CN103160562A - Method of synthetizing levo-praziquantel - Google Patents
Method of synthetizing levo-praziquantel Download PDFInfo
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Abstract
The invention relates to a novel method of synthetizing levo-praziquantel. High solid, locus and regioselectivity of enzyme are utilized to catalyze chemosynthesis racemic modification or a certain enantiomer of a derivative to conduct dynamic kinetic splitting and producing an optical homochiral levo-praziquantel midbody, and further the levo-praziquantel is obtained through various mature and high-yield conventional organic chemical reactions. The method is mature in process and low in cost, can be used for producing levo-praziquantel in mass, improves quality standard, establishes foundations for creating quality raw material medicine and preparation, and solves the industrial difficulty of purifying praziquantel which is suspended and unsolved for nearly 30 years. Raw materials can be easily obtained, and product purity can be higher than 98%.
Description
Technical field
The present invention relates to the synthetic method of a kind of left-handed praziquantel ((R)-praziquantel).
Background technology
Praziquantel has another name called the ring praziquantel, is the broad-spectrum anti-parasite medicine.Its anthelmintic spectrum is very wide, and Schistosoma japonicum, Schistosoma haematobium, Schistosoma mansoni etc. are all had to killing action.In addition, it also has killing action to paragonimus (lung fluke), clonorchis sinensis, Echinococcus hydatid cyst, cysticercus, Meng Shi pleroceroid, fasciloopsis, tapeworm etc.The effect characteristics of praziquantel are that curative effect is high, short treating period, dosage is little, metabolism is fast, toxicity is little and convenient oral.The appearance of praziquantel is an important breakthrough on the parasitosis chemotherapy, has become the choice drug of the multiple parasitosis for the treatment of now.
Praziquantel is at first synthetic by people such as Seubere in 1975, and German E-merck and Bayer two pharmaceutical factory develops go out this kind of medicine.1980, E-metck company took the lead in going on the market with trade(brand)name Cesol, worldwide widespread use at present.Except for human body, it also is widely used in the parasiticide treatment of animal, poultry etc.Need to use some poisonous, harmful chemical substances in traditional praziquantel production process, as the inferior phenol chlorine of potassium cyanide, hexamethylene etc., and its operational path grows (referring to following formula), and reaction conditions is also harsher.
Recently, the scientific research personnel splits and obtains left-handed praziquantel and dextrorotation praziquantel optical isomer from synthetic praziquantel.And by finding with first clinical trial phase before clinical: left-handed praziquantel is effective insecticidal constituent of praziquantel, and the dextrorotation praziquantel is invalid even objectionable constituent; Under same dose, left-handed praziquantel clinical efficacy is better than praziquantel.Although World Health Organization's expectation replaces praziquantel by left-handed praziquantel, the technique difficult problem that left-handed praziquantel chemosynthesis yield is low is for many years hanged always and is separated.
Summary of the invention
Technical problem to be solved by this invention is to provide the method for the synthetic left-handed praziquantel that a kind of Environmental Safety is good, yield is high.
For solving above technical problem, the present invention takes following technical scheme:
A kind of method of synthetic left-handed praziquantel, the method is taked following synthetic route:
In above formula, described Nitrile hydratase comprises: the Nitrile hydratase that comes from Arabidopis thaliana, come from the Nitrile hydratase of Gramineae, Cruciferae or Musaceae plant, come from the Nitrile hydratase of the fungi of sickle-like bacteria, aspergillus or mould, and come from that Bao Man is motionless, the Nitrile hydratase of the bacterium of comamonas, Cray Bai Shi, pseudomonas, Nocardia bacteria and rhodococcus.
Preferably, described Nitrile hydratase is rhodococcus erythropolis TA37, thermophilic Shi Shi bacillus SC-J05-1 or thermophilic Selective medium JCM3095.
Further, in step (2), make the racemic modification of compound 3d in the damping fluid and solubility promoter of pH7～11, under the effect of Nitrile hydratase, at 10～50 ℃ of temperature, reaction generates described compound 14.
Further, the specific implementation process of step (2) is: in reactor, add compound 3d, damping fluid, solubility promoter, stir, make reaction system add Nitrile hydratase at 10～50 ℃ of temperature, start reaction, reaction system stirs and carries out at 10～50 ℃ of temperature, HPLC monitoring reaction process, stopped reaction while to transformation efficiency, being more than or equal to 99%, salt acid for adjusting pH value the centrifugal zymoprotein that goes, anhydrate through concentrating under reduced pressure, and residuum adds acetone to separate out solid filtering, filter cake obtains white solid product through second alcohol and water recrystallization, is compound 14.
