CN103724294A - Novel preparation method of quetiapine - Google Patents
Novel preparation method of quetiapine Download PDFInfo
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- CN103724294A CN103724294A CN201210387133.XA CN201210387133A CN103724294A CN 103724294 A CN103724294 A CN 103724294A CN 201210387133 A CN201210387133 A CN 201210387133A CN 103724294 A CN103724294 A CN 103724294A
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- piperazine
- quetiapine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a high-efficient and simple method used for preparing high purity 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride. The preparation method is used for replacing a method used for preparing quetiapine by reacting a free alkali derivative with 11-chloro-dibenzo[b, f](1, 4)thiazepine. According to the preparation method, low-temperature recrystallization is adopted for purifying 1-[2-(2-hydroxyethoxy)ethyl]piperazine hydrochloride so as to avoid residue of unknown piperazidine impurities in high-temperature purification processes, and high purity quetiapine can be obtained in subsequent reactions.
Description
Technical field
The invention provides a kind of economical and practical Quetiapine key intermediate 1-[2-(2-hydroxyl-oxethyl) ethyl of preparing] piperazine hydrochloride and prepare the novel method of high purity quetiapine fumarate as critical materials.
Background technology
Quetiapine fumarate is atypical antipsychotics thing, the multiple neurotic acceptors such as the interior Dopamine HCL of brain capable of blocking, serotonin.Quetiapine fumarate has been reported its preparation method and antipsychotic class disease activity by U.S. Pat 4879288 the earliest, and the quetiapine fumarate of FDA approval subsequently goes on the market in the U.S., is used for the treatment of schizophrenia and dysthymia disorders; Because its curative effect is obvious and side effect is less, caused the light note of all multiple medicines enterprises and research and development institution.Quetiapine has following structure:
The preparation method that U.S. Pat 4879288 is reported is 11-piperazine-Dibenzo [b, f] [(1,4) sulphur azatropylidene and 1-[2-(2-chloroethoxy) ethanol synthesis obtains Quetiapine, but long reaction time, and purity is lower, need rapid column chromatography separation and purification, yield is low and be not suitable for scale production.The modification method of this route has been described subsequently in the patents such as US7071331/US7847094/WO2006/117700, but these methods are all with 11-piperazine-Dibenzo [b, f], [(Isosorbide-5-Nitrae) sulphur azatropylidene is starting raw material, and its preparation needs several steps, and its purifying is difficult.
Also have some bibliographical informations transamination method (CN101925587A) or sulphur drone salt exchange process, but these starting raw materials be more difficult for obtain.
Other document as the preparation method who has mentioned in CN101190902A/CN101198599A be the chloro-Dibenzo [b of 11-, f] [(Isosorbide-5-Nitrae) sulphur azatropylidene and 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine reaction obtains the method for Quetiapine.But what in these techniques, use is all 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine, this raw material is by high-temperature pressure-reduction distilation, the piperazines minute impurities of meeting product the unknown in high temperature purification process, can in further reacting, bring in final Quetiapine finished product, can cause the Quetiapine finished product toxic side effect larger to patient's product of this batch, because the content of the pharmacological action of Quetiapine and toxic side effect and piperazines impurity height has very large relation.And the energy consumption of high-temperature pressure-reduction distillation is high, to conversion unit require highly, thereby cause production cost high.
The traditional technology of monosubstituted piperazine is first with protections such as Boc/Cbz/Ac, first to protect the amino of one end, then does the substitution reaction of other one end with halide reaction, finally gets rid of protecting group, just obtains final monosubstituted product.These traditional technology routes are long, consuming time, and total recovery is low, have very large defect in suitability for industrialized production, are difficult to adopt.
Summary of the invention
It is to overcome the defect that above-mentioned technology exists that the present invention wants technical problem to be solved, a kind of method that practicality, the succinct high-purity Quetiapine of preparation are provided, is controlled at the related impurities in Quetiapine below 0.1%, improves combined coefficient, reduce costs, and reduce raw materials consumption and environmental pollution.Correspondingly, technical solution provided by the invention is to utilize our method newly developed to prepare high-purity 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine hydrochloride, and replace its free alkali form directly and the chloro-Dibenzo [b of 11-with this, f] [(1,4) sulphur azatropylidene reaction, to similarly react after suitable modification, can obtain Quetiapine by good productive rate, and avoid the ethyl by high temperature purification 1-[2-(2-hydroxyl-oxethyl)] piperazines minute impurities that can product the unknown in piperazine free alkali process brings in the finished product and goes.Shown in our following equation of synthetic route:
The traditional technology of monosubstituted piperazine is first with protections such as Boc/Cbz/Ac, first to protect the amino of one end, then does the substitution reaction of other one end with halide reaction, finally gets rid of protecting group, just obtains final monosubstituted product.These traditional technology routes are long, consuming time, and total recovery is low, have very large defect in suitability for industrialized production, are difficult to adopt.An aspect of of the present present invention is to have developed one to prepare high-purity 1-[2-(2-hydroxyl-oxethyl) ethyl] novel method of piperazine: under suitable solvent or condition of no solvent, piperazine and 2-(2-chloroethoxy) ethanol stirs and reacts under 100-150 degree Celsius; Do not need protection piperazine amino and directly high productivity obtain 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine hydrochloride.
