WO2007004234A1 - A PROCESS FOR THE PREPARATION OF 2-[2-(4-DIBENZO[b,f] [L,4] THIAZEPIN-11-yl-1- PIPERAZINYL)ETHOXY] ETHANOL FUMARATE - Google Patents

A PROCESS FOR THE PREPARATION OF 2-[2-(4-DIBENZO[b,f] [L,4] THIAZEPIN-11-yl-1- PIPERAZINYL)ETHOXY] ETHANOL FUMARATE Download PDF

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WO2007004234A1
WO2007004234A1 PCT/IN2005/000379 IN2005000379W WO2007004234A1 WO 2007004234 A1 WO2007004234 A1 WO 2007004234A1 IN 2005000379 W IN2005000379 W IN 2005000379W WO 2007004234 A1 WO2007004234 A1 WO 2007004234A1
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formula
dibenzo
quetiapine
piperazinyl
alcohol
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PCT/IN2005/000379
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French (fr)
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Venkatasubramanian Radhakrishnan Tarur
Dhananjay Govind Sathe
Avinash Venkatraman Naidu
Umesh Parashram Aher
Sachin Shivaji Patil
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Usv Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D281/00Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02Seven-membered rings
    • C07D281/04Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/12Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D281/16[b, f]-condensed

Abstract

A process for the preparation of 2-[2-(4-Dibenzo[b,f] [l,4] thiazepin-11-yl-1- ρiperazinyl)ethoxy] ethanol fumarate commonly known as Quetiapine hemifumarate. Dibenzo[b,f] [l,4] thiazepin-11-[10H]one is halogenated with a halogenating agent in the ratio of 1 : 0.5 to 3 w/v in an organic solvent in the presence of an organic base at reflux temperature followed by condensation of the reaction with piperazine without isolating the imino chloride. The piperazinyl-dibenzo[b,f] [l,4] thiazepine is converted to Quetiapine hemifumarate which is purified by crystallization with alcohol at reflux temperature and precipitated it by cooling the reaction mixture and recovered by filtration.

