CN102863437A - Preparation method of lurasidone - Google Patents
Preparation method of lurasidone Download PDFInfo
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- CN102863437A CN102863437A CN2012103220362A CN201210322036A CN102863437A CN 102863437 A CN102863437 A CN 102863437A CN 2012103220362 A CN2012103220362 A CN 2012103220362A CN 201210322036 A CN201210322036 A CN 201210322036A CN 102863437 A CN102863437 A CN 102863437A
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Abstract
The invention provides a preparation method of lurasidone. On the basis of the existing preparation method of lurasidone, a one-pot method is adopted to replace the method including multiple steps and obtain a target product once. The preparation method comprises the following steps: adding 3-(1-piperazinyl)-1,2-benzisothiazole in toluene, stirring to dissolve; adding (1R,2R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane and an inorganic alkali, heating and carrying out reflux reaction for 12-36 hours; adding (3alpha R,4S,7R,7alpha S)4,7-methano-1H-isoindole-1,3(2H)-dione; heating and refluxing; recycling toluene at reduced pressure; adding ethyl acetate in the residue, stirring to dissolve, washing for 2-3 times with 5% hydrochloric acid, separating out the organic layers, drying for 20-120 minutes, filtering to remove the drying agent, concentrating the obtained ethyl acetate solution, dropwise adding concentrated hydrochloric acid, precipitating the solid, and performing suction filtration to obtain crude lurasidone; and refining crude lurasidone to obtain pure lurasidone. By adopting the preparation method of lurasidone, the solvent can be recycled conveniently and the method is simple in operation.
Description
Technical field
The present invention relates to a kind of preparation method of medical compounds, be specifically related to a kind of preparation method of Lurasidone.
Background technology
Lurasidone is a novel atypical antipsychotic agents, 2010 U.S. food and medicine Surveillance Authority on October 28, (FDA) ratify its listing, commodity are called Latuda, are used for the treatment of schizophrenia.
Japanese Patent JP2800953 has reported the synthetic route take salt as intermediate the earliest:
This route is first with (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes (A) of 2-and 3-(piperazine-1-yl) parallel [d] isothiazole of benzene (B) does solvent refluxing with acetonitrile, then add entry and obtain intermediate salt D, at last with DMF do solvent and
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone (C) reaction obtains Lurasidone.This route needs the separation of intermediate, comprises that last extraction shares acetonitrile, DMF, 3 kinds of solvents of ether and phase-transfer catalyst benzo 18 hat 6 ethers (dibenzo-18-crown-6-ether), and whole piece route solvent load is large, kind is many, complex operation, cost is high, nor environmental protection.
Patent US20110263848 has reported similar route, the method of salify is take toluene and water as mixed solvent, adds the consisting of phase-transferring agent 4-butyl ammonium hydrogen sulfate, and this route has operation steps complicated, the shortcoming that labour intensity is large contains the unnecessary discharging of 4-butyl ammonium hydrogen sulfate waste water in addition.
Patent US20110063994 also is the method for fractional steps.At first make 150 ℃ of solvents with DMF and reflux and made salt D in 3 hours, further react with C take DMF as solvent after telling salt.The advantage of the method is that solvent is single, and shortcoming is that temperature of reaction is high, and DMF tends to decompose, and needs column chromatography.
The above method for preparing Lurasidone basically be through separation of intermediates salt, form Lurasidone, become the step such as Lurasidone HCl to finish at last.Its processing step is loaded down with trivial details, complicated operation, wasting manpower and material resources.
Lurasidone is used raw material in preparation process
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone, prior art is by following path implement:
Such as: Journal of Organic Chemistry, 1982,47(20): P3953-3959 and WO2012016569 etc. adopts the method for the two keys of palladium carbon catalytic hydrogenating reduction to obtain saturated acid anhydrides, and 130 ℃ of backflows of the latter and ammoniacal liquor made in 2 hours
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone, productive rate 75.54%; Document Chemical ﹠amp; Pharmaceutical Bulletin, 1991,39(9) yield that provides of P2288-2300 also only has the result of 80.5%, LC-MS to show that acid anhydrides is unstable, very easily in open loop, produces by product under the condition of hydrogenation, and this is the low reason of this process recovery ratio.
