CN102924439B - Preparation method of iloperidone - Google Patents
Preparation method of iloperidone Download PDFInfo
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- CN102924439B CN102924439B CN201110226361.4A CN201110226361A CN102924439B CN 102924439 B CN102924439 B CN 102924439B CN 201110226361 A CN201110226361 A CN 201110226361A CN 102924439 B CN102924439 B CN 102924439B
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- RBBVSSYQKVBALO-UHFFFAOYSA-N CC(c(cc1OC)ccc1OCCCCl)=O Chemical compound CC(c(cc1OC)ccc1OCCCCl)=O RBBVSSYQKVBALO-UHFFFAOYSA-N 0.000 description 2
- DAQWROFRHWHKFE-VBKFSLOCSA-N O/N=C(/C1CCNCC1)\c(c(F)c1)ccc1F Chemical compound O/N=C(/C1CCNCC1)\c(c(F)c1)ccc1F DAQWROFRHWHKFE-VBKFSLOCSA-N 0.000 description 2
- AOXGKWIPZAKQCW-UHFFFAOYSA-N CC(c(cc1)cc(OCCCN(CC2)CCC2c2n[o]c3cc(F)ccc23)c1OC)=O Chemical compound CC(c(cc1)cc(OCCCN(CC2)CCC2c2n[o]c3cc(F)ccc23)c1OC)=O AOXGKWIPZAKQCW-UHFFFAOYSA-N 0.000 description 1
- KALRQORCIWJUIG-PNHLSOANSA-N CC(c(cc1OC)ccc1OCCCN(CC1)CCC1/C(/c(ccc(F)c1)c1F)=N/O)=O Chemical compound CC(c(cc1OC)ccc1OCCCN(CC1)CCC1/C(/c(ccc(F)c1)c1F)=N/O)=O KALRQORCIWJUIG-PNHLSOANSA-N 0.000 description 1
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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 researched and developed by Titan company, within 2009, obtains U.S. FDA approval listing, for adult acute's treatment of schizophrenia.This indicate to much existing pharmacological agent only the effective schizophreniac of part be a new chance, this product can control their symptom better.Zomaril may become first personalized psychotherapeutic drug.The listing of Zomaril, it likely becomes schizoid first the gene target medicine for the treatment of.
EP0402644 (December 19 nineteen ninety is open) reports the general formula compound synthetic method of synthesis N-(aryloxy) heteroaryl piperidine base and heteroaryl piperazine, wherein contains 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) report the synthetic method of improvement, but synthetic method has continued the synthetic route of EP0402644 substantially, after this benzoxazoles structural compounds of first preparation formula 2 compound again with formula 3 compound condensation, obtain formula 1 compound Zomaril.Reaction process is as follows:
In European patent EP 196132, formula 2 compound is obtained by the cyclization under basic conditions of formula 4 compound.In reaction process, the fluorine atom and the oxime hydroxyl generation ring closure reaction that face position in formula 4 compound obtain formula 2 compound, but the fluorine atom of contraposition also can participate in reaction, dipolymer shown in production 8, this dipolymer participates in reaction further, can containing the impurity shown in formula 6 in the Zomaril finally obtained.
CN200910200105 adopts formula 4 compound (Z)-4-(2,4-difluorophenyl)-piperidyl methyl ketoxime and formula 3 compound 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone be obtained by reacting formula 5 compound, and then catalyze and synthesize Zomaril.
In the method, the first step needs in the basic conditions condensation reaction to occur, and generates carbonnitrogen bond, obtains formula 5 compound, and second step generates oxazole ring through ring-closure reaction in the basic conditions to obtain Zomaril.Alkali disclosed in it is the carbonate of metal, supercarbonate, oxyhydroxide, alkoxide, hydride, and amide is selected from sodium carbonate, sodium bicarbonate, sodium methylate, sodium hydroxide, potassium hydroxide, the one in amido sodium.Its Problems existing is:
1, after the first step reaction, need to obtain intermediate formula 5 compound through the step such as crystallization, filtration, unavoidably cause damage.And, condensation and ring-closure reaction mechanism similar, if first condensation reaction, cyclised products Zomaril is inevitably generated in condensation reaction, and last handling process after condensation reaction and crystallization condition are more suitable for the crystallization of condensation product formula 5 compound, the loss of Zomaril can be larger.Thus cause Zomaril yield low.Utilize multiple alkali disclosed in the method, as sodium carbonate, sodium bicarbonate, sodium methylate etc. provide alkaline environment to react time, formula 4 compound and formula 3 compound react and can not obtain formula 5 compound completely.
The yield that embodiment also demonstrates the Zomaril that the method finally obtains is lower, in embodiment 1, the yield of formula 5 compound is 85.0%, the yield of Zomaril is 89.0%, thus to calculate the yield preparing Zomaril by (Z)-4-(2,4 difluorobenzene base)-piperidyl methyl ketoxime be 75.65%.In like manner calculate the yield of Zomaril in embodiment 2-5 and be respectively 72.82%, 70.55%, 70.14% and 56.81%.
