CN101190902A - Method for preparing pharmaceutical pure quetiapine fumarate - Google Patents
Method for preparing pharmaceutical pure quetiapine fumarate Download PDFInfo
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- CN101190902A CN101190902A CNA2007100347619A CN200710034761A CN101190902A CN 101190902 A CN101190902 A CN 101190902A CN A2007100347619 A CNA2007100347619 A CN A2007100347619A CN 200710034761 A CN200710034761 A CN 200710034761A CN 101190902 A CN101190902 A CN 101190902A
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Abstract
The invention relates to a preparation method of pure quetiapine fumarate and the steps of the process thereof are that: (1)chlorination: four materials of dibenzo(b,f)(1,4)thiazepine-11-(10H)-ketone, chlorinated oxidant, N,N-Dimethylaniline and toluol react to obtain toluol solution of chloride; (2) addition and salification: the toluol solution of chloride reacts to obtain quetiapine according to the ratio of 1:0.5-1:0.5-0.8 of cyclic product (kg) to N-(2-(2-Hydroxyethoxy)ethyl)piperazine (kg) to anhydrous sodium carbonate; the mixture of the quetiapine (kg) and fumaric acid (kg) and ethanol (kg) is then salified to obtain the quetiapine fumarate according to the respective ratio 1:0.1-0.3:2-4. The invention effectively controls the impurity content of the quetiapine fumarate below 0.1 percent, improves the quality of products and achieves the standard of pharmaceutical purity and causes little side effects to patients. In addition, the invention also solves the problems of recovery of phosphorus oxychloride and environment pollution, shortens the cycle of reaction, improves the yield and reduces the cost.
Description
Technical field
The present invention relates to a kind of production for the treatment of schizoid chemicals, promptly prepare the production method of pharmaceutical purity quetiapine fumarate.
Background technology
To having had for many years now, its production stage and processing condition are as follows from Development and Production for quetiapine fumarate:
1. chlorination reaction, ratio of components: dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone (kilogram): phosphorus oxychloride (kilogram): N-N-xylidine (kilogram)=1: 9: 0.33
Above-mentioned three kinds of raw materials are dropped in the retort, stirring is warming up to backflow, and clock reaction 6.5 hours is when being reacted to, reclaim phosphorus oxychloride, add the toluene dissolving while hot, be cooled to 20 ℃, add frozen water, stirred 30 minutes, filtration, layering, be washed to neutrality, with anhydrous magnesium sulfate drying more than 20 hours, filter, reclaim under reduced pressure toluene gets muriate.
2. addition salify, ratio of components: muriate (kilogram): anhydrous sodium carbonate (kilogram): N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine (kilogram): dioxane (liter)=1: 0.45: 0.63: 5.5
Above-mentioned four kinds of raw materials are dropped in the retort, stirring is warming up to backflow, clock reaction 7 hours, when being reacted to, filter, reclaim dichloro six rings, add the chloroform dissolving again, add 1～10% hydrochloric acid extraction, layering, neutralize with solid sodium carbonate again, add the chloroform dissolving, be washed to neutrality, use anhydrous magnesium sulfate drying more than 2 hours, filtration, reclaim under reduced pressure chloroform are to doing, get Quetiapine, again in Quetiapine (kilogram): fumaric acid (kilogram): ethanol (kilogram)=1: 0.17: 2.4 ratio salify obtains quetiapine fumarate.
The height of the pharmacological action of quetiapine fumarate and side effect and relative substance has very big relation, the relative substance of the quetiapine fumarate of Sheng Chaning is than higher traditionally, generally between 0.5～1.5%, though meet the standard of country's formulation originally, but it is big that patient generally reacts side effect, and reaction time is long, and the unit productive rate is that labour productivity is not high, and environmental pollution is bigger.
Summary of the invention
The technical problem to be solved in the present invention is: the production method that the pharmaceutical purity quetiapine fumarate is provided, adopt the relative substance content of the quetiapine fumarate of this kind method production to be controlled at below 0.1%, quality is good, the productive rate height, reduce raw materials consumption, solve a difficult problem and the environmental pollution problems that reclaims phosphorus oxychloride simultaneously.
