CN107151246B - The preparation method of one kind (R)-praziquantel amine salt and levo-praziquantel - Google Patents
The preparation method of one kind (R)-praziquantel amine salt and levo-praziquantel Download PDFInfo
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Abstract
The present invention relates to the preparation methods and a kind of preparation method of levo-praziquantel of a kind of (R)-praziquantel amine salt, (R)-praziquantel amine salt is reacted with raceme praziquantel amine with chiral selectors in a solvent to be made, wherein, the chiral selectors are selected from one of (R)-brufen, (R)-naproxen, (R) -1- phenethyl sulfonic acid or a variety of.The present invention has many advantages, such as that raw material is easy to get, simple process, short preparation period, chiral selectors are stable, price is low and recycling is easy, is at low cost.
Description
Technical field
The invention belongs to chiral drugs to prepare chemical field, and in particular to one kind (R)-praziquantel amine salt and levo-praziquantel
The preparation method of ((R)-praziquantel).
Background technique
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 Schistosoma japonicum, Schistosoma haematobium, Mans
The diseases such as blood fluke, clonorchiasis, paragonimiasis, Meng Shi pleroceroid, fasciolopsis, Echinococcus hydatid cyst, tapeworm and cysticercus.It has anti-
Worm spectrum is wide, curative effect is high, toxicity is low, short treating period and it is easy to use the advantages that.In addition to for human body, it is also widely used in animal, family
The anti parasitic of fowl etc. is treated.The appearance of praziquantel is an important breakthrough in parasitic disease chemotherapy history, and praziquantel is currently
The choice drug of a variety of parasitic diseases is treated in the market.
Praziquantel is the racemic compound collectively constituted by left-handed and dextrorotation praziquantel, and scientific research personnel is from synthesis praziquantel
Middle fractionation obtains levo-praziquantel and dextrorotation praziquantel optical isomer, and passes through the discovery of preclinical and initial clinical experience: left
Rotation praziquantel is effective insecticidal constituent of praziquantel, and dextrorotation praziquantel is invalid even harmful components；It is left-handed under same dose
Praziquantel clinical efficacy is more preferable than praziquantel, dextrorotation praziquantel then almost inefficacy, bitter, and is the main of drug side-effect
Generate source.It is lower than d-isomer to the toxicity levo form of heart, therefore develop levo-praziquantel and replace praziquantel, there will be curative effect
Higher, toxic side effect is less, the better clinical value of medicine compliance.Although left-handed pyrrole quinoline it is expected by the World Health Organization
Ketone replaces praziquantel, but the low process difficulties of the yield of levo-praziquantel chemical synthesis for many years are hanged always and do not solved.
Praziquantel was synthesized in 1975 by Seubere et al. first, and German Merck and two pharmaceutical factory Bayer are successfully developed
This kind of drug.1980, Merck company took the lead in listing with trade name Cesol, was worldwide widely applied.Pyrrole quinoline
Ketone will use some toxic, harmful chemical substances, such as potassium cyanide, heavy metal, and its technique road in process of production
Line is longer, and reaction condition is also harsher (high temperature, high pressure).And this kind of reaction process control difficulty is larger, it is seriously polluted.
The preparation method of levo-praziquantel, which sums up, can be divided into asymmetric synthesis method, biological enzyme and racemic modification
Split Method.
1, symmetrical synthesis can direct synthesis of chiral molecule, but the preparation side of existing asymmetric syntheses levo-praziquantel
Method, the chiral auxiliary or chiral catalyst or specificity being related to are constantly expensive with the high reagent of selectivity and are not easy a large amount of
It obtains.
2, method of enzymatic resolution: needing dextrorotation racemization, and process is cumbersome, and total recovery is to be improved.(CN 102911979
A, a method of preparing levo-praziquantel).
3, enzymatic Dynamic Kinetic conversion method: crucial chiral intermediate is converted by lipase-catalyzed Dynamic Kinetic
To prepare.But enzyme catalyst dosage is big, and enzyme catalyst and raw material dosage reach 1:1, and post-processing is complicated, large labor intensity, product
Optical purity needs just to be able to satisfy pharmacy needs, higher cost by recrystallization.
