CN103864774A - Method for preparing lurasidone - Google Patents
Method for preparing lurasidone Download PDFInfo
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- CN103864774A CN103864774A CN201310007080.9A CN201310007080A CN103864774A CN 103864774 A CN103864774 A CN 103864774A CN 201310007080 A CN201310007080 A CN 201310007080A CN 103864774 A CN103864774 A CN 103864774A
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- lurasidone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides a method for preparing lurasidone. The preparation method comprises reacting 1-(1,2-benzisothiazol-3-yl) piperazine with (R, R)-1,2-bis(methylsulfonyl-methoxy) cyclohexane in a mixed solvent of acetonitrile/water in presence of bicarbonate as a base, adding toluene or xylene, separating an organic layer out, adding bicyclo [2.2.1] heptane-2,3-dicarboximide and carbonate into the organic layer and reacting to obtain lurasidone. The conventional separation and purification steps are omitted and the cost of production is greatly reduced; at the same time, the method has the characteristics of high yield and high purity of the product.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to a kind of preparation method of Lurasidone.
Background technology
Lurasidone (lurasidone, trade(brand)name Latuda) is a kind of novel atypical antipsychotic agents, belongs to benzisothiazole derivatives.Lurasidone is dopamine D 2 and serotonin 2A(5-HT2A) receptor antagonist, it all has high affinity to acceptor and Dopamine Receptors.2010 food and medicine Surveillance Authority of the U.S. on October 28, (FDA) ratify its listing, be used for the treatment of schizophrenia.
The chinesization formal name used at school of Lurasidone is called: (3aR, 4S, 7R, 7aS)-2{ (1R, 2R)-2-［ 4-(1,2-benzisothiazole-3-yl) piperazine-1-ylmethyl ］ cyclohexyl methyl } six hydrogen-1H-4,7-methyl isoindole-1,3-diketone, structure is suc as formula shown in one, i.e. chemical compounds I:
Formula one:
A kind of synthetic method of Lurasidone is disclosed in US5532372: formula (V) compound and formula (IV) compound sodium carbonate are added in acetonitrile to back flow reaction 23 hours, filtered while hot, cold filtration obtains formula (II) compound.Then by formula II compound and formula III compound, salt of wormwood and dibenzo-18-crown-6 (DB18C6) add in dimethylbenzene and reflux 16 hours, column chromatography for separation obtains Lurasidone raceme, then obtains Lurasidone with tartrate Chiral Separation.(as figure below)
Chinese patent CN102731512A discloses a kind of preparation method of Lurasidone; this is by (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene and the 1-(1 of 2-; 2 benzisothiazoles-3-yl) join in solvent under the condition that exists at acid binding agent and phase-transfer catalyst of piperazine; reflux obtains Lurasidone-raceme after dividing water, then uses the Lurasidone of tartrate Chiral Separation.This technique obtains need to first obtain Lurasidone raceme, then obtains Lurasidone after splitting, and total recovery is the highest is about 16.3%, and uses the phase-transfer catalyst that is difficult to separation in reaction.
The Lurasidone preparation method of prior art report wants separation of intermediates product (obtaining solid product), could obtain Lurasidone through splitting, and need to cross column purification and just can obtain purer Lurasidone product, thereby whole complex operation, product yield is lower, is not suitable for industrialized production.And its reaction times is totally longer, in purge process, use a large amount of organic solvents, this all makes its production cost higher.Therefore, provide a kind of easy and simple to handle, product yield is high, and purity is high, is suitable for the Lurasidone preparation method of industrialized production, has the meaning of highly significant for the further R&D and production of this medicine.
Summary of the invention
In order to solve the complex operation existing in above-mentioned prior art, product yield is low, could obtain the problems such as Lurasidone after needing to split, and the invention provides that a kind of operating procedure is simple, product yield is high and just can obtain the preparation method of the Lurasidone of single enantiomer without fractionation.
