CN103864774B - A kind of preparation method of Lurasidone - Google Patents
A kind of preparation method of Lurasidone Download PDFInfo
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- CN103864774B CN103864774B CN201310007080.9A CN201310007080A CN103864774B CN 103864774 B CN103864774 B CN 103864774B CN 201310007080 A CN201310007080 A CN 201310007080A CN 103864774 B CN103864774 B CN 103864774B
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- lurasidone
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- piperazine
- water
- benzisothiazole
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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
Abstract
The invention provides the preparation method of a kind of Lurasidone; use 1 (1; 2 benzisothiazole 3 bases) piperazine and (R, R) 1,2 pairs of (mesyl 2 oxygen methyl) hexamethylene are in the mixed solvent of acetonitrile/water; react with bicarbonate for alkali; add toluene or dimethylbenzene, separate organic layer, in organic layer, add bicyclo-［ 2.2.1 ］ heptane 2; 3 dicarboximides and carbonate react, and obtain Lurasidone.The method not only eliminates the purification procedures of routine, greatly reduces production cost, and has the advantages that product yield is high, purity is high.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to the preparation method of a kind of Lurasidone.
Background technology
Lurasidone (lurasidone, trade name Latuda) is a kind of novel atypical antipsychotic agents, belongs to benzo
Isothizole derivatives.Lurasidone is dopamine D 2 and 5-hydroxy tryptamine 2A(5-HT2A) receptor antagonist, it is to receptor and DOPA
Amine receptor is respectively provided with high affinity.Ratify its listing food and medicine Surveillance Authority of the U.S. on October 28 in 2010 (FDA), use
In treatment schizophrenia.
The chinesization formal name used at school of Lurasidone is referred to as: (3aR, 4S, 7R, 7aS)-2{ (1R, 2R)-2-［ 4-(1,2-benzisothia
Azoles-3-base) piperazine-1-ylmethyl ］ cyclohexyl methyl } hexahydro-1H-4,7-methyl iso-indoles-1,3-diketone, structure such as formula one institute
Show, i.e. compounds I:
Formula one:
US5532372 discloses the synthetic method of a kind of Lurasidone: by formula (V) compound and formula (IV) compound carbon
Acid sodium adds back flow reaction 23 hours in acetonitrile, and filtered while hot, cold filtration obtains formula (II) compound.Then by formula II
Compound and formula III compound, potassium carbonate and dibenzo-18-crown-6 (DB18C6) add backflow 16 hours, column chromatography for separation in dimethylbenzene
Obtain Lurasidone raceme, then obtain Lurasidone with tartaric acid Chiral Separation.(below figure)
Chinese patent CN102731512A discloses the preparation method of a kind of Lurasidone, and this is by (R, R)-1, the double (first of 2-
Sulfonyl-2-oxygen methyl) hexamethylene and 1-(1,2 benzisothiazole-3-base) piperazine exist at acid binding agent and phase transfer catalyst
Under conditions of join in solvent, be heated to reflux after point water obtaining Lurasidone-raceme, then use tartaric acid Chiral Separation
Lurasidone.This technique obtains to be needed first to obtain Lurasidone raceme, then obtains Lurasidone after splitting, and total recovery is
High being about in 16.3%, and reaction uses the phase transfer catalyst being difficult to separate.
Lurasidone preparation method midbody product to be separated (obtaining solid product) of prior art report, through splitting
Lurasidone can be obtained, and needed column purification just can obtain purer Lurasidone product, thus whole technological operation is multiple
Miscellaneous, product yield is relatively low, is not suitable for industrialized great production.And its response time is the longest, purge process use a large amount of
Organic solvent, this all makes its production cost higher.Therefore it provides 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 great 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 complex operation present in above-mentioned prior art, just product yield is low, needs can obtain after splitting
Obtaining the problems such as Lurasidone, operating procedure is simple, product yield is high and just can obtain list without splitting to the invention provides one
The preparation method of the Lurasidone of one enantiomer.
One aspect of the present invention provides a kind of new Lurasidone preparation method, and it comprises the following steps:
1-(1,2 benzisothiazole-3-base) piperazine (compound ii) and (R, R)-1,2-are double (mesyl-2-oxygen methyl)
Hexamethylene (compound III), with the mixed solution of acetonitrile/water as solvent, reacts with bicarbonate for alkali, adds first after reaction
Benzene or dimethylbenzene, separate organic layer, adds bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide (compound V) in organic layer
Carry out reaction with carbonate and be prepared into Lurasidone (type I compound).Reaction equation is shown in formula three:
The preparation method of Lurasidone provided by the present invention, wherein said bicarbonate is selected from sodium bicarbonate, bicarbonate
Potassium, calcium bicarbonate；Preferably sodium bicarbonate.
