CN102796090A - Method for preparing iloperidone - Google Patents
Method for preparing iloperidone Download PDFInfo
- Publication number
- CN102796090A CN102796090A CN2012103173253A CN201210317325A CN102796090A CN 102796090 A CN102796090 A CN 102796090A CN 2012103173253 A CN2012103173253 A CN 2012103173253A CN 201210317325 A CN201210317325 A CN 201210317325A CN 102796090 A CN102796090 A CN 102796090A
- Authority
- CN
- China
- Prior art keywords
- piperidyl
- zomaril
- fluoro
- mol ratio
- hydrochlorate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention relates to a method for preparing iloperidone. The method comprises the following steps of: dissolving 4-(2,4-difluorobenzoyl)-piperidine hydrochloride and hydroxylamine hydrochloride serving as raw materials into 95 percent ethanol serving as a cheap solvent by taking excessive triethylamine as an alkali to obtain an intermediate, i.e., 2,4-difluorophenyl-4-piperidylketoxime; dissolving potassium hydroxide powder with absolute ethyl alcohol, reacting with the intermediate, purifying and salting to obtain a second intermediate, i.e., 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazolehydrochloride; preparing and recrystallizing a third intermediate, i.e., 4-(3-chloropropyloxy)-3-methoxyacetophenone by taking 3-methoxyl-4-hydroxyacetophenone and 1-bromine-3-chloropropane serving raw materials; reacting the second intermediate, i.e., 6-fluoro-3-(4-piperidyl)-1,2-benzisoxazolehydrochloride with the third intermediate, i.e., 4-(3-chloropropyloxy)-3-methoxyacetophenone in a mixed solution of water and acetone under the action of potassium carbonate to obtain crude iloperidone; and refining the crude iloperidone with ethanol to obtain fine iloperidone.
Description
Technical field
The present invention relates to the preparation method of a kind of mixed type dopamine D 2/serotonin 5HT2A receptor blocking agent Zomaril, belong to pharmaceutical field.
Background technology
Zomaril (Iloperidone), commodity are called FANAPT, chemical name: 1-[4-[3-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] propoxy-]-3-p-methoxy-phenyl] ethyl ketone, molecular formula: C24H27FN2O4, structural formula shown in YPT-0,
Zomaril is by the research and development of Titan company and transfer Novartis Co.,Ltd, and the back transfers Vanda drugmaker by Novartis Co.,Ltd, goes on the market in the U.S. on May 6th, 2009, is used to treat schizophrenia.Zomaril is the atypia Antipsychotic drug of schizoid first gene target property of treatment; Be incorporated into serotonin 5HT2A and dopamine D 2, D3 acceptor (Ki value be respectively 5.6,6.3,7.1nM) the Zomaril high-affinity, can better control the symptoms of schizophrenia.Compare with the antipsychotics of present use; The spinoff that short-term, secular proof test result show Zomaril is less; The weight in patients increasing degree is lower; Zomaril can not induce the patient that mellitus take place, patient's EPS yet less (nothing cathisophobia, do not have hyperprolactinemia, drowsiness incidence descend, cognitive ability descends less).
At present; The chemical process of preparation Zomaril has multiple; Wherein preferably use general formula (YPT-003X) 4-(3-replaces propoxy-)-3-methoxyacetophenone and general formula (YPT-002X) 6-fluoro-3-(4-piperidyl)-1, the 2-benzoisoxazole synthesizes, and wherein X is a halogen atom.The compound method of bibliographical information also mostly comes from this two compounds and verivate thereof.
Report in the document EP 0402644:
This route is the method for the synthetic iloperidone reported the earliest; This route has more document support (being described below), and its step is short, and aftertreatment is simple; System easy to control the quality; And can make things convenient for and synthesize two reaction raw materials economically, and can reach the purity requirement of synthetic finished product after treatment, select the route of this route as synthetic iloperidone raw material.