One aspect of the present invention provides a kind of new Lurasidone preparation method, and it comprises the following steps:
1-(1; 2 benzisothiazoles-3-yl) piperazine (compound ii) and (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthenes (compound III) of 2-are take the mixing solutions of acetonitrile/water as solvent; react take supercarbonate as alkali; after reaction, add toluene or dimethylbenzene; separate organic layer; in organic layer, add two rings ［ 2.2.1 ］ heptane-2,3-dicarboximide (compound V) and carbonate react and are prepared into Lurasidone (formula I compound).Reaction formula is shown in formula three:
The preparation method of Lurasidone provided by the present invention, wherein said supercarbonate is selected from sodium bicarbonate, saleratus, Calcium hydrogen carbonate; Preferably sodium bicarbonate.
The preparation method of Lurasidone provided by the present invention, wherein said supercarbonate and 1-(1,2 benzisothiazole-3-yl) piperazine molar weight is than being 1.3-3:1.
The preparation method of Lurasidone provided by the present invention, wherein said carbonate is sodium carbonate, salt of wormwood; Preferably salt of wormwood.
The preparation method of Lurasidone provided by the present invention, wherein said carbonate and 1-(1,2 benzisothiazole-3-yl) piperazine molar weight is than being 1.5-3:1.
The preparation method of Lurasidone provided by the present invention; wherein said 1-(1; 2 benzisothiazoles-3-yl) piperazine and (R, R)-1, the temperature of reaction of two (methylsulfonyl-2-oxygen methyl) hexanaphthenes of 2-is the azeotropic temperature of acetonitrile/water mixing solutions.
The preparation method of Lurasidone provided by the present invention, in the mixing solutions of wherein said acetonitrile/water, the volume ratio of acetonitrile and water is elected 3:1-1:1 as; Preferably 2:1.
The preparation method of Lurasidone provided by the present invention, wherein said 1-(1,2 benzisothiazole-3-yl) piperazine and (R, R)-1, the reaction times of two (methylsulfonyl-2-oxygen methyl) hexanaphthenes of 2-is 22-26 hour; The preferred reaction time is 24 hours.
The preparation method of Lurasidone provided by the present invention, wherein adds two rings ［ 2.2.1 ］ heptane-2, and the reaction times after 3-dicarboximide and carbonate is 6-10 hour; The preferred reaction time is 8 hours.
The preparation method of Lurasidone provided by the present invention, wherein adds two rings ［ 2.2.1 ］ heptane-2, the reflux temperature that the temperature of reaction after 3-dicarboximide and carbonate is reaction system.
The preparation method of Lurasidone provided by the present invention, its step is further included in and adds two rings ［ 2.2.1 ］ heptane-2, and after 3-dicarboximide and carbonate react, gained Lurasidone carries out the highly finished product of recrystallization.
The preparation method of Lurasidone provided by the present invention, the solvent that wherein said recrystallization uses is selected from the mixed solvent of dehydrated alcohol/water, the mixed solvent of butanone/Virahol, ethyl acetate; The volume ratio of preferred described dehydrated alcohol and water is 1-8:1-5, and described butanone and the volume ratio of Virahol are 1:1.
Preparation technology provided by the present invention compared with prior art advantage is:
1, the preparation method of Lurasidone provided by the invention, simple to operate, do not need separation of intermediates, do not need product to carry out column purification and do not need splitting, the reagent using is simple and cheap and easy to get, do not need to add the catalyzer such as dibenzo-18-crown-6 (DB18C6), phase-transfer catalyst, be more suitable in industrialized production.
2, the preparation method of Lurasidone provided by the invention, total recovery is high, can reach 66%, and product purity can reach more than 99%.
3, the preparation method of Lurasidone provided by the invention, avoided routine operation to use silica gel column chromatography to expend a large amount of eluents, and the reaction times is short, thereby greatly reduces production cost.
Following embodiment is to further illustrate of the present invention, should not be considered to the restriction of protection domain of the present invention.
Embodiment
The HPLC of Compound I related substance detects:
Measure according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010).
The experiment of related substance chromatographic condition and system suitability: with octadecylsilane chemically bonded silica be weighting agent; Take acetonitrile: sodium-acetate buffer=70:30 as moving phase, detection wavelength is 230nm, and number of theoretical plate calculates and is not less than 2000 by Lurasidone.
