CN102924439A - Preparation method of iloperidone - Google Patents
Preparation method of iloperidone Download PDFInfo
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- CN102924439A CN102924439A CN2011102263614A CN201110226361A CN102924439A CN 102924439 A CN102924439 A CN 102924439A CN 2011102263614 A CN2011102263614 A CN 2011102263614A CN 201110226361 A CN201110226361 A CN 201110226361A CN 102924439 A CN102924439 A CN 102924439A
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Abstract
The invention provides a method for preparing iloperidone by a one-step method. Iloperidone is obtained directly by a one-step base catalytic reaction of a compound in formula 3 and a compound in formula 4. The operation is simplified greatly, and the product quality is not compromised; the obtained iloperidone has purity of more than 99% and a yield of more than 90%.
Description
Technical field
The present invention relates to a kind of new preparation method of Zomaril.
Background technology
Zomaril, English name iloperidone, chemical name: 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-y1)-1-piperidinyl] propoxy]-3-methoxyphenyl] ethanone.Structural formula is as follows:
Zomaril is the antagonist of serotonin, d2 dopamine receptor, is used for the treatment of atypical schizophrenia.Zomaril is the atypical antipsychotic agents class patent drugs by the research and development of Titan company, obtains the drugs approved by FDA listing in 2009, is used for the treatment of adult's acute schizophrenia.This indicate to many existing pharmacological agenies only part effectively the schizophreniac be a new chance, this product can be controlled their symptom better.Zomaril may become first personalized psychotherapeutic drug.The listing of Zomaril, it might become schizoid first gene target medicine for the treatment of.
EP0402644 (December 19 nineteen ninety is open) has reported the general formula compound synthetic method of synthetic N-(aryloxy) heteroaryl piperidine base and heteroaryl piperazine, has wherein comprised the synthetic method of Zomaril.
Later patents and the document (J.Med.Chem.1995 such as US5364866 (on November 15th, 1994 is open), US5776963 (on July 7th, 1998 is open), 38,1119-1131) reported improved synthetic method, but synthetic method has continued the synthetic route of EP0402644 substantially, behind elder generation's preparation formula 2 compounds this benzoxazoles structural compounds again with formula 3 compound condensations, obtain formula 1 compound Zomaril.Reaction process is as follows:
In the European patent EP 196132, formula 2 compounds are to be obtained by the cyclization under the highly basic condition of formula 4 compounds.In the reaction process, the fluorine atom and the oxime hydroxyl generation ring closure reaction that face the position in formula 4 compounds obtain formula 2 compounds, but the fluorine atom of contraposition also can be participated in reaction, dipolymer shown in the production 8, this dipolymer further participates in reaction, can contain the impurity shown in the formula 6 in the Zomaril that finally obtains.
CN200910200105 adopts formula 4 compounds (Z)-4-(2,4 difluorobenzene base)-piperidyl methyl ketoxime and formula 3 compound 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone reaction to obtain formula 5 compounds, and then catalyze and synthesize Zomaril.
Condensation reaction need to occur in the first step in the method under alkaline condition, generates carbonnitrogen bond, obtains formula 5 compounds, and second step is to generate the oxazole ring through ring-closure reaction to obtain Zomaril under alkaline condition.Its disclosed alkali is the carbonate of metal, supercarbonate, and oxyhydroxide, alkoxide, hydride, amide is selected from yellow soda ash, sodium bicarbonate, sodium methylate, sodium hydroxide, potassium hydroxide, a kind of in the amido sodium.The problem of its existence is:
1, after the first step reaction, needs to obtain intermediate formula 5 compounds through steps such as crystallization, filtrations, unavoidably cause damage.And, condensation and ring-closure reaction mechanism are similar, if first condensation reaction, in condensation reaction, inevitably can generate cyclization product Zomaril, and the last handling process after the condensation reaction and crystallization condition are more suitable for the crystallization of condensation product formula 5 compounds, and the loss meeting of Zomaril is larger.Thereby cause the Zomaril yield low.Utilize the disclosed multiple alkali of the method, when providing alkaline environment to react such as yellow soda ash, sodium bicarbonate, sodium methylate etc., formula 4 compounds and the reaction of formula 3 compounds can not obtain formula 5 compounds fully.
Embodiment has proved that also the yield of the Zomaril that the method finally obtains is lower, among the embodiment 1, the yield of formula 5 compounds is 85.0%, the yield of Zomaril is 89.0%, thereby calculating the yield for preparing Zomaril by (Z)-4-(2,4 difluorobenzene base)-piperidyl methyl ketoxime is 75.65%.The yield that in like manner calculates Zomaril among the embodiment 2-5 is respectively 72.82%, 70.55%, 70.14% and 56.81%.
