CN103130785A - Preparation method of iloperidone - Google Patents
Preparation method of iloperidone Download PDFInfo
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- CN103130785A CN103130785A CN2012105566863A CN201210556686A CN103130785A CN 103130785 A CN103130785 A CN 103130785A CN 2012105566863 A CN2012105566863 A CN 2012105566863A CN 201210556686 A CN201210556686 A CN 201210556686A CN 103130785 A CN103130785 A CN 103130785A
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- suction filtration
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- zomaril
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Abstract
The invention relates to the technical field of drug synthesis, in particular to a preparation method of iloperidone. 95-105 grams of 4-hydroxyl-3-methoxyacetophenone, 9.5-10.5 grams of hydroxylamine hydrochloride and 950-1050 millimeters of absolute ethyl alcohol are added into a reaction vessel in sequence and mixed with the temperate controlled between 35-45 DEG C, 124-126 millimeters of triethylamine are added dropwise, and heating of backflow are conducted for 15-16 hours after the droplet addition is finished, the temperature is reduced to room temperature, reaction products are subjected to suction filtration, a filter cake is washed and dried, and white powder is obtained. The preparation method of iloperidone is simple and direct in preparation process, suitable for industrial production, high in yield coefficient, and capable of effectively shortening reaction time. Meanwhile, purification processes are simple and direct, and product purity is high.
Description
Technical field
The present invention relates to technical field of medicine synthesis, be specifically related to a kind of preparation method of Zomaril.
Background technology
Zomaril (iloperidone, Fanapt) is mainly used in schizoid treatment.Its get permission to go on the market indicate to many existing pharmacological agenies only part effectively the schizophreniac be a new chance, this product can be controlled their symptom better.
The preparation technology of Zomaril in prior art, synthetic route is more, has that yield is lower, a defective such as severe reaction conditions, product purity are lower more.
Summary of the invention
The present invention is intended to overcome the technical problem that exists in above-mentioned prior art, proposes a kind of yield high, is convenient to the preparation method of the Zomaril of suitability for industrialized production.
The technical solution used in the present invention is as follows:
The preparation method of Zomaril is characterized in that, comprises the steps:
1., the preparation of 2,4 difluorobenzene base-4-piperidinyl ketone oxime hydrochloride
Add successively 4-hydroxy 3-methoxybenzene ethyl ketone 95～105g, oxammonium hydrochloride 9.5～10.5g, dehydrated alcohol 950～1050mL in reaction vessel, stir 35～45 ℃ of temperature controls, drip triethylamine 124～126mL, drip complete reflux 15～16h;
Be down to room temperature, suction filtration, filter cake washing, drying get white powder, are designated as intermediate I;
2., 6-fluoro-3-(4-piperidyl)-1, the preparation of 2-benzisoxa isoxazole hydrochloride salt
Add successively intermediate I 82.5～83.5g, solid potassium hydroxide powder 83.5～84.5g, acetone 545～555ml in reaction vessel, stir and be warming up to 58～60 ℃, back flow reaction 13～15h;
Add anhydrous sodium sulfate drying, be chilled to room temperature, stir 1h, suction filtration, filtrate is concentrated;
Concentrated solution adds 495～505mL methyl alcohol stirring and dissolving, and methanol solution to the pH value that drips hydrogenchloride is 3～4, stirs 0.5～1h, suction filtration, and filter cake washing, drying get the off-white color solid, are designated as the intermediate II;
The preparation of 3., 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone
Add 4-hydroxy 3-methoxybenzene ethyl ketone 45～55g, acetone 495～505mL, Anhydrous potassium carbonate 82.5～83.5g in reaction vessel, stir lower 1, the 3-of dropping bromo-chloropropane 14.1～14.3g, it is complete that 0.5～0.6h drips, and drips complete heating reflux reaction 23～25h;
Be chilled to room temperature, suction filtration, filtrate decompression is concentrated into 180～220mL, adds water 380～420ml, stirs 2～2.5h, separate out solid, suction filtration, filter cake adds 395～405mL water to stir 4～4.5h with 195～205mL acetone stirring and dissolving, suction filtration, filtration cakes torrefaction gets the off-white color solid, is designated as the intermediate III;
4., the preparation of Zomaril
Add successively intermediate II 49.5～50.5g, intermediate III 51.5～52.5g, Anhydrous potassium carbonate 89.5～90.5g and water 580～620ml in reaction vessel, be heated to 80～85 ℃ of stirring reaction 1.5～2h;
Be chilled to room temperature, suction filtration, filter cake washing, drying get the Zomaril crude product.