The preparation method of Lurasidone provided by the present invention, wherein said bicarbonate and 1-(1,2 benzisothiazole-
3-yl) piperazine mole is than for 1.3-3:1.
The preparation method of Lurasidone provided by the present invention, wherein said carbonate is sodium carbonate, potassium carbonate；Preferably carbon
Acid potassium.
The preparation method of Lurasidone provided by the present invention, wherein said carbonate and 1-(1,2 benzisothiazole-3-
Base) piperazine mole is than for 1.5-3:1.
The preparation method of Lurasidone provided by the present invention, wherein said 1-(1,2 benzisothiazole-3-base) piperazine and
The azeotropic temperature that reaction temperature is acetonitrile/water mixed solution of double (mesyl-2-oxygen methyl) hexamethylene of (R, R)-1,2-.
The preparation method of Lurasidone provided by the present invention, acetonitrile and water in the mixed solution of wherein said acetonitrile/water
Volume ratio elect 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-base) piperazine and
The response time of double (mesyl-2-oxygen methyl) hexamethylene of (R, R)-1,2-is 22-26 hour；The preferably response time is 24 little
Time.
The preparation method of Lurasidone provided by the present invention, wherein adds bicyclo-［ 2.2.1 ］ heptane-2, and 3-bis-formyl is sub-
Response time after amine and carbonate is 6-10 hour；The preferably response time is 8 hours.
The preparation method of Lurasidone provided by the present invention, wherein adds bicyclo-［ 2.2.1 ］ heptane-2, and 3-bis-formyl is sub-
Reaction temperature after amine and carbonate is the reflux temperature of reaction system.
The preparation method of Lurasidone provided by the present invention, its step further includes at and adds bicyclo-［ 2.2.1 ］ heptan
Alkane-2, 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 is used is selected from anhydrous second
The mixed solvent of alcohol/water, the mixed solvent of butanone/isopropanol, ethyl acetate；The most described dehydrated alcohol with the volume ratio of water is
1-8:1-5, described butanone is 1:1 with the volume ratio of isopropanol.
Preparation technology provided by the present invention compared with prior art advantage is:
1, the preparation method of the Lurasidone that the present invention provides, simple to operate, it is not necessary to separation of intermediates, it is not necessary to product
Product carried out column purification and were not required to split, and the reagent of use is simple and cheap and easy to get, it is not necessary to interpolation dibenzo-18-crown-6 (DB18C6),
The catalyst such as phase transfer catalyst, are more suitable for industrialized great production.
2, the preparation method of the Lurasidone that the present invention provides, total recovery is high, can reach 66%, and product purity can reach 99%
Above.
3, the preparation method of Lurasidone that the present invention provides, it is to avoid it is a large amount of that routine operation uses the silica gel column chromatography to expend
Eluant, and the response time is short, thus greatly reduce production cost.
Detailed description below is to further illustrate the present invention, is not considered as scope
Limit.
Detailed description of the invention
Compound I has the HPLC of related substance to detect:
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia two annex V D of version in 2010).
Related substance chromatographic condition and system suitability is had to test: to be filler with octadecylsilane chemically bonded silica；With second
Nitrile: sodium-acetate buffer=70:30 is flowing phase, and detection wavelength is 230nm, and number of theoretical plate is calculated by Lurasidone and is not less than
2000。
Sample preparation: weigh sample appropriate, adds acetonitrile and dissolves, and makes 1mg/ml solution as need testing solution, precision amount
Take need testing solution 10ul and inject chromatograph of liquid, record chromatogram, calculate according to area normalization.
Compound I isomer HPLC detects:
Measure according to high performance liquid chromatography (Chinese Pharmacopoeia two annex V D of version in 2010)
Chromatographic condition and system suitability with chiral chromatographic column (OJ-H)；With normal hexane-second
Alcohol-diethylamine (900:100:0.9)；Detection wavelength is 230nm.Number of theoretical plate is calculated by Lurasidone HCl peak and is not less than
2000。
Sample preparation: take this product about 20mg, accurately weighed, put in 10ml measuring bottle, add methanol solution ultrasonic dissolution and dilute
To scale, shake up, as need testing solution；Precision measures need testing solution 10 μ l and injects chromatograph of liquid, records chromatogram.