2, adopt two-step approach to react, step is many, and complex operation, two-step reaction all need to carry out last handling process, after obtaining formula 5 compounds, it must be separated out from reaction system, and then carry out ring-closure reaction.The a large amount of solvents of needs, reaction process are grown and energy consumption, equipment loss in the production are increased, and cost raises.
Summary of the invention
The present invention is directed to defects, provide a kind of single stage method to prepare the method for Zomaril.Adopt a step base catalyzed reactions directly to obtain Zomaril by formula 3 compounds and the reaction of formula 4 compounds.Simplified greatly operation, when simplifying the operation, not take the sacrifice quality product as cost, the Zomaril of gained, its purity is all more than 99%, and yield is all greater than 90%.
Single stage method provided by the invention prepares the method for Zomaril, and step is as follows: formula 4 compounds are dissolved in the organic solvent, adding formula 3 compounds, and potassiumiodide or sodium iodide add mineral alkali, back flow reaction, TLC detection reaction.Reaction times is 12-26 hour.React complete after, cooling, reaction solution is poured into water, stir, suction filtration, drying obtains Zomaril.
Wherein said mineral alkali is selected from potassium hydroxide, sodium hydroxide or lithium hydroxide.
Wherein organic solvent is selected from alcohols, acetonitrile or DMF.Preferred alcohol and acetonitrile.
Description of drawings
The HPLC figure of Fig. 1 embodiment 1 correspondence, wherein the peak of retention time 10.771min is the peak of Zomaril.
The HPLC figure of Fig. 2 Comparative Examples 1 correspondence, wherein the peak of retention time 10.844min is the peak of Zomaril, the peak of retention time 6.100min is the peak of formula 5 compounds.
The HPLC figure of Fig. 3 Comparative Examples 4 correspondences, wherein the peak of retention time 10.752min is the peak of Zomaril, the peak of retention time 6.220min is the peak of formula 5 compounds.
Embodiment
Following examples are to specify of the present invention, should not be construed as limiting scope of the present invention.
Embodiment 1,
1, the preparation of 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone (being formula 3 compounds)
Vanillone 17.6g is dissolved in the 75ml acetone, adds 13.8g salt of wormwood, be heated to backflow, drip the mixing solutions of 83.4g1-bromo-3-chloropropane and 20ml acetone, back flow reaction 10h.Be cooled to room temperature, suction filtration gets filtrate, steams except behind acetone and the 1-bromo-3-chloropropane, and underpressure distillation obtains (3-chloropropyl oxygen base)-3-methoxyacetophenone crude product 21.2g, yield 82.4%.
2, the preparation of (Z)-4-(2,4 difluorobenzene base)-piperidyl methyl ketoxime (being formula 4 compounds)
Dehydrated alcohol 136ml, oxammonium hydrochloride 11.2g joins in the 500ml there-necked flask, stirs the lower 20%NaOH of adding aqueous solution 54.7g, and the control temperature is at 20-30 ℃.After dropwising, stir 15min, about pH=10.Then add 27.9g tartrate, 4-(2,4 difluorobenzene base)-piperidyl methyl keto hydrochloride 32.5g is warming up to backflow, backflow 14h.Be cooled to 20 ℃ ± 2 ℃, stir 2h, suction filtration, filter cake washes with the 25ml dehydrated alcohol.Under-the 0.095MPa, 50 ℃ ± 2 ℃ dry 5h.Obtain the tartrate 55.8g of (the Z)-4-(2,4 difluorobenzene base) of white solid-piperidyl methyl ketoxime.
(Z)-and the tartrate 55.8g of 4-(2,4 difluorobenzene base)-piperidyl methyl ketoxime, water 560ml is added to the 2L reaction flask, is warming up to 60 ℃ ± 2 ℃.Add 5%NaOH aqueous solution 195g in the 3h, transfer to pH＞10.Stir 0.5h in this temperature.When being cooled to 40 ℃ ± 2 ℃, add 350ml water, be cooled to 20 ℃ and stir 4h.Suction filtration, filter cake washes with 120ml water.Product in vacuum tightness be-0.085Mpa under, 50 ℃ ± 2 ℃, dry 10h obtains white solid 23.6g, fusing point 214-218 ℃.