Above-mentioned asymmetric syntheses, enzyme Split Method, enzymatic Dynamic Kinetic conversion method, these method expensive reagents, operation
Cumbersome, yield is lower, realizes industrialized production not only severe reaction conditions, complex process, operation difficulty is big, and high cost has
Wait be further improved.
Chipal compounds technology maturation is prepared by racemic fractionation, method is more.Document report has with dibenzoyl-L-
Tartaric acid method for splitting successfully carries out chemical resolution to levo-praziquantel synthesis key intermediate racemization pyrrole quinoline amine.This method exists
The problem of be: although laboratory it is available preparation levo-praziquantel key intermediate levo-praziquantel amine, this method
In resolution reagent dibenzoyl-L-tartaric acid stability it is poor, it is susceptible to hydrolysis, especially during mass production, Hydrolysis Resolution
During gained dibenzoyl-L-tartaric acid-levo-praziquantel amine salt discharges free levo-praziquantel amine, dibenzoyl-L-
Tartaric acid resolution reagent is sensitive to the pH value of reaction system, susceptible to hydrolysis, causes resolution reagent recovery utilization rate low, it is difficult to
To high-purity levo-praziquantel amine, and remaining residue is unfavorable to environmental protection.And dibenzoyl-L-tartaric acid resolution reagent source
Not extensively, it is influenced by market supply, price fluctuation is big.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide the new levo-praziquantel of one kind
Preparation method, this method can not only obtain the levo-praziquantel product of more high-optical-purity, but also cost is lower.
In order to solve the above technical problems, the present invention adopts the following technical scheme that:
A kind of preparation method of (R)-praziquantel amine salt, in a solvent with raceme praziquantel amine and chiral selectors
React be made (R)-praziquantel amine salt, wherein the chiral selectors be selected from (R)-brufen, (R)-naproxen,
(R) one of -1- phenethyl sulfonic acid or a variety of.
Preferably, the molar ratio of the raceme praziquantel amine and the chiral selectors be 1:0.4~
0.6。
It is further preferable that the molar ratio of the raceme praziquantel amine and the chiral selectors is 1:
0.5。
Preferably, in initial reaction system, the concentration of the raceme praziquantel amine is 0.1~0.5g/mL.
Preferably, the solvent is selected from methanol, ethyl alcohol, water, methyl tertiary butyl ether(MTBE), isopropanol, methylene chloride, toluene
One of or it is a variety of.
Preferably, the raceme praziquantel amine and the chiral selectors are in the solvent and alkaline chemical combination
(the R)-praziquantel amine salt for being made described is reacted in object, wherein the alkali compounds is potassium hydroxide or potassium carbonate, described
Raceme praziquantel amine and the molar ratio of the alkali compounds be 1:0.25~0.5.
Preferably, the raceme praziquantel amine, chiral selectors, described molten is added into reactor
Agent is selectively added alkali compounds, and reactant dissolution is then heated at 45~80 DEG C, is subsequently cooled to solid analysis
Out, precipitating is collected, the precipitating is post-treated to obtain (R)-praziquantel amine salt.
According to the present invention, there are many post-processing approach of precipitating, can use conventional method, such as by the precipitating ice
Cold solvent washing, is then dried in vacuo to obtain (R)-praziquantel amine salt；Alternatively, by the precipitating with ice-cold
Solvent washing, be then dried in vacuo to obtain crude product, the crude product carried out to be recrystallized to give (R)-pyrrole quinoline
Ketoamine salt sterling；Alternatively, the precipitating is washed with ice-cold solvent, then it is dried in vacuo to obtain crude product, to described
Crude product in methanol is added, be heated under stirring 50~60 DEG C to crude product dissolve, be then gradually cooled to 0~20 DEG C to solid analyse
Out, precipitating is collected, is washed with methanol, then vacuum drying obtains (R)-praziquantel amine salt sterling；Alternatively, by described
Precipitating carries out being recrystallized to give (R)-praziquantel amine salt.Wherein, the ice-cold solvent is water, methyl tertbutyl
One of ether, isopropanol, isopropyl ether, toluene are a variety of；Use volume ratio for the mixing of the organic solvent of 6.25~7:1 and water
Solvent carries out the recrystallization, and the organic solvent is one of methanol, ethyl alcohol, the tert-butyl alcohol or a variety of.
