DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
“AN IMPROVED METHOD FOR MANUFACTURING OF AN INTERMEDIATE, DIBENZO[B,F][1,4]THIAZEPINE-11(10H)-ONE, OF QUETIAPINE”
2. APPLICANT
Name Nationality Address
UNICHEM LABORATORIES LTD. INDIAN COMPANY 47, KANDIVLI INDUSTRIAL ESTATE, KANDIVLI (W),
MUMBAI-400067, MAHARASHTRA, INDIA
IPCA LABORATORIES LTD. INDIAN COMPANY 48, KANDIVLI INDUSTRIAL ESTATE, KANDIVLI (W),
MUMBAI-400067, MAHARASHTRA, INDIA
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describe the invention and the manner in which it is to be performed

FIELD OF INVENTION
The present invention relates to an improved method for manufacturing of intermediate(s) of Quetiapine. Most particularly, it relates to improved method for manufacturing of Dibenzo[b,f][1,4]thiazepin-11(10H)-one and/or its intermediate(s), used in the synthesis of Quetiapine.

BACKGROUND OF THE INVENTION
Quetiapine, also known by the brand name Seroquel, is a medication used to treat schizophrenia, bipolar disorder, and depression. It is an antipsychotic medication that works by affecting the levels of certain chemicals in the brain.
Quetiapine is chemically known as 2-(2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy) ethanol, having the following chemical structure:

Quetiapine was first disclosed in US4879288 patent. It is prepared starting from dibenzo[b,f][1,4]thiazepin-11-[10H] one of formula II

Formula II
which is first halogenated with phosphorous oxychloride, then isolated and condensed with 1-(2-hydroxyethoxy) ethyl piperazine to obtain quetiapine.
The Dibenzo[b,f][1,4]thiazepin-11-[10H]one (Lactam) is an important intermediate in the synthesis of quetiapine. Its preparation requires several steps, and in most cases, it has to be even halogenated to the imino chloride before the piperazine moiety can be condensed with it.
Therefore, there is a need to develop the various strategies to prepare said intermediate compound which can be cost-effective and environment friendly and can reduce the overall cost of large-scale production of quetiapine.
Following are the references discloses synthesis of Dibenzo[b,f][1,4]thiazepin-11-[10H]one (Lactam).
Prasad et al. discloses synthesis of dibenzo [b, f][1,4] thiazepine-11(10H)-one (5),