2, adopt two-step approach to react, step is many, complex operation, and two-step reaction all needs to carry out last handling process, after obtaining formula 5 compound, it must be separated out from reaction system, and then carry out ring-closure reaction.Need a large amount of solvent, reaction process longer and make energy consumption in production, equipment loss increases, cost raises.
Summary of the invention
The present invention is directed to above-mentioned defect, provide a kind of method that single stage method prepares Zomaril.A step base catalyzed reactions is adopted directly to be obtained by reacting Zomaril by formula 3 compound and formula 4 compound.Greatly simplify operation, while simplifying the operation, not to sacrifice quality product for 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 compound is dissolved in organic solvent, and add formula 3 compound, potassiumiodide or sodium iodide, add mineral alkali, back flow reaction, TLC detection reaction.Reaction times is 12-26 hour.After completion of the reaction, cooling, reaction solution is poured into water, and stirs, suction filtration, dry, 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.
Accompanying drawing explanation
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 example 1 correspondence, wherein the peak of retention time 10.844min is the peak of Zomaril, and the peak of retention time 6.100min is the peak of formula 5 compound.
The HPLC figure of Fig. 3 comparative example 4 correspondence, wherein the peak of retention time 10.752min is the peak of Zomaril, and the peak of retention time 6.220min is the peak of formula 5 compound.
Embodiment
Following examples illustrate 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 (i.e. formula 3 compound)
Vanillone 17.6g is dissolved in 75ml acetone, adds 13.8g salt of wormwood, be heated to backflow, drip the mixing solutions of the bromo-3-chloropropane of 83.4g1-and 20ml acetone, back flow reaction 10h.Be cooled to room temperature, suction filtration obtains filtrate, steams except after acetone and the bromo-3-chloropropane of 1-, 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 (i.e. formula 4 compound)
Dehydrated alcohol 136ml, oxammonium hydrochloride 11.2g, join in 500ml there-necked flask, and add 20%NaOH aqueous solution 54.7g under stirring, control temperature is at 20-30 DEG C.After dropwising, stir about 15min, 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 DEG C ± 2 DEG C, stir 2h, suction filtration, filter cake 25ml dehydrated alcohol rinses.Under-0.095MPa, 50 DEG C ± 2 DEG C dry 5h.Obtain the tartrate 55.8g of (Z)-4-(2,4 difluorobenzene the base)-piperidyl methyl ketoxime of white solid.
(Z) the tartrate 55.8g of-4-(2,4 difluorobenzene base)-piperidyl methyl ketoxime, water 560ml is added to 2L reaction flask, is warming up to 60 DEG C ± 2 DEG C.Add 5%NaOH aqueous solution 195g in 3h, be adjusted to pH > 10.0.5h is stirred in this temperature.When being cooled to 40 DEG C ± 2 DEG C, add 350ml water, be cooled to 20 DEG C and stir 4h.Suction filtration, filter cake 120ml water rinses.Product is under vacuum tightness is-0.085Mpa, and 50 DEG C ± 2 DEG C, dry 10h obtains white solid 23.6g, fusing point 214-218 DEG C.
3, the preparation of Zomaril
(Z)-4-(2,4-difluorophenyl)-piperidyl methyl ketoxime 21g, acetonitrile 210ml, join in 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, TLC detection reaction.After completion of the reaction, be down to room temperature, reaction solution is poured in 700ml water, is down to 20 DEG C ± about 2 DEG C.Add the 50%KOH aqueous solution and adjust pH to 10.Stir 4h, suction filtration, filter cake 35ml water rinses.Product is 50 DEG C ± 2 DEG C dry 24h under vacuum tightness 0.090Mpa, obtain white solid 33.5g, yield 94.5%, and purity 99.6%, HPLC figure is shown in accompanying drawing 1.
HPLC condition:
Take octadecylsilane chemically bonded silica as weighting agent, (2.72g potassium primary phosphate is dissolved in 1L deionized water acetonitrile-potassium dihydrogen phosphate buffer solution, add 0.5% (V/V) triethylamine, be 6.0 by phosphoric acid adjust ph) (43: 57) be moving phase, determined wavelength is 229nm, and number of theoretical plate calculates should be not less than 3000 by Zomaril peak.
Embodiment 2, (Z)-4-(2,4-fluorophenyl)-piperidyl methyl ketoxime 5.0g, dehydrated alcohol 50ml, add 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone 4.58g successively, potassiumiodide 2.16g, 2%KOH176.5g, TLC detection reaction, is warmed up to 60 DEG C of reactions 14 hours, is warmed up to 70 DEG C, react 1.5 hours, be down to room temperature, separate out solid, filter, 10ml washes, and obtains Zomaril crude product.Crude product 120ml ethanol heating for dissolving, adds 1g gac, stirs, heat filtering, filtrate cool to room temperature, filters, obtains product 7.35g, yield 91.2%, purity 99.4%.
