CN107151246A - A kind of preparation method of (R)-praziquantel amine salt and levo-praziquantel - Google Patents
A kind of preparation method of (R)-praziquantel amine salt and levo-praziquantel Download PDFInfo
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Abstract
The present invention relates to a kind of preparation method and a kind of preparation method of levo-praziquantel of (R) praziquantel amine salt, (R) praziquantel amine salt reacts obtained with raceme praziquantel amine in a solvent with chiral selectors, wherein, described chiral selectors are the one or more in (R) brufen, (R) naproxen, (R) 1 phenethyl sulfonic acid.There is the present invention raw material to be easy to get, technique is simple, short preparation period, chiral selectors stable, price is low and reclaim easily, low cost and other advantages.
Description
Technical field
Chemical field is prepared the invention belongs to chiral drug, and in particular to a kind of (R)-praziquantel amine salt and a left side
Revolve the preparation method of praziquantel ((R)-praziquantel).
Background technology
Praziquantel is artificial synthesized pyrazine isoquinoline derivative, also known as ring praziquantel, white or off-white color
Crystalline powder, bitter is universally acknowledged high-efficiency broad spectrum anti-parasite medicine, is widely used in treatment Japan
Blood fluke, Schistosoma haematobium, Schistosoma mansoni, clonorchiasis, paragonimiasis, Meng Shi pleroceroids,
The diseases such as fasciolopsis, Echinococcus hydatid cyst, tapeworm and cysticercus.It has that pest-resistant spectrum is wide, curative effect is high, toxicity is low, treated
The advantages of journey is short and easy to use.In addition to for human body, it is also widely used in the anti-of animal, poultry etc. and posted
Infested treatment.The appearance of praziquantel is an important breakthrough in parasitic disease chemotherapy history, and praziquantel is current
It is the choice drug that in the market treats a variety of parasitic diseases.
Praziquantel is the racemic compound collectively constituted by left-handed and dextrorotation praziquantel, and scientific research personnel is from conjunction
Split into praziquantel and obtain levo-praziquantel and dextrorotation praziquantel optical isomer, and by preclinical and
Initial clinical experience is found：Levo-praziquantel is effective insecticidal constituent of praziquantel, and dextrorotation praziquantel is
Invalid or even harmful components；Under same dose, levo-praziquantel clinical efficacy is more preferable than praziquantel, dextrorotation
Praziquantel then almost inefficacy, bitter, and be the main generation source of drug side-effect.To heart
Toxicity levo form is lower than d-isomer, therefore exploitation levo-praziquantel replaces praziquantel, will have curative effect higher,
Toxic side effect is less, the more preferable clinical value of medical science compliance.Although the World Health Organization expects to use
Levo-praziquantel replaces praziquantel, but the low process difficulties one of the yield of levo-praziquantel chemical synthesis for many years
Directly hang and do not solve.
Praziquantel was synthesized first in 1975 by Seubere et al., German Merck and Bayer two
Successfully develop this kind of medicine in pharmaceutical factory.1980, Merck companies took the lead in listing with trade name Cesol,
Worldwide extensive use.Praziquantel will use that some are poisonous in process of production, harmful
Chemical substance, such as potassium cyanide, heavy metal, and its process route is longer, and reaction condition also compares
Harsh (high temperature, high pressure).It is seriously polluted and this kind of course of reaction controls difficulty larger.
The preparation method of levo-praziquantel, which is summed up, can be divided into asymmetric synthesis method, biological enzyme and outer
Mesotomy method.
1st, symmetrical synthesis can direct synthesis of chiral molecule, but existing asymmetric syntheses levo-praziquantel
Preparation method, the chiral auxiliary or chiral catalyst or selectivity being related to and the high reagent of selectivity are continuous
It is expensive and be difficult largely to obtain.
2nd, method of enzymatic resolution：Need dextrorotation racemization, process is cumbersome, and total recovery has much room for improvement.(CN
102911979 A, a kind of method for preparing levo-praziquantel).
3rd, enzymatic Dynamic Kinetic conversion method：Crucial chiral intermediate is dynamic by lipase-catalyzed dynamic
Mechanics is converted preparation.But enzyme catalyst consumption is big, enzyme catalyst reaches 1 with raw material dosage:1, post processing
Complexity, labor intensity is big, and product optical purity needs that by recrystallization pharmacy needs, cost could be met
It is higher.