Lurasidone HCl optical value measures:
Take Lurasidone HCl product to be tested appropriate, accurately weighed, add methanol and dissolve and quantitatively dilution is made in every 1ml about
Solution containing 10mg, measuring specific optical rotation according to Chinese Pharmacopoeia two annex VI E of version in 2010 is that-43 degree are to-52 degree.
Embodiment one
Add in reaction bulb double (mesyl-2-oxygen methyl) hexamethylene (10.0g, 0.033mol) of (R, R)-1,2-with
1-(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 100ml acetonitrile, sodium carbonate 7.0g
(0.066mol), it is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection also raw material 1-(1,2 benzisothia
Azoles-3-base) piperazine unreacted is complete, continues reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material point 1-(1,2 benzo
Isothiazole-3-base) piperazine has a little unreacted complete, is spin-dried for solvent, pull an oar 2 hours with 50ml toluene 100 DEG C, heat filtering, solid
Drying obtains product 7.12g, yield 51.0%.
By upper step product 7.12g and bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide (compound V) 2.78g
(0.0168mol) add reaction bulb, add solvent toluene 70ml, potassium carbonate 5.8g(0.042mol), heating reflux reaction 12 is little
Time, TLC(ethyl acetate: petroleum ether=1:1) point that walks product (compounds Ⅳ) in detection disappears, is spin-dried for solvent, uses ethyl acetate
Recrystallization, dries and obtains Lurasidone 7.04g, yield 84.8%, HPLC purity 98.477%, optical purity 98.187%.Two steps are anti-
Answer total recovery 43.2%.
Embodiment two
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 50ml acetonitrile, sodium carbonate 9.5g(0.090mol),
Be stirred at reflux reaction 48 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-base) piperazine the most anti-
Should be complete, continue reaction 8 hours, be subsequently adding bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide (compound V)
(5.45g.0.033mol) with toluene 100ml, back flow reaction is continued 12 hours, TLC(ethyl acetate: petroleum ether=1:1) detectionization
Compound IV unreacted is complete, and target product Lurasidone generates seldom, and impurity is more, is spin-dried for organic solvent, uses ethyl acetate weight
Crystallization cannot obtain solid.
Embodiment three
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 100ml acetonitrile, sodium carbonate 9.5g(0.090mol),
Be stirred at reflux reaction 48 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-base) piperazine the most anti-
Should be complete, continue reaction 8 hours, be subsequently adding bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide (compound V)
(5.45g.0.033mol), back flow reaction 12 hours, TLC(ethyl acetate: petroleum ether=1:1 are continued) detection compound IV is the most anti-
Should be complete, target product Lurasidone generates few, and impurity is more, is spin-dried for organic solvent, cannot obtain by re-crystallizing in ethyl acetate
Solid.
Embodiment four
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 100ml toluene, potassium carbonate 11.4g
(0.083mol), agitating heating back flow reaction 48 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothia
Azoles-3-base) piperazine is the most unchanged, continues reaction 8 hours, and raw material does not reacts or reacts slowly, under not carrying out
Step reaction.
Embodiment five
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 100ml acetonitrile, sodium bicarbonate 7.0g
(0.083mol), agitating heating back flow reaction 48 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothia
Azoles-3-base) piperazine major part do not reacts, and continues reaction 8 hours, and raw material reaction slowly, does not carries out the next step.
Embodiment six
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 50ml acetonitrile, 25ml water, sodium bicarbonate 8.7g
(0.104mol), it is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 100ml, separate water layer, in organic layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-bis-formyl is sub-
Amine (compound V) (5.45g.0.033mol) and sodium bicarbonate 8.7g(0.104mol), back flow reaction 48 hours, raw material reaction
Slowly, TLC(ethyl acetate: petroleum ether=1:1) detection also has compounds Ⅳ unreacted complete, and impurity is more, evaporates organic molten
Agent, by re-crystallizing in ethyl acetate, dries and obtains product 3.62g, yield 22.3%, HPLC purity 97.356%, optical purity
96.883%。
Embodiment seven
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 50ml acetonitrile, 25ml water, potassium carbonate 11.4g
(0.083mol), it is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, impure point it is obvious that add toluene 100ml, separates water layer, adds bicyclo-［ 2.2.1 ］ heptan in organic layer
Alkane-2,3-dicarboximide (compound V) (5.45g.0.033mol) and potassium carbonate 11.4g(0.083mol), back flow reaction 24
Hour, TLC(ethyl acetate: petroleum ether=1:1) detection compound IV has been reacted, but impurity is more, evaporates organic solvent, uses second
Acetoacetic ester recrystallization, dries and obtains product 6.44g, yield 39.2%, HPLC purity 96.319%, optical purity 96.477%.