A kind of preparation method of levo-praziquantel, the preparation method include the steps that (R)-praziquantel amine salt,
And the step of by (R)-praziquantel amine salt preparation levo-praziquantel.
It preferably, include by described by the step of (R)-praziquantel amine salt preparation levo-praziquantel
(R)-praziquantel amine salt reacts the step of (R)-praziquantel amine is made with alkali, and prepares a left side by (R)-praziquantel amine
The step of revolving praziquantel.
It is further preferred that (R)-praziquantel amine salt is hydrolyzed with acid reacts to obtain chiral selectors, institute
The chiral selectors stated can reuse to lower batch materials production, then add the alkali alkalized to obtain it is described
(R)-praziquantel amine；
Alternatively, (R)-praziquantel amine salt is hydrolyzed with the alkali reacts to obtain (the R)-praziquantel
Then amine adds the acid and is acidified to obtain chiral selectors, the chiral selectors can reuse under
The production of batch materials.
It is further preferred that the acid is hydrochloric acid, sulfuric acid or phosphoric acid, the alkali is potassium carbonate, sodium carbonate, hydroxide
Sodium, potassium hydroxide, saleratus or sodium bicarbonate.
According to the present invention, (R)-praziquantel amine salt is needed with the alkali or reacting for the acid organic molten
It is carried out in the presence of agent, alternatively, after the reaction was completed, needing to be extracted using organic solvent, then through modes such as drying, concentrations
Obtain the chiral selectors and (R)-praziquantel amine.Wherein, the organic solvent is methylene chloride, acetic acid
One of ethyl ester, diisopropyl ether, toluene are a variety of.
It is further preferred that (R)-praziquantel amine and hexamethylene formyl chloride are reacted in presence of organic solvent
Obtain the levo-praziquantel.
In the present invention, (R)-praziquantel amine and organic solvent are added in reactor, controlled at -5~5
DEG C, hexamethylene formyl chloride is then added dropwise into the reactor, reacted at 20~25 DEG C 15~20h obtain it is described left-handed
Praziquantel, wherein the molar ratio of (R)-praziquantel amine and the hexamethylene formyl chloride is 1:1~1.2.
It is further preferred that the organic solvent be one of triethylamine, methylene chloride, ethyl acetate, toluene or
It is a variety of.
Due to the implementation of above technical scheme, the invention has the following advantages over the prior art:
The present invention is with raw material is easy to get, simple process, short preparation period, chiral selectors are stable, price is low and recycling
The advantages that being easy, be at low cost.
Specific embodiment
Synthetic route of the invention are as follows:
A represents chiral selectors in above-mentioned reaction route, such as chiral (R)-brufen ((R)-Ibuprofen), chirality
(R)-naproxen ((R)-Naproxen), chiral (R) -1- phenethyl sulfonic acid ((R) -1-Phenylethanesulfonic
Acid, referred to as (R)-PES).
The present invention will be further described in detail combined with specific embodiments below, but the present invention is not limited to following implementations
Example.
Embodiment one, (R)-brufen split racemization praziquantel amine
Step 1: preparation (R)-brufen-(R)-praziquantel amine salt
In the reactor, racemization praziquantel amine (20.25g, 10mmol) is added, (R)-brufen (10.4g, 5mmol), first
It is complete to be heated to 80 DEG C of dissolutions for alcohol (200ml).10 DEG C are cooled to, stands 1 hour, precipitating, ice water washing, vacuum is collected by filtration
Dry, obtaining crude product (R)-brufen-(R)-praziquantel amine, (20.1g, 95%e.e., individual isomer (R)-praziquantel amine obtain
Rate 97.9%, total recovery 48.9%).
Crude product 20g is taken, is recrystallized by methanol (82ml) and water (12ml), obtains sterling (R)-brufen-(R)-pyrrole quinoline
Ketoamine (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 recycled
It takes sterling (R)-brufen-(R)-praziquantel amine 18g to be added in methylene chloride (80ml) solution, stirs lower be added dropwise
1N HCl (50ml), with the dropwise addition of hydrochloric acid, system gradually becomes clarification, continues that hydrochloric acid is added dropwise, reaction system is then precipitated solid again
Body, is recovered by filtration precipitation solid, dry white powder (R)-brufen (8.72g, the rate of recovery 95.87%, 99.9%e.e.).