Above-mentioned asymmetric syntheses, enzyme Split Method, enzymatic Dynamic Kinetic conversion method, these method reagents are held high
Expensive, cumbersome, yield is relatively low, realizes industrialized production not only severe reaction conditions, complex process,
Operation difficulty is big, and high cost is further improved.
Chipal compounds technology maturation is prepared by racemic fractionation, method is more.Document report has with hexichol
Formyl-L-TARTARIC ACID method for splitting is successfully changed to levo-praziquantel synthesis key intermediate racemization pyrrole quinoline amine
Learn and split.The problem of this method is present be：Although laboratory can obtain preparing the key of levo-praziquantel
Intermediate levo-praziquantel amine, but the resolution reagent dibenzoyl-L-tartaric acid stability in this method is poor,
It is susceptible to hydrolysis, in especially a large amount of production processes, dibenzoyl-L-tartaric acid-left-handed pyrrole obtained by Hydrolysis Resolution
During the free levo-praziquantel amine of quinoline ketoamine salt release, dibenzoyl-L-tartaric acid resolution reagent is to anti-
Answer the acid-base value of system sensitive, it is easy to hydrolyze, cause resolution reagent recovery utilization rate low, it is difficult to obtain height
Purity levo-praziquantel amine, and remaining residue is unfavorable to environmental protection.And dibenzoyl-L-tartaric acid is split
Reagent source is not extensive, is influenceed by market supply, and price fluctuation is big.
The content of the invention
The technical problems to be solved by the invention are to overcome the deficiencies in the prior art there is provided a kind of new left-handed pyrrole
The preparation method of quinoline ketone, this method can not only obtain the levo-praziquantel product of more high-optical-purity, and
And cost is lower.
To solve above technical problem, the present invention is adopted the following technical scheme that：
A kind of preparation method of (R)-praziquantel amine salt, it is existed with raceme praziquantel amine and chiral selectors
Reacted in solvent and (R)-praziquantel amine salt is made, wherein, described chiral selectors are selected from (R)-Bu Luo
One or more in sweet smell, (R)-naproxen, (R) -1- phenethyl sulfonic acid.
Preferably, the molar ratio of described raceme praziquantel amine and described chiral selectors is 1：
0.4~0.6.
It is further preferable that the molar ratio of described raceme praziquantel amine and described chiral selectors
For 1:0.5.
Preferably, in initial reaction system, the concentration of described raceme praziquantel amine is
0.1~0.5g/mL.
Preferably, described solvent is selected from methanol, ethanol, water, methyl tertiary butyl ether(MTBE), isopropanol, two
One or more in chloromethanes, toluene.
Preferably, described raceme praziquantel amine and described chiral selectors are in described solvent and alkali
Property compound in react (the R)-praziquantel amine salt for being made described, wherein, described alkali compounds is hydrogen-oxygen
Change potassium or potassium carbonate, the molar ratio of described raceme praziquantel amine and described alkali compounds is
1:0.25~0.5.
Preferably, added into reactor described raceme praziquantel amine, described chiral selectors,
Described solvent, is selectively added alkali compounds, and it is molten to be then heated to reactant at 45~80 DEG C
Solution, is subsequently cooled to solid precipitation, collects precipitation, and the precipitation is post-treated to obtain described (R)-pyrrole quinoline
Ketoamine salt.
According to the present invention, the post-processing approach of precipitation is a lot, can use conventional method, for example will be described
Precipitation is washed with ice-cold solvent, then carries out being dried in vacuo (R)-praziquantel amine salt described in obtaining；Or,
Described precipitation is washed with ice-cold solvent, then carries out being dried in vacuo and obtaining crude product, will be described thick
Product be recrystallized to give described in (R)-praziquantel amine salt sterling；Or, described is precipitated with ice-cold
Solvent is washed, and then be dried in vacuo obtaining crude product, methanol is added into described crude product, under stirring
50~60 DEG C are heated to dissolving crude product, 0~20 DEG C is then progressively cooled to and is separated out to solid, collect precipitation,
Washed with methanol, then vacuum drying obtains described (R)-praziquantel amine salt sterling；Or, will be described
Precipitate (R)-praziquantel amine salt described in being recrystallized to give.Wherein, described ice-cold solvent be water,
One or more in methyl tertiary butyl ether(MTBE), isopropanol, isopropyl ether, toluene；Volume ratio is used for 6.25~7:1
Organic solvent and the mixed solvent of water carry out described recrystallization, described organic solvent is methanol, second
One or more in alcohol, the tert-butyl alcohol.