wherein said synthesis is carried out by adding compound 4 slowly to a solution of polyphosphoric acid (PPA) at 65oC with stirring. Thereafter the reaction solution is heated to 100o-105oc for 6-8 hrs. After completion of reaction mixture is cooled to about 800C and then ice-cold water is added slowly. After cooling to ambient temperature, the product is filtered off as an off-white solid, washed sparingly with acetone and dried. (Prasad et al., “An Improved Profess For Synthesis Of Dibenzo-[B,F][1,4]- Thiazepine-11-(10H)-One”, International Journal of Chemtech Research, Vol.5, No.4, pp 1902-1905, April-June 2013).
Due to high viscosity, PPA is difficult to pour and stir at room temperature. To remove this difficult, use of additional cosolvents (xylene) is required. Thus, problem in difficult in handling of PPA, use of additional cosolvent said process is not commercially and operationally viable on large scale production.
WO2006001619A1 discloses a process for the preparation of 2-(2-aminophenylthio)benzoic acid, wherein said process is carried out by (a) reacting 2,2'-dithiosalicylic acid with 1-chloro-2-nitrobenzene in a basic aqueous solution in the presence of or in the absence of a reducing agent, to produce 2-(2-nitrophenylthio)benzoic acid; (b) reducing a nitro group of 2-(2-nitrophenylthio)benzoic acid in the presence of hydrogen and a solvent under a heterogeneous metal catalyst (e. g. Raney-Ni, ruthenium (Ru), palladium (Pd), platinum (Pt), and rhodium (Rh)), to produce 2-(2-aminophenylthio) benzoic acid.
Thus, WO’619 involves use of expensive catalyst and hydrogen for reduction of step (b). Hydrogen gas is a highly inflammable and explosive in nature; it cannot be easily transported from one place to another; difficult to handle, storage complications. Thus, it is not feasible to use on large scale production.
US5399703A discloses process for preparation of 2-(2-Aminophenylthio) Benzonitrile. The said process is carried out by dissolving ortho-amino thiophenol in DMF followed by addition of potassium carbonate at 100°C. Furthermore, o-chlorobenzonitrile is added to the above mixture and stirred at 100oC. for 1 hour under inert atmosphere. After completion reaction is quenched with ice cold water and extracted with ethyl acetate. The residue obtained after distillation is crystallized from mixture of solvent of n-hexane-isopropyl ether. Thus US’703 invention requires additional purification step resulting in increased overall production cost.
US5589474A discloses synthesis of 2-(2-aminophenylthio)-benzoic acid (formula (III)) can be prepared by hydrolysis of a corresponding 2-(2-aminophenylthio)-benzonitrile (formula (V), wherein hydrolysis may be carried out in the presence of an acid (sulphuric acid, and/or acetic acid (in a 1:1:1 (v/v/v) mixture of acetic acid, water and conc. sulphuric acid) under reflux for about 4 hrs to 8 hrs. Sulfuric acid (H2SO4) is a corrosive substance, destructive to the skin, eyes, teeth, and lungs. Severe exposure can result in death. It has drawbacks in that it requires expensive equipment to withstand highly acidic conditions (may corrode reactors), as well as the need to recover the acid for the process to be economically viable, and to reduce waste.
CN103304515A describes a process for preparation of 11-amino-dibenzo [b,f][1,4]thiazepine. The said process involves use of 2-amino-2'-nitrilediphenyl sulphide. The process for the preparation of 2-amino-2’-nitrilediphenyl sulfide is carried out by reacting 2-aminobenzenethiol with 2-chlorobenzonitrile in N, N-dimethylformamide and benzene solvent mixture. Use of multiple solvents ultimately increases production cost (does not involve the formation of 2-(2-aminophenylthio) benzoic acid neither directly nor indirectly.) Cyclization at second step is carried out by employing sodium tert-butoxide or potassium tertiary butoxide.
WO2009095529 discloses preparation of 2-amino-2’nitrile diphenyl sulfide by using amino thiophenols and o-chlorobenzonitrile. Furthermore, cyclization makes also sulphur azatropylidene. This synthetic method the first step adopts the DMF single solvent, and the saleratus that reaction generates under the high temperature has decomposition, generates water, can make raw material generation side reaction; Second step is used excessive NaH, and aftertreatment adds water generates hydrogen, easily causes danger; And per step post-reaction treatment all is directly to strengthen water gaging to use a large amount of solvent extraction products again, and this has brought a large amount of waste water, and suitability for industrialized production can strengthen the cost of processing waste water, and complicated operation.
CN101987846 discloses synthesis of quetiapine. In the said synthesis o-chloronitrobenzene is used as a raw material to react with sodium hydrosulfide to obtain o-nitrothiophenol, and furthermore reduction of o-nitrothiophenol to amino thiophenol is obtained. The by-product is a disulfide. In the reduction step of the process, because sulfydryl is exposed and impurities of disulfide are easily generated. The impurities of disulfide are difficult to completely remove from the product result in reduced yield and purity of product and/or its intermediate.
Manufacture on an industrial scale using the known process is rendered difficult and extremely uneconomical, respectively, by the fact that a crystalline product of acceptable purity can be obtained only after purification by column chromatography. When handling larger quantities, this side-reaction reduces the yield, and the side reaction product contaminates the end-product. A further drawback resides in the fact that also the preparation of quetiapine intermediate can be carried out in several reaction steps which renders the known process still less economical.
Above mentioned synthesis of quetiapine and/ or its intermediates involves the use of toxic or flammable chemicals, posing risks to workers and the environment. Therefore, care should be taken during handling and containment measures.
Complex synthesis of quetiapine intermediate (Lactam) involves multiple steps, each with its own potential for low yield or by-product formation, reducing overall efficiency. Furthermore, separating the desired product from impurities and by-products can be difficult and time-consuming, impacting yield and cost. The catalyst or reagent used to accelerate reactions can deactivate over time, requiring replacement or regeneration, which adding complexity and cost. Said synthesis generates hazardous waste, requiring proper disposal or treatment, adding cost and environmental burden. Synthesis processes of quetiapine and/or its intermediate rely on organic solvents, which can be volatile, toxic, and contribute to greenhouse gas emissions. Heating, cooling, and stirring required in synthesis can consume significant energy, impacting environmental footprint.
Furthermore, pharmaceutical production must adhere to strict GMPs, ensuring product quality, safety, and consistency. Manufacturers must comply with regulations regarding waste disposal, solvent emissions, and other environmental concerns.
The disclosures of above references for preparation of lactam intermediate involves multiple reaction steps. Utmost, multiple reaction conditions, parameters, by-products, wastage of reaction materials and like are maximum and need to be monitored.
Therefore, there is a need to design various strategies to prepare said intermediate compound which can be cost-effective and environment friendly and can reduce the overall cost of large-scale production of quetiapine.
The present invention provides an improved method for manufacturing of Dibenzo[b,f][1,4]thiazepin-11(10H)-one (lactam) with minimum reaction steps, use of green solvent, optimised reaction conditions resulting in low rate of formation of by-product, without isolation of one or more intermediates and/or solvent recovery and recycling of solvent used for continuous production of said quetiapine intermediate.