Sample preparation: take sample appropriate, add acetonitrile and dissolve, make 1mg/ml solution as need testing solution, precision measures need testing solution 10ul injection liquid chromatography, records color atlas, calculates according to area normalization.
Compound I isomer HPLC detects:
Measure according to high performance liquid chromatography (two appendix V D of Chinese Pharmacopoeia version in 2010)
Chromatographic condition and chiral chromatographic column for system suitability (
oJ-H); With normal hexane-ethanol-diethylamine (900:100:0.9); Detection wavelength is 230nm.Number of theoretical plate calculates and is not less than 2000 by Lurasidone HCl peak.
Sample preparation: get the about 20mg of this product, accurately weighed, put in 10ml measuring bottle, add methanol solution ultrasonic dissolution and be diluted to scale, shake up, as need testing solution; Precision measures need testing solution 10 μ l injection liquid chromatographies, records color atlas.
Lurasidone HCl optical value is measured:
Get Lurasidone HCl product to be tested appropriate, accurately weighed, add dissolve with methanol and quantitatively dilution make in every 1ml the approximately solution containing 10mg, according to two appendix VI E of Chinese Pharmacopoeia version in 2010, to measure specific optical rotations be-43 degree spends to-52.
Embodiment mono-
In reaction flask, add (R, R)-1, two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10.0g of 2-, 0.033mol) with 1-(1, 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), add again 100ml acetonitrile, sodium carbonate 7.0g(0.066mol), stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1 in addition, 2 benzisothiazoles-3-yl) piperazine unreacted is complete, continue reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material point 1-(1, 2 benzisothiazoles-3-yl) piperazine has a little unreacted complete, be spin-dried for solvent, with 100 ℃ of making beating of 50ml toluene 2 hours, heat filtering, solid is dried and is obtained product 7.12g, yield 51.0%.
By upper step product 7.12g and two ring ［ 2.2.1 ］ heptane-2,3-dicarboximide (compound V) 2.78g(0.0168mol) add reaction flask, add solvent toluene 70ml, salt of wormwood 5.8g(0.042mol), heating reflux reaction 12 hours, TLC(ethyl acetate: sherwood oil=1:1) point of step product (compounds Ⅳ) disappears in detection, be spin-dried for solvent, by re-crystallizing in ethyl acetate, oven dry obtains Lurasidone 7.04g, yield 84.8%, HPLC purity 98.477%, optical purity 98.187%.Two-step reaction total recovery 43.2%.
Embodiment bis-
In reaction flask, add (R, R)-1, two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-, 0.033mol) with 1-(1, 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), add again 50ml acetonitrile, sodium carbonate 9.5g(0.090mol), stirring and refluxing reaction 48 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine unreacted is complete, continue reaction 8 hours, then add two rings ［ 2.2.1 ］ heptane-2, 3-dicarboximide (compound V) (5.45g.0.033mol) and toluene 100ml, continue back flow reaction 12 hours, TLC(ethyl acetate: sherwood oil=1:1) detection compound IV unreacted is complete, target product Lurasidone generates seldom, impurity is more, be spin-dried for organic solvent, cannot obtain solid by re-crystallizing in ethyl acetate.
Embodiment tri-
In reaction flask, add (R, R)-1, two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-, 0.033mol) with 1-(1, 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), add again 100ml acetonitrile, sodium carbonate 9.5g(0.090mol), stirring and refluxing reaction 48 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine unreacted is complete, continue reaction 8 hours, then add two rings ［ 2.2.1 ］ heptane-2, 3-dicarboximide (compound V) (5.45g.0.033mol), continue back flow reaction 12 hours, TLC(ethyl acetate: sherwood oil=1:1) detection compound IV unreacted is complete, target product Lurasidone generates few, impurity is more, be spin-dried for organic solvent, cannot obtain solid by re-crystallizing in ethyl acetate.