Technical solution of the present invention is, on the basis of original method, reduced the consumption of phosphorus oxychloride, adopts toluene to carry out chlorination reaction as solvent, simultaneously, chlorination reaction liquid changed the dry toluene processed that is; Change the feed ratio of reaction in the salifiable reaction of addition, and change the solvent of reaction and aftertreatment.
Pharmaceutical purity quetiapine fumarate of the present invention adopts following processing step and processing condition:
1. chlorination is with dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone, chloride oxidation agent, N-N-xylidine, four kinds of raw materials of toluene drops in the retort in proportion, and stir and be warming up to backflow, and logical N
2Protection, clock reaction 6～7 hours reacts and finishes, and is cooled to 17～25 ℃, slowly adds frozen water, stirs 20～40 minutes, filters, and layering is extracted, and is washed to neutrality, decompression dehydration, the decolouring removal of impurities gets muriatic toluene liquid;
2. addition salify, ratio of components, muriatic toluene liquid is by cyclocomplex (kilogram): N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine (kilogram): anhydrous sodium carbonate (kilogram)=1: 0.3～1.2: 0.5～1, cyclocomplex are dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone; Above-mentioned three kinds of raw materials are dropped in the retort, stir and be warming up to backflow, clock reaction 6～10 hours, then filter, add 1～10% hydrochloric acid layering and extract, neutralize with solid sodium carbonate again, add the toluene dissolving at last and extract, decompression dehydration reclaims toluene, obtains Quetiapine; Again in Quetiapine (kilogram): fumaric acid (kilogram): ethanol (kilogram)=1: 0.1～0.5: 2～5 ratio salifies obtains quetiapine fumarate.
In the chloridization process step, the chloride oxidation agent is a phosphorus oxychloride, and four kinds of proportion of raw materials are: dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone (kilogram): phosphorus oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 1～2: 0.3～0.7: 5～9.
In the chloridization process step, the chloride oxidation agent is a phosphorus oxychloride, its optimum process condition is: dibenzo [b.f] [1.4] sulphur azatropylidene 11-[10H] ketone (kilogram): phosphorus oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 1.65: 0.35: 6.4, the reaction Best Times is 6.5 hours, and it is 20 ℃ that the reaction back adds the frozen water optimum temps.
In the chloridization process step, the chloride oxidation agent is a sulfur oxychloride, and four kinds of proportion of raw materials are: dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone (kilogram): sulfur oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 1.5～2.5: 0.3～0.7: 5～9.
In the chloridization process step, the chloride oxidation agent is a sulfur oxychloride, its optimum process condition is: dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone (kilogram): sulfur oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 2: 0.35: 6.4, the reaction Best Times is 6.5 hours, and it is 20 ℃ that the reaction back adds the frozen water optimum temps.
In the salifiable processing step of addition, optimum process condition is that muriatic toluene liquid is in cyclocomplex (kilogram): N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine (kilogram): anhydrous sodium carbonate (kilogram)=1: 0.5: 0.5, in 6.5 hours reaction times, the hydrochloric acid layering with 7% is extracted.
The quetiapine fumarate production method of pharmaceutical purity of the present invention is compared with the production method of original quetiapine fumarate, has following outstanding advantage and significant beneficial effect:
One, effectively the relative substance content of quetiapine fumarate is controlled at below 0.1%, has greatly improved the quality of product, reached the standard of pharmaceutical purity, solved this product relative substance content height reveals stronger side reaction to patient table technical problem.
Two, solve phosphorus oxychloride effectively and reclaimed difficult problem.
Three, solved the serious and difficult problem strong of environmental pollution to people's toxic side effect.
Four, shorten reaction time, improved yield, reduced cost.
Description of drawings
Fig. 1 is the collection of illustrative plates of product quetiapine fumarate among the embodiment 1
Fig. 2 is the collection of illustrative plates of product quetiapine fumarate among the embodiment 2
Fig. 3 is the collection of illustrative plates of product quetiapine fumarate among the embodiment 3
Embodiment
Embodiment is provided below, and the invention will be further described, but the present invention is not limited only to following examples.