Filtrate added drop-wise 4N NaOH solution, layering, water phase extract three times (40ml x 3) using methylene chloride, merge two
Chloromethanes layer, magnesium sulfate is dry, and vacuum concentration obtains resolved product light yellow oil, is stored at room temperature lower solidification and obtains (R)-pyrrole
Quinoline ketoamine (8.7g, 99.7%e.e., individual isomer (R)-praziquantel amine yield 97.6%, total recovery 43.73g, fusing point 122-
123℃)。
Embodiment two splits racemization praziquantel amine using recycling (R)-brufen
Method is as in the first embodiment, split racemization praziquantel amine using recycling gained (R)-brufen.In the reactor, it is added
Racemization praziquantel amine (1.0eq, 15.7g, 7.76mmol), recycling gained (R)-brufen (0.5eq, 8g, 3.88mmol), ethyl alcohol
(5eq, 77.5mL) is heated to 80 DEG C of dissolutions, and (15.4g, 95%e.e., individual isomer (R)-praziquantel amine obtain cooling crystallization
Rate 97.5%, total recovery 48.75%).
Gained crystal (15.4g) is recrystallized by methanol-water (72mL, 7:1, v/v), obtains product (R)-Bu Luo after purification
Sweet smell-(R)-praziquantel amine (14.2g, 99.5%e.e., individual isomer (R)-praziquantel amine yield 92%, total recovery
44.8%).
Product (R)-brufen-(R)-praziquantel amine (14.2g) hydrolyzes gained by hydrochloric acid after purification, ethyl acetate extraction
Take, vacuum concentration go ethyl acetate obtain recycling resolution reagent white powder (R)-brufen (7.1g, the rate of recovery 99%,
99.9%e.e.).4N NaOH solution, layering is added dropwise in water phase, and water phase is extracted three times (40ml x 3) using ethyl acetate, closed
And ethyl acetate layer, magnesium sulfate are dry, vacuum concentration obtains resolved product light yellow oil, be stored at room temperature lower solidification obtain it is white
Color powder (R)-praziquantel amine (6.86g, 99.7%e.e., individual isomer (R)-praziquantel amine yield 97.5%, total recovery
43.73g, 122-123 DEG C of fusing point).
Embodiment three, (R)-brufen split racemization praziquantel amine
Step 1: preparation (R)-brufen-(R)-praziquantel amine salt
In the reactor, racemization praziquantel amine (20.23g, 10mmol), (R)-brufen (10.4g, 5mmol), hydrogen is added
Potassium oxide (85%, 0.33g, 5mmol), water (50ml), heat 60-70 DEG C, and the reaction was continued half an hour, and mixture stands cooling
To room temperature, precipitating, ice water washing is collected by filtration, vacuum drying obtains crude product (R)-brufen-(R)-praziquantel amine salt
(19..4g, 94.3% yield, 96.5%e.e., total recovery 47.2%).
Crude product 19g is taken, is recrystallized by ethyl alcohol (82ml) and water (12ml), obtains sterling (R)-brufen-(R)-pyrrole quinoline
Ketoamine (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 recycled
Recrystallization gained sterling (R)-brufen-(R)-praziquantel amine salt (17.8g, 44.0mmol) is taken to be added to 4N hydrogen-oxygen
Change in sodium water solution (52ml), hydrolysis liquid extracts three times (30mlx2) by diisopropyl ether, merges isopropyl ether layer, magnesium sulfate
Dry, vacuum concentration obtains resolved product colorless oil (8.16g, 92.6% yield, 98.7%e.e.), is stored at room temperature lower solid
Change, 122-123 DEG C of fusing point.Water phase is acidified (3.0M, 30ml) through aqueous hydrochloric acid solution, and precipitation solid is recovered by filtration, dry, recycles
(R)-brufen white powder (8.54g, the rate of recovery 95%).
