- An Improved and single pot process for the production of quetiapine hemifumarate substantially free from potential impurities
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An improved and single pot process for the preparation of Quetiapine hemifumarate (1), an antipsychotic drug, free from potential impurities is reported with an overall yield of 80%. The reported process for its preparation suffers from the drawback of producing potential impurities identified as 11-piperazin-1- yldibenzo[b,f][1,4]thiazepine (6), 2-(4-dibenzo[b,f][1,4] thiazepin-11- ylpiperazin-1-yl)ethanol (10), dimer (9), and N-methyl- Nphenyldibenzo[ b,f][1,4]thiazapine-11-amine (14). Elimination of these impurities in the process is achieved by chlorination of 3 followed by in situ condensation of obtained 4 with highly pure 8 and subsequently establishing the pH based workup to obtain free base 2, which is further converted to quetiapine hemifumarate salt free from all these impurities. In this report, different aspects of process development such as scheme selection, optimization of different process parameters, identification, synthesis, origin and control of impurities, and development of an accurate analytical method during the development of a scalable process for quetiapine hemifumarate are discussed.
- Niphade, Navnath C.,Mali, Anil C.,Pandit, Bhushan S.,Jagtap, Kunal M.,Jadhav, Sanjay A.,Jachak, Madhukar N.,Mathad, Vijayavitthal T.
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Read Online
- New method for preparing quetiapine
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The invention provides an efficient and concise method for preparing highly-pure 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride, and a method for preparing quetiapine through directly reacting 11-chloro-dibenzo[b,f][(1,4)]thiazepine with 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride which substitutes the free alkali form. A low-temperature recrystallization technology adopted to purify the 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride avoids the residual of unknown tiny piperazine impurities in the product during high-temperature purification, so the highly-pure quetiapineis obtained in subsequent reactions.
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Paragraph 0030; 0032
(2018/04/21)
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- A [...] synthesis process (by machine translation)
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The present invention discloses a process for synthesizing [...], comprises the following steps: compound of formula (II), C1 - C4 acid mixed, and heated to 80 - 100 °C, adding zinc powder or iron powder, thermal insulation reaction 4 - 6h, shall quetiapine; with the resulting quetiapine fumaric acid salifying, [...], wherein quetiapine with fumaric acid feeding molar ratio of 1: 0.5. The process of the invention has simple operation, high yield, the resulting high purity of the product advantages, and is easy to realize industrial. (by machine translation)
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- Pyrophosphoryl Chloride: A Green, Reductive Chlorination Reagent Utilized in the One-Pot Synthesis of Quetiapine
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A one-pot synthesis of quetiapine from dibenzo[b,f][1,4]thiazepin-11(10H)-one and 4-hydroxyethoxy ethyl piperazine (HEEP) in toluene using N,N-dimethylaniline (DMA) and pyrophosphoryl chloride (P2O3Cl4) as a green reductive chlorination agent is described. A significant shortening of reaction times, a nearly quantitative yield, and high atom economy in the product were observed. The simplicity of the reaction, ease of execution, simple workup, and good yields, together with the use of easily accessible starting materials and an environmentally friendly procedure, are hallmarks of this process.
- Mahmoodi,Pourhossein Parizad,Hosseini
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p. 1029 - 1034
(2015/08/04)
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- PROCESS FOR THE PREPARATION OF QUETIAPINE FUMARATE
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The present invention relates to an improved process for the preparation of quetiapine and pharmaceutically acceptable salts. It also relates to improved process for the preparation of intermediates of quetiapine.
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Page/Page column 10
(2012/04/04)
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- PROCESS FOR THE PREPARATION OF QUETIAPINE FUMARATE
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The present invention relates to an improved process for the preparation of quetiapine and pharmaceutically acceptable salts. It also relates to improved process for the preparation of intermediates of quetiapine.
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Page/Page column 24-25
(2010/09/18)
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- A PROCESS FOR THE PREPARATION OF QUETIAPINE
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The invention relates to a method for the preparation of 11- (4- [2- (2- hydroxyethoxy) ethyl] -1-piperazinyl] dibenzo [b, f ] -1, 4-thiazepine and pharmaceutically acceptable salts thereof comprising the reaction of 1- [2- (hydroxyethoxy) -ethyl] piperazine with dibenzo [b, f] [1, 4] thiazepin-11-ylamine.
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Page/Page column 11-12
(2009/09/05)
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- PROCESS FOR PREPARING QUETIAPINE AND QUETIAPINE FUMARATE
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The invention comprises a process for preparing quetiapine and/or its salts, including, quetiapine fumarate. The process generally comprises reacting dibenzothiazepinone (dibenzo[bf][1,4]thiazepin-11(10H)-one) with phosphorous oxychloride in the presence of triethylamine in an aromatic organic solvent such as toluene or, preferably, xylene at reflux temperature to obtain an aromatic hydrocarbon solution of 11-chloro-dibenzo[bf][1,4]thiazepine. Thereafter, the 11-chloro-dibenzo[bf][1,4]thiazepine is reacted with 2-(2-piperazin-1-ylethoxy)-ethanol to yield, following several processing steps, quetiapine. Compound I can then be further reacted with fumaric acid at elevated temperature to yield quetiapine fumarate. The resulting quetiapine fumarate obtained is suitable for use in pharmaceutical preparations.