Document US 4804663 has been described the midbody 6-fluoro-3-(4-piperidyl)-1 of above-mentioned route, the preparation of the reactant 2,4 difluorobenzene base of 2-benzo isoxazole hydrochlorate (YPT-002)-4-piperidyl methyl ketoxime (YPT-001).Its report is a raw material with 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate (YPT-S-001) and oxammonium hydrochloride (IV), does alkali with the triethylamine of 2 times of molar weights, is dissolved in the absolute ethyl alcohol and reacts.Reaction cost is slightly high, haves much room for improvement.
Document " Chinese pharmaceutical chemistry magazine 2007vol 17 (2) p89 " and CN200810055506.7 have described the midbody 6-fluoro-3-(4-piperidyl)-1 of above-mentioned route, the preparation of 2-benzo isoxazole hydrochlorate (YPT-002).Its report is used the hydrogenchloride salify then with Pottasium Hydroxide and 2,4 difluorobenzene base-4-piperidyl methyl ketoxime.Reaction is water or acetone solution Pottasium Hydroxide respectively, and effect haves much room for improvement.
Document CN200910067734.0 and US4366162A have described the preparation of midbody 4-(3-replaces propoxy-)-3-methoxyacetophenone.Its report is with two the reactant 3-methoxyl groups-4-hydroxy acetophenone (YPT-S-002) and the l of midbody; 3-bromo-chloropropane (YPT-S-003) and salt of wormwood react in acetone, and the product underpressure distillation distillates, the high temperature high vacuum; Very high to equipment requirements, be unfavorable for producing.
Document EP 0402644 has been described the preparation of Zomaril bullion with WO2011032404A1 and has been made with extra care.Its report in 80 ~ 90 ℃ of reactions, wherein adds salt of wormwood with above-mentioned two kinds of midbody YPT-002 and YPT-003, is solvent with DMF or water, and effect haves much room for improvement.Document is also with twice of ethyl alcohol recrystallization or with toluene recrystallizing and refining Zomaril bullion, and twice productive rate of recrystallization reduces, and toluene toxicity is bigger, and these problems have much room for improvement.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing high purity Zomaril (YPT-0) of highly effective.It is characterized in that prepared Zomaril purity is high, foreign matter content is little, and yield is high, and agents useful for same is inexpensive and environmentally friendly, and preparation technology is simple, is fit to suitability for industrialized production.
The present invention relates to a kind of preparation method of Zomaril, this method is a raw material with 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate and oxammonium hydrochloride; With excessive triethylamine is alkali; Be dissolved in inexpensive solvent 95% ethanol, obtain midbody 2,4 difluorobenzene base-4-piperidyl methyl ketoxime; With anhydrous alcohol solution Pottasium Hydroxide powder, with above-mentioned midbody reaction, purifying, salify obtain second midbody 6-fluoro-3-(4-piperidyl)-1,2-benzo isoxazole hydrochlorate then; Be feedstock production, the 3rd midbody 4-of recrystallization (3-chloropropyl oxygen base)-3-methoxyacetophenone with 3-methoxyl group-4-hydroxy acetophenone and 1-bromo-3-chloropropane again; Second midbody 6-fluoro-3-(4-piperidyl)-1,2-benzo isoxazole hydrochlorate and the 3rd midbody 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone under the salt of wormwood effect, obtain the Zomaril bullion with the reaction of the mixing solutions of water and acetone; The Zomaril bullion is refining through ethanol to be elaboration.
For this reason, the present invention provides a kind of preparation method of Zomaril, and the synthetic route of this method is following:
Preparing method of the present invention specifically comprises following process step:
The first step: with 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate (YPT-S-001) and oxammonium hydrochloride (IV) is raw material, does alkali with triethylamine; Be dissolved in 95% ethanol; Reaction obtains compound 2,4 difluorobenzene base-4-piperidyl methyl ketoxime (YPT-001) under 75 ~ 90 ℃ temperature condition; Wherein oxammonium hydrochloride and 4-(2; The 4-difluoro benzoyl)-and the mol ratio of piperidine hydrochlorate is 3.5:1 ~ 4.5:1, the mol ratio of triethylamine and 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate is 2.05:1 ~ 3.0:1; Wherein, the optimum mole ratio of described triethylamine and 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate is 2.2:1.