OBJECTS OF THE INVENTION
One of the objects of the present invention is to provide an improved method for manufacturing of one or more intermediate compound(s) which can be used in the synthesis of quetiapine free base and/or its pharmaceutically acceptable salt.
Another object of the present invention is to provide a method for synthesising intermediate compound of formula 3 and/or compound of formula 4 and/or compound of formula 5.
Another object of the present invention is to provide a method for manufacturing compound of formula 5 which may involve minimum number of reaction steps, use of green solvent, optimised reaction conditions resulting in low rate of formation of by-product.
Yet object of embodiment of the present invention is to provide a method for manufacturing intermediate compound of formula 5 which is used in the synthesis of quetiapine.
Another object of the present invention is to provide a method for manufacturing of compound of formula 5 without isolating one or more intermediate compound, preferably compound 3 and/or compound 4.
Yet another object of the present invention is to provide a method for manufacturing intermediate compound of formula 5 with high yield as well as high purity.
Yet further another object of the present invention is to provide an improved method for manufacturing compound of formula 5 that is economically viable and industrially feasible.

SUMMARY OF THE INVENTION
Main aspect of the present invention provides an improved method for manufacturing compound of formula 5,

the method comprising:
a) combining a compound of formula 1 with a compound of formula 2 in presence of a base in a solvent to obtain a compound of formula 3;

b) contacting the compound of formula 3 with a base in a solvent followed by an acid to obtain a compound of formula 4; and

c) contacting the compound of formula 4 with a catalyst (monochlorobenzene) to obtain the compound of formula 5;

