (7 g) was added to resulting mixture at ambient temperature under nitrogen pressure. Reaction mixture was hydrogenated by applying hydrogen pressure (4-5 kg/cm2) at ambient temperature and heated to 70 -75 °C and stirred at same temperature for 3 to 4 hours. After completion of reaction (monitored by GC), reaction mixture was cooled to 25 - 30 °C. Reaction mixture was filtered through hyflow bed and bed was washed with ethanol (200 ml). Solvents were distilled out completely under vacuum at 45 - 55 °C from the filtrate. Demineralized water (200 ml) was added to resulting residue, stirred for 30 minutes at ambient temperature and cooled to 5-10 °C. Phenyl chloroformate (44.2 g) was
added to the reaction mixture at 5 - 10 °C and stirred at same temperature for 3 hours. 8 % Aqueous solution of sodium hydroxide (200 ml) was added to the resulting reaction mixture and stirred at 5 - 10 °C for 30 minutes. Reaction mixture was filtered and washed with cold demineralized water (300 ml). Methanol (75 ml) was added to the resulting residue and refluxed for 1 hour. Thereafter, reaction mixture was cooled to 10 - 15 °C, filtered, washed with cold methanol (25 ml) and dried under vacuum at 40 - 45 °C to give 60 g of title product having purity 99.1 % by HPLC.
Example 2: Preparation of phenyl-2-(phenylthio)phenyl carbamate
2-Amino-diphenyl sulphide (42 g) was added to demineralized water (200 ml) and stirred for 30 minutes at ambient temperature. Reaction mixture was cooled to 5 - 10 °C. Phenyl chloroformate (44.2 g) was added to the reaction mixture at 5 - 10 °C and was stirred at same temperature for 3 hours. 8 % Aqueous solution of sodium hydroxide (200 ml) and phenyl chloroformate (4.0 g) were added to the resulting reaction mixture at same 5 - 10 °C and maintained at same temperature for 30 minutes. After completion of the reaction, reaction mixture was filtered, washed with cold demineralized water (300 ml). Methanol (75 ml) was added to resulting wet residue and heated at 60 - 68 °C for 1 hour. Thereafter, reaction mixture was cooled to 10 - 15 °C, filtered and washed with cold methanol (25 ml) and dried under vacuum at 40 - 45 °C to give 61 g of title product having purity 99.08 % by HPLC.
Example 3: Preparation of phenyl-2-(phenylthio)phenyl carbamate
2-Aminodiphenyl sulphide (42.0 g) was added to demineralized water (200 ml) and stirred for 30 minutes at ambient temperature. Reaction mixture was cooled to 5 - 10 °C. Phenyl chloroformate (30.0 g) was added to the reaction mixture at 5 - 10 °C and maintain at same temperature for 2.5 hours. Thereafter, another lot of phenyl chloroformate (18.0 g) was added to reaction mixture followed by addition of 8 % aqueous solution of sodium hydroxide (200 ml). Then reaction mixture was stirred at
the same temperature for 2 hours. Reaction mixture was filtered, washed with cold demineralized water (300 ml) and dried to give 68 g of title compound having purity 98.0 % by HPLC.
Example 4: Preparation of dibenzo[b,f][l,4]-thiazepine-l 1 [10H]one
Polyphosphoric acid (229 g) was heated at 60-65 °C and phenyl-2-(phenylthio)phenyl carbamate (50 g) was added at same temperature. Reaction mixture was heated to 95 - 105 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to about 75 - 80 °C. Demineralized water (1020 ml) was added to the reaction mixture, cooled to 20 - 25 °C for 2 hours. Product thus formed was filtered and washed with demineralized water (300 ml). Methanol (180 ml) was added to resulting residue and refluxed for 1 hour. Thereafter, reaction mixture was cooled to 10 - 20 °C and stirred for I hour. Resulting product was filtered, slurry washed with methanol (30 ml) and dried under vacuum at 50 - 60 °C to give 29.5 g of title product having purity 99.8 % by HPLC.
Example 5: Preparation of ll-chloro-dibenzo[b,f|[l,4]-thiazepine
To a mixture of dibenzo[b,f][l,4]-thiazepine-l l[10H]one (50 g) and toluene (250 ml), N,N-dimethyl aniline (17 g) and phosphorous oxychloride (55 ml) were added at ambient temperature and mixture was refluxed for 16 hours. Reaction mixture was cooled to ambient temperature and quenched in a mixture of toluene (300 ml) and demineralized water (200 ml) at a temperature of 0 - 5 °C. Resulting reaction mixture was filtered through hyflo bed and bed was washed with toluene (100 ml). Layers were separated and aqueous layer was extracted with toluene (2 x 100 ml). Combined toluene layer was washed with demineralized water (3 x 300 ml). Resulting organic layer was dried over anhydrous sodium sulphate (50 g) and then solvent was partially distilled to obtain a reaction mass, which was used as such for further reaction.