Second step: the Pottasium Hydroxide powder of 1.5 ~ 3.5 times of molar weights is dissolved in the alcoholic solvent, adds the compound YPT-001 of gained in the first step, under 35 ~ 50 ℃ of temperature, reacted 1 ~ 3 hour; Suction filtration is used the alcoholic solvent washing leaching cake, merging filtrate then; Steaming desolventizes, and the resistates that obtains adds after the entry with methylene dichloride or ethyl acetate extraction 2 ~ 4 times, merges organic layer; With saturated aqueous common salt and pure water washing, use anhydrous sodium sulfate drying then respectively, steaming afterwards desolventizes; The residue that obtains adds homemade saturated hydrogen chloride methanol solution with the dissolve with methanol of 5 ~ 15 times of volumes down at 5 ~ 20 ℃, makes pH less than 3; Obtain white solid 6-fluoro-3-(4-piperidyl)-1,2-benzo isoxazole hydrochlorate (YPT-002); Wherein, described reaction times the best is 1.5 ~ 2.5 hours; Described temperature of reaction the best is 40 ~ 50 ℃; Described alcoholic solvent the best is an ethanol, for example: absolute ethyl alcohol; Mol ratio the best of described Pottasium Hydroxide and 2,4 difluorobenzene base-4-piperidyl methyl ketoxime is 2.0:1 ~ 2.5:1; Described salify temperature the best is 8 ~ 12 ℃; Described salify solvent volume amount and free 6-fluoro-3-(4-piperidyl)-1, ratio the best of the weight of 2-benzoisoxazole bullion is 10:1 ~ 15:1 (ml/g).
The 3rd step: in the acetone soln of 3-methoxyl group-4-hydroxy acetophenone (YPT-S-002), add salt of wormwood, reflux 0.5 ~ 1 hour; Add again and be dissolved in the 1-bromo-3-chloropropane (YPT-S-003) in the acetone; Continue to reflux 25 ~ 30 hours, and concentrated then and obtain oily matter, with it with non-alcohols low polar solvent recrystallization; At 0 ~ 15 ℃ of following crystallization, obtain white solid 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone (YPT-003); Wherein, described non-alcohols low polar solvent the best is a hexanaphthene; Described recrystallization recrystallization temperature the best is 5 ~ 10 ℃; The mol ratio of described 1-bromo-3-chloropropane and 3-methoxyl group-4-hydroxy acetophenone is 1.2:1 ~ 1.4:1; The mol ratio of described salt of wormwood and 3-methoxyl group-4-hydroxy acetophenone is 1.05:1 ~ 1.1:1.
The 4th step: the YPT-003 of YPT-002,1 ~ 1.5 molar weight, salt of wormwood, water and the acetone of 3 ~ 4 molar weights are heated with stirring to 70-90 ℃ together; Reacted 3.5 ~ 5.5 hours; Cooling is then filtered, and the filter cake that obtains is a bullion white solid Zomaril bullion (YPT-0-R); Wherein, described temperature of reaction the best is 75 ~ 80 ℃; Described reaction times the best is 4 ~ 5 hours; Described 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone and 6-fluoro-3-(4-piperidyl)-1, mol ratio the best of 2-benzo isoxazole hydrochlorate is 1.05:1 ~ 1.2:1; Described salt of wormwood and 6-fluoro-3-(4-piperidyl)-1, mol ratio the best of 2-benzo isoxazole hydrochlorate is 3.2:1 ~ 3.4:1; Described filter cake washs with alcoholic solvent, and alcoholic solvent the best is a methyl alcohol; Described alcoholic solvent volume and 6-fluoro-3-(4-piperidyl)-1, the ratio of 2-benzo isoxazole hydrochlorate weight is 1.05:1 ~ 1.2:1 (ml/g).
The 5th step: with the activated carbon decolorizing of 0.1 ~ 0.2 times of weight, the alcoholic solvent recrystallizing and refining of 5 ~ 10 times of volumes, recrystallization temperature is 0 ~ 20 ℃, obtains white solid Zomaril elaboration (YPT-0); Wherein, described alcoholic solvent the best is ethanol, for example absolute ethyl alcohol; Described alcoholic solvent volume is 7.5:1 (ml/g) with ratio the best of Zomaril bullion weight; Described recrystallization temperature the best is 0 ~ 5 ℃.More than or equal to 99.95 weight %, total impurities is no more than 0.05 weight % according to the prepared Zomaril purity of aforesaid method.Single impurity is no more than 0.0273%.