In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, the method comprising:
a) mixing a base and a solvent to obtain a suspension;
b) adding a compound of formula 1 into the suspension obtained from step (a) at a temperature ranging from about 25oC to 40oC to obtain a reaction mixture;
c) contacting a solution of compound of formula 2 in a solvent with the reaction mixture at a temperature ranging from 80oC to 90oC and thereafter maintaining at a temperature ranging from about 85oC to 90°C for a period ranging from about 4 hrs to 8 hrs to obtain a reaction mass 1;
d) cooling the reaction mass 1 to a temperature ranging from 70oC to75oC and recovering the solvent by concentrating the reaction mass 1 and thereafter degassing at 90oC to 95oC to obtain a residue;
e) adding a solvent or water to the residue and heating at temperature ranging from about 90oC to 95oC to obtain an organic layer comprising a compound of formula 3 and aqueous layer (containing impurity);
f) separating the organic layer from the aqueous layer and concentrating the organic layer and degassing at temperature ranging from 85oC to 95oC to obtain the compound of formula 3;
g) making a mixture comprising the compound of formula 3 and a solvent;
h) treating an aqueous solution of a base with the mixture at a temperature ranging from about 98oC to about 108oC for a period ranging from about 16 hrs to about 24 hrs to obtain reaction mass 2;
i) cooling, diluting, and acidifying the reaction mass 2 to pH ranging from 8 to 9 and then filtering and washing with solvent to eliminate solid material containing organic or inorganic salt and impurities and then again acidifying filtrate containing reaction mass 2 then filtering & washing with solvent to obtain a wet cake of compound of formula 4; and
j) contacting the wet cake of compound of formula 4 with a catalyst at a temperature ranging from about 90oC to about 135oC for a period ranging from 16 hrs to 20 hrs to obtain a compound of formula 5 with yield ranging from about 75% to about 85% and purity ranging from about 99.5% to about 99.99% (by HPLC);

BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows GC purity of compound of formula 3.
Figure 2 depicts HPLC purity of compound of formula 4.
Figure 3 illustrates the HPLC purity of compound of formula 5.

DETAILED DESCRIPTION OF THE INVENTION
In the specification, certain terms are used to describe the present invention. The definitions of the said terms are provided below.
The term ‘compound’ or 'an intermediate’ or ‘intermediate compound’ or ‘compound of formula 3 or 4’ or ‘intermediate compound of formula 3 or 4’ or ‘formula 3 or 4’ or ‘compound 3 or 4’ used herein refers to a compound formed within the sequence of a stepwise chemical reaction. It is formed as the reaction product of an elementary step from the reactants and/or preceding intermediates but is consumed in a later step of reaction. In the present invention, the reaction product of step (a) and/or step (b) which are consumed in later step (b) and/or step (c) respectively.
In the present invention intermediate compound may be formed including such as but is not limited to compound of formula 3, and compound of formula 4. The terms used 'an intermediate’, ‘intermediate compound’, ‘compound of formula 5, ‘intermediate compound of formula 5’, ‘formula 5’ can be used interchangeably throughout the specification.
The term, ‘catalyst’ or ‘reagent’ or ‘agent’ used herein refers to a substance which can extend rate of chemical reaction without getting consumed resulting in the formation of end product. In the present invention, the catalyst may be used include such as but is a not limited to monochlorobenzene, polyphosphoric acid and like. The terms ‘catalyst’, ‘reagent’, and ‘agent’ can be used interchangeably in the specification.
The term ‘reaction mass 1’ used herein refers to a product with or without by-product formed by combining compound of formula 1 with compound of formula 2 in a reaction solvent.
The term ‘reaction mass 2’ used herein refers to a product with or without by-product formed by combining compound of formula 3 with a base in a reaction solvent.
The term ‘base’ used herein refers to a chemical compound that has the capacity to remove a proton from a molecule of even a very weak acid in an acid-base reaction. In the present invention the base may be used organic and/or inorganic base.
The term ‘suspension’ used herein refers to a heterogeneous mixture in which the solid particles are spread throughout the liquid without dissolving in it.
The term ‘residue’ used herein refers to the material remaining after distillation/ evaporation after removing solvent. It may be solid or oil or oily sticky mass.
The term ‘solvent’ used herein refers to a chemical substance that dissolves another chemical substance to form a solution. The said chemical substance allows to solubilize another chemical substance at the extent rate which makes reaction to be occurred feasible. Solvent may be used include polar, non-polar and mixture thereof.
One of the embodiments of the present invention provides an improved method for manufacturing compound of formula 5,

the method comprising the steps of:
a) combining a compound of formula 1 with a compound of formula 2 in presence of a base in a solvent to obtain a compound of formula 3;

b) contacting the compound of formula 3 with a base in a solvent followed by an acid to obtain a compound of formula 4; and

c) contacting the compound of formula 4 with a reagent (monochlorobenzene) to obtain the compound of formula 5.