Summary of the invention
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of Lurasidone simple to operate.
It is a kind of that the present invention also provides
(3 α R, 4S, 7R, 7 α S) 4, the 7-methylene radical-1H-isoindole-1,3 (2H)-diketone is easy, the synthetic method of high yield.
Technical scheme of the present invention is as follows:
A kind of preparation method of Lurasidone, may further comprise the steps: with 3-(1-piperazinyl)-1, the 2-benzisothiazole drops in the toluene, and stirring and dissolving adds (1R, 2R)-1, two (methanesulfonic oxygen methyl) hexanaphthene and the mineral alkalis of 2-heat up 110～130 ℃ back flow reaction 12～36h, to adopting TLC to detect to 3-(1-piperazinyl)-1,2-benzisothiazole raw material spot disappears.Then add
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone stirs and heats up 110～130 ℃ back flow reaction 4～12h, cooling, reclaim under reduced pressure toluene, resistates adds ethyl acetate, stirring and dissolving, with 5% hydrochloric acid soln washing 2～3 times, separate organic layer, dry 20～120 minutes, the filtering siccative, concentrated ethyl acetate solution drips concentrated hydrochloric acid, solid is separated out, and suction filtration obtains the Lurasidone crude product.The Lurasidone crude product is soluble in water, stir, drip saturated aqueous sodium hydroxide solution and transfer PH to 9～10, with ethyl acetate extraction twice, combined ethyl acetate layer, add anhydrous magnesium sulfate drying 2h, underpressure distillation concentrates and drips the concentrated hydrochloric acid solid and separates out, and suction filtration obtains the Lurasidone sterling to doing.
Raw materials used mol ratio is: 3-(1-piperazinyl)-1, and the 2-benzisothiazole: (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-:
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone=1:0.8-1.5:0.8-1.5.
Preferably, the mol ratio of raw material is: 3-(1-piperazinyl)-1, and the 2-benzisothiazole: (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-:
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone=1:1.05:1.05.
Every gram substrate (1R, 2R)-1, the two required toluene 8-50ml of (methanesulfonic oxygen methyl) hexanaphthene of 2-.
Described mineral alkali is a kind of in salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, sodium phosphate or the Sodium phosphate dibasic, and using molar weight be (1R, 2R)-1, the 2-10 times of molar weight of two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-, preferably 4-5 times of molar weight.
(3 α R, 4S, 7R provided by the invention, 7 α S) 4, the synthesis step of the synthetic method of 7-methylene radical-1H-isoindole-1,3 (2H)-diketone is as follows: every mole of suitable-5-norbornylene-external form-2, the 3-dicarboxylic acid anhydride adds in the 200-400ml tetrahydrofuran (THF), and stirring at room drips ammoniacal liquor 1-3 mole, after the system clarification, be warming up to 80-100 ℃ of backflow 2-3h, underpressure distillation to absence of liquid oozes, and gets solid, add the refining heavy crystallization of dehydrated alcohol, obtain noreximide; Every mole of noreximide is added 0.5-2L hydrogenation solvent, add the Pd-C of 1-10 times of molar weight tetrahydrobenzene and 2.5-10%, reflux 4-24 hour, complete to the HPLC analytical reaction.The sample that takes a morsel filters, and desolventizing adopts HPLC to analyze take noreximide as control sample, and transformation efficiency about 98.5% can think and react completely have greater than 1% impurity consistent with raw material noreximide retention time.Stopped reaction, filtering Pd-C, filtrate is spin-dried for, and obtains target product.
Preferably, the usage quantity of tetrahydrobenzene is 1.5 times of molar weights.
The hydrogenation solvent can be ethanol, methyl alcohol, tetrahydrofuran (THF), preferred tetrahydrofuran (THF).
The preparation method of Lurasidone provided by the invention can be a plurality of steps of the preparation method of prior art by the disposable target product that obtains of the method for the treatment of different things alike, and the solvent in the reaction process also can reclaim easily, and is simple to operate.(3 α R provided by the invention, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1, in the synthetic method of 3 (2H)-diketone, adopt first ammonia solution, then the method for hydrogenation, obviously imide is than stable many of acid anhydrides, to the solvent inertia of water, alcohol and so on, the hydrogenation product is single, does not almost have the generation of by product.Owing to adopting liquid tetrahydrobenzene to substitute hydrogen in the hydrogenation, the purifying of product is simple simultaneously, and reaction does not need high pressure resistant equipment yet, can carry out with the common response still amplification of random scale.