Embodiment eight
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 30ml acetonitrile, 15ml water, sodium bicarbonate 8.7g
(0.104mol), it is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 60ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g.0.033mol), potassium carbonate 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: petroleum ether=1:1)
Detection compound IV disappears, heat filtering, evaporates organic solvent, dehydrated alcohol 50ml and water 30ml recrystallization, dries and obtain 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, H1-NMR data is shown in Table 1, C13-NMR data is shown in Table 2.
Formula four:
Table 11H NMR (300M, CDCl3)
Table 2C13-NMR(CDCl3,400MHz)
| Chemical shift (ppm) | C type | C number | C belongs to |
| 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
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 45ml acetonitrile, 22ml water, sodium bicarbonate 8.7g
(0.104mol).It is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 90ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g, 0.033mol), sodium carbonate 7.0g(0.066mol), back flow reaction 10 hours, TLC(ethyl acetate: petroleum ether=1:1)
Detection compound IV disappears, heat filtering, evaporates organic solvent, dehydrated alcohol 100ml and water 60ml recrystallization, dries and obtain product
Lurasidone 10.54g, yield 64.8%, HPLC purity 99.194%, optical purity 99.691%.
Lurasidone room-temperature dissolution in the mixed solvent of ethyl acetate and ethanol, dropping dropping 2ml concentrated hydrochloric acid Cheng Lu
Drawing western keto hydrochloride, filter, dry and obtain Lurasidone HCl 10.7g, yield 94.4%, purity is 99.687%, optical voidness
Degree 99.896%, optical value is-46.4 degree.
Embodiment ten
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 60ml acetonitrile, 30ml water, potassium bicarbonate 8.2g
(0.082mol).It is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 150ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g.0.033mol), potassium carbonate 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: petroleum ether=1:1)
Detection compound IV disappears, heat filtering, evaporates organic solvent, dehydrated alcohol 90ml and water 60ml recrystallization, dries and obtain product
Lurasidone 10.87g, yield 66.79%, HPLC purity 99.574%, optical purity 99.746%.
Lurasidone room-temperature dissolution in the mixed solvent of 5 times of ethyl acetate and 5 times of dehydrated alcohol, drip the dense salt of 2ml
Acid becomes Lurasidone HCl, filters, and dries and obtains Lurasidone HCl 11g, yield 94.0%, and purity is 99.967%, light
Learning purity 99.936%, optical value is-48.9 degree.
Embodiment 11
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 40ml acetonitrile, 20ml water, potassium bicarbonate 8.2g
(0.082mol).It is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 100ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g.0.033mol), sodium carbonate 7.0g(0.066mol), back flow reaction 10 hours, TLC(ethyl acetate: petroleum ether=1:1)
Detection compound IV disappears, heat filtering, evaporates organic solvent, dehydrated alcohol 60ml and water 60ml recrystallization, dries and obtain product
Lurasidone 10.63g, yield 65.32%, HPLC purity 99.235%, optical purity 99.833%.
Lurasidone room-temperature dissolution in the mixed solvent of ethyl acetate and ethanol, dropping dropping 2ml concentrated hydrochloric acid Cheng Lu
Drawing western keto hydrochloride, filter, dry and obtain Lurasidone HCl 10.9g, yield 95.4%, purity is 99.718%, optical voidness
Degree 99.990%, optical value is-47.8 degree.
Embodiment 12
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 30ml acetonitrile, 15ml water, calcium bicarbonate 7.0g
(0.043mol).It is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 60ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g.0.033mol), potassium carbonate 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: petroleum ether=1:1)
Detection compound IV disappears, heat filtering, evaporates organic solvent, dehydrated alcohol 80ml and water 50ml recrystallization, dries and obtain product
Lurasidone 10.37g, yield 63.18%, HPLC purity 99.658%, optical purity 99.927%.
Embodiment 13
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 50ml acetonitrile, 25ml water, calcium bicarbonate 7.0g
(0.043mol).It is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 120ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g.0.033mol), sodium carbonate 10.5g(0.099mol), back flow reaction 10 hours, TLC(ethyl acetate: petroleum ether=1:
1) detection compound IV disappears, heat filtering, evaporates organic solvent, dehydrated alcohol 70ml and water 50ml recrystallization, dries and produced
Thing Lurasidone 10.48g, yield 63.82%, HPLC purity 99.392%.
Embodiment 14
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 30ml acetonitrile, 15ml water, potassium bicarbonate 7.0g
(0.070mol).It is stirred and heated to back flow reaction 22 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisoxa
Thiazole-3-base) piperazine disappears substantially, adds dimethylbenzene 60ml, separates water layer, adds bicyclo-［ 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:
Petroleum ether=1:1) detection compound IV disappears, heat filtering, and evaporate organic solvent, dehydrated alcohol 80ml and water 50ml recrystallization, dry
Dry obtain product Lurasidone 10.0g, yield 61.12%, HPLC purity 99.490%.
Embodiment 15
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 30ml acetonitrile, 30ml water, sodium bicarbonate 8.7g
(0.104mol).It is stirred at reflux reaction 26 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 60ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g.0.033mol), potassium carbonate 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: petroleum ether=1:1)
Detection compound IV disappears, heat filtering, evaporates organic solvent, ethyl acetate 80ml recrystallization, dries and obtain product Lurasidone
10.69g, yield 65.10%, HPLC purity 99.30%, optical purity 99.970%.
Embodiment 16
Double (mesyl-2-oxygen methyl) hexamethylene (10g, 0.033mol) of (R, R)-1,2-and 1-is added in reaction bulb
(1,2 benzisothiazole-3-base) piperazine (7.7g, 0.033mol), adds 45ml acetonitrile, 15ml water, sodium bicarbonate 8.7g
(0.104mol).It is stirred at reflux reaction 24 hours, TLC(methanol: petroleum ether=8:1) detection raw material 1-(1,2 benzisothiazole-3-
Base) piperazine disappearance, add toluene 60ml, separate water layer, add bicyclo-［ 2.2.1 ］ heptane-2,3-dicarboximide to organic layer
(5.45g.0.033mol), potassium carbonate 6.8g(0.050mol), back flow reaction 8 hours, TLC(ethyl acetate: petroleum ether=1:1)
Detection compound IV disappears, heat filtering, evaporates organic solvent, butanone 50ml and isopropanol 50ml recrystallization, dries and obtains product
Lurasidone 10.31g, yield 62.80%, H PLC purity 99.85%, optical purity 99.967%.
Claims (14)
1. the preparation method of a Lurasidone, it is characterised in that comprise the steps of 1-(1,2 benzisothiazole-3-base) piperazine
Piperazine and (R, R)-1, double (mesyl-2-oxygen methyl) hexamethylene of 2-is with the mixed solution of acetonitrile/water as solvent, with bicarbonate
React for alkali, add toluene or dimethylbenzene after reaction, separate organic layer, add in organic layer bicyclo-[2.2.1] heptane-
2,3-dicarboximide and carbonate carry out reacting to obtain Lurasidone；Wherein said bicarbonate is selected from sodium bicarbonate, bicarbonate
Potassium, calcium bicarbonate；Described bicarbonate and 1-(1,2 benzisothiazole-3-base) piperazine mole ratio is for 1.3-3:1；Described second
In the mixed solution of nitrile/water, acetonitrile is 3:1-1:1 with the volume ratio of water；Described carbonate is sodium carbonate, potassium carbonate；Described carbonic acid
Salt and 1-(1,2 benzisothiazole-3-base) piperazine mole ratio is for 1.5-3:1.
The preparation method of Lurasidone the most according to claim 1, it is characterised in that described bicarbonate is sodium bicarbonate.
The preparation method of Lurasidone the most according to claim 1, it is characterised in that described carbonate is potassium carbonate.
The preparation method of Lurasidone the most according to claim 1, it is characterised in that in the mixed solution of described acetonitrile/water
Acetonitrile is 2:1 with the volume ratio of water.
The preparation method of Lurasidone the most according to claim 1, it is characterised in that described 1-(1,2 benzisothiazole-3-
Base) temperature of piperazine and (R, R)-1,2-double (mesyl-2-oxygen methyl) hexamethylene reaction is being total to of acetonitrile/water mixed solution
Boiling temperature.