Description

TITLE OF THE INVENTION
A process for the preparation of 2-[2-(4-Dibenzo[b,f)[l,4] thiazepin-ll-yl-1- piperazinyl)ethoxy] ethanol fumarate
TECHNICAL FIELD OF INVENTION:
The invention relates to a process for the preparation of 2-[2-(4-Dibenzo[b,f][l,4] thiazepin- 1 l-yl-l-piperazinyl)ethoxy] ethanol hemifumarate, commonly known as Quetiapine hemifumarate of the formula (I):
Figure imgf000002_0001
Formula I
Quetiapine hemifumarate of the formula (I) is a psychotropic agent belonging to the chemical class of dibenzothiazepine derivatives. It is useful in treating psychosis and hyperactivity (severe mental disorders characterized by distorted thoughts, perceptions and emotions) such as schizophrenia. While the exact mechanism of action of Quetiapine is unknown, it appears to interfere with receptors for certain critical natural substances (neurotransmitters) in the brain to produce a trariquilizing and antipsychotic effect.
BACKGROUND AND PRIOR ART:
Several approaches are described in the literature to make Quetiapine hemifumarate of the formula (I). Broadly, they fall in two categories:
1. The first approach, uses Dibenzo[b,f][l,4] thiazepin-1 l-[10H]one of the formula (II)
Figure imgf000003_0001
Formula (II)
as an intermediate to which the side chain is then attached.
2. The second approach, uses cyclization of urea or amide intermediate to build a thiazepine moiety.
US 4879288 (EP 0240228), EP 0282236 and WO 2005014590 describe preparation of Quetiapine hemifumarate of the formula (I) starting from Dibenzo[b,fJ[l,4] thiazepin-11- [10H]one of the formula (II) whereas WO 0155125, WO 2005012274, WO 2005028458 and WO 2005028459 describe the latter approach.
EP 0240228 describes a process for the preparation of Quetiapine hemifumarate of the formula (I) by halogenating Dibenzo[b,fj[l,4] thiazepin-l l-[10H]one of the formula (II) with a phosphorous oxychloride (1: 6 w/v) in the presence of a base, dimethylaniline to obtain imino chloride, which is then isolated and condensed with l-(2-hydroxyethoxy) ethyl piperazine to get Quetiapine base as shown in the following reaction scheme 1.
Scheme 1
Figure imgf000003_0002
Figure imgf000003_0003
The oily crude base thus obtained is subjected to purification by a column chromatography using a silica gel column. The Quetiapine base is then converted to its corresponding hemifumarate of the formula (I). A crystalline product of acceptable purity can be obtained by this process only after purification by column chromatography thereby making the process uneconomical on an industrial scale. Further the process uses l-(2-hydroxyethoxy) ethyl piperazine as an intermediate that needs to be synthesized in several reaction steps thereby making the process time consuming and uneconomical. The overall yield of the Quetiapine is reported to be 62.6 % based on the starting material.
EP 0282236 describes a process, which avoids the use of l-(2-hydroxyethoxy) ethyl piperazine as an intermediate. Dibenzo[b,fj[l,4] thiazepin-ll-[10H]one is reacted with a phosphorus oxychloride (1: 6 w/v) in the presence of a base, N,N-dimethyl aniline to obtain imino chloride. The imino chloride is then isolated and condensed with piperazine followed by reaction with 2- haloethoxy ethanol to give the Quetiapine base. The quetipine base is further converted into its salt, hemifumarate as shown in following reaction scheme 2.
Scheme 2
Figure imgf000004_0001
The overall yield reported for Quetiapine hemifumarate is about 55.3 % based on the starting material.
Both the above mentioned processes use excess amount of the halogenating agent like phosphorous oxychloride (1 : 6 w/v) which requires to be removed in vacuo using a rotary evaporator followed by treatment of the brown syrup obtained with toluene and ice-water mixture and separation of the toluene layer. The toluene layer is washed with water, dried and concentrated in a rotary evaporator to give crude imino chloride. Isolation of the imino chloride is a long and time consuming procedure. Besides excess use of the halogenating agent renders the process expensive and also creates disposal and environmental problems. Therefore, the process is not environmental friendly. Further the imino chloride obtained as an intermediate is unstable and gets hydrolyzed due to humidity in the atmosphere. Due to hydrolysis, the final product may get contaminated. Isolation of the imino chloride requires stringent conditions due to its sensitivity towards moisture. Handling of imino chloride especially at industrial scale is problematic.