In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, the method comprising:
k) mixing a base and a solvent to obtain a suspension;
l) adding a compound of formula 1 into the suspension obtained from step (a) at a temperature ranging from about 25oC to 40oC to obtain a reaction mixture;
m) contacting a solution of compound of formula 2 in a solvent with the reaction mixture at a temperature ranging from 80oC to 90oC and thereafter maintaining at a temperature ranging from about 85oC to 90°C for a period ranging from about 4 hrs to 8 hrs to obtain a reaction mass 1;
n) cooling the reaction mass 1 to a temperature ranging from 70oC to75oC and recovering the solvent by concentrating the reaction mass 1 and thereafter degassing at 90oC to 95oC to obtain a residue;
o) adding a solvent or water to the residue and heating at temperature ranging from about 90oC to 95oC to obtain an organic layer comprising a compound of formula 3 and aqueous layer (containing impurity);
p) separating the organic layer from the aqueous layer and concentrating the organic layer and degassing at temperature ranging from 85oC to 95oC to obtain the compound of formula 3;
q) making a mixture comprising the compound of formula 3 and a solvent;
r) treating an aqueous solution of a base with the mixture at a temperature ranging from about 98oC to about 108oC for a period ranging from about 16 hrs to about 24 hrs to obtain reaction mass 2;
s) cooling, diluting, and acidifying the reaction mass 2 to pH ranging from 8 to 9 and then filtering and washing with solvent to eliminate solid material containing organic or inorganic salt and impurities and then again acidifying filtrate containing reaction mass 2 then filtering & washing with solvent to obtain a wet cake of compound of formula 4; and
t) contacting the wet cake of compound of formula 4 with a catalyst at a temperature ranging from about 90oC to about 135oC for a period ranging from 16 hrs to 20 hrs to obtain a compound of formula 5 with yield ranging from about 75% to about 85% and purity ranging from about 99.5% to about 99.99% (by HPLC);
wherein the water formed during the reaction is continuously removed by azeotropically.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein compound of formula 4 is not isolated during the synthesis of compound of formula 5.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the said method is carried out with or without isolating compound of formula 3, compound of formula 4.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein combining the compound of formula 1 with compound of formula 2 in presence of base in the solvent to obtain compound of formula 3 is carried out at a temperature ranging from about 80oC to about 90°C for a period from about 4 hrs to 8 hrs.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein contacting the compound of formula 3 with a base in a solvent followed by with acid to obtain compound of formula 4 is carried out at a temperature ranging from about 98oC to about 108oC for a period from about 16 hrs to about 24 hrs.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein contacting the compound of formula 4 with the reagent (monochlorobenzene) to obtain the compound of formula 5 is accomplished by without use of solvent at a temperature from about 90oC to about 135oC for the period ranging from about 16hrs to about 24 hrs.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein synthesising compound of formula 3, wherein the said method is carried out by combining the compound of formula 1 with the compound of formula 2 in presence of base in a solvent at a temperature ranging from about 80oC to about 90°C for a period from about 4 hrs to 8 hrs.
Yet another embodiment of the present invention provides a method for synthesising compound of formula 5, wherein the method is carried out by contacting the compound of formula 4 with monochlorobenzene at a temperature ranging from about 90oC to about 135oC for the period ranging from about 16hrs to about 24 hrs; wherein said method is carried out with or without use of solvent.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein reagent or monochlorobenzene acts as solvent as well as cyclisation agent.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein water molecule formed or liberated during reaction is removed by using any technique known in the prior art including such as but is not limited to a Dean-Stark trap or activated molecular sieves.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the base is used organic and/or inorganic base.