The present invention's beneficial effect compared with prior art is: the midbody of the Zomaril that the present invention is prepared and the yield of finished product are higher, and purity is higher, and foreign matter content is less; Agents useful for same is inexpensive and environmentally friendly; Cost is lower, and preparation technology is simple, and the reaction times is shorter.In addition, great advantage of the present invention is can be used for suitability for industrialized production.
Below in conjunction with accompanying drawing and embodiment the synthetic route of said Zomaril with the chemical structural formula description further specified.
Description of drawings
Fig. 1 Zomaril highly finished product HPLC spectrogram
Fig. 2 Zomaril highly finished product 1HNMR figure
Embodiment
Below in conjunction with specific embodiment the present invention is done explanation further, but the present invention not only is confined to following embodiment.
Embodiment 1: the preparation of midbody 2,4 difluorobenzene base-4-piperidyl methyl ketoxime (YPT-001)
The first step: in the 2000mL there-necked flask, add 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate (100g, 0.38mol) and oxammonium hydrochloride (100g; 1.44mol), add 1050mL95% ethanol, stir; Add triethylamine (88g; 0.87mol), reflux 4.5h, TLC show that raw material reaction finishes (developping agent: DCM:MeOH=15:1 adds a little TEA).Be chilled to room temperature, suction filtration is used the 500ml washing with alcohol, gets the about 67g of white solid, yield 73 ﹪, purity 91% behind 40 ℃ of drying under reduced pressure.
Embodiment 2: the preparation of midbody 2,4 difluorobenzene base-4-piperidyl methyl ketoxime (YPT-001)
The first step: in the 250mL there-necked flask, add 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate (15g, 0.057mol) and oxammonium hydrochloride (15g; 0.216mol), add 160ml95% ethanol, stir; Add triethylamine (20ml; 0.144mol), reflux 3h, TLC show that raw material reaction finishes (developping agent: DCM:MeOH=15:1 adds a little TEA).Be chilled to room temperature, suction filtration is used the 80ml washing with alcohol, gets white solid 10.5g, yield 77 ﹪, purity 91% after the drying.
Embodiment 3: midbody 6-fluoro-3-(4-piperidyl)-1, the preparation of 2-benzo isoxazole hydrochlorate (YPT-002)
Second step: (135.3g 2.41mol) and the 3.5L absolute ethyl alcohol, stirs in the 20L reaction kettle, to add Pottasium Hydroxide; Adding bullion 2,4 difluorobenzene base-(4-piperidyl) ketoxime (290g, 1.21mol); 40 ℃ of reactions of temperature control 2.5h, TLC shows that raw material reaction finishes (developping agent: DCM:MeOH=15:1 adds a little TEA), removes oil bath; Be chilled to room temperature, suction filtration, a little ethanol filter wash cake.The filtrating evaporate to dryness, residue adds about 5L water, and methylene dichloride (4.5L 2.5L) extracts, and saturated aqueous common salt 5L washes once, and water 5L washes once, anhydrous sodium sulfate drying.Filter, neat solvent is steamed in decompression, obtains free 6-fluoro-3-(4-piperidyl)-1; 2-benzoisoxazole bullion 200g (0.908mol) adds the 2.2L dissolve with methanol, splashes into the about 260ml of saturated HCl methanol solution under 10 ℃ of stirrings; PH=2～3, suction filtration, 40 ℃ reduce pressure white solid 215g; Yield 69%, purity 98.99%.