Further, the process for purification of described Zomaril crude product is:
In container, add Zomaril crude product 59～61g, toluene 470～490mL, the stirring heating dissolving adds gac 5.5～6.5g, insulation reaction 15～20min, suction filtration, after filtrate was chilled to room temperature, ice-water bath stirred 2～2.5h, suction filtration, filter cake is with cold toluene wash, and vacuum-drying gets the off-white color solid;
Add ethanol 580～620mL again, be heated with stirring to the 15～20min that refluxes, after being chilled to room temperature, ice-water bath stirs 2～2.5h, and suction filtration, filter cake are with cold washing with alcohol, and vacuum-drying gets the off-white color solid, i.e. the Zomaril highly finished product.
The preparation method of Zomaril of the present invention, preparation technology is simple and direct, is suitable for suitability for industrialized production, and yield is higher, effectively Reaction time shorten.Simultaneously, process for refining is comparatively simple and direct, and product purity is higher.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.
1., the preparation of 2,4 difluorobenzene base-4-piperidinyl ketone oxime hydrochloride
Be furnished with mechanical stirring, in the dry four-hole reaction flask of the 2000ml of thermometer, adding successively 4-hydroxy 3-methoxybenzene ethyl ketone 100g, oxammonium hydrochloride 10g, dehydrated alcohol 1000mL starts stirring; Temperature control drips triethylamine 125mL below 45 ℃, drip to finish reflux 15h; Be down to room temperature, suction filtration, the 100mL washing with alcohol, 60 ℃ of vacuum-dryings get white powder 83.8g, are designated as intermediate I, productive rate 79.1%.
2., 6-fluoro-3-(4-piperidyl)-1, the preparation of 2-benzisoxa isoxazole hydrochloride salt
Be furnished with mechanical stirring, thermometer in the four-hole reaction flask of the drying of the 1000ml of reflux condensing tube, adds intermediate I 83g, solid potassium hydroxide powder 84g, acetone 550ml successively, starts stirring, is warming up to 60 ℃, back flow reaction 13h; Add anhydrous sodium sulfate drying, be chilled to room temperature, stir 1h, suction filtration, filtrate is concentrated, adds 500mL methyl alcohol stirring and dissolving, methanol solution to the pH value that drips hydrogenchloride is 3～4, stir 0.5h, suction filtration, 100mL methanol wash, 60 ℃ of vacuum-dryings, get off-white color solid 57.1 g, be designated as the intermediate II, productive rate 75.7%.
The preparation of 3., 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone
Be furnished with mechanical stirring, thermometer adds 4-hydroxy 3-methoxybenzene ethyl ketone 50g in the four-hole bottle of the drying of the 1000ml of reflux condensing tube, acetone 500mL, Anhydrous potassium carbonate 83g stirs lower dropping 1,3-bromo-chloropropane 14.2g, approximately 0.5h drips completely, drips complete heating reflux reaction 24h; Be chilled to room temperature, suction filtration, 100mL washing with acetone, filtrate decompression is concentrated into 200mL, adds water 400ml, stirs 2h, separate out solid, suction filtration, filter cake 200mL acetone stirring and dissolving, add 400mL water to stir 4h, suction filtration, 60 ℃ of vacuum-dryings of filter cake get off-white color solid 60.1g, be designated as the intermediate III, productive rate 82.3%.