WO 0155125 discloses a process for the preparation of Quetiapine hemifumarate of the formula (I) by cyclizing N-[4-(2-chloroethyl) piperazine-l-carbonyl]-2-aminodiphenyl sulfide in the presence of a dehydrating agent to obtain ll-[4-(2-chloroethyl) piperazinyl]- dibenzo[b,fj-l,4-thiazepine which is further condensed with ethylene glycol to get the Quetiapine base, which is converted to Quetiapine hemifumarate as shown in the reaction scheme 3 below:
Scheme 3
Figure imgf000005_0001
The overall yield reported for Quetiapine hemifumarate is 56.9 % based on the starting material. This process requires an extremely strong deprotonization agent, sodium in order to generate anion and excess ethylene glycol (30 equivalent) in order to minimize undesired side reactions. The excess ethylene glycol must be removed after treating with a large quantity of water thereby causing disposal of large quantity of residual aqueous waste.
WO 2005012274 describes a process for preparation of l l-(10-piperazinyl)-dibenzo [b,fj[l,4]thiazepine which is an intermediate of Quetiapine. In this process phenyl 2-(phenyl thio) phenyl carbamate is reacted with piperazine followed by cyclization of the intermediate in the presence of dehydrating agent like POCl3ZP2O5 to obtain l l-(10-piperazinyl)-dibenzo [b,f][l,4]thiazepine as shown in the reaction scheme 4 below:
Scheme 4
Figure imgf000006_0001
The l l-(10-piperazinyl)-dibenzo [b,fj[l,4]thiazepine is converted into Quetiapine hemifumarte. The overall yield of l l-(10-piperazinyl)-dibenzo [b,fj[l,4] thiazepine is reported to be 65%. The process is also lengthy and time consuming.
WO 2005014590 describes another route for preparation Quetiapine in which 2-(4- dibenzo[b,fj[l,4] thiazepine- 11-yl-piperazine-l-yl) ethanol is reacted with 2-(2-chloroethoxy)- tetrahydro-2H-pyran in the presence of base and phase transfer catalyst followed by deprotection to obtain Quetiapine base which is optionally converted into its salts as shown in the reaction scheme 5 below:
Scheme 5
Figure imgf000007_0001
P= protective group X=leavinq group
Deprotection
Figure imgf000007_0002
The intermediate, 2-(2-chloroethoxy)-tetrahydro-2H-pyran, required in this process is prepared separately. The use of protected intennediates increases the number of steps and hence the procedure is lengthy and time consuming.
Another process for the preparation of Quetiapine is described in WO 2005028457. 2-[(2- benzyloxyethoxy)ethyl] bis(2-chloroethyl)amine is condensed with Dibenzo[b,f][l,4]thiazepin- 11-yl amine to obtain l l-{4-[2-(2-benzyloxy-ethoxy)ethyl]-piperazin-l-yl} dibenzo[b,f]-l,4- thiazepine which on deprotection with borontrichloride gave Quetiapine base. Tetrahydropyran has also been used as -OH protective group as shown in the reaction scheme 6 below:
Scheme 6
Figure imgf000007_0003
Figure imgf000007_0004
The overall yield reported is 14.55 %. The use of protected intermediates increases the number of steps and hence the procedure is lengthy and time consuming. WO 2005028458 discloses another process for the preparation of Quetiapine starting from 2- (2-amino-phenylsulfanyl)-phenyl-{4-[2-(2-hydroxy-ethoxy)ethyl-piperazin-l-yl}-methanone. In this process 2-(2-amino-phenylsulfanyl)-phenyl-{4-[2-(2-hydroxy-ethoxy)ethyl-piperazm- l-yl}-methanone is acetylated to protect hydroxy group followed by cyclization to obtain 11- [4-[2-(2-acetyloxy ethoxy) ethyl]-l-piperazinyl)-dibenzo[b,fj-l,4-thiazepine which on deprotection gives Quetiapine base as shown in the reaction Scheme 7 below.
Scheme 7
Figure imgf000008_0001
Deprotection
Figure imgf000008_0002
The overall yield reported for Quetiapine base is 61.74 %. This process also lengthy and time consuming as it use protected intermediates leading to increased number of steps.
WO 2005028459 describes a process starting from 4-[2-(2-hydroxyethoxy)-ethyl]piperazine carboxylic acid (2-phenylsulfanyl phenyl)-amide. Hydroxyl group of the starting material is protected with benzoyl group followed by cyclization to obtain benzoyl protected Quetiapine base, which on deprotection gave Quetiapine base as shown in the reaction scheme 8 below: Scheme 8
Figure imgf000009_0001
The overall yield of Quetiapine reported is 32.39 %. The use of protected intermediates increases the number of steps and hence the procedure is lengthy and time consuming.