Embodiment 4: midbody 6-fluoro-3-(4-piperidyl)-1, the preparation of 2-benzo isoxazole hydrochlorate (YPT-002)
Second step: (12.75g 0.227mol) and the 350ml absolute ethyl alcohol, stirs in the 2000ml there-necked flask, to add Pottasium Hydroxide; Adding bullion 2,4 difluorobenzene base-(4-piperidyl) ketoxime (25g, 0.104mol); 40 ℃ of reactions of temperature control 2.5h, TLC shows that raw material reaction finishes (developping agent: DCM:MeOH=15:1 adds a little TEA), removes oil bath; Be chilled to room temperature, suction filtration, a little ethanol filter wash cake.The filtrating evaporate to dryness, residue adds about 500ml water, and methylene dichloride (450ml 250ml) extracts, and saturated aqueous common salt 500ml washes once, and water 500ml washes once, anhydrous sodium sulfate drying.Filter, neat solvent is steamed in decompression, obtains free 6-fluoro-3-(4-piperidyl)-1; 2-benzoisoxazole bullion 17.2g (0.078mol) adds the 200ml dissolve with methanol, splashes into the about 270ml of saturated HCl methanol solution under 10 ℃ of stirrings; PH=2～3, suction filtration, 40 ℃ reduce pressure white solid 18.7g; Yield 70%, purity 98.99%.
Embodiment 5: the preparation of midbody 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone (YPT-003)
The 3rd step: (50g 0.301mol) and 280mL acetone, stirs in the 500mL there-necked flask, to add 3-methoxyl group-4-hydroxy acetophenone; Adding salt of wormwood (42g, 0.304mol), heating reflux reaction 0.5h; (62.5g 0.397mol), finishes to be added dropwise to the 1-bromo-3-chloropropane that is dissolved in 50mL acetone; Continue heating reflux reaction 27h, TLC shows the raw material reaction (developping agent: PE:EA=2:1) that finishes.Be chilled to room temperature, suction filtration, filtrating concentrates, and gets oily matter 80g, adds 700ml hexanaphthene recrystallization, gets white solid 63.5g, yield 87%, purity 98%.
Embodiment 6: the preparation of midbody 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone (YPT-003)
The 3rd step: (500g 3.00mol) and 5L acetone, stirs in the 20L reaction kettle, to add 3-methoxyl group-4-hydroxy acetophenone; Adding salt of wormwood (420g, 3.04mol), heating reflux reaction 0.5h; (625g 3.97mol), finishes to be added dropwise to the 1-bromo-3-chloropropane that is dissolved in 500mL acetone; Continue heating reflux reaction 28h, TLC shows the raw material reaction (developping agent: PE:EA=2:1) that finishes.Be chilled to room temperature, suction filtration, filtrating concentrates, and gets oily matter 795g, adds 7L hexanaphthene recrystallization, gets white solid 640g, yield 88%, purity 98%.
Embodiment: 7: the preparation of end product Zomaril bullion (YPT-0-R)
The 4th step: in the 20L reaction kettle, add YPT-002 (450g, 1.75mol), YPT-003 (470g, 1.94mol), salt of wormwood (810g; 5.86mol), 5.4L water and 0.54L acetone; Stir heating, temperature control 75-80 ℃ of reaction .5h; TLC monitoring raw material point is shallower than impure point (developping agent: DCM: methyl alcohol=15:1 adds a little TEA), handles.Be chilled to room temperature, filter, water 1L*2 washing, methyl alcohol 0.5L*3 washing.Get bullion 680g, yield 91%, purity 98.5% behind 40 ℃ of drying under reduced pressure
Embodiment 8: the preparation of end product Zomaril bullion (YPT-0-R)
The 4th step: in the 2000ml there-necked flask, add YPT-002 (50g, 0.195mol), YPT-003 (61.6g, 0.254mol), salt of wormwood (94g; 5.86mol), 500mL water and 55mL acetone; Stir heating, temperature control 75-80 ℃ of reaction 4.5h; TLC monitoring raw material point is shallower than impure point (developping agent: DCM: methyl alcohol=15:1 adds a little TEA), handles.Be chilled to room temperature, filter, water 250ml*2 washing, methyl alcohol 150ml*3 washing.Get bullion 76.5g, yield 92%, purity 98.5% behind 40 ℃ of drying under reduced pressure.