Embodiment tetra-
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g; 0.033mol); add again 100ml toluene; salt of wormwood 11.4g(0.083mol), stirring heating back flow reaction 48 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1; 2 benzisothiazoles-3-yl) piperazine is substantially unchanged; continue reaction 8 hours, raw material does not substantially react or reacts very slow, does not carry out the next step.
Embodiment five
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g; 0.033mol); add again 100ml acetonitrile; sodium bicarbonate 7.0g(0.083mol), stirring heating back flow reaction 48 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1; 2 benzisothiazoles-3-yl) the most of not reaction of piperazine; continue reaction 8 hours, raw material reaction is very slow, does not carry out the next step.
Embodiment six
In reaction flask, add (R, R)-1, two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-, 0.033mol) with 1-(1, 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), add again 50ml acetonitrile, 25ml water, sodium bicarbonate 8.7g(0.104mol), stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 100ml, divide water-yielding stratum, in organic layer, add two rings ［ 2.2.1 ］ heptane-2, 3-dicarboximide (compound V) (5.45g.0.033mol) and sodium bicarbonate 8.7g(0.104mol), back flow reaction 48 hours, raw material reaction is very slow, TLC(ethyl acetate: sherwood oil=1:1) compounds Ⅳ unreacted is complete in addition in detection, impurity is more, evaporate organic solvent, by re-crystallizing in ethyl acetate, oven dry obtains product 3.62g, yield 22.3%, HPLC purity 97.356%, optical purity 96.883%.
Embodiment seven
In reaction flask, add (R, R)-1, two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-, 0.033mol) with 1-(1, 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), add again 50ml acetonitrile, 25ml water, salt of wormwood 11.4g(0.083mol), stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, impure point clearly, add toluene 100ml, divide water-yielding stratum, in organic layer, add two rings ［ 2.2.1 ］ heptane-2, 3-dicarboximide (compound V) (5.45g.0.033mol) and salt of wormwood 11.4g(0.083mol), back flow reaction 24 hours, TLC(ethyl acetate: sherwood oil=1:1) detection compound IV reacted, but impurity is more, evaporate organic solvent, by re-crystallizing in ethyl acetate, oven dry obtains product 6.44g, yield 39.2%, HPLC purity 96.319%, optical purity 96.477%.
Embodiment eight
In reaction flask, add (R, R)-1, two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-, 0.033mol) with 1-(1, 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), add again 30ml acetonitrile, 15ml water, sodium bicarbonate 8.7g(0.104mol), stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 60ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), salt of wormwood 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, dehydrated alcohol 50ml and water 30ml recrystallization, oven dry obtains product Lurasidone 10.89g, yield 66.28%, HPLC purity 99.272%, optical purity 99.887%.The carbon numbering of Lurasidone is shown in formula four, H
1-NMR data are in table 1, C
13-NMR data are in table 2.
Formula four:
Table 1
1h NMR (300M, CDCl
3)
Table 2C
13-NMR (CDCl
3, 400MHz)
| Chemical shift (ppm) | C type | C number | C ownership |
| 179.495 | Season | 2 | C7、C8 |
| 161.622 | Season | 1 | C22 |
| 152.938 | Season | 1 | C23 |
| 128.002 | Uncle | 1 | C26 |
| 127.360 | Season | 1 | C24 |
| 124.484 | Uncle | 1 | C25 |
| 123.357 | Uncle | 1 | C27 |
| 120.770 | Uncle | 1 | C28 |
| 61.683 | Secondary | 1 | C17 |
| 52.897 | Secondary | 1 | C18 |
| 49.981 | Secondary | 1 | C19 |
| 48.659~48.635 | Uncle | 2 | C5、C6 |
| 46.261 | Secondary | 2 | C20、C21 |
| 46.172 | Secondary | 2 | C5、C6 |
| 41.671 | Secondary | 1 | C10 |
| 39.884~39.744 | Uncle | 3 | C3、C4、C16 |
| 34.537 | Uncle | 1 | C11 |
| 33.364 | Secondary | 1 | C9 |
| 31.366 | Secondary | 1 | C15 |
| 29.862 | Secondary | 1 | C12 |
| 27.984 | Secondary | 2 | C13、C14 |
| 24.392 | Secondary | 1 | C2 |
| 24.329 | Secondary | 1 | C1 |
Embodiment nine
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 45ml acetonitrile; 22ml water, sodium bicarbonate 8.7g(0.104mol).Stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 90ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g, 0.033mol), sodium carbonate 7.0g(0.066mol), back flow reaction 10 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, dehydrated alcohol 100ml and water 60ml recrystallization, oven dry obtains product Lurasidone 10.54g, yield 64.8%, HPLC purity 99.194%, optical purity 99.691%.