Example 6: Preparation of quetiapine
1 l-Chloro-dibenzo[b,f][l,4]-thiazepine (as obtained in example 5) was added to sodium carbonate (50 g) and stirred for 15 minutes at ambient temperature. l-[2-[2-hydroxyethoxyethyl] piperazine (48.0 g) was added to reaction mixture and reaction mixture was heated to reflux for 4 hours. After completion of the reaction, the reaction mass was cooled to ambient temperature and demineralized water (300 ml) was added to the reaction mixture. Layers were separated, organic layer was washed with demineralized water (300 ml). A solution of 1 N hydrochloric acid (440 ml) was added to the organic layer till it pH of the mixture reaches 2 to 3 followed by layer separation. Aqueous layer was washed with toluene (2 x 100 ml). Toluene (700 ml) was added to resulting aqueous layer and stirred for 15 minutes. Sodium carbonate (80 g) was added to the reaction mixture till it attains pH more than 8. Layers were separated, washed the toluene layer with demineralized water (3 x 300 ml) and dried over anhydrous sodium sulphate. Resulting organic layer was distilled out completely under vacuum. Ethanol (100ml) was added to the resulting residue at 40-45 °C and then heated to 50 to 60 °C. Ethanol was distilled out under vacuum to give 70 g of the title compound having purity 99.8 % by HPLC.
Example 7: Preparation of quetiapine hemifumarate
Ethanol (400 ml) was added to quetiapine (70 g) and stirred for 30 minutes. Activated carbon (5 g) was added to the reaction mixture and stirred for 30 minutes at ambient temperature. Reaction mixture was filtered through hyflo bed and bed was washed with ethanol (200 ml). Fumaric acid (20.5 g) was added to resulting filtrate and heated to reflux for 30 minutes. Thereafter reaction mixture was cooled to 30 to 35 °C followed by addition of ethanol (800 ml). Reaction mixture was heated to 75-80°C and stirred to obtain clear solution. The reaction mass was filtered and washed with ethanol (50 ml). Combined filtrate was distilled out (approximately half of total
volume) under atmospheric pressure at 75-80 °C. Thereafter, reaction mixture was cooled to ambient temperature followed by cooling to 10-15 °C for 2 hours and filtered. Ethanol (120 ml) was added to the resulting product and stirred for 15 minutes at ambient temperature. The reaction mass was cooled to 10 to 15 °C and filtered. The resulting product was washed with cold ethanol (50 ml), dried under vacuum to give 79 g of the title compound having purity 99.93 % by HPLC.

WE CLAIM:
1). A process for preparation of phenyl carbamate derivative of formula I,
(Formula Removed)
which comprises the steps of:
a), providing 2-amino diphenyl sulfide of formula II,
(Formula Removed)
or salts thereof;
b). reacting the same with phenyl chloroformate in the presence of a base in
water;
c). isolating phenyl carbamate derivative of formula I from the reaction mixture;
and
d). optionally, purifying phenyl carbamate derivative of formula I using a suitable solvent.
2). The process according to claim 1, wherein in step b) base is an inorganic base.
3). The process according to claim 2, wherein in inorganic base is selected from
alkali or alkaline metal hydroxide, carbonates, bicarbonates thereof.
4). The process according to claim 2, inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate and the like or combination thereof.
5). The process according to claim 1, wherein in step d) suitable solvent is selected from alcohol such as methanol, ethanol, isopropanol and the like or mixture thereof or aqueous alcohols.
6). The process according to claim 1, wherein 2-amino diphenyl sulfide of formula II or salt thereof is prepared by a process which comprises:
a), reducing 2-nitro diphenyl sulfide of formula III,
(Formula Removed)
using a suitable reducing agent; and
b). optionally, isolating 2-amino diphenyl sulfide of formula II or salt thereof from the reaction mixture.
7). The process according to claim 6, wherein in step a) a suitable reducing agent is selected from iron dust in presence of acid, Raney nickel, palladium with or without support (carbon), platinum (IV) oxide and the like under hydrogen pressure.
8). The process according to claim I, further comprises converting compound of
formula I to quetiapine.
9). A process for preparation of quetiapine, which comprises the steps of:
a), reducing 2-nitro diphenyl sulfide of formula III,
(Formula Removed)
using a suitable reducing agent; and
b). optionally, isolating 2-amino diphenyl sulfide of formula II or salt thereof from the reaction mixture,
c). reacting 2-amino diphenyl sulfide or salts thereof with phenyl chloroformate
in the presence of a base in water;
d). isolating phenyl carbamate derivative of formula I from the reaction mixture;
e). optionally, purifying phenyl carbamate derivative of formula I using a suitable
solvent; and
f). converting compound of formula I to quetiapine.
10). The process according to claim 9, wherein in step b) 2-amino diphenyl sulfide of formula II is not isolated.