A kind of preparation method of levo-praziquantel, the preparation method includes described (R)-praziquantel amine salt
Step, and the step of prepare described levo-praziquantel by described (R)-praziquantel amine salt.
Preferably, the step of preparing described levo-praziquantel by described (R)-praziquantel amine salt is included by institute
The step of (R)-praziquantel amine is made with alkali reaction in (the R)-praziquantel amine salt stated, and by described (R)-pyrrole
The step of quinoline ketoamine is to prepare levo-praziquantel.
It is further preferred that reaction, which is hydrolyzed, with acid in described (R)-praziquantel amine salt obtains chiral resolution examination
Agent, described chiral selectors can reuse to the production of lower batch materials, then add described alkali
Alkalize and obtain described (R)-praziquantel amine；
Or, described (R)-praziquantel amine salt is hydrolyzed reaction with described alkali and obtains described (R)-pyrrole quinoline
Ketoamine, then adds described acid and be acidified obtaining chiral selectors, described chiral resolution examination
Agent can reuse to lower batch materials production.
It is further preferred that described acid is hydrochloric acid, sulfuric acid or phosphoric acid, described alkali is potassium carbonate, sodium carbonate, hydroxide
Sodium, potassium hydroxide, saleratus or sodium acid carbonate.
According to the present invention, described (R)-praziquantel amine salt needs having with described alkali or described sour reaction
Carried out in the presence of machine solvent, or, it is necessary to be extracted using organic solvent after the completion of reaction, so
Described chiral selectors and described (R)-praziquantel amine are obtained by modes such as drying, concentrations.Wherein,
Described organic solvent is the one or more in dichloromethane, ethyl acetate, diisopropyl ether, toluene.
It is further preferred that by described (R)-praziquantel amine and hexamethylene formyl chloride organic solvent presence
Lower reaction obtains described levo-praziquantel.
In the present invention, described (R)-praziquantel amine and organic solvent are added in reactor, temperature is controlled
For -5~5 DEG C, hexamethylene formyl chloride is then added dropwise into described reactor, in reaction at 20~25 DEG C
15~20h obtains described levo-praziquantel, wherein, described (R)-praziquantel amine and described hexamethylene formyl
The molar ratio of chlorine is 1:1~1.2.
It is further preferred that described organic solvent is in triethylamine, dichloromethane, ethyl acetate, toluene
It is one or more.
Due to the implementation of above technical scheme, the present invention has the following advantages that compared with prior art：
There is the present invention raw material to be easy to get, technique is simple, short preparation period, chiral selectors are stable, price
Low and recovery is easy, low cost and other advantages.
Embodiment
The present invention synthetic route be：
A represents chiral selectors in above-mentioned reaction scheme, such as chiral (R)-brufen
((R)-Ibuprofen), chiral (R)-naproxen ((R)-Naproxen), chirality (R) -1- phenethyl sulphurs
Acid ((R) -1-Phenylethanesulfonic acid, referred to as (R)-PES).
With reference to specific embodiment, the present invention will be further described in detail, but the present invention is not limited to
Following examples.
Embodiment one, (R)-brufen splits racemization praziquantel amine
Step one：Prepare (R)-brufen-(R)-praziquantel amine salt
In the reactor, addition racemization praziquantel amine (20.25g, 10mmol), (R)-brufen (10.4g,
5mmol), methanol (200ml), is heated to 80 DEG C of dissolvings complete.10 DEG C are cooled to, 1 hour is stood,
Precipitation is collected by filtration, frozen water washing, vacuum drying obtains crude product (R)-brufen-(R)-praziquantel amine
(20.1g, 95%e.e., individual isomer (R)-praziquantel amine yield 97.9%, total recovery 48.9%).
Take crude product 20g, recrystallized by methanol (82ml) and water (12ml), obtain sterling (R)-
Brufen-(R)-praziquantel amine (18.3g, 99.7%e.e., individual isomer (R)-praziquantel amine yield
91.5%, total recovery 44.8%).
Step 2：Free (R)-praziquantel amine is prepared, (R)-brufen resolution reagent is reclaimed
Sterling (R)-brufen-(R)-praziquantel amine 18g is taken to be added in dichloromethane (80ml) solution,
Stirring is lower to be added dropwise 1N HCl (50ml), and with the dropwise addition of hydrochloric acid, system progressively becomes clarification, continues that salt is added dropwise
Acid, reaction system then separates out solid again, is recovered by filtration precipitation solid, dry white powder (R)-Bu Luo
Fragrant (8.72g, the rate of recovery 95.87%, 99.9%e.e.).