Lurasidone room temperature is dissolved in the mixed solvent of ethyl acetate and ethanol, drips 2ml concentrated hydrochloric acid and become Lurasidone HCl, filter, oven dry obtains Lurasidone HCl 10.7g, yield 94.4%, and purity is 99.687%, optical purity 99.896%, optical value is-46.4 degree.
Embodiment ten
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 60ml acetonitrile; 30ml water, saleratus 8.2g(0.082mol).Stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 150ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), salt of wormwood 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, dehydrated alcohol 90ml and water 60ml recrystallization, oven dry obtains product Lurasidone 10.87g, yield 66.79%, HPLC purity 99.574%, optical purity 99.746%.
Lurasidone room temperature is dissolved in the mixed solvent of 5 times of ethyl acetate and 5 times of dehydrated alcohols, drips 2ml concentrated hydrochloric acid and become Lurasidone HCl, filter, oven dry obtains Lurasidone HCl 11g, yield 94.0%, and purity is 99.967%, optical purity 99.936%, optical value is-48.9 degree.
Embodiment 11
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 40ml acetonitrile; 20ml water, saleratus 8.2g(0.082mol).Stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 100ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), sodium carbonate 7.0g(0.066mol), back flow reaction 10 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, dehydrated alcohol 60ml and water 60ml recrystallization, oven dry obtains product Lurasidone 10.63g, yield 65.32%, HPLC purity 99.235%, optical purity 99.833%.
Lurasidone room temperature is dissolved in the mixed solvent of ethyl acetate and ethanol, drips 2ml concentrated hydrochloric acid and become Lurasidone HCl, filter, oven dry obtains Lurasidone HCl 10.9g, yield 95.4%, and purity is 99.718%, optical purity 99.990%, optical value is-47.8 degree.
Embodiment 12
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 30ml acetonitrile; 15ml water, Calcium hydrogen carbonate 7.0g(0.043mol).Stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 60ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), salt of wormwood 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, dehydrated alcohol 80ml and water 50ml recrystallization, oven dry obtains product Lurasidone 10.37g, yield 63.18%, HPLC purity 99.658%, optical purity 99.927%.
Embodiment 13
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 50ml acetonitrile; 25ml water, Calcium hydrogen carbonate 7.0g(0.043mol).Stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 120ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), sodium carbonate 10.5g(0.099mol), back flow reaction 10 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, dehydrated alcohol 70ml and water 50ml recrystallization, oven dry obtains product Lurasidone 10.48g, yield 63.82%, HPLC purity 99.392%.
Embodiment 14
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 30ml acetonitrile; 15ml water, saleratus 7.0g(0.070mol).Be stirred and heated to back flow reaction 22 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappears substantially, add dimethylbenzene 60ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), sodium carbonate 7.0g(0.066mol), back flow reaction 6 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, dehydrated alcohol 80ml and water 50ml recrystallization, oven dry obtains product Lurasidone 10.0g, yield 61.12%, HPLC purity 99.490%.
Embodiment 15
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 30ml acetonitrile; 30ml water, sodium bicarbonate 8.7g(0.104mol).Stirring and refluxing reaction 26 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 60ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), salt of wormwood 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, ethyl acetate 80ml recrystallization, oven dry obtains product Lurasidone 10.69g, yield 65.10%, HPLC purity 99.30%, optical purity 99.970%.