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Page/Page column 3; 7-9
(2009/04/24)
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- METHODS FOR THE PREPARATION OF SALTS OF 2-[2-(4-DIBENZO[B,F][l,4]THIAZEPIN-11-YL-1-PIPERAZINYL)ETHOXYL]ETHANOL (QUETIAPINE) AND FOR THE PURIFICATION THEREOF
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A method for the preparation of salts of 2-[2-(4-dibenzo[b,fj[l,4]thiazepin-11-yl-1- piperazinyl)ethoxy]ethanol (quetiapine) from the quetiapine base and the respective acid, wherein the salt is precipitated from a mixture of solvents, the mixture being either a mixture of an aromatic hydrocarbon and a ketone or ester, or that of an aromatic hydrocarbon, water and a ketone or ester. The salts of quetiapine are purified by partial crystallization, wherein only a part of the salt of quetiapine is dissolved in a C1 to C6 alcohol used.
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Page/Page column 7
(2008/06/13)
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- QUETIAPINE HEMIFUMARATE PURIFICATION BY CRYSTALLIZATION
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ABSTRACT The present invention relates to a process for preparing and purifying crystalline quetiapine hemifumarate, which comprises preparing crystalline quetiapine hemifumarate via a crystalline salt, which is not a salt of fumaric acid.
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Page/Page column 6
(2008/06/13)
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- A PROCESS FOR THE PREPARATION OF AN 11-(4-SUBSTITUTED-I-PIPERAZINYL)DIBENZO[b,f][1,4]THIAZEPINE DERIVATIVE
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A process for the preparation of an 11-(4-substituted-1-piperazinyl)dibenzo[b,f][1,4]thiazepine derivative, of general Formula (I), where A is hydrogen or a -(CH2)2-OH group or a -(CH2)2-0-(CH2)2-OH group, or of a salt thereof, comprises a step in which 10H-dibenzo[b,f][1,4]thiazepin-11-one is reacted with a piperazine derivative in the presence of a titanium alkoxide of general formula Ti(OR)4, where R is a straight or branched alkyl group, having from one to eight carbon atoms to obtain said Formula I derivative or a salt thereof. Where A is -(CH2)2-0-(CH2)2-OH, then the piperazine derivative is 1-(2-(2-hydroxyethoxy)ethyl)piperazine and the 11-(4-substituted-1-piperazinyl)dibenzo[b,f][1,4]thiazepine is quetiapine, (11-(4-(2-(2-hydroxyethoxy)ethyl)-1-piperazinyl)dibenzo[b,f][1,4]thiazepine). The process may comprise an additional step of reacting the quetiapine with fumaric acid to obtain quetiapine hemifumarate.
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Page/Page column 15
(2008/06/13)
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- INDUSTRIAL PREPARATION OF 11-[4-{2-(2-HYDROXYETHOXY ETHYL}-1-PIPERAZINYL] DIBENZO [b,f]-1[1, 4] THIAZEPINE
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Disclosed herein is an industrial process for preparation of Quetiapine by the reaction of 11-piperazinyldibenzo[b,f][1,4]-thiazepine or its salt with 2-(2-chloroethoxy)ethanol in presence of an inorganic base in aqueous condition to form 11-[4-{2-(2-hydroxyethoxy)ethyl}-1-piperazinyl] dibenzo [b,f]-[1,4]thiazepine. The quetiapine free base obtained is further converted to its hemi-fumarate salt.
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Page/Page column 6-7
(2008/06/13)
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- PROCESS FOR PREPARING QUETIAPINE FUMARATE
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Provided is a novel synthesis of quetiapine, and pharmaceutically acceptable salts thereof, in which an alkali metal halide or siliyl halide is included in the reaction mixture.
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Page/Page column 18; 19; 20-21
(2008/06/13)
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- PROCEDURE FOR PREPARING A PHARMACEUTICALLY ACTIVE COMPOUND
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The invention relates to a procedure for preparing quetiapine by reaction between a compound of formula (II) and a compound of formula (III), in which X means a leaving group and P a protective group of alcohols resistant to alkaline conditions, in the presence of a base, followed by a step of deprotection and, optionally, obtaining a pharmaceutically acceptable salt thereof. Said procedure permits the obtaining of quetiapine with a high degree of purity under soft temperature conditions, with short reaction times and avoiding the use of toxic solvents.
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Page/Page column 16; 17
(2008/06/13)
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- SYNTHESIS OF QUETIAPINE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
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Provided are a novel synthesis of quetiapine, quetiapine made by such process and its acid addition salts, and pharmaceutical composition comprising quetiapine so mad, or its acid addition salts.
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- Crystalline dibenzothiazepine derivative and its use as an antipsychotic agent
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Crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine (I) may be prepared by crystallizing 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine from a non-aromatic solvent such as ethyl acetate, isobutyl acetate, methyl iso-butylketone or methyl tert-butyl ether, preferably in the absence of water. The crystalline material produced may be converted into a pharmaceutically acceptable salt such as a fumarate. The crystalline 11-(4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl)-dibenzo[b,f][1,4]thiazepine may be used to treat psychoses.
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