3, the preparation of Zomaril
(Z)-4-(2, the 4-difluorophenyl)-piperidyl methyl ketoxime 21g, acetonitrile 210ml, join in the 500ml four-hole bottle, add 20.15g 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone, potassiumiodide 8.72g adds potassium hydroxide 7.25g, be warming up to back flow reaction 26h, the TLC detection reaction.React complete after, be down to room temperature, reaction solution is poured in the 700ml water, is down to about 20 ℃ ± 2 ℃.Add the 50%KOH aqueous solution and transfer pH to 10.Stir 4h, suction filtration, filter cake washes with 35ml water.Product is 50 ℃ ± 2 ℃ dry 24h under vacuum tightness 0.090Mpa, obtain white solid 33.5g, yield 94.5%, and purity 99.6%, HPLC figure sees accompanying drawing 1.
The HPLC condition:
Take octadecylsilane chemically bonded silica as weighting agent, (the 2.72g potassium primary phosphate is dissolved in the 1L deionized water acetonitrile-potassium dihydrogen phosphate buffer solution, add 0.5% (V/V) triethylamine, be 6.0 with the phosphorus acid for adjusting pH value) (43: 57) be moving phase, the detection wavelength is 229nm, and number of theoretical plate calculates by the Zomaril peak should be not less than 3000.
Embodiment 2, (Z)-4-(2,4-fluorophenyl)-piperidyl methyl ketoxime 5.0g, dehydrated alcohol 50ml, add successively 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone 4.58g, potassiumiodide 2.16g, 2%KOH176.5g, the TLC detection reaction is warmed up to 60 ℃ of reactions 14 hours, is warmed up to 70 ℃, reacted 1.5 hours, be down to room temperature, separate out solid, filter, the 10ml washing obtains the Zomaril crude product.Crude product adds the 1g gac with 120ml ethanol heating for dissolving, stirs, and heat filtering, the filtrate cool to room temperature filters, and obtains product 7.35g, yield 91.2%, purity 99.4%.
Embodiment 3, (Z)-4-(2, the 4-difluorophenyl)-piperidyl methyl ketoxime 21.0g, acetonitrile 210ml, join in the 500ml four-hole bottle, add 20.1g 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone, potassiumiodide 1.5g adds potassium hydroxide 7.3g, be warming up to back flow reaction 26h, the TLC detection reaction.React complete after, be down to room temperature, reaction solution is poured in the 700ml water, is cooled to about 20 ℃ ± 2 ℃.Stir 4h, suction filtration, filter cake washes with 35ml water.Product is 50 ℃ ± 2 ℃ dry 24h under vacuum tightness 0.090Mpa, obtain white solid 33.5g, yield 94.5%, purity 99.4%.。
Embodiment 4, (Z)-4-(2, the 4-difluorophenyl)-piperidyl methyl ketoxime 10g, ethanol 100ml, join in the 500ml four-hole bottle, add 9.6g 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone, potassiumiodide 1g adds solid potassium hydroxide 6.9g, be warming up to back flow reaction 20h, the TLC detection reaction.React complete after, be down to room temperature, reaction solution is poured in the 350ml water, is cooled to about 20 ℃ ± 2 ℃.Stir 4h, suction filtration, filter cake washes with water, and drying obtains white solid 15.3g, yield 91.3%, purity 99.5%.
As seen, utilize technical scheme of the present invention to prepare Zomaril, its purity is all more than 99%, and yield is all greater than 90%.
Following Comparative Examples 1-3 is according to single stage method of the present invention, uses disclosed other alkali except potassium hydroxide, sodium hydroxide or lithium hydroxide of CN200910200105, the preparation Zomaril.
Comparative Examples 1: under nitrogen protection, 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride 10g; add the 250ml there-necked flask, add the 150ml acetonitrile, add sodium bicarbonate 7.0g; sodium iodide 0.4g stirred 10 minutes, with 1-(4-(3-chloropropyl)-3-methoxyacetophenone 8.8g; add reaction flask, reflux, TLC detection reaction process; reacted 20 hours, and had by product to generate, be cooled to 0 degree; separate out solid, the washing of suction filtration solid, oven dry obtains product 13g.HPLC detects as can be known compound 5 content 75.17%, Zomaril content 24.83%.HPLC figure sees accompanying drawing 2.
Comparative Examples 2: under nitrogen protection, 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride 15g; add the 500ml there-necked flask, add 225ml ethanol, add yellow soda ash 6.2g; sodium iodide 0.6g stirred 10 minutes, with 1-(4-(3-chloropropyl)-3-methoxyacetophenone 13.2g; add reaction flask, reflux, TLC detection reaction process; reacted 20 hours, and had by product to generate, be cooled to 0 degree; separate out solid, the washing of suction filtration solid, oven dry obtains product 7.3g.HPLC detects as can be known compound 5 content 9.46%, Zomaril content 89.21%, other impurity 1.33%.