Example IV, (R)-brufen split racemization praziquantel amine
Step 1: preparation (R)-brufen-(R)-praziquantel amine salt
In the reactor, be added methyl tertiary butyl ether(MTBE) (4.8L) and water (600g), racemization praziquantel amine (1.01kg,
5mol), reaction mixture is heated to 50-55 DEG C to reaction system clarification.Into reaction solution be added (R)-brufen (0.52kg,
2.5mol) at 50-55 DEG C, added in 30 minutes.Mixture is cooled to 35 DEG C, begins with solid precipitation, continues cool to 10
DEG C, and stir 1 hour at this temperature.The solid of precipitating is collected by filtration, ice-cold methyl tertiary butyl ether(MTBE) washing is three times
(0.5Lx3), vacuum drying obtains (R)-brufen-(R)-praziquantel amine salt, and (0.9kg, 43.7% yield are based on racemization praziquantel
Amine, wherein chiral (R)-praziquantel amine optical purity 99.1%e.e.).
Step 2: free (R)-praziquantel amine is prepared, (R)-brufen resolution reagent is recycled
Fractionation gained (R)-brufen-(R)-praziquantel amine salt (0.9kg) is taken, 2N HCl (1300ml) hydrochloric acid water is added to
In solution, mixture is heated to 60 DEG C until obtaining supernatant liquid.Then 15 DEG C are gradually cooled to, when having solid precipitation, after
It is continuous to be cooled to 10 DEG C, the solid of precipitation is collected by filtration, three times (0.5Lx3), vacuum drying obtains (R)-brufen white powder for washing
Last (447g, 98.3% yield).Filtrate added drop-wise 4N NaOH solution, layering, water phase extract (400ml x three times using toluene
3), combining methylbenzene layer, magnesium sulfate is dry, and vacuum concentration obtains resolved product light yellow oil, is stored at room temperature lower solidification and obtains
(R) (438.1g, 99.4%e.e., 98.3% yield are based on individual isomer (R)-praziquantel amine, total recovery to-praziquantel amine
43.%, 122-123 DEG C of fusing point).
Embodiment five, (R)-naproxen split racemization praziquantel amine
Step 1: preparation (R)-naproxen-(R)-praziquantel amine salt
In the reactor, isopropanol (320ml), racemization praziquantel amine (101.1g, 0.5mol) is added, reaction mixture adds
Heat to 70 DEG C to reaction system clarify.(R)-naproxen (57.6g, 0.25mol) is added into reaction solution, is stirred at 50-55 DEG C
Mix reaction half an hour.Mixture is cooled to 40 DEG C, begins with solid precipitation, continues cool to 20 DEG C, and stir 1 at this temperature
Hour.The solid of precipitating is collected by filtration, ice-cold isopropanol washed once (15mL), and vacuum drying obtains (R)-naproxen-
(R) (108.1g, yield 96.0% are based on racemization praziquantel amine yield 48% to-praziquantel amine salt, wherein chiral (R)-praziquantel
Amine optical purity 89.5%e.e.), (R)-naproxen-(the R)-praziquantel amine salt (108.1g, 0.25mol) for taking gained thick adds
Enter methanol (250mL), stirs lower mixture and be heated to 55 DEG C of fully dissolveds, be then gradually cooled to 10 DEG C, precipitation is collected by filtration
Solid salt, methanol washed once (80mL), vacuum drying, 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 recycled
Fractionation gained (R)-naproxen-(R)-praziquantel amine salt (93g, 215mmol) is taken, aqueous hydrochloric acid solution is added to
It in (2.5M, 200mL), is extracted twice (100mLX2) under stirring with methylene chloride, organic layer washing, concentration, remaining solid suspends
It is beaten half an hour in petroleum ether (100mL), the solid of precipitation is recovered by filtration, vacuum drying obtains (R)-naproxen white powder
(48.83g, 98.6% yield, 99.6%e.e.).