Embodiment 9: the preparation of end product Zomaril elaboration (YPT-0)
The 5th step: get 70g Zomaril bullion, ethanol 50mL, gac 7g decolouring, heat filtering, the 0-5 ℃ of crystallization of lower the temperature filters, washing, drying, off-white color solid Zomaril 66.5g, yield 95%, purity 99.56%, is no more than 0.32% at maximum single u that mixes; Use ethyl alcohol recrystallization once more, yield 95%, last purity 99.95%, total mixing is no more than 0.05%, and single impurity is no more than 0.0273%.
1HNMR:
1.95~2.07(6H,m),2.08~2.17(2H,m),2.51(3H,s),2.53~2.55(2H,t),3.01~3.04(3H,m),3.86(3H,s),4.12~4.15(2H,t),6.87~6.89(1H,d),6.91~7.01(1H,t),7.16~7.19(1H,dd),7.47~7.48(1H,d),7.49~7.52(1H,dd),7.62~7.65(1H,q)
13CNMR:
196.90,165.87 and 162.55,164.07 and 163.89,161.23,153.03,149.40,130.53,117.47 (8 quaternary carbons); 123.36,122.71 and 122.64,112.50 and 112.33,111.34,110.55,97.61 and 97.43,56.13 (7 CH); 67.44,55.20,53.68.30.68,26.71 (7 CH2), 56.13,26.33 (2 CH3)
MS：427.5(M+H)，394.5(M-CH3O)，374.5(394.5-F)。
Claims (8)
1. a method for preparing Zomaril is characterized in that, comprises the steps:
The first step: with 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate and oxammonium hydrochloride is raw material, does alkali with triethylamine; Be dissolved in 95% ethanol, reaction obtains compound 2 under 75 ~ 90 ℃ temperature condition; 4-difluorophenyl-4-piperidyl methyl ketoxime, wherein the mol ratio of oxammonium hydrochloride and 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate is 3.5:1 ~ 4.5:1; The mol ratio of triethylamine and 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate is 2.05:1 ~ 3.0:1;
Second step: the dense potassium hydroxide aqueous solution of 1.5 ~ 3.5 times of molar weights is dissolved in the alcoholic solvent, adds the 2,4 difluorobenzene base-4-piperidyl methyl ketoxime of gained in the first step, under 35 ~ 50 ℃ of temperature, reacted 1 ~ 3 hour; Suction filtration is used the alcoholic solvent washing leaching cake, merging filtrate then; Steaming desolventizes, and the resistates that obtains adds after the entry with methylene dichloride or ethyl acetate extraction 2 ~ 4 times, merges organic layer; Steaming desolventizes, and the residue that obtains adds saturated hydrogen chloride methanol solution with the dissolve with methanol of 5 ~ 15 times of volumes down at 5 ~ 20 ℃; Make pH less than 3, obtain white solid 6-fluoro-3-(4-piperidyl)-1, the 2-benzo isoxazole hydrochlorate;
The 3rd step: in the acetone soln of 3-methoxyl group-4-hydroxy acetophenone, add salt of wormwood, reflux 0.5 ~ 1 hour; Add again and be dissolved in the 1-bromo-3-chloropropane in the acetone; Continue to reflux 25 ~ 30 hours, and concentrated then and obtain oily matter, with it with non-alcohols low polar solvent recrystallization; At 0 ~ 15 ℃ of following crystallization, obtain white solid 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone;
The 4th step: with 6-fluoro-3-(4-piperidyl)-1; Salt of wormwood, water and the acetone of the 4-of 2-benzo isoxazole hydrochlorate, 1 ~ 1.5 molar weight (3-chloropropyl oxygen base)-3-methoxyacetophenone, 3 ~ 4 molar weights are heated with stirring to 70-90 ℃ together; Reacted 3.5 ~ 5.5 hours, cooling is then filtered; The cake solids that obtains is the Zomaril bullion
The 5th step: with the activated carbon decolorizing of 0.1 ~ 0.2 molar weight, the alcoholic solvent recrystallizing and refining of 5 ~ 10 molar weights, recrystallization temperature is 0 ~ 20 ℃, obtains white solid Zomaril elaboration.
2. method according to claim 1 is characterized in that, in the first step: the mol ratio of described triethylamine and 4-(2,4 difluorobenzene formyl radical)-piperidine hydrochlorate is 2.2:1.