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein the organic base may be used include such as but is not limited to amine, alkylamines, dialkylanilines, imidazole, benzimidazole, metal alkoxides, and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein organic base may be used include such as but is not limited to triethylamine, tributylamine, diisopropylethylamine (DIPEA), triisopropylamine, N-methyl morpholine, pyridine, substituted pyridines, N, N-diethylamino pyridine, and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein inorganic bases include amine, metal hydroxide(s), metal carbonate(s), metal hydrogen carbonate(s), ammonia and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein metal alkoxides may be used include such as but is not limited to sodium methoxide, sodium ethoxide, sodium isopropoxide and potassium tert-butoxide; 1,8-diazobicyclo [5,4,0] undecene and N-benzyltrimethylammonium hydroxide, and a combination thereof.
In an embodiment, the base used in the step (a) is metal carbonate(s).
In another embodiment of the present inventio n there is provided an improved method for manufacturing compound of formula 5, wherein the metal carbonate may be used include such as but is not limited to lithium carbonate (Li2CO3) sodium carbonate (Na2CO3), potassium carbonate, rubidium carbonate (Rb2CO3) Iron (II) carbonate (FeCO3), copper (II) carbonate (CuCO3), zinc carbonate (ZnCO3), lead (II) carbonate (PbCO3), barium carbonate (BaCO3), calcium carbonate (CaCO3), Magnesium carbonate (MgCO3), strontium carbonate (SrCO3), and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the base used in the step (b) is metal hydroxide.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the metal hydroxide is used selected from potassium hydroxide, magnesium hydroxide, barium hydroxide, calcium hydroxide, zinc hydroxide, sodium hydroxide, zirconium(IV) hydroxide, lithium hydroxide, rubidium hydroxide, nickel(II) hydroxide, tin(II) hydroxide, Aluminium hydroxide, Cobalt(II) hydroxide, copper(II) hydroxide, curium hydroxide, gold(III) hydroxide, iron(II) hydroxide, mercury(II) hydroxide, and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the acid is organic acid and/or inorganic acid.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the organic acid is selected from acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene sulfonic acid, salicylic acid, and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein inorganic acid is used selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the reagent can be utilised include such as but is not limited to monochlorobenzene, polyphosphoric acid, and combinations thereof.
n another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the reagent is monochlorobenzene (MCB).
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the solvent can be used polar and/or non- polar solvent.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein solvent may include such as but is not limited to water, alcohols, ethers, ketones, esters, hydrocarbons halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, nitriles, diols, triols, acids, pyridine, amides, sulfoxides, and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein solvent may include such as but is not limited to acetone, methyl ethyl ketone, methylisobutylketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-propanol, isopropanol, 1-butanol, 2-butanol, tertiary butanol, and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein solvent used in step (a) is DMF, water and combinations thereof.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein step (c) of the method is carried out without use of any solvent.
In another embodiment of the present invention, reagent acts as solvent as well as agent. It may have dual nature.
In another embodiment of the present invention, there is provided an improved method for manufacturing of compound of formula 5, wherein compound of formula 4 is used in the synthesis of formula 5 either isolating the compound of formula or without isolating the compound of formula 4.
In another embodiment of the present invention, there is provided an improved method for manufacturing of compound of formula 5, wherein synthesis of quetiapine may be carried out either with isolating compound of formula 5 or without isolating the compound of formula 5.
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein OCBN addition is recommended at 80-90oC within 1 to 3 hrs specifically, as per chemistry to ensure complete product conversion. as delay in addition leads incomplete conversion of 2-ATP and OCBN due to 2-ATP Degradation
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein after maintaining, DMF Distillation is recommended to eliminate maximum unreacted OCBN from Reaction mass subsequent to make industrially viable process by recycling of Rec. DMF.