Filtrate added drop-wise 2N KOH solution (100mL) neutralizes, and water phase extracts three times (300ml x 3) using toluene, merges
Toluene layer, magnesium sulfate is dry, and vacuum concentration obtains resolved product light yellow oil, is stored at room temperature lower solidification and obtains (R)-pyrrole quinoline
(42.76g, 99.4%e.e., 98.3% yield are based on individual isomer (R)-praziquantel amine, total recovery 42.3%, fusing point to ketoamine
122–123℃)。
Embodiment six, (R)-naproxen split racemization praziquantel amine
Step 1: preparation (R)-naproxen-(R)-praziquantel amine salt
In the reactor, (R)-naproxen (57.6g, 0.25mol), potassium carbonate (17.25g, 0.125mol), water is added
(250ml), racemization praziquantel amine (101.1g, 0.5mol), is heated to 80 DEG C, and is stirred to react 20 minutes, and mixture stands cold
But to 25 DEG C of room temperature, be collected by filtration precipitating, ice water washing, vacuum drying, obtain crude product (104.1g, 96.3% yield, 92.1%
E.e.), total recovery 48.2%.Crude product 101g is taken, is recrystallized by the tert-butyl alcohol (250ml) and water (40ml), obtains purified product
(90.36g, 86.8% yield, 98.8%e.e.).
Step 2: free (R)-praziquantel amine is prepared, (R)-naproxen resolution reagent is recycled
Recrystallization gained sterling salt (90g, 20.8mmol) is taken to be added in 4N sodium hydrate aqueous solution (52ml), hydrolysis is anti-
Liquid is answered to extract three times (80mlx2) by toluene, combining methylbenzene layer, magnesium sulfate is dry, and vacuum concentration obtains resolved product colorless oil
Shape object (39.4g, 93.6% yield, 98.8%e.e.), is stored at room temperature lower solidification, and 122-123 DEG C of fusing point.Water phase is water-soluble through hydrochloric acid
Liquid is acidified (3.0M, 30ml), precipitation solid is recovered by filtration, dried recovered obtains (R)-naproxen white powder (47.35g, the rate of recovery
98.78%, 99.8%e.e.).
Embodiment seven, (R)-naproxen split racemization praziquantel amine
Step 1: preparation (R)-naproxen-(R)-praziquantel amine salt
In the reactor, methylene chloride (2.80L) and water (600g), racemization praziquantel amine (1.01kg, 5mol) is added, instead
Mixture is answered to be heated to 45 DEG C to reaction system clarification.(R)-naproxen (0.58kg, 2.5mol) is added into reaction solution in 45
At DEG C, stir lower reaction 1 hour.Mixture is cooled to 25 DEG C, begins with solid precipitation, continues cool to 5 DEG C, and in this temperature
Lower stirring 1 hour.The solid of precipitating is collected by filtration, three times (1.0.Lx3), vacuum drying obtains (R)-for ice-cold isopropyl ether washing
(1.0kg, 45.7% yield are based on racemization praziquantel amine to naproxen-(R)-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 recycled
Fractionation gained (R)-naproxen-(R)-praziquantel amine salt (1Kg, 2.31mol) is taken, aqueous hydrochloric acid solution is added to
It in (2.5M, 200mL), is extracted twice (800mL x 2) under stirring with ethyl acetate, organic layer washing, concentration, remaining solid is outstanding
Float on and be beaten half an hour in n-hexane (100mL), the solid of precipitation is recovered by filtration, vacuum drying obtains (R)-naproxen white powder
Last (524.5g, 98.5% yield, 99.8%e.e.).