Comparative Examples 3: under nitrogen protection, 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride 15g; add the 250ml there-necked flask, add the 150ml acetonitrile, add sodium methylate 6.6g; sodium iodide 0.2g stirred 10 minutes, with 1-(4-(3-chloropropyl)-3-methoxyacetophenone 13.2g; add reaction flask, reflux, TLC detection reaction process; reacted 20 hours, and had by product to generate, be cooled to 0 degree; separate out solid, the washing of suction filtration solid, oven dry obtains product 7.1g.HPLC detects as can be known compound 5 content 7.53%, Zomaril content 86.58%, other impurity 5.89%.
As seen, utilize single stage method of the present invention, and use disclosed other alkali except potassium hydroxide, sodium hydroxide or lithium hydroxide of CN200910200105, the preparation Zomaril, yield is all below 90%.
Following Comparative Examples 4 is to react according to the condition of the preparation of the first step compound (5) among the disclosed embodiment 5 of CN200910200105.
Comparative Examples 4: under nitrogen protection; add 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride 20.0g, add the 250ml there-necked flask; add 150mlDMF; add sodium hydroxide 7.24g, sodium iodide 0.6g stirred 10 minutes; with 1-(4-(3-chloropropyl)-3-methoxyacetophenone 17.6g; add reaction flask, be heated to 90 ℃, reacted 10 hours; be cooled to room temperature; be cooled to 0 degree, separate out solid, the washing of suction filtration solid; oven dry obtains product 12.1g; HPLC shows that the compound that generates mainly is Zomaril, and content is 89.76%, and compound 5 content are 10.16%.HPLC figure sees accompanying drawing 3.
As seen, the disclosed two-step approach of CN200910200105 prepares Zomaril, when used alkali during for highly basic as sodium hydroxide, the reaction conditions of its first step can not control at all product be mainly compound 5.
Claims (7)
1. a single stage method prepares the method for Zomaril, and step is as follows: formula 4 compounds are dissolved in the organic solvent, and adding formula 3 compounds add potassiumiodide or sodium iodide, add mineral alkali, back flow reaction
2. the method for preparing Zomaril as claimed in claim 1 is characterized in that described mineral alkali is selected from potassium hydroxide, sodium hydroxide or lithium hydroxide.
3. the method for preparing Zomaril as claimed in claim 1 is characterized in that described organic solvent is selected from alcohols, acetonitrile or DMF.
4. the method for preparing Zomaril as claimed in claim 3 is characterized in that described alcohols is selected from ethanol.
5. the method for preparing Zomaril as claimed in claim 1 is characterized in that the control reaction is in reflux state.
6. the method for preparing Zomaril as claimed in claim 1 is characterized in that the reaction times is 12-26 hour.
7. the method for preparing Zomaril as claimed in claim 1, it is characterized in that reacting complete after, cooling, reaction solution is poured into water, stir, suction filtration, drying obtains Zomaril.
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| CN103319472A (en) * | 2013-07-23 | 2013-09-25 | 河北科技大学 | Preparation method of iloperidone |
| CN111777601A (en) * | 2020-05-23 | 2020-10-16 | 白银京宇新药业有限公司 | Preparation method of 6-fluoro-3- (4-piperidyl) -1, 2 benzisoxazole hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101735208A (en) * | 2009-12-08 | 2010-06-16 | 华东师范大学 | Method for synthesizing Iloperidone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101735208A (en) * | 2009-12-08 | 2010-06-16 | 华东师范大学 | Method for synthesizing Iloperidone |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103319472A (en) * | 2013-07-23 | 2013-09-25 | 河北科技大学 | Preparation method of iloperidone |
| CN103319472B (en) * | 2013-07-23 | 2016-07-06 | 河北科技大学 | A kind of preparation method of iloperidone |
| CN111777601A (en) * | 2020-05-23 | 2020-10-16 | 白银京宇新药业有限公司 | Preparation method of 6-fluoro-3- (4-piperidyl) -1, 2 benzisoxazole hydrochloride |
| CN111777601B (en) * | 2020-05-23 | 2021-07-16 | 白银京宇新药业有限公司 | Preparation method of 6-fluoro-3- (4-piperidyl) -1, 2 benzisoxazole hydrochloride |
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