Embodiment 3, (Z)-4-(2,4-difluorophenyl)-piperidyl methyl ketoxime 21.0g, acetonitrile 210ml, join in 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, TLC detection reaction.After completion of the reaction, be down to room temperature, reaction solution is poured in 700ml water, is cooled to 20 DEG C ± about 2 DEG C.Stir 4h, suction filtration, filter cake 35ml water rinses.Product is 50 DEG C ± 2 DEG C dry 24h under vacuum tightness 0.090Mpa, obtain white solid 33.5g, yield 94.5%, purity 99.4%.。
Embodiment 4, (Z)-4-(2,4-difluorophenyl)-piperidyl methyl ketoxime 10g, ethanol 100ml, join in 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, TLC detection reaction.After completion of the reaction, be down to room temperature, reaction solution is poured in 350ml water, is cooled to 20 DEG C ± about 2 DEG C.Stir 4h, suction filtration, filter cake washes with water, dry, obtains white solid 15.3g, yield 91.3%, purity 99.5%.
Visible, 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 example 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, prepares Zomaril.
Comparative example 1: under nitrogen protection, 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride 10g; add 250ml there-necked flask, add 150ml acetonitrile, add sodium bicarbonate 7.0g; sodium iodide 0.4g, stirs 10 minutes, by 1-(4-(3-chloropropyl)-3-methoxyacetophenone 8.8g; add reaction flask, reflux, TLC detection reaction process; react 20 hours, have by product to generate, be cooled to 0 degree; separate out solid, suction filtration solid is washed, and dries and obtains product 13g.HPLC detects known compound 5 content 75.17%, Zomaril content 24.83%.HPLC figure is shown in accompanying drawing 2.
Comparative example 2: under nitrogen protection, 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride 15g; add 500ml there-necked flask, add 225ml ethanol, add sodium carbonate 6.2g; sodium iodide 0.6g, stirs 10 minutes, by 1-(4-(3-chloropropyl)-3-methoxyacetophenone 13.2g; add reaction flask, reflux, TLC detection reaction process; react 20 hours, have by product to generate, be cooled to 0 degree; separate out solid, suction filtration solid is washed, and dries and obtains product 7.3g.HPLC detects known compound 5 content 9.46%, Zomaril content 89.21%, other impurity 1.33%.
Comparative example 3: under nitrogen protection, 2,4 difluorobenzene base (4-piperidyl) ketoxime hydrochloride 15g; add 250ml there-necked flask, add 150ml acetonitrile, add sodium methylate 6.6g; sodium iodide 0.2g, stirs 10 minutes, by 1-(4-(3-chloropropyl)-3-methoxyacetophenone 13.2g; add reaction flask, reflux, TLC detection reaction process; react 20 hours, have by product to generate, be cooled to 0 degree; separate out solid, suction filtration solid is washed, and dries and obtains product 7.1g.HPLC detects known compound 5 content 7.53%, Zomaril content 86.58%, other impurity 5.89%.
Visible, utilize single stage method of the present invention, and use other alkali disclosed in CN200910200105 except potassium hydroxide, sodium hydroxide or lithium hydroxide, prepare Zomaril, yield is all below 90%.
Following comparative example 4 is reacted according to the condition of the preparation of the first step compound (5) in embodiment disclosed in CN200910200105 5.
Comparative example 4: under nitrogen protection, add 2, 4-difluorophenyl (4-piperidyl) ketoxime hydrochloride 20.0g, add 250ml there-necked flask, add 150mlDMF, add sodium hydroxide 7.24g, sodium iodide 0.6g, stir 10 minutes, by 1-(4-(3-chloropropyl)-3-methoxyacetophenone 17.6g, add reaction flask, be heated to 90 DEG C, react 10 hours, be cooled to room temperature, be cooled to 0 degree, separate out solid, suction filtration solid is washed, oven dry obtains product 12.1g, the compound mainly Zomaril that HPLC display generates, content is 89.76%, compound 5 content is 10.16%.HPLC figure is shown in accompanying drawing 3.
Visible, the two-step approach disclosed in CN200910200105 prepares Zomaril, when alkali used is the highly basic as sodium hydroxide, the reaction conditions of its first step can not control at all product be mainly compound 5.
Claims (3)
1. single stage method prepares a method for Zomaril, and step is as follows: formula 4 compound is dissolved in organic solvent, adds formula 3 compound, adds potassiumiodide or sodium iodide, add mineral alkali, back flow reaction,
Wherein, described organic solvent is selected from ethanol or acetonitrile, and described mineral alkali is selected from potassium hydroxide, sodium hydroxide or lithium hydroxide.
2. prepare the method for Zomaril as claimed in claim 1, it is characterized in that the reaction times is 12-26 hour.
3. prepare the method for Zomaril as claimed in claim 1, it is characterized in that after completion of the reaction, cooling, reaction solution is poured into water, and stirs, suction filtration, dry, obtains Zomaril.
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