Embodiment 16
In reaction flask, add (R; R)-1; two (methylsulfonyl-2-oxygen methyl) hexanaphthene (10g of 2-; 0.033mol) with 1-(1; 2 benzisothiazoles-3-yl) piperazine (7.7g, 0.033mol), then add 45ml acetonitrile; 15ml water, sodium bicarbonate 8.7g(0.104mol).Stirring and refluxing reaction 24 hours, TLC(methyl alcohol: sherwood oil=8:1) detection raw material 1-(1, 2 benzisothiazoles-3-yl) piperazine disappearance, add toluene 60ml, divide water-yielding stratum, add two rings ［ 2.2.1 ］ heptane-2 to organic layer, 3-dicarboximide (5.45g.0.033mol), salt of wormwood 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: sherwood oil=1:1) disappearance of detection compound IV, heat filtering, evaporate organic solvent, butanone 50ml and Virahol 50ml recrystallization, oven dry obtains product Lurasidone 10.31g, yield 62.80%, H PLC purity 99.85%, optical purity 99.967%.
Claims (10)
1. the preparation method of a Lurasidone; it is characterized in that comprising following steps: 1-(1; 2 benzisothiazoles-3-yl) piperazine and (R; R)-1, two (methylsulfonyl-2-oxygen methyl) hexanaphthenes of 2-, take the mixing solutions of acetonitrile/water as solvent, react take supercarbonate as alkali; after reaction, add toluene or dimethylbenzene; separate organic layer, in organic layer, add two rings ［ 2.2.1 ］ heptane-2,3-dicarboximide and carbonate react to obtain Lurasidone.
2. the preparation method of Lurasidone according to claim 1, is characterized in that described supercarbonate is selected from sodium bicarbonate, saleratus, Calcium hydrogen carbonate, preferably sodium bicarbonate; Described supercarbonate and 1-(1,2 benzisothiazole-3-yl) piperazine molar weight is than being 1.3-3:1.
3. the preparation method of Lurasidone according to claim 1, is characterized in that described carbonate is sodium carbonate, salt of wormwood, preferably salt of wormwood; Described carbonate and 1-(1,2 benzisothiazole-3-yl) piperazine molar weight is than being 1.5-3:1.
4. the preparation method of Lurasidone according to claim 1, is characterized in that in the mixing solutions of described acetonitrile/water, the volume ratio of acetonitrile and water is 3:1-1:1; Preferably 2:1.
5. the preparation method of Lurasidone according to claim 1; it is characterized in that described 1-(1; 2 benzisothiazoles-3-yl) piperazine and (R; R)-1, the temperature of two (methylsulfonyl-2-oxygen methyl) hexanaphthene reactions of 2-is the azeotropic temperature of acetonitrile/water mixing solutions.
6. the preparation method of Lurasidone according to claim 1, it is characterized in that described 1-(1,2 benzisothiazoles-3-yl) piperazine and (R, R)-1, the reaction times of two (methylsulfonyl-2-oxygen methyl) hexanaphthenes of 2-is 22-26 hour; The preferred reaction time is 24 hours.
7. the preparation method of Lurasidone according to claim 1, adds two rings ［ 2.2.1 ］ heptane-2 described in it is characterized in that, the time of reacting after 3-dicarboximide and carbonate is 6-10 hour; The preferred reaction time is 8 hours.
8. the preparation method of Lurasidone according to claim 1, is characterized in that adding two rings ［ 2.2.1 ］ heptane-2, the reflux temperature that the temperature of reacting after 3-dicarboximide and carbonate is reaction system.
9. the preparation method of Lurasidone according to claim 1, is characterized in that adding two rings ［ 2.2.1 ］ heptane-2, and after 3-dicarboximide and carbonate react, gained Lurasidone carries out obtaining highly finished product after recrystallization.
10. the preparation method of Lurasidone according to claim 9, is characterized in that solvent that described recrystallization uses is selected from the mixed solvent of dehydrated alcohol/water, the mixed solvent of butanone/Virahol, ethyl acetate; The volume ratio of preferred described dehydrated alcohol and water is 1-8:1-3, and described butanone and the volume ratio of Virahol are 1:1.
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