Embodiment
Embodiment 1
With 3.8g (17.4mmol) 3-(1-piperazinyl)-1, the 2-benzisothiazole drops in the 150ml toluene, stirring and dissolving adds 5.7g(19.0mmol) (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-, and 7.2g(52mmol) salt of wormwood heats up 110-130 ℃ of back flow reaction 30h, detect intermediate 3-(1-piperazinyl)-1 to TLC, 2-benzisothiazole (the main peak LC-MS:M that substantially disappears
+=328.2), add 3.1g(18.7mmol)
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone, stir and heat up, 110-130 ℃ of back flow reaction 8h, cooling, reclaim under reduced pressure toluene, resistates adds 200ml ethyl acetate, stirring and dissolving, with 5% hydrochloric acid soln washing three times, tell organic layer, add anhydrous magnesium sulfate drying 2h, the filtering siccative gets ethyl acetate solution.Above ethyl acetate solution is subtracted inspissation be reduced to approximately 80ml, drip concentrated hydrochloric acid, have a large amount of white solids to separate out, suction filtration obtains Lurasidone crude product 5.95g, yield 74.3%.5.27g Lurasidone crude product is added in the 150ml water, stir, drip saturated aqueous sodium hydroxide solution and transfer PH to 9-10, with twice of ethyl acetate extraction, use ethyl acetate 150ml, the combined ethyl acetate layer adds anhydrous magnesium sulfate drying 2h at every turn, underpressure distillation is concentrated into approximately 50ml of residual volume, drip concentrated hydrochloric acid 10ml, have a large amount of solids to separate out, suction filtration is to doing, obtain Lurasidone sterling 4.9g, yield: 93.0%.
Embodiment 2
With 3.8g (17.3mmol) 3-(1-piperazinyl)-1, the 2-benzisothiazole drops in the 150ml toluene, stirring and dissolving, add 7.84g(26.10mmol) (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-, and 7.2g(52mmol) salt of wormwood heats up 110-130 ℃ of back flow reaction 24h, to TLC detection intermediate 3-(1-piperazinyl)-1, the 2-benzisothiazole disappears substantially, adds 4.3g(26.1mmol) (3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone, stir and heat up, 110-130 ℃ of back flow reaction 4h, cooling, reclaim under reduced pressure toluene, resistates adds the 200ml ethyl acetate, and stirring and dissolving is with 5% hydrochloric acid soln washing three times, tell organic layer, add anhydrous magnesium sulfate drying 2h, the filtering siccative gets ethyl acetate solution.Above ethyl acetate solution is subtracted inspissation be reduced to approximately 80ml, drip concentrated hydrochloric acid, have a large amount of white solids to separate out, suction filtration obtains Lurasidone crude product 6.12g, yield 66.9%.All the other make the Lurasidone sterling with embodiment 1.
Embodiment 3
With 3.8g (17.3mmol) 3-(1-piperazinyl)-1, the 2-benzisothiazole drops in the 120ml toluene, stirring and dissolving, add 4.2g(13.8mmol) (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-, and 7.2g(52mmol) salt of wormwood heats up 110-130 ℃ of back flow reaction 30h, to TLC detection intermediate 3-(1-piperazinyl)-1, the 2-benzisothiazole disappears substantially, adds 2.8g(13.9mmol) (3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone, stir and heat up, 110-130 ℃ of back flow reaction 8h, cooling, reclaim under reduced pressure toluene, resistates adds the 150ml ethyl acetate, and stirring and dissolving is with 5% hydrochloric acid soln washing three times, tell organic layer, add anhydrous magnesium sulfate drying 2h, the filtering siccative gets ethyl acetate solution.Above ethyl acetate solution is subtracted inspissation be reduced to approximately 60ml, drip concentrated hydrochloric acid, have a large amount of white solids to separate out, suction filtration obtains Lurasidone crude product 5.24g, yield 57.3%.All the other make the Lurasidone sterling with embodiment 1.