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein water extraction process to reduce inorganic salt and water-soluble impurities. Apart from this DMF Traces removal to enhance product output and quality.
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein distillation and degassing of product layer is the part of process to ensure control of OCBA and OHBA formation due to higher OCBN content.
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein pre-batch filtration at 8-5-9.0 to remove unwanted known and unknown impurities and salts to ensure final compound of formula 5 (DBTO) Quality meets acceptance criteria.
In another embodiment of the present invention there is provided an improved method for manufacturing of compound of formula 5, wherein isolation of product at specifically at 3.0 to 4.0 and effective water washing to remove salts and free acidity ensuring as per safety issue in final compound of formula 5.
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the compound of formula 5 is obtained in the yield ranging from about 85% to about 99.99%
In another embodiment of the present invention there is provided an improved method for manufacturing compound of formula 5, wherein the compound of formula 5 is obtained with purity ranging from about 80% to 99.99% by High Performance Liquid Chromatography (HPLC).
Advantages of the present inventions:
1. The present invention requires less reaction time
2. The present invention is carried out in minimum steps.
3. The present invention provides high purity and high yield.
4. The reagent used in the step (c) acts as solvent as well as agent.
5. The present invention does not involve isolation of compound of formula 4.
6. The present invention provides recovery and recycling of solvent (DMF) which makes method continuous and economically feasible.
7. The reagents/ reagents, solvents used in the present invention are mild, less expensive, less toxic, and environmentally friendly.
8. The present invention involves steps to ensure higher product purity by extractions, distillation and elimination of organic/Inorganic salt and impurities from reaction mass.
9. The present invention provides compound of formula 5 with yield ranging from about 75% to about 85% and purity ranging from about 99.5% to about 99.99% (by HPLC).
The following examples are given by way of illustration of the present invention and should not be construed to limit the scope of present disclosure. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the claimed subject matter.
Examples:
1. Synthesis of Aminophenylthiobenzonitrile (compound of formula 3):
To the suspension of potassium carbonate (1.02 eq) and DMF (2.4 vol.) was added solution of 2-Aminothiophenol (compound 1) (200 gm in 0.8 vol of DMF) at 25-40°C. Then was added, solution of Ortho-chlorobenzonitrile (compound 2) i. e. OCBN in 0.8 vol DMF at temp. 80-90°C. Reaction mass was maintained for 6.0±2 hours at 85-90°C. After reaction completion, cooled to 75°C and solvent was distilled out under vacuum, residue was degassed at 90-95°C. Then, was added 3.2 volume of water to the residue and reaction mass was heated to 90-95°C, organic and aqueous layer was separated, product layer washed with 3.2 volume of water at 90-95°C and oily product was degassed under vacuum at temp. 90±5°C to obtain compound of formula 3. Yield: 340gm; Purity: 95% (by Ga Chromatography (GC)).
2. One pot synthesis of Dibenzo[b,f][1,4]thiazepin-11(10H)-one from compound of example 1:
To this compound of formula 3 of example 1 was added 3.85 volume of water and reaction mass was heated to reflux at 103±5°C. To this resulting reaction mass, was added aqueous NaOH solution (NaOH-216 gm in 1.25 vol water) at temp. 103±5°C and maintained for 20±4.0 hours at temp. 103±5°C. After reaction completion, reaction mixture was cooled, diluted with 2.3 vol of water and acidified using conc. HCl, the reaction mass to certain pH Range 8-9 and then filter and wash with solvent to eliminate solid material containing organic or inorganic salt and impurities. Then again filtrate acidifying the reaction mass then filtering & washing with water to get Aminophenylthiobenzoic acid (compound 4). Wet cake Wt.: 400-600 gm).
Compound 4 wet cake (400-600gm) was suspended in 1225ml of monochlorobenzene and reaction mixture was heated to 90-135°C and water is removed azeotropically using dean stark. Then reaction mixture was stirred for 20±4 hours at temp. 130-135°C. After completion of the reaction, reaction mixture was cooled to 30±5°C and filtered. Wet cake was washed with chlorobenzene (300 ml) followed by wash with 300 ml of water. Obtained wet cake was dried in oven at temp. 90-95°C to get final compound of formula 5. Wt. obtained: 270 gm; Yield: 270 gm, purity: 99.5%.