4N sodium hydrate aqueous solution (100mL) is added in water phase, and toluene extracts three times (800ml x 3), combining methylbenzene layer, sulphur
Sour magnesium is dry, and vacuum concentration obtains resolved product colorless oil, is stored at room temperature lower solidification and 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 ethanesulfonic acid split racemization praziquantel amine
Step 1: preparation (R) -1- phenethyl sulfonic acid-(R)-praziquantel amine salt
In the reactor, water (45g), toluene (450g), racemization praziquantel amine (202.3g, 1mol), reaction mixing is added
Object is heated to 60 DEG C, this temperature to reaction system is maintained to clarify.Be added into reaction solution chiral (R) -1- phenethyl sulfonic acid (93g,
0.5mol), it is stirred to react at 60 DEG C 15 minutes, mixture progressively cools to 42 DEG C, and (R) -1- phenethyl sulfonic acid-(R)-is added
Praziquantel amine salt crystal seed (99.9%e.e., 0.01g).Continue to slowly cool to 10 DEG C, and stirs 1 hour at this temperature.It crosses
The solid of precipitating is collected in filter, and toluene washed once (120g), and vacuum drying obtains (R) -1- phenethyl sulfonic acid-(R)-praziquantel amine
(168.9g, yield 43.5% are 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 reagent is recycled
Fractionation gained (R) -1- phenethyl sulfonic acid-(R)-praziquantel amine salt (168g, 0.43mol) is taken, 1N carbonic acid is added to
In sodium water solution (500g), under stirring three times (300g x 3) with toluene extraction, merges organic layer, wash, concentration, residue adds
Enter normal heptane (100mL) stirring half an hour precipitation solid, the solid of precipitation is collected by filtration, vacuum drying obtains (R)-praziquantel amine
White powder (83.5g, 95.5% yield, 99.0%e.e.), 122-123 DEG C of fusing point.
Recycle resolution reagent.Water layer concentrated hydrochloric acid, which is acidified, adjusts pH value less than 2, and methanol, filtering is added in rotary evaporated to dryness
The inorganic salts being precipitated are removed, methanol layer is spin-dried for obtaining solid, and it is white that vacuum drying obtains free chirality (R) -1- phenethyl sulfonic acid
Color powder (78.6g, 98.1% yield, 99.6%e.e).
Embodiment nine, (R) -1- benzene ethanesulfonic acid split racemization praziquantel amine
Step 1: preparation (R) -1- phenethyl sulfonic acid-(R)-praziquantel amine salt
In the reactor, toluene (4.5kg) and water (450g), racemization praziquantel amine (2.02kg, 10mol), reaction is added
Mixture is heated to 50-55 DEG C to reaction system clarification.Be added into reaction solution chiral (R) -1- phenethyl sulfonic acid (0.93kg,
5mol), it is stirred to react at 60 DEG C 15 minutes.Mixture is cooled to 45 DEG C, and (R) -1- phenethyl sulfonic acid-(R)-praziquantel is added
Amine salt crystal seed (99.9%e.e., 1g).10 DEG C are continued cool to, and is stirred 2 hours at this temperature.Consolidating for precipitating is collected by filtration
Body, three times (0.5Lx3), vacuum drying obtains (R) -1- phenethyl sulfonic acid-(R)-praziquantel amine salt white for ice-cold toluene washing
(1.7kg, yield 43.8% is based on raceme praziquantel amine to powder, wherein chirality-(R)-praziquantel amine optical purity 99.1%
e.e.)。
Step 2: free (R)-praziquantel amine is prepared, (R) -1- phenethyl sulfonic acid resolution reagent is recycled
Fractionation gained (R) -1- phenethyl sulfonic acid-(R)-praziquantel amine salt (1.7kg, 4.38mol) is taken, 1N carbonic acid is added to
In aqueous solutions of potassium (4kg), under stirring three times (3kg x 3) with toluene extraction, merges organic layer, wash, concentration, residue is added
Normal heptane (1L) stirs half an hour precipitation solid, and the solid of precipitation is collected by filtration, and vacuum drying obtains (R)-praziquantel amine white
Powder (846.3g, 95.6% yield, 99.1%e.e.), 122-123 DEG C of fusing point.
Recycle resolution reagent.Water layer concentrated hydrochloric acid, which is acidified, adjusts pH value less than 2, and methanol, filtering is added in rotary evaporated to dryness
The inorganic salts being precipitated are removed, methanol layer is spin-dried for obtaining solid, and it is white that vacuum drying obtains free chirality (R) -1- phenethyl sulfonic acid
Color 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.) is added, triethylamine (378g,
522mL, 3.75mol, 1.5eq.), methylene chloride (12.4L), ice bath is cooled to 0 DEG C.Ring is added dropwise into this mixture under stirring
Hexane formyl chloride (405g, 369mL, 2.75mol, 1.1eq.) is kept for 0 DEG C of temperature.It is added dropwise, is stirred to react in 20-25 DEG C
16 hours.HPLC tracks fully reacting.With water (1.6L) quenching reaction and continue stirring 45 minutes.Separation organic layer is simultaneously used respectively
Saturated sodium carbonate solution, 0.5N HCl solution and brine It, anhydrous sodium sulfate is dry, and solvent, residue are removed in reduced pressure
It is recrystallized with acetone/n-hexane mixed liquor (5.5L, 1/1, v/v), obtaining 746.6g clear crystal is sterling levo-praziquantel, is received
Rate 95.6%, purity 99.3%, 99.5%ee, 113-115 DEG C of fusing point.