3. method according to claim 1; It is characterized in that in second step: the described reaction times is 1.5 ~ 2.5 hours, and described temperature of reaction is 40 ~ 50 ℃; Described alcoholic solvent is an absolute ethyl alcohol; The mol ratio of described Pottasium Hydroxide and 2,4 difluorobenzene base-4-piperidyl methyl ketoxime is 2.0:1 ~ 2.5:1, and described salify temperature is 8 ~ 12 ℃; Described salify solvent volume amount and free 6-fluoro-3-(4-piperidyl)-1, the ratio of the weight of 2-benzoisoxazole bullion is 10:1 ~ 15:1.
4. method according to claim 1; It is characterized in that; In the 3rd step: described non-alcohols low polar solvent is a hexanaphthene; Described recrystallization recrystallization temperature is 5 ~ 10 ℃, and the mol ratio of described 1-bromo-3-chloropropane and 3-methoxyl group-4-hydroxy acetophenone is 1.2:1 ~ 1.4:1, and the mol ratio of described salt of wormwood and 3-methoxyl group-4-hydroxy acetophenone is 1.05:1 ~ 1.1:1.
5. method according to claim 1 is characterized in that, in the 4th step: described temperature of reaction is 75 ~ 80 ℃; The described reaction times is 4 ~ 5 hours, described 4-(3-chloropropyl oxygen base)-3-methoxyacetophenone and 6-fluoro-3-(4-piperidyl)-1, and the mol ratio of 2-benzo isoxazole hydrochlorate is 1.05:1 ~ 1.2:1; Described salt of wormwood and 6-fluoro-3-(4-piperidyl)-1; The mol ratio of 2-benzo isoxazole hydrochlorate is 3.2:1 ~ 3.4:1, and described filter cake is used methanol wash, and wherein said filter cake is used methanol wash; The volume of methyl alcohol and 6-fluoro-3-(4-piperidyl)-1, the ratio of 2-benzo isoxazole hydrochlorate weight is 1.05:1 ~ 1.2:1.
6. method according to claim 1 is characterized in that, in the 5th step: described alcoholic solvent is an absolute ethyl alcohol, and described alcoholic solvent volume is 7.5:1 with the ratio of Zomaril bullion weight, and described recrystallization temperature is 0 ~ 5 ℃.
7. method according to claim 1, the purity that it is characterized in that the gained Zomaril is more than or equal to 99.95 weight %, and total impurities is no more than 0.05 weight %.
8. method according to claim 1 is characterized in that the single impurity of gained Zomaril is no more than 0.0273%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210317325.3A CN102796090B (en) | 2012-08-30 | 2012-08-30 | Method for preparing iloperidone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210317325.3A CN102796090B (en) | 2012-08-30 | 2012-08-30 | Method for preparing iloperidone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102796090A true CN102796090A (en) | 2012-11-28 |
| CN102796090B CN102796090B (en) | 2015-03-25 |
Family
ID=47195426
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210317325.3A Active CN102796090B (en) | 2012-08-30 | 2012-08-30 | Method for preparing iloperidone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102796090B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130785A (en) * | 2012-12-20 | 2013-06-05 | 安徽悦康凯悦制药有限公司 | Preparation method of iloperidone |
| 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 |
| CN111393425A (en) * | 2019-01-02 | 2020-07-10 | 浙江京新药业股份有限公司 | Preparation method of 6-fluoro-3-piperidine-4-yl-1, 2-benzisoxazole hydrochloride |
| CN112830922A (en) * | 2021-01-08 | 2021-05-25 | 常州恒邦药业有限公司 | Preparation method of paliperidone intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012063269A2 (en) * | 2010-11-12 | 2012-05-18 | Cadila Healthcare Limited | Process for preparing iloperidone |
| CN102516236A (en) * | 2011-11-18 | 2012-06-27 | 哈尔滨三联药业有限公司 | Preparation method of antipsychotic drug iloperidone |