Filtrate added drop-wise 4N NaOH solutions, layering, aqueous phase extracts three (40ml by dichloromethane again
X 3), combined dichloromethane layer, magnesium sulfate is dried, and vacuum concentration obtains resolved product pale yellow oil,
It is stored at room temperature lower solidification and obtains (R)-praziquantel amine (8.7g, 99.7%e.e., individual isomer (R)-praziquantel
Amine yield 97.6%, total recovery 43.73g, 122-123 DEG C of fusing point).
Embodiment two, racemization praziquantel amine is split using (R)-brufen is reclaimed
Method be the same as Example one, racemization praziquantel amine is split using gained (R)-brufen is reclaimed.In reaction
In device, add racemization praziquantel amine (1.0eq, 15.7g, 7.76mmol), reclaim gained (R)-brufen
(0.5eq, 8g, 3.88mmol), ethanol (5eq, 77.5mL), is heated to 80 DEG C of dissolvings, cooling
Crystallization (15.4g, 95%e.e., individual isomer (R)-praziquantel amine yield 97.5%, total recovery 48.75%).
Gained crystal (15.4g) is by methanol-water (72mL, 7：1, v/v) recrystallize, obtain pure
Product (R)-brufen-(R)-praziquantel amine (14.2g, 99.5%e.e., individual isomer (R)-pyrrole after change
Quinoline ketoamine yield 92%, total recovery 44.8%).
Product (R)-brufen-(R)-praziquantel amine (14.2g) is hydrolyzed gained by hydrochloric acid after purification, acetic acid second
Ester extract, vacuum concentration go ethyl acetate be recycled resolution reagent white powder (R)-brufen (7.1g,
The rate of recovery 99%, 99.9%e.e.).4N NaOH solutions are added dropwise in aqueous phase, and layering, aqueous phase passes through second again
Acetoacetic ester extracts three times (40ml x 3), and combined ethyl acetate layer, magnesium sulfate is dried, and vacuum concentration is obtained
Resolved product pale yellow oil, be stored at room temperature it is lower solidification obtain white powder (R)-praziquantel amine (6.86g,
99.7%e.e., individual isomer (R)-praziquantel amine yield 97.5%, total recovery 43.73g, fusing point
122–123℃)。
Embodiment three, (R)-brufen splits racemization praziquantel amine
Step one：Prepare (R)-brufen-(R)-praziquantel amine salt
In the reactor, add racemization praziquantel amine (20.23g, 10mmol), (R)-brufen (10.4g,
5mmol), potassium hydroxide (85%, 0.33g, 5mmol), water (50ml), 60-70 DEG C of heating, and
Continue to react half an hour, mixture stands and is cooled to room temperature, precipitation, frozen water washing, vacuum is collected by filtration
Dry, obtain crude product (R)-brufen-(R)-praziquantel amine salt (19..4g, 94.3% yield, 96.5%e.e.,
Total recovery 47.2%).
Take crude product 19g, recrystallized by ethanol (82ml) and water (12ml), obtain sterling (R)-
Brufen-(R)-praziquantel amine (17.8g, 98.7%e.e., 93.5% yield, total recovery 44.2%).
Step 2：Free (R)-praziquantel amine is prepared, (R)-brufen resolution reagent is reclaimed
Recrystallization gained sterling (R)-brufen-(R)-praziquantel amine salt (17.8g, 44.0mmol) is taken to add
Enter into 4N sodium hydrate aqueous solutions (52ml), hydrolysis liquid is extracted three times by diisopropyl ether
(30mlx2), merges isopropyl ether layer, and magnesium sulfate is dried, and vacuum concentration obtains resolved product colorless oil
Thing (8.16g, 92.6% yield, 98.7%e.e.), is stored at room temperature lower solidification, 122-123 DEG C of fusing point.Water
Be acidified (3.0M, 30ml) through aqueous hydrochloric acid solution, precipitation solid be recovered by filtration, dry, reclaim (R)-
Brufen white powder (8.54g, the rate of recovery 95%).