Solvent used can make the high boiling point non-polar solvents such as toluene, dimethylbenzene, preferably solvent-free system.Temperature of reaction can be at 100-150 degree Celsius, and best temperature range is 120-140 degree Celsius.Reaction substrate can be the combined action of Piperazine anhydrous or piperazine and piperazine hydrochloride, preferably the mixture of piperazine and piperazine hydrochloride.The final purifying of product can obtain its free alkali form with high-temperature pressure-reduction distillation, or form hydrochloride and carry out low temperature recrystallization and obtain the hydrochloride form of product, best high purity product can be by recrystallization its hydrochloride of purifying, obtain more than 99.5% high purity product of content, avoid the piperazines impurity producing in pyrogenic distillation purge process, the conversion unit of also having avoided high-temperature pressure-reduction to distill required harshness requires and expensive high energy consumption.
Another aspect of the present invention is directly with high-purity 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine hydrochloride and the chloro-Dibenzo [b of 11-, f] [(1,4) reaction of sulphur azatropylidene provides the Quetiapine of good yield, need to this hydrochloride be transformed into its free alkali form before reaction, improve efficiency.Both reaction ratios can be 0.8～1.5, and preferred ratio is 0.9～1.1, and optimum proportion is 1: 1.Under optimized condition, the crude product of Quetiapine can reach more than 99%; Crude product is further purified after forming quetiapine fumarate with fumaric acid, and content can reach 99.5%, and arbitrary single contaminant 0.1% once.And use free alkali form to obtain Quetiapine content in crude product in 90～97% scopes, and through formation the purge process of quetiapine fumarate, purity to 99%; But single contaminant content is in 0.2～0.5% scope.
Processing condition of the present invention can be carried out in wider scope, and the reaction conditions that the present invention enumerates as solvent/temperature/reaction ratio/substrate selection etc. be not restrictive, and only corresponding to preferred conclusion of the present invention.
Below will illustrate method of the present invention by specific examples.
Embodiment
Below by following instance, the present invention is further detailed.The synthesis technique that example of the present invention is explained is only for the present invention is described, rather than limitation of the present invention.In operational path situation of the present invention, technique of the present invention is carried out to simple modifications and all belong to the claimed content of the present invention.
Example one:
100 grams of (1.2mol) Piperazine anhydrous and 240 grams of (1.5mol) piperazine dihydrochlorides are heated to 120 degrees Celsius, drip 150 grams of (1.2mol) 2-(2-chloroethoxy) ethanol, add rear continuation heated and stirred, be warming up to 136-140 degree Celsius, keep 1 hour, after TLC demonstration reacts completely, stop heating.When temperature is down to 80 degrees Celsius, add 500 milliliters of 95% ethanol, in refrigerator and cooled, but spend the night, next day filtered and recycled piperazine dihydrochloride, filter cake fully washs with a small amount of ethanol, merging filtrate, add 200 grams of alkalization of 30% sodium hydroxide solution, filter out undissolved inorganic salt; Concentrated removing after solvent, extracts residue by ethyl acetate, passes into dry hydrogen chloride gas, obtains white solid 1-[2-(2-hydroxyl-oxethyl) ethyl after filtration drying] piperazine hydrochloride; This solids content is more than 98%.Through 90% aqueous ethanolic solution recrystallization once, can obtain 207 grams of white crystals, yield 70%, content can reach more than 99.5%;
Example two:
100 grams of (1.2mol) Piperazine anhydrous and 240 grams of (1.5mol) piperazine dihydrochlorides are heated to 120 degrees Celsius, drip 150 grams of (1.2mol) 2-(2-chloroethoxy) ethanol, add rear continuation heated and stirred, be warming up to 136-140 degree Celsius, keep 1 hour, after TLC demonstration reacts completely, stop heating.When temperature is down to 80 degrees Celsius, add 500 milliliters of 95% ethanol, in refrigerator and cooled, but spend the night, next day filtered and recycled piperazine dihydrochloride, filter cake fully washs with a small amount of ethanol, merging filtrate, add 200 grams of alkalization of 30% sodium hydroxide solution, filter out undissolved inorganic salt; Concentrated removing after solvent, the cut of 168-172 degree Celsius/10 mmhg is collected in underpressure distillation, obtains colourless to 145 grams of 1-[2-of light yellow transparent liquid (2-hydroxyl-oxethyl) ethyl] piperazine, yield 70%, content is more than 98%; There is unknown foreign matter content in 0.5～1% scope.