Embodiment 1:
1. chlorination: with dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H of 20Kg] phosphorus oxychloride of the toluene of ketone and 128Kg, the N-N-xylidine of 6.5Kg, 28Kg adds in the retort logical N
2, stirring is warming up to backflow, and clock reaction 6.5 hours when being reacted to, is cooled to 17 ℃, adds ice (slowly) 100Kg, stirs 30 minutes, and filtration, layering are extracted, are washed to neutrality, and decompression dehydration, decolouring get muriatic toluene liquid.
2. addition salify: with above-mentioned muriatic toluene liquid, press the 20Kg cyclocomplex, N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine 10Kg, anhydrous sodium carbonate 12Kg drops in the retort, stirring is warming up to backflow, clock reaction 6.5 hours when being reacted to, filters, add 5% hydrochloric acid 40Kg layering and extract, add solid Na again
2CO
3Regulate PH10-11, add the dissolving of 55Kg toluene, wash with water to neutrality, decompression dehydration reclaims toluene, get Quetiapine 23.4Kg, add the 3.5Kg fumaric acid again, 56Kg95% ethanol salify gets quetiapine fumarate 22.9Kg, addition salify yield 63.7%, relative substance 0.088%, its collection of illustrative plates as shown in Figure 1, the peak area table is as follows:
Amount to: 6144.296
Embodiment 2:
1. chlorination: processing step is some technical parameter difference with embodiment 1: add toluene 120Kg, and the N-N-xylidine of 7.2Kg, the sulfur oxychloride of 40Kg, clock reaction 7 hours is cooled to 20 ℃, stirs 20 minutes.
2. addition salify: processing step is with embodiment 1, be some technical parameter difference: add N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine 13Kg, anhydrous sodium carbonate 11Kg, clock reaction 6 hours, the hydrochloric acid of adding 7%, regulate PH9-10, get Quetiapine 24Kg, the fumaric acid that adds 4Kg gets quetiapine fumarate 24.0Kg, addition salify yield 67%, relative substance content 0.085%.Its collection of illustrative plates as shown in Figure 2, the peak area table is as follows:
Amount to: 10056.302
Embodiment 3:
1. chlorination: processing step is some technical parameter difference with embodiment 1: add toluene 130Kg, and the N-N-xylidine of 7Kg, the phosphorus oxychloride of 39Kg, clock reaction 7 hours is cooled to 20 ℃, stirs 30 minutes.
2. addition salify: processing step is with embodiment 1, be some technical parameter difference: add N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine 14Kg, anhydrous sodium carbonate 13Kg, clock reaction 6.5 hours, the hydrochloric acid of adding 7% is regulated PH10-11, gets Quetiapine 24.0Kg, the fumaric acid that adds 3.8Kg, get quetiapine fumarate 24.3Kg, once through yield 67.8%, relative substance content 0.075%.Its collection of illustrative plates as shown in Figure 3, the peak area table is as follows:
Amount to: 6444.376
Claims (6)
1. the production method of preparation pharmaceutical purity quetiapine fumarate comprises chlorination reaction and addition salify two big steps, it is characterized in that, adopts following processing step and processing condition:
1. chlorination is with dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone, chloride oxidation agent, N-N-xylidine, four kinds of raw materials of toluene drops in the retort in proportion, and stir and be warming up to backflow, and logical N
2Protection, clock reaction 6～7 hours reacts and finishes, and is cooled to 17～25 ℃, slowly adds frozen water, stirs 20～40 minutes, filters, and layering is extracted, and is washed to neutrality, decompression dehydration, the decolouring removal of impurities gets muriatic toluene liquid;
2. addition salify, ratio of components, muriatic toluene liquid is by cyclocomplex (kilogram): N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine (kilogram): anhydrous sodium carbonate (kilogram)=1: 0.3～1.2: 0.5～1, cyclocomplex are dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone; Above-mentioned three kinds of raw materials are dropped in the retort, stir and be warming up to backflow, clock reaction 6～10 hours, then filter, add 1～10% hydrochloric acid layering and extract, neutralize with solid sodium carbonate again, add the toluene dissolving at last and extract, decompression dehydration reclaims toluene, obtains Quetiapine; Again in Quetiapine (kilogram): fumaric acid (kilogram): ethanol (kilogram)=1: 0.1～0.5: 2～5 ratio salifies obtains quetiapine fumarate.