Example IV, (R)-brufen splits racemization praziquantel amine
Step one：Prepare (R)-brufen-(R)-praziquantel amine salt
In the reactor, methyl tertiary butyl ether(MTBE) (4.8L) and water (600g), racemization praziquantel amine are added
(1.01kg, 5mol), reactant mixture is heated to 50-55 DEG C to reaction system clarification.Into reaction solution
(R)-brufen (0.52kg, 2.5mol) is added at 50-55 DEG C, is added in 30 minutes.Mixture
35 DEG C are cooled to, solid precipitation is begun with, 10 DEG C are continued cool to, and stir 1 hour at this temperature.
The solid of precipitation is collected by filtration, ice-cold methyl tertiary butyl ether(MTBE) washs three times (0.5Lx3), and vacuum drying is obtained
(R) (0.9kg, 43.7% yield is based on racemization praziquantel amine, wherein hand to-brufen-(R)-praziquantel amine salt
Property (R)-praziquantel amine optical purity 99.1%e.e.).
Step 2：Free (R)-praziquantel amine is prepared, (R)-brufen resolution reagent is reclaimed
Fractionation gained (R)-brufen-(R)-praziquantel amine salt (0.9kg) is taken, 2N is added to
In HCl (1300ml) aqueous hydrochloric acid solution, mixture is heated to 60 DEG C until obtaining supernatant liquid.Then by
15 DEG C are gradually cooled to, when having solid precipitation, continues to be cooled to 10 DEG C, the solid of precipitation, water is collected by filtration
Wash three times (0.5Lx3), vacuum drying obtains (R)-brufen white powder (447g, 98.3% yield).
Filtrate added drop-wise 4N NaOH solutions, layering, aqueous phase extracts three times (400ml x 3) by toluene again, closes
And toluene layer, magnesium sulfate drying, it is concentrated in vacuo and obtains resolved product pale yellow oil, is stored at room temperature down
Solidification obtain (R)-praziquantel amine (438.1g, 99.4%e.e., 98.3% yield be based on individual isomer (R)-
Praziquantel amine, total recovery 43.%, 122-123 DEG C of fusing point).
Embodiment five, (R)-naproxen splits racemization praziquantel amine
Step one：Prepare (R)-naproxen-(R)-praziquantel amine salt
In the reactor, isopropanol (320ml), racemization praziquantel amine (101.1g, 0.5mol) are added,
Reactant mixture is heated to 70 DEG C to reaction system clarification.Into reaction solution add (R)-naproxen (57.6g,
0.25mol), in stirring reaction half an hour at 50-55 DEG C.Mixture is cooled to 40 DEG C, begins with solid
Separate out, continue cool to 20 DEG C, and stir 1 hour at this temperature.The solid of precipitation is collected by filtration,
Ice-cold isopropanol washed once (15mL), and vacuum drying obtains (R)-naproxen-(R)-praziquantel amine salt
(108.1g, yield 96.0%, based on racemization praziquantel amine yield 48%, wherein chiral (R)-praziquantel
Amine optical purity 89.5%e.e.), take thick (R)-naproxen-(the R)-praziquantel amine salt of gained (108.1g,
0.25mol), methanol (250mL) is added, the lower mixture of stirring is heated to 55 DEG C of fully dissolveds, then
10 DEG C are progressively cooled to, the solid salt of precipitation is collected by filtration, methanol washed once (80mL), vacuum is done
It is dry, obtain pure (R)-naproxen-(R)-praziquantel amine salt (93.4g, 86.4% yield, 99.2%e.e.).
Step 2：Free (R)-praziquantel amine is prepared, (R)-naproxen resolution reagent is reclaimed
Fractionation gained (R)-naproxen-(R)-praziquantel amine salt (93g, 215mmol) is taken, hydrochloric acid is added to
In the aqueous solution (2.5M, 200mL), (100mLX2) is extracted twice with dichloromethane under stirring, had
Machine layer washing, concentration, remaining solid is suspended in mashing half an hour in petroleum ether (100mL), filtered back
Receive separate out solid, vacuum drying obtain (R)-naproxen white powder (48.83g, 98.6% yield,
99.6%e.e.).
Filtrate added drop-wise 2N KOH solutions (100mL), are neutralized, and aqueous phase is extracted three times by toluene again
(300ml x 3), combining methylbenzene layer, magnesium sulfate is dried, and vacuum concentration obtains the faint yellow oil of resolved product
Shape thing, is stored at room temperature lower solidification and obtains (R)-praziquantel amine (42.76g, 99.4%e.e., 98.3% yield
Based on individual isomer (R)-praziquantel amine, total recovery 42.3%, 122-123 DEG C of fusing point).