4., the preparation of Zomaril
Be furnished with mechanical stirring, thermometer in the four-hole bottle of the drying of the 1000ml of reflux condensing tube, adds intermediate II 50g, intermediate III 52g successively, Anhydrous potassium carbonate 90g, and water 600ml is heated to 85 ℃ of stirring reaction 1.5h; Be chilled to room temperature, suction filtration, filter cake water (100mL * 2 time) washing, then use methyl alcohol (100mL * 2 time) washing, 60 ℃ of vacuum-dryings get Zomaril crude product 69.1g, productive rate 83.3%.
5., the Zomaril crude product is refining
In the 1000mL flask, add under Zomaril crude product 60g, toluene 480mL stirring heating for dissolving, add gac 6g, insulation reaction 15min, suction filtration is after filtrate is chilled to room temperature, ice-water bath stirs 2h, the a small amount of cold toluene wash of suction filtration, filter cake, 60 ℃ of vacuum-dryings, get off-white color solid 53.5g, yield 89.2%.
In the 1000mL flask, add the Zomaril crude product 53.5g of toluene crystallization, under ethanol 600mL stirs, heating for dissolving, backflow 15min, after being chilled to room temperature, ice-water bath stirs 2h, suction filtration, the a small amount of cold washing with alcohol of filter cake, 60 ℃ of vacuum-dryings get off-white color solid 48.5g, yield 90.6%.
Above content is only that the present invention is conceived example and explanation; affiliated those skilled in the art make various modifications to described specific embodiment or replenish or adopt similar mode to substitute; only otherwise depart from the design of invention or surmount this scope as defined in the claims, all should belong to protection scope of the present invention.
Claims (2)
1. the preparation method of Zomaril, is characterized in that, comprises the steps:
1., the preparation of 2,4 difluorobenzene base-4-piperidinyl ketone oxime hydrochloride
Add successively 4-hydroxy 3-methoxybenzene ethyl ketone 95～105g, oxammonium hydrochloride 9.5～10.5g, dehydrated alcohol 950～1050mL in reaction vessel, stir 35～45 ℃ of temperature controls, drip triethylamine 124～126mL, drip complete reflux 15～16h;
Be down to room temperature, suction filtration, filter cake washing, drying get white powder, are designated as intermediate compound I;
2., 6-fluoro-3-(4-piperidyl)-1, the preparation of 2-benzisoxa isoxazole hydrochloride salt
Add successively intermediate compound I 82.5～83.5g, solid potassium hydroxide powder 83.5～84.5g, acetone 545～555ml in reaction vessel, stir and be warming up to 58～60 ℃, back flow reaction 13～15h;
Add anhydrous sodium sulfate drying, be chilled to room temperature, stir 1h, suction filtration, filtrate is concentrated;
Concentrated solution adds 495～505mL methyl alcohol stirring and dissolving, and methanol solution to the pH value that drips hydrogenchloride is 3～4, stirs 0.5～1h, suction filtration, and filter cake washing, drying get the off-white color solid, are designated as intermediate II;
3., the preparation of 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone
Add 4-hydroxy 3-methoxybenzene ethyl ketone 45～55g, acetone 495～505mL, Anhydrous potassium carbonate 82.5～83.5g in reaction vessel, stir lower 1, the 3-of dropping bromo-chloropropane 14.1～14.3g, it is complete that 0.5～0.6h drips, and drips complete heating reflux reaction 23～25h;
Be chilled to room temperature, suction filtration, filtrate decompression is concentrated into 180～220mL, adds water 380～420ml, stirs 2～2.5h, separate out solid, suction filtration, filter cake adds 395～405mL water to stir 4～4.5h with 195～205mL acetone stirring and dissolving, suction filtration, filtration cakes torrefaction gets the off-white color solid, is designated as intermediate III;
4., the preparation of Zomaril
Add successively intermediate II 49.5～50.5g, intermediate III 51.5～52.5g, Anhydrous potassium carbonate 89.5～90.5g and water 580～620ml in reaction vessel, be heated to 80～85 ℃ of stirring reaction 1.5～2h;
Be chilled to room temperature, suction filtration, filter cake washing, drying get the Zomaril crude product.