2. the production method of preparation pharmaceutical purity quetiapine fumarate according to claim 1, it is characterized in that, in the chloridization process step, the chloride oxidation agent is a phosphorus oxychloride, and four kinds of proportion of raw materials are: dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone (kilogram): phosphorus oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 1～2: 0.3～0.7: 5～9.
3. the production method of preparation pharmaceutical purity quetiapine fumarate according to claim 1, it is characterized in that, in the chloridization process step, the chloride oxidation agent is a phosphorus oxychloride, its processing condition are: dibenzo [b.f] [1.4] sulphur azatropylidene 11-[10H] ketone (kilogram): phosphorus oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 1.65: 0.35: 6.4, the reaction Best Times is 6.5 hours, and it is 20 ℃ that the reaction back adds the frozen water optimum temps.
4. the production method of preparation pharmaceutical purity quetiapine fumarate according to claim 1, it is characterized in that, in the chloridization process step, the chloride oxidation agent is a sulfur oxychloride, and four kinds of proportion of raw materials are: dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone (kilogram): sulfur oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 1.5～2.5: 0.3～0.7: 5～9.
5. the production method of preparation pharmaceutical purity quetiapine fumarate according to claim 1, it is characterized in that, in the chloridization process step, the chloride oxidation agent is a sulfur oxychloride, its processing condition are: dibenzo [b.f] [1.4] sulphur azatropylidene-11-[10H] ketone (kilogram): sulfur oxychloride (kilogram): N-N-xylidine (kilogram): toluene (kilogram)=1: 2: 0.35: 6.4, the reaction Best Times is 6.5 hours, and it is 20 ℃ that the reaction back adds the frozen water optimum temps.
6. the production method of preparation pharmaceutical purity quetiapine fumarate according to claim 1, it is characterized in that, in the salifiable processing step of addition, processing condition are, muriatic toluene liquid, in cyclocomplex (kilogram): N-[2-(2-hydroxyl-oxethyl) ethyl] piperazine (kilogram): anhydrous sodium carbonate (kilogram)=1: 0.5: 0.5, in 6.5 hours reaction times, the hydrochloric acid layering with 7% is extracted.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7687622B2 (en) | 2005-04-14 | 2010-03-30 | Teva Pharmaceutical Industries, Ltd | Process for preparing quetiapine fumarate |
| CN103804320A (en) * | 2013-06-03 | 2014-05-21 | 浙江工业大学 | Preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of Vilsmeier reagent |
| 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 |
| CN104744401A (en) * | 2013-12-30 | 2015-07-01 | 上海医药工业研究院 | Quetiapine fumarate relevant substance and preparation method and use thereof |
| CN114149384A (en) * | 2021-02-05 | 2022-03-08 | 南宁师范大学 | Synthetic method of quetiapine |
| CN114181172A (en) * | 2021-12-27 | 2022-03-15 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8607684D0 (en) * | 1986-03-27 | 1986-04-30 | Ici America Inc | Thiazepine compounds |
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2007
- 2007-04-18 CN CNB2007100347619A patent/CN100569761C/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7687622B2 (en) | 2005-04-14 | 2010-03-30 | Teva Pharmaceutical Industries, Ltd | Process for preparing quetiapine fumarate |
| CN103804320A (en) * | 2013-06-03 | 2014-05-21 | 浙江工业大学 | Preparation method of 11-chlorodibenzo[b,f][1,4]thiazepine in presence of Vilsmeier reagent |
| CN103804320B (en) * | 2013-06-03 | 2016-03-09 | 浙江工业大学 | The preparation method of 11-chlorodiphenyl also [b, f] [Isosorbide-5-Nitrae] sulphur azatropylidene that Vilsmeier reagent participates in |
| 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 |
| CN104744401A (en) * | 2013-12-30 | 2015-07-01 | 上海医药工业研究院 | Quetiapine fumarate relevant substance and preparation method and use thereof |
| CN114149384A (en) * | 2021-02-05 | 2022-03-08 | 南宁师范大学 | Synthetic method of quetiapine |
| CN114181172A (en) * | 2021-12-27 | 2022-03-15 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
| CN114181172B (en) * | 2021-12-27 | 2023-12-22 | 浙江苏泊尔制药有限公司 | Efficient preparation method of quetiapine fumarate |
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