-
2012
- 2012-08-30 CN CN201210317325.3A patent/CN102796090B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012063269A2 (en) * | 2010-11-12 | 2012-05-18 | Cadila Healthcare Limited | Process for preparing iloperidone |
| CN102516236A (en) * | 2011-11-18 | 2012-06-27 | 哈尔滨三联药业有限公司 | Preparation method of antipsychotic drug iloperidone |
Non-Patent Citations (1)
| Title |
|---|
| 陆学华,等: "利培酮的合成", 《中国药物化学杂志》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103130785A (en) * | 2012-12-20 | 2013-06-05 | 安徽悦康凯悦制药有限公司 | Preparation method of iloperidone |
| 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 |
| CN111393425A (en) * | 2019-01-02 | 2020-07-10 | 浙江京新药业股份有限公司 | Preparation method of 6-fluoro-3-piperidine-4-yl-1, 2-benzisoxazole hydrochloride |
| CN111393425B (en) * | 2019-01-02 | 2021-11-26 | 浙江京新药业股份有限公司 | Preparation method of 6-fluoro-3-piperidine-4-yl-1, 2-benzisoxazole hydrochloride |
| CN112830922A (en) * | 2021-01-08 | 2021-05-25 | 常州恒邦药业有限公司 | Preparation method of paliperidone intermediate |
| CN112830922B (en) * | 2021-01-08 | 2022-04-15 | 常州恒邦药业有限公司 | Preparation method of paliperidone intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102796090B (en) | 2015-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2004238447C1 (en) | Piperazine derivatives and their use for the treatment of neurological and psychiatric diseases | |
| JP5680624B2 (en) | 7-aza-spiro [3.5] nonane-7-carboxylic acid ester derivatives, their preparation and their therapeutic use | |
| EP2837628B1 (en) | Method for preparing rivaroxaban intermediate | |
| US10100047B2 (en) | Piperidine derivatives as orexin receptor antagonist | |
| US20100076196A1 (en) | Process for the preparation of iloperidone | |
| JP2010535742A (en) | Process for the preparation or purification of olmesartan medoxomil | |
| KR20110034020A (en) | Alkyl thiazole carbamate derivatives, preparation thereof, and use thereof as faah enzyme inhibitors | |
| CN102796090A (en) | Method for preparing iloperidone | |
| CN101735208B (en) | Method for synthesizing Iloperidone | |
| NO821616L (en) | 1-SUBSTITUTED SPIRO (PIPERIDIN-OXOBENZOCSAZIN) IS AND PROCEDURE FOR THEIR PREPARATION | |
| CN103857672A (en) | Method for preparing 1-(4-(4-(3,4-dichloro-2-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)piperidin-1-yl)-prop-2-en-1-one hydrochloride and intermediates used therein | |
| CN101768154A (en) | New preparation method of iloperidone | |
| US20140073787A1 (en) | Preparation of 3-[2-[4-((6-fluoro-1, 2-benzisoxazol-3-yl)-l-piperidinyl)-6, 7, 8, 9-tetrahydro-9-hydroxy-2-methyl-4h-pyrido[ 1, 2-a]-pyrimidin-4-one (paliperidone) and paliperidone palmitate. | |
| CN101939311A (en) | The heterocyclic compound that M-ChR is had avidity | |
| CN102977142A (en) | Preparation method of fosaprepitant dimeglumine | |
| CN102924439B (en) | Preparation method of iloperidone | |
| US20060004024A1 (en) | Method for preparing risperidone | |
| KR101012134B1 (en) | Process for preparing imatinib or mesylate thereof | |
| CN101137646A (en) | Synthesis of ccr5 antagonists | |
| US11939322B2 (en) | Method for producing tetracyclic compound | |
| EA011748B1 (en) | A process for the preparation of risperidone | |
| CN101824030B (en) | Preparation method of Iloperidone | |
| HU202228B (en) | Process for producing 4-piperidinyl-methyl-derivatives of 2,3-dihydro-1h-isoindol and 2,3,4,5-tetrahydro-1h-benzazepines and pharmaceutical compositions containing them | |
| EP1975169A1 (en) | Process for the preparation of ziprasidone | |
| CN111269203A (en) | N-cyclohexyl-furan-2-formamide compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |