CN110128412A - The preparation method of dextrorotation Iprazole sylvite mother liquor, dextrorotation Iprazole and preparation method thereof - Google Patents
The preparation method of dextrorotation Iprazole sylvite mother liquor, dextrorotation Iprazole and preparation method thereof Download PDFInfo
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- CN110128412A CN110128412A CN201910541784.1A CN201910541784A CN110128412A CN 110128412 A CN110128412 A CN 110128412A CN 201910541784 A CN201910541784 A CN 201910541784A CN 110128412 A CN110128412 A CN 110128412A
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
The invention discloses the preparation methods of dextrorotation Iprazole sylvite mother liquor, dextrorotation Iprazole and preparation method thereof, are related to pharmaceutical intermediate.The preparation method of dextrorotation Iprazole sylvite mother liquor includes: to be mixed with beating dextrorotation Iprazole sylvite and the first organic solvent to be purified, so that Iprazole sylvite dextroisomer enters mother liquor, it is separated by solid-liquid separation again, obtains the mother liquor for being enriched dextrorotation Iprazole sylvite.Using above-mentioned mother liquor as raw material with react with acid carry out reaction generate dextrorotation Iprazole, using water and the second organic solvent play dissolution assistant effect avoid dextrorotation Iprazole be precipitated, then dextrorotation Iprazole is purified again.Obtained dextrorotation Iprazole has very high e.e value, and is not influenced by dextrorotation Iprazole sylvite e.e value, and product e.e value is stablized, and differences between batches are small.
Description
Technical field
The present invention relates to pharmaceutical intermediate technical fields, and in particular to a kind of dextrorotation Iprazole and preparation method thereof.
Background technique
Iprazole is a kind of novel proton pump inhibitor, for treating duodenal ulcer, gastric ulcer and erosive food
Guan Yan.Iprazole contains a chiral centre, is the racemic mixture of two kinds of single enantiomer R and S type enantiomers.
The preparation method of Iprazole single enantiomer is disclosed in CN101098867A, animal experiment shows that Iprazole optics is different
Structure body, that is, dextrorotation or left-handed Iprazole have more excellent compared with its racemic modification in treating disease relevant to hyperhydrochloria
Different therapeutic effect.
Patent CN1098261C discloses the method for purification of the high compound of several Enantiomeric excess for drawing azole, with solvent
Selectively crystallization racemic, re-evaporation remove the solvent in solution, have been improved the single enantiomer of polarimetry purity.
But since Iprazole and other drawing azoles have difference in structure and in nature, this method is not particularly suited for Iprazole body
System, not only e.e value is lower for products therefrom, and differences between batches are very big.
Patent CN108689995A is disclosed using 5- (1H- pyrroles -1- base) -2-mercaptobenzimidazole as starting material,
By series of chemical, optical activity Iprazole is made, this method reaction process is complicated, complex steps, organic solvent
Dosage is larger.And the patent does not refer to how from Iprazole raceme or dextrorotation Iprazole crude product obtaining high e.e value
Dextrorotation Iprazole.
Patent CN101098867B discloses the method purified to dextrorotation Iprazole crude product, by (+)-Iprazole
Crude product is dissolved in organic solvent, obtains clear solution, and the decoloration of activated carbon room temperature is filtered, evaporation.Residue is dissolved in methylene chloride
It in the mixture of butanone, is stirred at room temperature one or two day, refrigerator is stood overnight, and filtering obtains white solid (+)-Iprazole.
This method takes a long time, and experiment condition is more harsh, need to stand overnight at low temperature, is not suitable for industrialized production.
Summary of the invention
The purpose of the present invention is to provide a kind of preparation methods of dextrorotation Iprazole sylvite mother liquor, pass through organic solvent
Selection, in selected organic solvent be added the lower dextrorotation Iprazole sylvite of e.e value be beaten, make Iprazole potassium
Salt d-isomer is selectively entered in liquid phase, so that the e.e value of dextrorotation Iprazole sylvite significantly improves in liquid phase, and result is steady
Qualitative height is conducive to the quality stability for improving dextrorotation Iprazole product.
Another object of the present invention is to provide a kind of preparation methods of dextrorotation Iprazole, and this method is not by raw material e.e
The e.e value of the restriction of value, the dextrorotation Iprazole of available high-optical-purity, product is stablized, and differences between batches are small, reaction process
It is simple and easy to do to be suitable for industrial applications.
The third object of the present invention is to provide a kind of dextrorotation Iprazole, and with very high e.e value, and e.e value is steady
Fixed, production cost is low.
The present invention is creatively beaten dextrorotation Iprazole sylvite using organic solvent, so that Iprazole sylvite
D-isomer is enriched in liquid phase, can significantly improve the e.e value of dextrorotation Iprazole sylvite in mother liquor, then to the right side in the liquid phase
Rotation Iprazole sylvite further purifies, can obtain e.e value higher than 98%, differences between batches are small, product of high income.
The present invention solves its technical problem and adopts the following technical solutions to realize.
The present invention provides a kind of preparation methods of dextrorotation Iprazole sylvite mother liquor, include the following steps:
Dextrorotation Iprazole sylvite and the first organic solvent to be purified are mixed with beating, then are separated by solid-liquid separation, is obtained
It is enriched the dextrorotation Iprazole sylvite mother liquor of Iprazole sylvite d-isomer；
Wherein, the first organic solvent in acetonitrile, ethyl acetate, methylene chloride and tetrahydrofuran any one or it is more
Kind；Preferably, the first organic solvent is methylene chloride and/or ethyl acetate；
Preferably, the mixing of dextrorotation Iprazole sylvite and the first organic solvent is stirred under the conditions of 20-30 DEG C of temperature
1-17h is mixed, and dextrorotation Iprazole sylvite and the first organic solvent form slurries；It is highly preferred that mixing time is 1-4h.
The present invention provides a kind of preparation methods of dextrorotation Iprazole comprising following steps: with above-mentioned preparation method
The dextrorotation Iprazole sylvite mother liquor being prepared be raw material, by dextrorotation Iprazole sylvite mother liquor, water, the second organic solvent and
The sour hybrid reaction of reaction, then the dextrorotation Iprazole in mixed liquor after reaction is purified；
Preferably, the purification process of dextrorotation Iprazole includes: and extracts the mixed liquor after reaction, then will extract
The organic phase arrived is mixed with third organic solvent so that dextrorotation Iprazole is precipitated.
The present invention also provides a kind of dextrorotation Iprazoles, are prepared using the preparation method of above-mentioned dextrorotation Iprazole；
Preferably, the e.e value of dextrorotation Iprazole is 98.0-99.5%.
The beneficial effect that the embodiment of the present invention provides a kind of preparation method of dextrorotation Iprazole sylvite mother liquor is: it passes through
The selection of organic solvent is enriched in Iprazole sylvite d-isomer in liquid phase, mother liquor is isolated by filtration out, makes right in mother liquor
The e.e value of rotation Iprazole sylvite significantly improves, and result stability is high.
The embodiment of the present invention also provides a kind of preparation method of dextrorotation Iprazole, using above-mentioned mother liquor as raw material with react
Reaction is carried out with acid and generates dextrorotation Iprazole, is played dissolution assistant effect using water and the second organic solvent and is avoided dextrorotation Iprazole
It is precipitated, then dextrorotation Iprazole is purified again.Obtained dextrorotation Iprazole has very high e.e value, and not by original
Expect the influence of dextrorotation Iprazole sylvite e.e value, it is small that product e.e value stablizes batch gap；The process is simple and easy to do, is suitble to
In popularization and application, it is not necessarily to a large amount of organic solvent.
The present invention also provides a kind of dextrorotation Iprazoles, using the preparation method preparation of above-mentioned dextrorotation Iprazole
, there is very high e.e value, and the production cost of product is low.
Specific embodiment
It in order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below will be in the embodiment of the present invention
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, according to normal conditions or manufacturer builds
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
Dextrorotation Iprazole provided in an embodiment of the present invention and preparation method thereof is specifically described below.
A kind of preparation method of dextrorotation Iprazole provided in an embodiment of the present invention, includes the following steps:
The preparation of S1, dextrorotation Iprazole sylvite mother liquor
Dextrorotation Iprazole sylvite and the first organic solvent are mixed with beating, then are separated by solid-liquid separation, obtains being enriched Chinese mugwort
The dextrorotation Iprazole sylvite mother liquor of pula azoles sylvite d-isomer.It makes dextrorotation Iprazole potassium by the selection of organic solvent
Salt enters in liquid phase, and mother liquor is isolated by filtration out, significantly improves the e.e value of dextrorotation Iprazole sylvite in mother liquor, and ties
Fruit stability is high.
You need to add is that dextrorotation Iprazole sylvite cannot replace with other raw materials, such as dextrorotation Iprazole sodium salt,
The dextrorotation Iprazole of high e.e value cannot be obtained using other salts, this may be since both sodium and potassium belong to alkali metal
Element, and potassium ion ionic radius is big bigger than sodium ion, to preferably enhance the distinction between two optical isomers.
Specifically, dextrorotation Iprazole sylvite can using existing method synthesize or use commercial products.Dextrorotation
The synthetic method of Iprazole sylvite is referred to draw the synthetic method of azole drug to obtain (Rajendra D.Mahale etc.
Davis Oxaziridine-Mediated Asymmetric Synthesis of Proton Pump Inhibitors
Using DBU Salt of Prochiral Sulfide.Organic Process Research&Development2010,
14,1264-1268).Specific method: at normal temperature, sequentially adding thioether 10g into the three-neck flask of 100mL, DBU 6.53g,
Isopropanol 50ml, toluene 50ml.Then the mute piperazine 7.22g of (S-) camphor sulphur is added, after 10 DEG C are reacted 2 hours, stops reaction, mistake
Leaching mother liquor (e.e value is 70~80%), is spin-dried for solvent, 50ml water is added, open stirring, 25% mass is added dropwise toward mixed phase system
The glacial acetic acid aqueous solution of score adjusts pH to ≈ 8.0, and 50ml/ methylene chloride is added, is extracted twice.Separate organic layer, rotation
It is dry, the methanol of the KOH and 2mL that are 1.2mL relative to the quality of every gram of Iprazole are added into grease, stirs certain time
After start be precipitated sylvite, be slowly added to relative to every gram of Iprazole quality be 10mL isopropyl ether, promote sylvite be precipitated, mistake
Filter, obtains dextrorotation Iprazole sylvite solid, and e.e value is 70~80%.Dextrorotation Iprazole potassium in the specific embodiment of the invention
The preparation method of salt is all made of the above method and is prepared.
You need to add is that the e.e value mentioned in the present invention is the meaning routinely understood, (R-S)/(R+ can be passed through
S it) is calculated multiplied by 100%, is not done excessively repeat herein.
Specifically, the first organic solvent in acetonitrile, ethyl acetate, methylene chloride and tetrahydrofuran any one or
It is a variety of；Preferably, the first organic solvent is methylene chloride and/or ethyl acetate；Dextrorotation Iprazole sylvite to be purified and
The mixing of one organic solvent is that 1-4h is stirred under the conditions of 20-30 DEG C of temperature, and gained mixture is slurries.Using above several the
One organic solvent can form slurries, after stirring by certain time, Iprazole sylvite with dextrorotation Iprazole sylvite
D-isomer enters liquid phase, then liquid phase is isolated by filtration out.
In a preferred embodiment, the first organic solvent is methylene chloride；Preferably, every gram of dextrorotation Ai Pula to be purified
The dosage that azoles sylvite corresponds to methylene chloride is 4-12mL；More preferably 4-8mL.In a preferred embodiment, the first organic solvent
For ethyl acetate；Preferably, it is 6-16mL that every gram of dextrorotation Iprazole sylvite to be purified, which corresponds to the dosage of ethyl acetate,；It is more excellent
It is selected as 12-16mL.The dosage of first organic solvent can influence the e.e value of product to a certain extent, if the use of the first organic solvent
The excessive or too small e.e value that will affect product is measured, methylene chloride and ethyl acetate are conducive to the e.e for further promoting product
Value.
S2, reaction step
By dextrorotation Iprazole sylvite mother liquor, water, the second organic solvent and reaction acid hybrid reaction.With dextrorotation Ai Pula
Azoles sylvite be reaction raw materials, after dissolution with react with acid carry out reaction generate dextrorotation Iprazole, it is organic molten using water and second
Agent plays dissolution assistant effect and dextrorotation Iprazole is avoided to be precipitated.Inventors have found that potassium can be made using the reaction method in the present invention
Salt is converted into hydrogen salt, and prevents from being precipitated.
It being closed in reaction step with acid-mixed in dextrorotation Iprazole sylvite mother liquor with reacting, the pH of reaction mixture is 8-9,
The control of pH can specifically be reached by the dosage of regulation reaction acid.Preferably, reaction is weak acid with acid；It is highly preferred that
Any one sour in spirit of vinegar, phosphoric acid, potassium dihydrogen phosphate and ammonium chloride of reaction；It is even more preferably spirit of vinegar.
In general, weak acid can reach reaction purpose, it is easy to get using spirit of vinegar raw material, the e.e value for obtaining product is also ideal.
Specifically, dextrorotation Iprazole sylvite mother liquor was rapidly completed with reacting with the step of sour hybrid reaction, was needed not move through longer
Time.
Further, any one or more of the second organic solvent in methanol, ethyl alcohol and isopropanol；Preferably first
Alcohol.Second organic solvent and water play the effect of hydrotropy together, are located at the dextrorotation Iprazole generated in liquid phase, more than
Several raw materials can achieve the goal.
S3, purification step
Mixed liquor after reaction is extracted, then the organic phase being obtained by extraction is mixed with third organic solvent so that right
Iprazole is revolved to be precipitated.Extracted using the solvent that can dissolve dextrorotation Iprazole, and by the organic phase of extraction with cannot
The third organic solvent mixing for dissolving dextrorotation Iprazole, is precipitated dextrorotation Iprazole, obtains the higher product of purity.
Specifically, organic solvent used in extraction process is methylene chloride, and inventor's discovery can using methylene chloride
Product yield is significantly improved, but other organic solvents can influence yield, this may be due to methylene chloride energy
Enough solvent dextrorotation Iprazoles well, separate product in organic phase.
Preferably, before the organic phase being obtained by extraction being mixed with third organic solvent, desiccant is added into organic phase,
Then it refilters, and filtrate is spin-dried for.Remaining moisture in organic phase can be removed by desiccant, it is dry using filtering removal
Drying prescription finally recycles Rotary Evaporators to be rotated, and solvent is removed complete.
Further, third organic solvent is selected from isopropanol and/or acetonitrile, preferably isopropanol.Dextrorotation Iprazole exists
Dissolubility is weaker in isopropanol or acetonitrile, is further purified so that dextrorotation Iprazole can be precipitated.Preferably, every gram to
The dosage that the dextrorotation Iprazole sylvite of purifying corresponds to third organic solvent is 8-10mL, and organic phase is mixed with third organic solvent
It is to be stirred under the conditions of 20-30 DEG C of temperature.The dosage of third organic solvent is excessive to cause wastage of material, and dosage is too small to incite somebody to action
Dextrorotation Iprazole is precipitated completely, influences product yield.
The embodiment of the invention also provides a kind of dextrorotation Iprazoles, using the preparation method system of above-mentioned dextrorotation Iprazole
It is standby and obtain.There is very high e.e value, substantially 98.0-99.5% by the dextrorotation Iprazole that the above method is prepared；By
Simple and easy to do in preparation method, the amount of required organic solvent is less, can substantially reduce production cost.
Feature and performance of the invention are described in further detail with reference to embodiments.
Embodiment 1
The present embodiment provides a kind of preparation methods of dextrorotation Iprazole comprising following steps:
(+)-Iprazole sylvite (e.e 79.4%) 2.00g is taken, 24ml methylene chloride is added, is beaten at 20 DEG C
4h.After filter out filtrate, 10ml water is added after being spin-dried in filtrate, 8ml methanol is stirring evenly and then adding into spirit of vinegar and adjusts pH to 8.0,
Methylene chloride is added to be extracted twice, respectively adds 10mL every time, merges organic phase, the dry 30mins of anhydrous magnesium sulfate, triethylamine is added,
Filtering, filtrate are added 16mL isopropanol, (+)-Iprazole solid, vacuum are obtained by filtration after 20~30 DEG C of stirring 1.5h after being spin-dried for
Weigh to obtain 0.79g after drying, and measuring e.e value is 99.3%, and measuring product yield in above-mentioned (+)-Iprazole sylvite mother liquor is
49%, (+)-Iprazole solid yields are 79.8% in final products.
It should be noted that (+)-ends in product yield and final products in (+)-Iprazole sylvite mother liquor in the present invention
The calculation method of pula azoles solid yields is as follows:
The calculation method of product yield in (+)-Iprazole sylvite mother liquor are as follows: it is female that Iprazole sylvite is filtered out after mashing
Liquid, obtained solid are weighed as m after being dried in vacuo 16h, and the weight of raw material Iprazole sylvite is M, then yield are as follows:
The calculation method of (+)-Iprazole solid yields in final products are as follows: (final gained (+)-Iprazole solid
Iprazole weight in weight/mother liquor) × 100%.
Embodiment 2
The present embodiment provides a kind of preparation methods of dextrorotation Iprazole comprising following steps: taking (+)-Iprazole
Sylvite (e.e 79.4%) 2.00g is added 24ml methylene chloride, carries out mashing 1h at 30 DEG C.After filter out filtrate, filtrate is spin-dried for
Addition 10ml water, 8ml methanol are stirring evenly and then adding into dilution vinegar acid for adjusting pH to 8.0 afterwards, and methylene chloride is added and is extracted twice, often
It is secondary respectively to add 10mL, merge organic phase, the dry 30mins of anhydrous magnesium sulfate, triethylamine, filtering is added, 16mL is added after being spin-dried in filtrate
(+)-Iprazole solid is obtained by filtration after 20~30 DEG C of stirring 1.5h in acetonitrile, and weigh to obtain 0.75g after vacuum drying, measures e.e
Value is 99.0%, and measuring product yield in above-mentioned (+)-Iprazole sylvite mother liquor is 51%, and (+)-Iprazole solid is received
Rate is 81.3%.
Embodiment 3-6
The present embodiment provides a kind of preparation method of dextrorotation Iprazole, specific steps differences same as Example 2
It is: is beaten solvent for use, solvent volume and beating time in the preparation of dextrorotation Iprazole sylvite mother liquor, referring to table 1.
Pulping process design parameter in 1 embodiment 3-6 of table
Embodiment 7-11
The present embodiment provides a kind of preparation methods of dextrorotation Iprazole comprising following steps:
(+)-Iprazole sylvite (e.e 77%) 0.9g is taken, the methylene chloride of certain volume is added, is beaten at 30 DEG C
Starch about 16h.Subsequent step referring to embodiment 2, in embodiment 7-11 the volume of corresponding methylene chloride be followed successively by 3.6mL,
7.2mL, 9.0mL, 10.8mL and 16.2mL；In embodiment 7-11 corresponding beating time be followed successively by 16.4h, 16.45h,
16.5h, 16.55h and 16.6h.
Embodiment 12-16
The present embodiment provides a kind of preparation methods of dextrorotation Iprazole comprising following steps:
(+)-Iprazole sylvite (e.e 77%) 0.9g is taken, the ethyl acetate of certain volume is added, is beaten at 30 DEG C
Starch about 16h.Subsequent step referring to embodiment 2, in embodiment 12-16 the volume of corresponding ethyl acetate be followed successively by 7.2mL,
9.0mL, 12.6mL, 14.4mL and 18mL；In embodiment 12-16 corresponding beating time be followed successively by 16.0h, 16.05h,
16.10h, 16.15h and 16.20h.
Embodiment 17-20
The present embodiment provides a kind of preparation methods of dextrorotation Iprazole, and specific steps are roughly the same with embodiment 2, no
Be the e.e value of raw material dextrorotation Iprazole sylvite with place, in embodiment 17-20 corresponding e.e value be followed successively by 70.6,
75.8,78.7 and 80.5.
Comparative example 1
This comparative example provides a kind of preparation method of high-optical-purity Iprazole sylvite, includes the following steps:
(+)-Iprazole sylvite (e.e 73.1%, grease) is taken, solvent is spin-dried for, 1.2 equivalents is added into grease
KOH and relative to every gram of Iprazole quality be 8mL methanol, stirring nearly racemization sylvite (e.e can be precipitated after a certain period of time
Value is 0~10%), filtering.It is 92.0% that filtrate, which detects e.e value,.
Comparative example 2
This comparative example provides a kind of preparation method of high-optical-purity Iprazole sylvite, includes the following steps:
(+)-Iprazole sylvite (e.e 75.4%, grease) is taken, solvent is spin-dried for, 1.2 equivalents is added into grease
KOH and relative to every gram of Iprazole quality be 8mL methanol, stirring nearly racemization sylvite (e.e can be precipitated after a certain period of time
Value is 0~10%), filtering.It is 86.2% that filtrate, which detects e.e value,.
Comparative example 3
This comparative example provides a kind of preparation method of high-optical-purity Iprazole sylvite, includes the following steps:
(+)-Iprazole sylvite (e.e 76.6%, grease) is taken, solvent is spin-dried for, 1.2 equivalents is added into grease
KOH and relative to every gram of Iprazole quality be 8mL methanol, stirring nearly racemization sylvite (e.e can be precipitated after a certain period of time
Value is 0~10%), filtering.It is 88.6% that filtrate, which detects e.e value,.
Comparative example 4
This comparative example provides a kind of preparation method of dextrorotation Iprazole, specific steps difference same as Example 2
It is: is beaten solvent for use, solvent volume and beating time in the preparation of dextrorotation Iprazole sylvite mother liquor, mashing solvent is first
Alcohol, beating time 16.15h.
Comparative example 5
This comparative example provides a kind of preparation method of dextrorotation Iprazole, specific steps difference same as Example 2
It is: is beaten solvent for use, solvent volume and beating time in the preparation of dextrorotation Iprazole sylvite mother liquor, mashing solvent is first
Base tertbutyl ether, beating time 16.2h.
Test example 1
The e.e value of test comparison example 1-3 filtrate.The e.e value of comparative example 1-3 filtrate is followed successively by 92.0%, 86.2% and
88.6%.This group the experimental results showed that, by the way that solvent methanol is added, stirring and crystallizing cannot effectively improve in mother liquor (+)-Ai Pu
The e.e value of azoles sylvite is drawn, not only the e.e value of (+)-Iprazole sylvite is still lower in mother liquor, and difference between each group experiment
It is larger, unstable result.Therefore, using nearly raceme crystallization is promoted disclosed in the prior art using solvent selectivity, to mention
The content of single enantiomer in high mother liquor, is not particularly suited for Iprazole system.
Test example 2
The e.e value of filtrate, test result such as 2 institute of table are obtained after mashing filtering in testing example 3-6 and comparative example 4-5
Show.
Table 2 using dextrorotation Iprazole sylvite in mother liquor when different solvent mashing e.e value
As can be known from Table 2, when solvent selection methanol, the e.e value of dextrorotation Iprazole sylvite in mother liquor can not be improved, when molten
When acetonitrile, ethyl acetate, methylene chloride, tetrahydrofuran are selected in agent, the available a degree of raising of mother liquor e.e value, wherein
Ethyl acetate and methylene chloride can improve the e.e value of dextrorotation Iprazole sylvite to 98% or more.
Test example 3
The e.e value of filtrate is obtained after testing example 7-20 mashing filtering, the e.e of dextrorotation Iprazole is finally prepared
Value and product yield the results are shown in Table 3.
The e.e value test result of 3 dextrorotation Iprazole sylvite mother liquor of table and dextrorotation Iprazole
The test result of embodiment 7-16 shows when the additional amount of methylene chloride is relative to (+)-Iprazole sylvite quality
(g) when being 4-12mL, when especially 4-8mL, mother liquor e.e value be can be improved to 98.5% or more, and product yield reaches in mother liquor
To 50% or more, the yield of product reaches 80% or more after mother liquor purification；When the additional amount of ethyl acetate is relative to (+)-Ai Pu
When to draw azoles sylvite quality (g) be 8-20mL, when especially 12-20mL, mother liquor e.e value is increased to 98.0% or more.
The test result of embodiment 17-20 show when raw material (+)-Iprazole sylvite e.e value be 70.6%,
75.8%, 78.7% and 80.5% when, e.e value can be improved using method of the invention to 99.0% or so, product
E.e value is not restricted by raw material e.e value.
To sum up, the preparation method of dextrorotation Iprazole sylvite mother liquor provided by the invention, by the selection of organic solvent,
It stays dextrorotation Iprazole sylvite in the liquid phase, is removed by filtration impurity, make the e.e value of dextrorotation Iprazole sylvite in mother liquor
It significantly improves.
The embodiment of the present invention also provides a kind of preparation method of dextrorotation Iprazole, using above-mentioned mother liquor as raw material with react
Reaction is carried out with acid and generates dextrorotation Iprazole, is played dissolution assistant effect using water and the second organic solvent and is avoided dextrorotation Iprazole
It is precipitated, then dextrorotation Iprazole is purified again.Obtained dextrorotation Iprazole has very high e.e value, and not by the right side
The influence of Iprazole sylvite e.e value is revolved, it is small that product e.e value stablizes batch gap；This method since synthesis technology is simple and easy to do,
It is suitable for promoting and applying, is not necessarily to a large amount of organic solvent.The present invention also provides a kind of dextrorotation Iprazoles, apply the above-mentioned right side
The preparation method of rotation Iprazole is prepared, and has very high e.e value.
Embodiments described above is a part of the embodiment of the present invention, instead of all the embodiments.Reality of the invention
The detailed description for applying example is not intended to limit the range of claimed invention, but is merely representative of selected implementation of the invention
Example.Based on the embodiments of the present invention, obtained by those of ordinary skill in the art without making creative efforts
Every other embodiment, shall fall within the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of dextrorotation Iprazole sylvite mother liquor, which comprises the steps of:
Dextrorotation Iprazole sylvite and the first organic solvent to be purified are mixed with beating, and is separated by solid-liquid separation and is enriched
The dextrorotation Iprazole sylvite mother liquor of dextrorotation Iprazole sylvite；
Wherein, first organic solvent in acetonitrile, ethyl acetate, methylene chloride and tetrahydrofuran any one or it is more
Kind；
Preferably, first organic solvent is methylene chloride and/or ethyl acetate；
Preferably, the mixing of the dextrorotation Iprazole sylvite and the first organic solvent is stirred under the conditions of 20-30 DEG C of temperature
1-17h is mixed, and dextrorotation Iprazole sylvite and the first organic solvent form slurries；It is highly preferred that mixing time is 1-4h.
2. preparation method according to claim 1, which is characterized in that first organic solvent is methylene chloride；It is preferred that
Ground, the dosage that every gram of dextrorotation Iprazole sylvite to be purified corresponds to methylene chloride is 4-12mL；More preferably 4-8mL.
3. preparation method according to claim 1, which is characterized in that first organic solvent is ethyl acetate；It is preferred that
Ground, the dosage that every gram of dextrorotation Iprazole sylvite to be purified corresponds to ethyl acetate is 6-16mL；More preferably 12-16mL.
4. a kind of preparation method of dextrorotation Iprazole, which comprises the steps of:
The dextrorotation Iprazole sylvite mother liquor being prepared using preparation method described in any one of claim 1-3, will as raw material
The sour hybrid reaction of the dextrorotation Iprazole sylvite mother liquor, water, the second organic solvent and reaction, then will be in mixed liquor after reaction
Dextrorotation Iprazole purification；
Preferably, the purification process of the dextrorotation Iprazole includes: and extracts the mixed liquor after reaction, then will extract
The organic phase arrived is mixed with third organic solvent so that dextrorotation Iprazole is precipitated.
5. the preparation method of dextrorotation Iprazole according to claim 4, which is characterized in that in the dextrorotation Iprazole
Sylvite mother liquor is closed in reaction step with acid-mixed with reacting, and the pH of reaction mixture is 8-9；
Preferably, the reaction is weak acid with acid；It is highly preferred that the reaction is selected from spirit of vinegar, phosphoric acid, potassium dihydrogen phosphate with acid
With any one in ammonium chloride；It is even more preferably spirit of vinegar.
6. the preparation method of dextrorotation Iprazole according to claim 4, which is characterized in that the second organic solvent choosing
From any one or more in methanol, ethyl alcohol and isopropanol；Preferably methanol.
7. the preparation method of dextrorotation Iprazole according to claim 4, which is characterized in that have used in extraction process
Solvent is methylene chloride.
8. the preparation method of dextrorotation Iprazole according to claim 4, which is characterized in that the third organic solvent choosing
From isopropanol and/or acetonitrile, preferably isopropanol；
Preferably, it is 8-10mL that every gram of dextrorotation Iprazole sylvite to be purified, which corresponds to the dosage of the third organic solvent,.
9. the preparation method of dextrorotation Iprazole according to claim 4, which is characterized in that have described in being obtained by extraction
Before machine phase is mixed with the third organic solvent, desiccant is added in Xiang Suoshu organic phase, then refilters, and filtrate is revolved
It is dry；
Preferably, the organic phase is mixed with the third organic solvent is stirred under the conditions of 20-30 DEG C of temperature.
10. a kind of dextrorotation Iprazole, which is characterized in that using dextrorotation Iprazole described in any one of claim 4-9
Preparation method be prepared；
Preferably, the e.e value of the dextrorotation Iprazole is 98.0-99.5%.
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| CN105566294A (en) * | 2014-10-08 | 2016-05-11 | 江苏奥赛康药业股份有限公司 | D-ilaprazole sodium compound and pharmaceutical composition thereof |
| CN106045975A (en) * | 2016-05-05 | 2016-10-26 | 丽珠医药集团股份有限公司 | A preparing method for high-purity ilaprazole sodium |
| CN108794451A (en) * | 2017-04-26 | 2018-11-13 | 深圳市华先医药科技有限公司 | A kind of synthesis of chiral Iprazole method |
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| CN105566294A (en) * | 2014-10-08 | 2016-05-11 | 江苏奥赛康药业股份有限公司 | D-ilaprazole sodium compound and pharmaceutical composition thereof |
| CN106045975A (en) * | 2016-05-05 | 2016-10-26 | 丽珠医药集团股份有限公司 | A preparing method for high-purity ilaprazole sodium |
| CN108794451A (en) * | 2017-04-26 | 2018-11-13 | 深圳市华先医药科技有限公司 | A kind of synthesis of chiral Iprazole method |
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| CN111187255A (en) * | 2020-01-13 | 2020-05-22 | 丽珠医药集团股份有限公司 | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole |
| CN111187255B (en) * | 2020-01-13 | 2021-07-20 | 丽珠医药集团股份有限公司 | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole |
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