Example three:
100 grams of (1.2mol) Piperazine anhydrous are dissolved in to 1L toluene, be heated to reflux, drip 150 grams of (1.2mol) 2-(2-chloroethoxy) ethanol, add rear continuation return stirring, keep 5 hours, after TLC demonstration reacts completely, stop heating.After temperature is down to room temperature, add 200 grams of alkalization of 30% sodium hydroxide solution, filter out undissolved inorganic salt; Concentrated removing after solvent, extracts residue by ethyl acetate, passes into dry hydrogen chloride gas, obtains white solid 1-[2-(2-hydroxyl-oxethyl) ethyl after filtration drying] piperazine hydrochloride; Through 90% aqueous ethanolic solution recrystallization once, can obtain 180 grams of white crystals, yield 60%, content can reach more than 99%;
Example four:
In the round bottom reaction flask that agitator, prolong, thermometer are housed, add 100 grams of chloro-Dibenzo [b of (0.40mol) 11-, f] [(1,4) in sulphur azatropylidene and 1L toluene, under stirring under room temperature, add 90 grams of (0.36mol) 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine hydrochloride, 127 grams of (1.2mol) anhydrous sodium carbonates and 6 grams of (0.04mol) sodium iodides, by reaction mixture reflux 12 hours, only surplus below 1% to starting raw material.Cooling reaction system, to room temperature, with 2L 1N mixed in hydrochloric acid, obtains the solution of pH 1-2, separates and obtains water layer, adds 1L toluene, adds sodium carbonate to be adjusted to neutrality, separatory, 1L toluene extracting twice for water layer; Merge organic phase, washing and drying, concentrated 108 grams of oily matter, the HPLC content 99.2% of obtaining.
Above-mentioned oily matter is dissolved in 300mL Virahol, adds 25 grams of (0.21mo1) fumaric acid, after reflux is all dissolved for 1 hour, cooling standing, after suction filtration is dry, obtain 115 grams of quetiapine fumarates, content 99.5%, single contaminant is less than 0.1%; Total recovery 74%.
Example five:
In the round bottom reaction flask that agitator, prolong, thermometer are housed, add 100 grams of chloro-Dibenzo [b of (0.40mol) 11-, f] [(1,4) in sulphur azatropylidene and 1L toluene, under stirring under room temperature, add 100 grams of (0.40mol) 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine hydrochloride, 127 grams of (1.2mol) anhydrous sodium carbonates and 6 grams of (0.04mol) sodium iodides, by reaction mixture reflux 12 hours, only surplus below 1% to starting raw material.Cooling reaction system, to room temperature, with 2L 1N mixed in hydrochloric acid, obtains the solution of pH 1-2, separates and obtains water layer, adds 1L toluene, adds sodium carbonate to be adjusted to neutrality, separatory, 1L toluene extracting twice for water layer; Merge organic phase, washing and drying, concentrated 118 grams of oily matter, the HPLC content 99.2% of obtaining.
Above-mentioned oily matter is dissolved in 300mL Virahol, adds 25 grams of (0.21mol) fumaric acid, after reflux is all dissolved for 1 hour, cooling standing, after suction filtration is dry, obtain 126 grams of quetiapine fumarates, content 99.5%, single contaminant is less than 0.1%; Total recovery 81%.
Example six:
In the round bottom reaction flask that agitator, prolong, thermometer are housed, add 100 grams of chloro-Dibenzo [b of (0.40mol) 11-, f] [(1,4) in sulphur azatropylidene and 1L toluene, under stirring under room temperature, add 110 grams of (0.44mol) 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine hydrochloride, 127 grams of (1.2mol) anhydrous sodium carbonates and 6 grams of (0.04mol) sodium iodides, by reaction mixture reflux 12 hours, only surplus below 1% to starting raw material.Cooling reaction system, to room temperature, with 2L 1N mixed in hydrochloric acid, obtains the solution of pH 1-2, separates and obtains water layer, adds 1L toluene, adds sodium carbonate to be adjusted to neutrality, separatory, 1L toluene extracting twice for water layer; Merge organic phase, washing and drying, concentrates and obtains 120 grams of oily matter, and HPLC content 98.5%, shows 1% unnecessary piperazine raw material.