WO 9906381 describes a process of crystallization of Quetiapine fumarate using aromatic solvent like toluene to obtain highly pure crystalline Quetiapine fumarate for pharmaceutical use.
The prior art processes invariably isolate the intermediates thereby increasing the process duration and cost. Due to the unstable nature of imino chloride derivative, its isolation and handling is difficult and inconvenient. Use of large excess of phosphorous oxychloride (1 :6 w/v) for chlorination causes recovery and disposal problems and is uneconomical. Use of protecting group increases the number of reaction steps. Because of steps like column purification and multipurification the processes are industrially and commercially unviable. They also require large amounts of solvents increasing the cost and creating disposal problems and rendering them non-ecofriendly. .
OBJECTS OF INVENTION
An object of the invention is to provide a process for the preparation of Quetiapine hemifumarate in high yield and purity. Another object of the invention is to provide a process for the preparation of Quetiapine hemifumarate, which process is simple, easy and convenient to carry out, economical and efficient.
Another object of the invention is to provide a process for the preparation of Quetiapine hemifumarate, which process reduces waste generation and disposal problems and is eco- friendly.
Another object of the invention is to provide a process for the preparation of Quetiapine hemifumarate which process is of reduced duration.
DETAILED DESCRIPTION OF INVENTION
According to the invention there is provided a process for the preparation of 2-[2-(4- Dibenzo[b,fJ[l,4] thiazepin-l l-yl-l-piperazinyl)ethoxy] ethanol fumarate (Quetiapine hemifumarate) of the formula (I):
Figure imgf000010_0001
the process comprising: a. preparing l l-piperazinyl-dibenzo[b,fj[l,4] thiazepine dihydrochloride of the formula (IV)
Figure imgf000010_0002
Formula (IV) by halogenating Dibenzo[b,fJ[l,4] thiazepin-1 l-[10H]one of the formula (II)
Figure imgf000011_0001
Formula (II) with a halogenating agent selected from thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxybromide or phosphorus oxychloride in the ratio of 1 : 0.5 to 3 w/v in an organic solvent in the presence of an organic base selected from N,N-dimethyl aniline, N,N-diethyl aniline or triethylamine at reflux temperature, distilling out the organic solvent from the reaction mixture, dissolving the residue in an organic solvent followed by adding aqueous alkali solution to form a biphasic reaction mixture, separating the organic layer from the aqueous layer, adding piperazine to the organic layer and refluxing it followed by distilling out the solvent from the reaction mixture to obtain a residue containing piperazinyl-dibenzo[b,fj[ 1,4] thiazepine of the formula (III),
Figure imgf000011_0002
Formula (III) dissolving the residue in a lower aliphatic alcohol followed by treating the solution with a alcoholic solution of hydrogen chloride to obtain 11-piperazinyl- dibenzo[b,f][l,4] thiazepine dihydrochlori.de of the formula (IV); condensing the compound of the formula (IV) with chloro ethoxy ethanol in a solvent mixture to obtain Quetiapine base of the formula (V)
Figure imgf000012_0001
Formula (V) and converting it into Quetiapine hemifumarate of the formula (T); and c. purifying the Quetiapine hemifumarate of the formula (I) by crystallization from alcohol by refluxing the Quetiapine hemifumarate with alcohol in the ratio of 1:5 to 15 w/v, precipitating the compound of the formula (I) by cooling the reaction mixture to a temperature range of O0C to 300C followed by filtration.
Preferably, the organic solvent used in step (a) is selected from the group comprising aromatic hydrocarbon including toluene, xylene, chloro benzene or nitro benzene or mixtures thereof. Preferably, the ratio of the Dibenzo[b,f][l,4] thiazepin-l l-[10H]one and the halogenating agent used in step (a) is 1:1.25 w/v. The halogenation of step (a) is carried out for 2.0 to 5.0 hours. The organic layer comprising imino chloride is refluxed with piperazine for 10 to 30 hours, preferably 24 hours. Preferably, the aqueous alkali solution used in step (a) is aqueous potassium carbonate solution, sodium carbonate solution or sodium hydroxide solution or more preferably aqueous potassium carbonate solution. Preferably, the lower aliphatic alcohol used to dissolve the