Embodiment six, (R)-naproxen splits racemization praziquantel amine
Step one：Prepare (R)-naproxen-(R)-praziquantel amine salt
In the reactor, add (R)-naproxen (57.6g, 0.25mol), potassium carbonate (17.25g,
0.125mol), water (250ml), racemization praziquantel amine (101.1g, 0.5mol), is heated to 80 DEG C,
And stirring reaction 20 minutes, mixture stands and is cooled to 25 DEG C of room temperature, precipitation is collected by filtration, frozen water is washed
Wash, be dried in vacuo, obtain crude product (104.1g, 96.3% yield, 92.1%e.e.), total recovery 48.2%.
Take crude product 101g, recrystallized by the tert-butyl alcohol (250ml) and water (40ml), obtain purified product (90.36g,
86.8% yield, 98.8%e.e.).
Step 2：Free (R)-praziquantel amine is prepared, (R)-naproxen resolution reagent is reclaimed
Recrystallization gained sterling salt (90g, 20.8mmol) is taken to be added to 4N sodium hydrate aqueous solutions
In (52ml), hydrolysis liquid extracts three times (80mlx2), combining methylbenzene layer, magnesium sulfate by toluene
Dry, vacuum concentration obtains resolved product colorless oil (39.4g, 93.6% yield, 98.8%e.e.),
It is stored at room temperature lower solidification, 122-123 DEG C of fusing point.Aqueous phase is acidified (3.0M, 30ml) through aqueous hydrochloric acid solution,
Be recovered by filtration precipitation solid, dried recovered obtain (R)-naproxen white powder (47.35g, the rate of recovery 98.78%,
99.8%e.e.).
Embodiment seven, (R)-naproxen splits racemization praziquantel amine
Step one：Prepare (R)-naproxen-(R)-praziquantel amine salt
In the reactor, add dichloromethane (2.80L) and water (600g), racemization praziquantel amine (1.01kg,
5mol), reactant mixture is heated to 45 DEG C to reaction system clarification.(R)-Nabumetone is added into reaction solution
Raw (0.58kg, 2.5mol) reacts 1 hour at 45 DEG C under stirring.Mixture is cooled to 25 DEG C,
Solid precipitation is begun with, 5 DEG C are continued cool to, and stir 1 hour at this temperature.It is heavy to be collected by filtration
The solid in shallow lake, ice-cold isopropyl ether washs three times (1.0.Lx3), vacuum drying obtain (R)-naproxen-(R)-
(1.0kg, 45.7% yield is based on racemization praziquantel amine to praziquantel amine salt, wherein chiral (R)-praziquantel amine light
Learn purity 99.1%e.e.).
Step 2：Free (R)-praziquantel amine is prepared, (R)-naproxen resolution reagent is reclaimed
Fractionation gained (R)-naproxen-(R)-praziquantel amine salt (1Kg, 2.31mol) is taken, hydrochloric acid is added to
In the aqueous solution (2.5M, 200mL), (800mL x 2) is extracted twice with ethyl acetate under stirring, had
Machine layer washing, concentration, remaining solid is suspended in mashing half an hour in n-hexane (100mL), filtered back
Receive separate out solid, vacuum drying obtain (R)-naproxen white powder (524.5g, 98.5% yield,
99.8%e.e.).
Aqueous phase adds 4N sodium hydrate aqueous solutions (100mL), and toluene extracts three times (800ml x 3), closes
And toluene layer, magnesium sulfate drying, it is concentrated in vacuo and obtains resolved product colorless oil, is stored at room temperature lower solid
Change obtains (R)-praziquantel amine (437.8g, 93.6% yield, 99.1%e.e.), 122-123 DEG C of fusing point.
Embodiment eight, (R) -1- benzene ethyl sulfonic acid splits racemization praziquantel amine
Step one：Prepare (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine salt
In the reactor, water (45g), toluene (450g), racemization praziquantel amine (202.3g, 1mol) are added,
Reactant mixture is heated to 60 DEG C, maintains this temperature to reaction system to clarify.Added into reaction solution chiral
(R) -1- phenethyls sulfonic acid (93g, 0.5mol), in stirring reaction 15 minutes at 60 DEG C, mixture is slow
Be cooled to 42 DEG C, add (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine salt crystal seed (99.9%e.e.,
0.01g).Continue to slowly cool to 10 DEG C, and stir 1 hour at this temperature.Precipitation is collected by filtration
Solid, toluene washed once (120g), and vacuum drying obtains (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine
(168.9g, yield 43.5% is based on raceme praziquantel amine to salt white powder, wherein chiral (R)-praziquantel
Amine optical purity 99.0%e.e.).