,CLAIMS:We claim:
1. An improved method for manufacturing compound of formula 5,

the method comprising:
a) combining a compound of formula 1 with a compound of formula 2 in presence of a base in a solvent to obtain a compound of formula 3;

b) contacting the compound of formula 3 with a base in a solvent followed by an acid to obtain a compound of formula 4; and

c) contacting the compound of formula 4 with a catalyst to obtain the compound of formula 5;

2. An improved method for manufacturing compound of formula 5,

the method comprising:
a) mixing a base and a solvent to obtain a suspension;
b) adding a compound of formula 1 into the suspension obtained from step (a) to obtain a reaction mixture;
c) contacting a solution of compound of formula 2 in a solvent with the reaction mixture obtained from step (a) and thereafter maintaining to obtain a reaction mass 1;
d) cooling the reaction mass 1 and recovering the solvent by concentrating the reaction mass 1 and thereafter degassing to obtain a residue;
e) adding a solvent or water to the residue and heating to obtain an organic layer comprising a compound of formula 3 and aqueous layer (containing impurity);
f) separating the organic layer from the aqueous layer and concentrating the organic layer & degassing to obtain the compound of formula 3;
g) making a mixture comprising the compound of formula 3 and a solvent;
h) treating an aqueous solution of a base with the mixture to obtain reaction mass 2;
i) cooling, diluting, and acidifying the reaction mass 2, then filtering and washing with solvent to eliminate solid material containing organic or inorganic salt and impurities and then again acidifying filtrate containing reaction mass 2 then filtering & washing with solvent to obtain a wet cake of compound of formula 4; and
j) contacting the wet cake of compound of formula 4 with a catalyst to obtain a compound of formula 5 with yield ranging from about 75% to about 85% and purity ranging from about 99.5% to about 99.99% (by High Performance Liquid Chromatography (HPLC));
wherein the water formed during the reaction is continuously removed by azeotropically.
3. The method as claimed in any claim of 1 to 2, wherein combining a compound of formula 1 with a compound of formula 2 in presence of a base in a solvent is carried out at a temperature ranging from about 80oC to about 90°C for a period from about 4 hrs to 8 hrs.
4. The method as claimed in any claim of 1 to 2, wherein contacting the compound of formula 3 with a base in a solvent followed by with acid is carried out at a temperature ranging from about 98oC to about 108oC for a period from about 16 hrs to about 24 hrs.
5. The method as claimed in any claim of 1 to 2, wherein contacting the compound of formula 4 with a catalyst is accomplished by without use of solvent at a temperature from about 90oC to about 135oC for the period ranging from about 16hrs to about 24 hrs.
6. The method as claimed in any claim of 1 to 2, wherein solvent is selected from water, acetone, methyl ethyl ketone, methyl-isobutyl ketone (MIBK), dichloromethane, ethylene dichloride, chloroform, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile, diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, methanol, ethanol, 2-propanol, isopropanol, 1-butanol, 2-butanol, tertiary butanol, pentanol and combinations thereof.
7. The method as claimed in in claim of 1 to 2, wherein base is selected from amine, metal hydroxide(s), metal carbonate(s), metal hydrogen carbonate(s), ammonia and combinations thereof; wherein base is metal carbonate selected from Li2CO3, Na2CO3, KCO3, Rb2CO3, FeCO3, CuCO3, ZnCO3, PbCO3, BaCO3, CaCO3, MgCO3, SrCO3, and combinations thereof; wherein metal hydroxide is selected from KOH, Mg(OH)2, barium hydroxide, Ba(OH)2, Ca(OH)2, Zn(OH)2, NaOH, Li(OH), Al(OH)3, Cu(OH)2 and combinations thereof.
8. The method as claimed in any claim of 1 to 2, wherein the reagent is monochlorobenzene.
9. The method as claimed in any claim of 1 to 2, wherein the reagent has dual nature, acts as solvent as well as initiator or catalyst.
10. The method as claimed in any claim of 1 to 2, wherein compound of formula 4 is not isolated during said process.

Dated this:

For Unichem Laboratories Ltd.

Gautam Bakshi
IN/PA-1069
Head-IPM
To,
The Controller of Patents,
The Patent Office, Mumbai