residue in step (a) is isopropanol. Preferably, the alcoholic solution of hydrogen chloride used in step (a) is ethanolic hydrogen chloride. Preferably, the solvent mixture used in step (b) is selected from dipolar aprotic solvent and lower aliphatic alcohol. Preferably, the dipolar aprotic solvent is DMF and the lower aliphatic alcohol is n-propanol. Preferably, the ratio of the Quetiapine hemifumarate and the alcohol used in the purification step (c) is 1:10 w/v. Preferably an alcohol used in the purification step (c) is selected from methanol, ethanol or isopropyl alcohol or mixtures thereof. Preferably, precipitating Quetiapine hemifumarate in step (c) is carried out by cooling the reaction mixture to the temperature range of 100C to 150C.
According to the invention the overall yield of Quetiapine hemifumarate is 76.95% with a high purity of > 99.8 %. The chlorinating agent is used in reduced quantity in the ratio of 0.5 to 3: 1 with respect to Dibenzo[b,fj[l,4] thiazepin-ll-[10H]one thereby eliminating the need for recovery of excess chlorinating agent and disposal of the same. As the imino chloride derivative is not isolated, the isolation, purification and drying steps involved have been eliminated thereby reducing the process time. Formation of impurities due to side reactions and hydrolysis has also been eliminated. The crude Quetiapine hemifumarate is purified by crystallization using alcohol, which is easier and economical as compared to purification by column chromatography. Overall solvent requirement is reduced thereby reducing waste generation and disposal problems. The process is simple, easy and convenient to carry out, efficient, economical and eco-friendly and also industrially and commercially viable.
The process of the present invention is described herein below with reference to the following example, which is illustrative only and should not be construed to limit the scope of the present invention in any manner.
Example:
a) ll-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride (IV)
Figure imgf000013_0001
Dibenzo[b,fj[l,4] thiazepin-l l-[10H]one 100 gm, phosphorus oxychloride 125 ml, N5N- dimethyl aniline 33 ml in toluene 500 ml were refluxed for 4 hour. Toluene was distilled off under vacuum to obtain residue. The residue was dissolved in 250 ml toluene and the reaction mixture was cooled to 100C. Aqueous Potassium carbonate solution (100 g in 200 ml water) was added to the reaction mixture below 150C. The toluene layer was separated and refluxed with piperazine 100 g for 24 hour. The reaction mixture was cooled and filtered to remove unreacted piperazine. Toluene was distilled off under vacuum. The residue was dissolved in 390 ml of isopropyl alcohol. 100 ml of 33% ethanolic hydrochloride was added to the reaction mixture at 25-35° C. White solid obtained was filtered, washed with 100 ml ethanol and dried at 60-700C. Yield : 138 g (90 %). b) 2-[2-(4-Dibenzo[b,f][l,4] thiazepin-ll-yl-l-piperazinyl)ethoxy] ethanol hemifumarate (Crude Quetiapine hemifumarate) (I)
Figure imgf000014_0001
l l-piperazinyl-dibenzo[b,f][l,4] thiazepine dihydrochloride (138 gm), chloroethoxy ethanol (92.7 gm), Sodium carbonate (238 gm), Sodium iodide (2.83 gm), DMF (391 ml) and n- propanol (552 ml) were refluxed for 24 hour. After the completion of the reaction, the reaction mixture was filtered off to remove the insolubles. The filtrate was distilled off to remove solvent. The residue obtained was dissolved in 2.3 Liter of methylene dichloride. The methylene dichloride layer was washed with 2.75 Liter of water. Methylene dichloride was then distilled off and the oily residue was dissolved in 225 ml of ethanol. To this solution, ethanolic solution of fumaric acid (22.9 gm dissolved in 312 ml ethanol) was added slowly with stirring. The reaction mixture was cooled to 10-200C. The solid obtained was filtered and dried at 60-700C.
Yield : 149 g (95 %) Melting point 172-760C.
c) 2-[2-(4-Dibenzo[b,f][l,4] thiazepm-ll-yl-l-piperazinyl)ethoxy] ethanol hemifumarate (Quetiapine hemifumarate Pure)
149 gm of crude 2-[2-(4-Dibenzo[b,fJ[l,4]thiazepm-l l-yl-l-piperazmyl) ethoxy] ethanol hemifumarate and 1490 ml of methanol were refluxed for 1 hour. Filtered hot and the filtrate gradually cooled to 10-15° C to precipitate solid. Solid obtained was filtered and washed twice with 300 ml of cooled methanol each time and dried at 60-700C.
Yield : 134 g (90 %) % ofPurity = 98.8%