Embodiment 4
With suitable-5-norbornylene-external form-2,3-dicarboxylic acid anhydride 150g(914mmol) add in the 270ml tetrahydrofuran (THF), stirring at room drips 7% ammoniacal liquor 450ml(914mmol), the system clarification, then be warming up to 100 ℃ of backflow 2-3h, underpressure distillation to absence of liquid oozes, and gets solid 145.7g, add the refining heavy crystallization of 650ml dehydrated alcohol, get the 138g noreximide, be white solid, yield 90.7%.(69 grams are 423mmol) (according to literature method Chemical ﹠amp for noreximide; Pharmaceutical Bulletin, 1991,39,9,2288-2300 preparation) be dissolved in 400 milliliters of tetrahydrofuran (THF)s, add tetrahydrobenzene (10 grams, 123mmol) and 10% Pd-C (3.5 gram) reflux 12 hours, sample takes a morsel, filter, desolventizing gets sample and analyzes through HPLC, product purity is 98.34%, and unreacting material and foreign matter content are 1.66%.Stopped reaction, filtering Pd-C, filtrate is spin-dried for, and obtains
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone 68 grams, productive rate is 97.3%.
Claims (10)
1. the preparation method of a Lurasidone, may further comprise the steps: with 3-(1-piperazinyl)-1, the 2-benzisothiazole drops in the toluene, and stirring and dissolving adds (1R, 2R)-1, two (methanesulfonic oxygen methyl) hexanaphthene and the mineral alkalis of 2-heat up 110～130 ℃ back flow reaction 12～36h, to adopting TLC to detect to 3-(1-piperazinyl)-1,2-benzisothiazole raw material spot disappears; Then add
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone stirs and heats up 110～130 ℃ back flow reaction 4～12h, cooling, reclaim under reduced pressure toluene, resistates adds ethyl acetate, stirring and dissolving, with 5% hydrochloric acid soln washing 2～3 times, separate organic layer, dry 20～120 minutes, the filtering siccative, concentrated ethyl acetate solution drips concentrated hydrochloric acid, solid is separated out, and suction filtration obtains the Lurasidone crude product; The Lurasidone crude product is soluble in water, stir, drip saturated aqueous sodium hydroxide solution and transfer PH to 9～10, with ethyl acetate extraction twice, combined ethyl acetate layer, add anhydrous magnesium sulfate drying 2h, underpressure distillation concentrates and drips the concentrated hydrochloric acid solid and separates out, and suction filtration obtains the Lurasidone sterling to doing.
2. the preparation method of Lurasidone according to claim 1 is characterized in that, raw materials used mol ratio is: 3-(1-piperazinyl)-1, and the 2-benzisothiazole: (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-:
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone=1:0.8-1.5:0.8-1.5.
3. the preparation method of Lurasidone according to claim 2 is characterized in that, the mol ratio of raw material is: 3-(1-piperazinyl)-1, and the 2-benzisothiazole: (1R, 2R)-1, two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-:
(3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1,3 (2H)-diketone=1:1.05:1.05.
4. the preparation method of Lurasidone according to claim 1 is characterized in that, every gram (1R, 2R)-1, the two required toluene 8-50ml of (methanesulfonic oxygen methyl) hexanaphthene of 2-.
5. the preparation method of Lurasidone according to claim 1, it is characterized in that, described mineral alkali is a kind of in salt of wormwood, saleratus, yellow soda ash, sodium bicarbonate, sodium phosphate or the Sodium phosphate dibasic, the use molar weight is (1R, 2R)-1, the 2-10 times of molar weight of two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-.
6. the preparation method of Lurasidone according to claim 5 is characterized in that, the use molar weight of described inorganic salt is (1R, 2R)-1, the 4-5 times of molar weight of two (the methanesulfonic oxygen methyl) hexanaphthenes of 2-.