Step 2：Free (R)-praziquantel amine is prepared, (R) -1- phenethyl sulfonic acid resolution reagents are reclaimed
Fractionation gained (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine salt (168g, 0.43mol) is taken, is added
Into 1N aqueous sodium carbonates (500g), three times (300g x 3) is extracted with toluene under stirring, is associated with
Machine layer, is washed, concentration, and residue addition normal heptane (100mL) stirring half an hour separates out solid, mistake
The solid separated out is collected in filter, and vacuum drying obtains (R)-praziquantel amine white powder, and (83.5g, 95.5% receives
Rate, 99.0%e.e.), 122-123 DEG C of fusing point.
Reclaim resolution reagent.Water layer adjusts pH value less than 2 with concentrated hydrochloric acid acidifying, rotary evaporated to dryness,
Methanol is added, the inorganic salts of precipitation are filtered to remove, methanol layer is spin-dried for obtaining solid, and vacuum drying is swum
From chirality (R) -1- phenethyl sulfonic acid white powder (78.6g, 98.1% yield, 99.6%e.e).
Embodiment nine, (R) -1- benzene ethyl sulfonic acid splits racemization praziquantel amine
Step one：Prepare (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine salt
In the reactor, add toluene (4.5kg) and water (450g), racemization praziquantel amine (2.02kg,
10mol), reactant mixture is heated to 50-55 DEG C to reaction system clarification.Added into reaction solution chiral
(R) -1- phenethyls sulfonic acid (0.93kg, 5mol), in stirring reaction 15 minutes at 60 DEG C.Mixture is cold
But to 45 DEG C, (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine salt crystal seed (99.9%e.e., 1g) is added.After
It is continuous to be cooled to 10 DEG C, and stir 2 hours at this temperature.The solid of precipitation, ice-cold first is collected by filtration
Benzene washs three times (0.5Lx3), and vacuum drying obtains (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine salt white
(1.7kg, yield 43.8% is based on raceme praziquantel amine to powder, wherein chirality-(R)-praziquantel amine optics
Purity 99.1%e.e.).
Step 2：Free (R)-praziquantel amine is prepared, (R) -1- phenethyl sulfonic acid resolution reagents are reclaimed
Fractionation gained (R) -1- phenethyls sulfonic acid-(R)-praziquantel amine salt (1.7kg, 4.38mol) is taken, is added
Into 1N wet chemicals (4kg), three times (3kg x 3) is extracted with toluene under stirring, merged organic
Layer, is washed, concentration, and residue addition normal heptane (1L) stirring half an hour separates out solid, is collected by filtration
The solid of precipitation, vacuum drying obtain (R)-praziquantel amine white powder (846.3g, 95.6% yield,
99.1%e.e.), 122-123 DEG C of fusing point.
Reclaim resolution reagent.Water layer adjusts pH value less than 2 with concentrated hydrochloric acid acidifying, rotary evaporated to dryness,
Methanol is added, the inorganic salts of precipitation are filtered to remove, methanol layer is spin-dried for obtaining solid, and vacuum drying is swum
From chirality (R) -1- phenethyl sulfonic acid white powder (801g, 98.3% yield, 99.6%e.e).
Embodiment ten, the synthesis of levo-praziquantel
In the reactor, intermediate R- (-)-praziquantel amine (505g, 2.5mol, 1eq.), three second is added
Amine (378g, 522mL, 3.75mol, 1.5eq.), dichloromethane (12.4L), ice bath is cooled to 0
℃.Hexamethylene formyl chloride (405g, 369mL, 2.75mol, 1.1 is added dropwise under stirring into this mixture
Eq.), 0 DEG C of keeping temperature.Completion of dropping, in 20-25 DEG C of stirring reaction 16 hours.HPLC is tracked
Reaction is complete.It is quenched with water (1.6L) and reacts and continue stirring 45 minutes.Separation organic layer is simultaneously used respectively
Saturated sodium carbonate solution, 0.5N HCl solutions and brine It, anhydrous sodium sulfate drying, are concentrated under reduced pressure
Solvent is removed, residue is recrystallized with acetone/n-hexane mixed liquor (5.5L, 1/1, v/v), obtains 746.6g
Clear crystal is sterling levo-praziquantel, yield 95.6%, purity 99.3%, 99.5%ee, fusing point
113-115℃。
Levo-praziquantel nuclear magnetic data：1H NMR(DMSO-d6,400MHz,δppm)：
1.21-1.96(m,10H,5xCH2),2.45-2.50(m,1H,CH),2.78-3.05(m,4H,CH2),
4.10(d,1H,CH2),4.48(d,1H,CH2),4.79-4.85(m,2H,CH2),5.20(d,1H,
CH),7.12-7.30(m,4H,Ar-H).