Claims

1. A process for the preparation of 2-[2-(4-Dibenzo[b,fj[l,4] thiazepin-ll-yl-1- piperazinyl)ethoxy] ethanol fumarate (Quetiapine hemifumarate) of the formula (I):
Figure imgf000015_0001
Formula (I) the process comprising; a) preparing l l-piperazinyl-dibenzo[b,fj[l,4] thiazepine dihydrochloride of the formula (IV)
Figure imgf000015_0002
Formula (IV) by halogenating Dibenzo[b,fJ[l,4] thiazepin-1 l-[10H]one of the formula (II)
Figure imgf000015_0003
Formula (II) with a halogenating agent selected from thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus oxybromide or phosphorus oxychloride in the ratio of 1 : 0.5 to 3 w/v in an organic solvent in the presence of an organic base selected from N,N-dimethyl aniline, N,N-diethyl aniline or triethylamine at reflux temperature, distilling out the organic solvent from the reaction mixture, dissolving the residue in an organic solvent followed by adding aqueous alkali solution to form a triphasic reaction mixture, separating the organic layer from the aqueous layer, adding piperazine to the organic layer and refluxing it followed by distilling out the solvent from the reaction mixture to obtain a residue containing piperazinyl-dibenzo[b,fj[l,4] thiazepine of the formula (III),
Figure imgf000016_0001
Formula (III) dissolving the residue in a lower aliphatic alcohol followed by treating the solution with a alcoholic solution of hydrogen chloride to obtain 11-piperazinyl- dibenzo[b,fj[l,4] thiazepine dihydrochloride of the formula (IV); b." condensing the compound of the formula (IV) with chloro ethoxy ethanol in a solvent mixture to obtain Quetiapine base of the formula (V)
Figure imgf000016_0002
Formula (V) and converting it into Quetiapine hemifumarate of the formula (T); and c. purifying the Quetiapine hemifumarate of the formula (I) by crystallization from alcohol by refluxing the Quetiapine hemifumarate with alcohol in the ratio of 1:5 to 15 w/v, precipitating the compound of the formula (I) by cooling the reaction mixture to a temperature range of O0C to 300C followed by filtration.
2. The process as claimed in claim 1, wherein the organic solvent used in step (a) is selected from the group comprising aromatic hydrocarbon including toluene, xylene, chloro benzene or nitro benzene or mixtures thereof.
3. The process as claimed in claim 1, wherein the ratio of the Dibenzo[b,f][l,4] thiazeρin-l l-[10H]one and halogenating agent used in step (a) is 1:1.25 w/v.
4. The process as claimed in claim 1, wherein the aqueous alkali solution used in step (a) is aqueous potassium carbonate solution, sodium carbonate solution or sodium hydroxide solution.
5. The process as claimed in claim 1, wherein the lower aliphatic alcohol used to dissolve the residue in step (a) is isopropanol.
6. The process as claimed in claim 1, wherein the alcoholic solution of hydrogen chloride used in step (a) is ethanolic hydrogen chloride.
7. The process as claimed in claim 1, wherein the solvent mixture used in step (b) is selected from dipolar aprotic solvent and lower aliphatic alcohol.
8. The process as claimed in claim 7, wherein the dipolar aprotic solvent is DMF and the lower aliphatic alcohol is n-propanol.
9. The process as claimed in claim 1, wherein the ratio of the Quetiapine hemifumarate and the alcohol used in the purification step (c) is 1 :10 w/v.
10. The process as claimed in claim 1, wherein the alcohol used in the purification step (c) is selected from methanol, ethanol or isopropyl alcohol or mixtures thereof.
11. The process as claimed in claim 1, wherein the precipitation of Quetiapine hemifumarate in step (c) is carried out by cooling the reaction mixture to the temperature range of 100C to 150C.
PCT/IN2005/000379 2005-07-04 2005-11-23 A PROCESS FOR THE PREPARATION OF 2-[2-(4-DIBENZO[b,f] [L,4] THIAZEPIN-11-yl-1- PIPERAZINYL)ETHOXY] ETHANOL FUMARATE WO2007004234A1 (en)

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WO2008121415A2 (en) * 2007-03-29 2008-10-09 Teva Pharmaceutical Industries Ltd. Improved process for preparing quetiapine fumarate
JP2010053044A (en) * 2008-08-26 2010-03-11 Sumitomo Chemical Co Ltd Method for producing 11-chlorodibenzo[b,f][1,4]thiazepine
US7687622B2 (en) 2005-04-14 2010-03-30 Teva Pharmaceutical Industries, Ltd Process for preparing quetiapine fumarate
WO2010100623A1 (en) 2009-03-04 2010-09-10 Ranbaxy Laboratories Limited Process for the preparation of quetiapine fumarate
US8420807B2 (en) 2008-01-31 2013-04-16 Fermion Oy Process for the preparation of quetiapine
CN104710383A (en) * 2013-12-11 2015-06-17 上海医药工业研究院 Quetiapine fumarate related substance, preparation method and applications thereof
CN108586385A (en) * 2017-12-26 2018-09-28 齐鲁天和惠世制药有限公司 A method of preparing big granularity quetiapine fumarate

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US7687622B2 (en) 2005-04-14 2010-03-30 Teva Pharmaceutical Industries, Ltd Process for preparing quetiapine fumarate
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CN104710383A (en) * 2013-12-11 2015-06-17 上海医药工业研究院 Quetiapine fumarate related substance, preparation method and applications thereof
CN108586385A (en) * 2017-12-26 2018-09-28 齐鲁天和惠世制药有限公司 A method of preparing big granularity quetiapine fumarate
CN108586385B (en) * 2017-12-26 2020-03-20 山东安信制药有限公司 Method for preparing large-particle-size quetiapine fumarate

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