7. the preparation method of Lurasidone according to claim 1, it is characterized in that, described (3 α R, 4S, 7R, 7 α S) 4,7-methylene radical-1H-isoindole-1, the synthesis step of the synthetic method of 3 (2H)-diketone is as follows: every mole of suitable-5-norbornylene-external form-2, the 3-dicarboxylic acid anhydride adds in the 200-400ml tetrahydrofuran (THF), and stirring at room drips ammoniacal liquor 1-3 mole, after the system clarification, be warming up to 80-100 ℃ of backflow 2-3h, underpressure distillation to absence of liquid oozes, and gets solid, add the refining heavy crystallization of dehydrated alcohol, obtain noreximide; Every mole of noreximide is added 0.5-2L hydrogenation solvent, add the Pd-C of 1-10 mole tetrahydrobenzene and 2.5-10%, reflux 4-24 hour, complete to the HPLC analytical reaction; The sample that takes a morsel filters, and desolventizing adopts HPLC to analyze take noreximide as control sample, and transformation efficiency about 98.5% can think and react completely have greater than 1% impurity consistent with raw material noreximide retention time; Stopped reaction, filtering Pd-C, filtrate is spin-dried for, and obtains target product.
8. the preparation method of Lurasidone according to claim 7 is characterized in that, the usage quantity of described tetrahydrobenzene is 1.5 moles.
9. the preparation method of Lurasidone according to claim 7 is characterized in that, described hydrogenation solvent is a kind of in ethanol, methyl alcohol or the tetrahydrofuran (THF).
10. the preparation method of Lurasidone according to claim 9 is characterized in that, described hydrogenation solvent is tetrahydrofuran (THF).
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| CN102936243A (en) * | 2012-11-16 | 2013-02-20 | 上海伯倚化工科技有限公司 | Synthetic method of lurasidone |
| CN105985304A (en) * | 2015-03-04 | 2016-10-05 | 四川科瑞德制药股份有限公司 | Method for preparing external methylene tetrahydrophthalic anhydride |
| US10196400B2 (en) | 2015-01-08 | 2019-02-05 | Piramal Enterprises Limited | Process for the preparation of lurasidone and its intermediate |
| CN109705112A (en) * | 2013-03-06 | 2019-05-03 | 江苏恩华药业股份有限公司 | The preparation method of the novel crystal forms of Lurasidone HCl |
| US10426770B2 (en) | 2014-10-14 | 2019-10-01 | Jubilant Generics Limited | Process for the preparation of Lurasidone hydrochloride |
| CN110734434A (en) * | 2019-11-19 | 2020-01-31 | 湖南洞庭药业股份有限公司 | Method for preparing lurasidone and salt thereof |
| CN115611866A (en) * | 2022-10-31 | 2023-01-17 | 南京海纳医药科技股份有限公司 | Preparation method of tandospirone citrate |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102936243A (en) * | 2012-11-16 | 2013-02-20 | 上海伯倚化工科技有限公司 | Synthetic method of lurasidone |
| CN102936243B (en) * | 2012-11-16 | 2015-08-05 | 上海伯倚化工科技有限公司 | A kind of synthetic method of Lurasidone |
| CN109705112A (en) * | 2013-03-06 | 2019-05-03 | 江苏恩华药业股份有限公司 | The preparation method of the novel crystal forms of Lurasidone HCl |
| US10426770B2 (en) | 2014-10-14 | 2019-10-01 | Jubilant Generics Limited | Process for the preparation of Lurasidone hydrochloride |
| US10196400B2 (en) | 2015-01-08 | 2019-02-05 | Piramal Enterprises Limited | Process for the preparation of lurasidone and its intermediate |
| CN105985304A (en) * | 2015-03-04 | 2016-10-05 | 四川科瑞德制药股份有限公司 | Method for preparing external methylene tetrahydrophthalic anhydride |
| CN105985304B (en) * | 2015-03-04 | 2018-05-08 | 四川科瑞德制药股份有限公司 | A kind of preparation method of outer methylene tetrabydrophthalic anhydride |
| CN110734434A (en) * | 2019-11-19 | 2020-01-31 | 湖南洞庭药业股份有限公司 | Method for preparing lurasidone and salt thereof |
| CN110734434B (en) * | 2019-11-19 | 2022-11-11 | 湖南洞庭药业股份有限公司 | Method for preparing lurasidone and salt thereof |
| CN115611866A (en) * | 2022-10-31 | 2023-01-17 | 南京海纳医药科技股份有限公司 | Preparation method of tandospirone citrate |
| CN115611866B (en) * | 2022-10-31 | 2024-04-23 | 南京海纳医药科技股份有限公司 | Preparation method of tandospirone citrate |
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Application publication date: 20130109 |