Above-mentioned oily matter is dissolved in 300mL Virahol, adds 25 grams of (0.21mol) fumaric acid, after reflux is all dissolved for 1 hour, cooling standing, after suction filtration is dry, obtain 130 grams of quetiapine fumarates, content 99.5%, single contaminant is less than 0.1%; Total recovery 84%.
Example seven:
In the round bottom reaction flask that agitator, prolong, thermometer are housed, add 100 grams of chloro-Dibenzo [b of (0.40mol) 11-, f] [(1,4) in sulphur azatropylidene and 1L toluene, under stirring under room temperature, add 77 grams of (0.44mol) 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine, 84.6 grams of (0.8mol) anhydrous sodium carbonates and 6 grams of (0.04mol) sodium iodides, by reaction mixture reflux 12 hours, only surplus below 1% to starting raw material.Cooling reaction system, to room temperature, with 2L 1N mixed in hydrochloric acid, obtains the solution of pH1-2, separates and obtains water layer, adds 1L toluene, adds sodium carbonate to be adjusted to neutrality, separatory, 1L toluene extracting twice for water layer; Merge organic phase, washing and drying, concentrated 122 grams of oily matter, the HPLC content 97% of obtaining.
Above-mentioned oily matter is dissolved in 300mL Virahol, adds 25 grams of (0.21mol) fumaric acid, after reflux is all dissolved for 1 hour, cooling standing, after suction filtration is dry, obtain 128 grams of quetiapine fumarates, content 99.1%, total recovery 82%.HPLC shows that single contaminant is in 0.2～0.5% scope.
Claims (8)
1. prepare high purity Quetiapine key intermediate 1-[2-(2-hydroxyl-oxethyl) ethyl] the efficient succinct method of piperazine hydrochloride, take piperazine and 2-(2-chloroethoxy) ethanol as the direct single step reaction of raw material, obtain.
2. the method for claim 1, is characterized in that: reaction substrate can be the combined action of Piperazine anhydrous or piperazine and piperazine hydrochloride.
3. method as claimed in claim 2, is characterized in that: solvent used can make the high boiling point non-polar solvents such as toluene, dimethylbenzene, can be also solvent-free system.
4. method as claimed in claim 3, is characterized in that: temperature of reaction can be at 100-150 degree Celsius, and best temperature range is 120-140 degree Celsius.
5. method as claimed in claim 4, is characterized in that: the final purifying of product can obtain its free alkali form with high-temperature pressure-reduction distillation, or forms hydrochloride and carry out low temperature recrystallization and obtain the hydrochloride form of product.
6. with 1-[2-(2-hydroxyl-oxethyl) ethyl] piperazine hydrochloride replaces its free alkali form directly [(Isosorbide-5-Nitrae) sulphur azatropylidene reacts the method for preparing Quetiapine with the chloro-Dibenzo of 11-[b, f].
7. method as claimed in claim 6, is characterized in that: the reaction ratio of two reaction substrates can be 0.8～1.5, and better mol ratio is 0.9～1.1.
8. method as claimed in claim 6, is characterized in that: the crude product obtaining does not need through purifying, after forming quetiapine fumarate with fumaric acid, is further purified, and content can reach 99.5%, and arbitrary single contaminant 0.1% once.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104016945A (en) * | 2014-05-27 | 2014-09-03 | 渭南畅通药化科技有限公司 | Preparation method of quetiapine hemifumarate |
| CN104447616A (en) * | 2014-12-23 | 2015-03-25 | 齐鲁天和惠世制药有限公司 | Preparation method of quetiapine fumarate impurity D |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008152434A1 (en) * | 2007-06-12 | 2008-12-18 | Richter Gedeon Nyrt. | Synthesis for the preparation of quetiapine |
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- 2012-10-12 CN CN201210387133.XA patent/CN103724294A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008152434A1 (en) * | 2007-06-12 | 2008-12-18 | Richter Gedeon Nyrt. | Synthesis for the preparation of quetiapine |
Non-Patent Citations (1)
| Title |
|---|
| 余一成等: "《安他乐生产路线的研究》", 《药学学报》, vol. 13, no. 7, 31 July 1966 (1966-07-31), pages 514 - 517 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104016945A (en) * | 2014-05-27 | 2014-09-03 | 渭南畅通药化科技有限公司 | Preparation method of quetiapine hemifumarate |
| CN104447616A (en) * | 2014-12-23 | 2015-03-25 | 齐鲁天和惠世制药有限公司 | Preparation method of quetiapine fumarate impurity D |
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Application publication date: 20140416 |