The preparation method of Lurasidone the most according to claim 1, it is characterised in that described 1-(1,2 benzisothiazole-3-
Base) response time of double (mesyl-2-oxygen methyl) hexamethylene of piperazine and (R, R)-1,2-is 22-26 hour.
The preparation method of Lurasidone the most according to claim 6, it is characterised in that described 1-(1,2 benzisothiazole-3-
Base) response time of double (mesyl-2-oxygen methyl) hexamethylene of piperazine and (R, R)-1,2-is 24 hours.
The preparation method of Lurasidone the most according to claim 1, it is characterised in that described addition bicyclo-[2.2.1] heptan
The time carrying out after alkane-2,3-dicarboximide and carbonate reacting is 6-10 hour.
The preparation method of Lurasidone the most according to claim 8, it is characterised in that described addition bicyclo-[2.2.1] heptan
The time carrying out after alkane-2,3-dicarboximide and carbonate reacting is 8 hours.
The preparation method of Lurasidone the most according to claim 1, it is characterised in that add bicyclo-[2.2.1] heptane-2,
The reflux temperature that temperature is reaction system reacted is carried out after 3-dicarboximide and carbonate.
The preparation method of 11. Lurasidones according to claim 1, it is characterised in that add bicyclo-[2.2.1] heptane-2,
After 3-dicarboximide and carbonate react, gained Lurasidone obtains highly finished product after carrying out recrystallization.
The preparation method of 12. Lurasidones according to claim 11, it is characterised in that the used solvent of described recrystallization
Selected from the mixed solvent of dehydrated alcohol/water, the mixed solvent of butanone/isopropanol, ethyl acetate.
The preparation method of 13. Lurasidones according to claim 12, it is characterised in that mixing of described dehydrated alcohol/water
In bonding solvent, dehydrated alcohol is 1-8:1-3 with the volume ratio of water.
The preparation method of 14. Lurasidones according to claim 12, it is characterised in that mixing of described butanone/isopropanol
In bonding solvent, butanone is 1:1 with the volume ratio of isopropanol.
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| EP3207041B1 (en) | 2014-10-14 | 2019-12-04 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | An improved 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 |
| CN113185508A (en) * | 2015-04-21 | 2021-07-30 | 上海医药集团股份有限公司 | Method for preparing lurasidone with high purity and high yield |
| CN106632358A (en) * | 2016-10-31 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | Method for preparing lurasidone hydrochloride intermediate |
| CN106946872A (en) * | 2017-03-20 | 2017-07-14 | 常州工程职业技术学院 | A kind of method for preparing Lurasidone key intermediate |
| CN107688069B (en) * | 2017-09-08 | 2020-11-03 | 顾世海 | Method for detecting (1R,2R) -cyclohexane-1, 2-dimethanol |
| 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 |
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| US5532372A (en) * | 1990-07-06 | 1996-07-02 | Sumitomo Pharmaceuticals Company, Ltd. | Imide derivatives, and their production and use |
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| JP4175800B2 (en) * | 2001-11-27 | 2008-11-05 | 住友化学株式会社 | Method for producing imide derivative |
| JP2006169154A (en) * | 2004-12-15 | 2006-06-29 | Sumitomo Chemical Co Ltd | Method for producing quaternary ammonium salt |
| JP4708012B2 (en) * | 2004-12-15 | 2011-06-22 | 大日本住友製薬株式会社 | Method for producing quaternary ammonium salt |
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| US5532372A (en) * | 1990-07-06 | 1996-07-02 | Sumitomo Pharmaceuticals Company, Ltd. | Imide derivatives, and their production and use |
| US20110263847A1 (en) * | 2010-04-26 | 2011-10-27 | Dainippon Sumitomo Pharma Co, Ltd. | Process of a quaternary ammonium salt |
| US20110263848A1 (en) * | 2010-04-26 | 2011-10-27 | Dainippon Sumitomo Pharma Co., Ltd. | Process of a quaternary ammonium salt using phosphate |
| WO2012131606A1 (en) * | 2011-04-01 | 2012-10-04 | Ranbaxy Laboratories Limited | Process for the preparation of an antipsychotic agent |
| CN102731512A (en) * | 2011-04-12 | 2012-10-17 | 天津药物研究院 | Preparation method of lurasidone intermediate and lurasidone |
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