MS(ESI,+ve):m/z:313.1[M+H]+。
The above embodiments merely illustrate the technical concept and features of the present invention, and its object is to allow be familiar with this
The personage of technology can understand present disclosure and implement according to this, and the guarantor of the present invention can not be limited with this
Protect scope.Any equivalent change or modification in accordance with the spirit of the invention, should all cover in the present invention
Protection domain within.
Claims (10)
1. a kind of preparation method of (R)-praziquantel amine salt, it is characterised in that：It reacts obtained (R)-praziquantel amine salt in a solvent with raceme praziquantel amine and chiral selectors, wherein, described chiral selectors are the one or more in (R)-brufen, (R)-naproxen, (R) -1- phenethyl sulfonic acid.
2. the preparation method of (R)-praziquantel amine salt according to claim 1, it is characterised in that：The molar ratio of described raceme praziquantel amine and described chiral selectors is 1：0.4~0.6.
3. the preparation method of (R)-praziquantel amine salt according to claim 1, it is characterised in that：In initial reaction system, the concentration of described raceme praziquantel amine is 0.1 ~ 0.5g/mL.
4. the preparation method of (R)-praziquantel amine salt according to claim 1, it is characterised in that：Described solvent is the one or more in methanol, ethanol, water, methyl tertiary butyl ether(MTBE), isopropanol, dichloromethane, toluene.
5. the preparation method of (R)-praziquantel amine salt according to claim 1, it is characterised in that：Described raceme praziquantel amine reacts (the R)-praziquantel amine salt for being made described with described chiral selectors in described solvent and alkali compounds, wherein, described alkali compounds is potassium hydroxide or potassium carbonate, and described raceme praziquantel amine and the molar ratio of described alkali compounds are 1:0.25~0.5.
6. the preparation method of (R)-praziquantel amine salt according to any one of claim 1 to 5, it is characterised in that：Described raceme praziquantel amine, described chiral selectors, described solvent are added into reactor, it is selectively added alkali compounds, then reactant dissolving is heated at 45 ~ 80 DEG C, it is subsequently cooled to solid precipitation, precipitation is collected, the precipitation is post-treated to obtain described (R)-praziquantel amine salt.
7. a kind of preparation method of levo-praziquantel, it is characterised in that：The step of preparation method includes (R)-praziquantel amine salt as any one of claim 1 to 6, and by described (R)-praziquantel amine salt prepare described in levo-praziquantel the step of.
8. the preparation method of levo-praziquantel according to claim 7, it is characterised in that：The step of described levo-praziquantel is prepared by described (R)-praziquantel amine salt including reacting the step of (R)-praziquantel amine is made by described (R)-praziquantel amine salt and alkali, and by described (R)-praziquantel amine to prepare levo-praziquantel the step of.
9. the preparation method of levo-praziquantel according to claim 8, it is characterised in that：Described (R)-praziquantel amine salt is hydrolyzed reaction with acid and obtains chiral selectors, described chiral selectors can reuse to the production of lower batch materials, then add described alkali and alkalize and obtain described (R)-praziquantel amine；
Or, described (R)-praziquantel amine salt is hydrolyzed reaction with described alkali and obtains described (R)-praziquantel amine, then described acid is added be acidified obtaining chiral selectors, described chiral selectors can reuse to lower batch materials production.
10. the preparation method of levo-praziquantel according to claim 8, it is characterised in that：Described (R)-praziquantel amine and hexamethylene formyl chloride are reacted in presence of organic solvent and obtain described levo-praziquantel.
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| WO2022171150A1 (en) * | 2021-02-09 | 2022-08-18 | Tongli Biomedical Co., Ltd. | Methods and pharmaceutical composition for treating diseases |
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| CN108250008A (en) * | 2018-02-05 | 2018-07-06 | 浙江大学 | 3,3,3`, 3`- tetramethyl -1,1`- spiro indan -6,6`- diol, derivatives chiral separation methods |
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