2. the preparation method of Zomaril according to claim 1, is characterized in that, the process for purification of described Zomaril crude product is:
In container, add Zomaril crude product 59～61g, toluene 470～490mL, the stirring heating dissolving adds gac 5.5～6.5g, insulation reaction 15～20min, suction filtration, after filtrate was chilled to room temperature, ice-water bath stirred 2～2.5h, suction filtration, filter cake is with cold toluene wash, and vacuum-drying gets the off-white color solid;
Add ethanol 580～620mL again, be heated with stirring to the 15～20min that refluxes, after being chilled to room temperature, ice-water bath stirs 2～2.5h, and suction filtration, filter cake are with cold washing with alcohol, and vacuum-drying gets the off-white color solid, i.e. the Zomaril highly finished product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105566863A CN103130785A (en) | 2012-12-20 | 2012-12-20 | Preparation method of iloperidone |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012105566863A CN103130785A (en) | 2012-12-20 | 2012-12-20 | Preparation method of iloperidone |
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| CN103130785A true CN103130785A (en) | 2013-06-05 |
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| CN2012105566863A Pending CN103130785A (en) | 2012-12-20 | 2012-12-20 | Preparation method of iloperidone |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831742A (en) * | 2016-12-28 | 2017-06-13 | 北京医药集团有限责任公司 | A kind of preparation method of Iloperidone intermediate |
| CN107033133A (en) * | 2017-04-05 | 2017-08-11 | 上海华源医药科技发展有限公司 | A kind of preparation method of Iloperidone |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101768154A (en) * | 2009-09-19 | 2010-07-07 | 浙江华海药业股份有限公司 | New preparation method of iloperidone |
| WO2012090138A1 (en) * | 2010-12-27 | 2012-07-05 | Ranbaxy Laboratories Limited | Processes for the preparation of iloperidone |
| WO2012123963A2 (en) * | 2011-02-24 | 2012-09-20 | Megafine Pharma (P) Ltd. | A process for preparation of iloperidone and amorphous co- precipitate of iloperidone with pharmaceutically acceptable excipient |
| WO2012153341A1 (en) * | 2011-05-12 | 2012-11-15 | Arch Pharmalabs Limited | A process for the preparation of iloperidone and pharmaceutically acceptable salts thereof |
| CN102796090A (en) * | 2012-08-30 | 2012-11-28 | 天津华津制药有限公司 | Method for preparing iloperidone |
-
2012
- 2012-12-20 CN CN2012105566863A patent/CN103130785A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101768154A (en) * | 2009-09-19 | 2010-07-07 | 浙江华海药业股份有限公司 | New preparation method of iloperidone |
| WO2012090138A1 (en) * | 2010-12-27 | 2012-07-05 | Ranbaxy Laboratories Limited | Processes for the preparation of iloperidone |
| WO2012123963A2 (en) * | 2011-02-24 | 2012-09-20 | Megafine Pharma (P) Ltd. | A process for preparation of iloperidone and amorphous co- precipitate of iloperidone with pharmaceutically acceptable excipient |
| WO2012153341A1 (en) * | 2011-05-12 | 2012-11-15 | Arch Pharmalabs Limited | A process for the preparation of iloperidone and pharmaceutically acceptable salts thereof |
| CN102796090A (en) * | 2012-08-30 | 2012-11-28 | 天津华津制药有限公司 | Method for preparing iloperidone |
Non-Patent Citations (1)
| Title |
|---|
| 徐勤耀，等: "伊潘立酮的合成", 《中国医药工业杂志》, vol. 42, no. 2, 10 February 2011 (2011-02-10) * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106831742A (en) * | 2016-12-28 | 2017-06-13 | 北京医药集团有限责任公司 | A kind of preparation method of Iloperidone intermediate |
| CN106831742B (en) * | 2016-12-28 | 2019-08-23 | 北京医药集团有限责任公司 | A kind of preparation method of Iloperidone intermediate |
| CN107033133A (en) * | 2017-04-05 | 2017-08-11 | 上海华源医药科技发展有限公司 | A kind of preparation method of Iloperidone |
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Application publication date: 20130605 |