Levo-praziquantel nuclear magnetic data:1H NMR(DMSO-d6, 400MHz, δ ppm): 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 person skilled in the art
Scholar cans understand the content of the present invention and implement it accordingly, and it is not intended to limit the scope of the present invention.It is all according to the present invention
Equivalent change or modification made by Spirit Essence, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of (R)-praziquantel amine salt, it is characterised in that: it is tried with raceme praziquantel amine and chiral resolution
Agent is reacted in a solvent is made (R)-praziquantel amine salt, wherein the chiral selectors are selected from (R)-brufen, (R)-
One of 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 raceme pyrrole quinoline
The molar ratio of ketoamine and the 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
In, the concentration of the 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: the solvent be selected from
One of methanol, ethyl alcohol, water, methyl tertiary butyl ether(MTBE), isopropanol, methylene chloride, toluene are a variety of.
5. the preparation method of (R)-praziquantel amine salt according to claim 1, it is characterised in that: the raceme pyrrole quinoline
Ketoamine reacts (the R)-praziquantel amine for being made described with the chiral selectors in the solvent and alkali compounds
Salt, wherein the alkali compounds is potassium hydroxide or potassium carbonate, the raceme praziquantel amine and the alkalization
The molar ratio for closing object is 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: to anti-
It answers and the raceme praziquantel amine, the chiral selectors, the solvent is added in device, be selectively added alkalinity
Then compound is heated to reactant dissolution at 45 ~ 80 DEG C, be subsequently cooled to solid precipitation, collects precipitating, the precipitating warp
Post-processing obtains (R)-praziquantel amine salt.
7. a kind of preparation method of levo-praziquantel, it is characterised in that: the preparation method includes as appointed in claim 1 to 6
Described in one the step of (R)-praziquantel amine salt, and the levo-praziquantel described by (R)-praziquantel amine salt preparation
The step of.
8. the preparation method of levo-praziquantel according to claim 7, it is characterised in that: by (R)-praziquantel amine
The step of levo-praziquantel described in salt preparation includes being reacted that (R)-praziquantel is made with alkali by (R)-praziquantel amine salt
The step of amine, and by (R)-praziquantel amine come the step of preparing levo-praziquantel.
9. the preparation method of levo-praziquantel according to claim 8, it is characterised in that: (R)-praziquantel amine salt
Be hydrolyzed with acid and react to obtain chiral selectors, the chiral selectors can reuse to lower batch materials production,
Then the alkali is added to be alkalized to obtain (R)-praziquantel amine；
Alternatively, (R)-praziquantel amine salt is hydrolyzed with the alkali reacts to obtain (R)-praziquantel amine, so
Add the acid afterwards and be acidified to obtain chiral selectors, the 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: by (the R)-praziquantel
Amine and hexamethylene formyl chloride react in presence of organic solvent obtains the levo-praziquantel.
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| MX2012009920A (en) * | 2012-08-27 | 2014-02-26 | Univ Nac Autónoma De México | Process for the obtention of praziquantel enantiomers and 4' ûhydroxylated derivatives thereof. |
| CN107001359A (en) * | 2014-11-21 | 2017-08-01 | 默克专利股份有限公司 | The method for preparing praziquantel and its precursor |
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| CN103421007A (en) * | 2013-08-27 | 2013-12-04 | 绍兴民生医药有限公司 | Preparation method for levo-praziquantel |
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| A straightforward and efficient synthesis of praziquantel enantiomers and their 40-hydroxy derivatives;Alberto Cedillo-Cruz et al;《Tetrahedron: Asymmetry》;20131216;第25卷;133-140 |
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