Preferably, described damping fluid is the Tris-HCl damping fluid, and described solubility promoter is one or more the combination be selected from methyl alcohol, ethanol and dimethyl sulfoxide (DMSO).
Preferably, the temperature of step (2) reaction is 20～40 ℃.
Usually, in step (2), described Nitrile hydratase add 1%～10% of quality that quality is described compound 3d.
According to a concrete aspect of the present invention, in step (3): in reactor, add compound 14, triethylamine, methylene dichloride, ice bath is cooled to 0 ℃～2 ℃, under stirring, in this mixture, drips Benzoyl chloride, keeps 0 ℃～2 ℃ of temperature, dropwise, in 20～25 ℃ of lower stirring reactions 6～8 hours, HPLC followed the tracks of reaction process, after reacting completely, water cancellation reaction, and continue to stir 30～40 minutes, separate organic layer, through washing, dry, the concentrating under reduced pressure desolventizing, the residuum ethyl alcohol recrystallization, obtain compound 16.
According to another concrete aspect of the present invention, in step (4): in encloses container, add compound 16 and anhydrous methanol and ruthenium-containing catalyst Ru/C, after the interior air of hydrogen exchange container, pass into hydrogen, be warming up to 90～95 ℃, stirring reaction 16～18 hours, detection reaction is complete, filtering recovering catalyst.Reaction solution is through concentrating under reduced pressure, and residuum obtains faint yellow solid through ethanol and the normal hexane mixed solvent recrystallization that 1:2～4 form by volume, is compound 17.
According to an also concrete aspect of the present invention, in step (5): compound 17, organic solvent and alkaline solution are added in reactor, stir, drip chloroacetyl chloride in this reaction mixture, after dropwising, stirring at room reaction 3～4 hours, the HPLC detection reaction is complete, directly carries out next step reaction; In step (6): in the reaction mixture of step (5), add benzyltriethylammoinium chloride, be heated to 75 ℃～85 ℃, react 1～2 hour, the HPLC detection reaction is complete, remove by filter insolubles, organic solvent layer is successively through washing, after drying, decompression is removed solvent and is obtained crude product, and crude product is obtained to compound 19 with the dehydrated alcohol recrystallization;
According to a concrete aspect of the present invention, step (7) minute following two steps are carried out:
1., make compound 19 under phosphoric acid or hydrochloric acid effect, reaction generates intermediate R-(-)-praziquantel amine;
R-(-)-praziquantel amine
2., make intermediate R-(-)-praziquantel amine and hexanaphthene formyl chloride in solvent, triethylamine exists reaction at 20～25 ℃ of lower and temperature to generate described left-handed praziquantel.
Due to the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
The present invention has lot of advantages by the route of synthesis of biological enzyme, is more suitable for large-scale industrial production.The method is to utilize height solid, site, the regioselectivity of enzyme to come a certain enantiomorph in the synthetic racemic modification of catalytic chemistry or derivative to carry out the Dynamic Kinetic Resolution production left-handed praziquantel intermediate of optical homochiral (R)-type compound 14.The technique of these methods is very ripe, raw material is easy to get, cost is low.Be convenient to scale operation levo form praziquantel, product purity can reach more than 98%, has promoted quality standard, for formulating high quality raw material medicine and preparation, lays the first stone, and has solved thus over nearly 30 years the industrial problem of the left-handed praziquantel separation and purification of high purity of hanging and not separating.
This patent adopts the core technology of its biological enzyme, developed environmental protection, the technique of the chiral synthesis of levorotatory praziquantel that yield is high, for further carry out clinical before and clinically become property of medicine evaluation, the left-handed praziquantel of large-scale industrialized production also enters world market and has paved road.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described in detail, but the present invention is not limited to following examples.
Embodiment 1 takes following route tetrahydrobiopterin synthesis isoquinolinecarbonitrile
Example 1-1: in encloses container, add compound 3c(78.1g, 0.5mol), ethanol (0.7L) and 10% catalyst P d/C (6g); with after air in the hydrogen exchange container, continue to pass into hydrogen (1MPa), be warming up to 30 ℃; stirring reaction 8 hours; detection reaction is complete, filtering recovering catalyst, and reaction solution is through concentrating under reduced pressure; obtain the 74.82g solid chemical compound; be compound 3d(tetrahydroisoquinoline formonitrile HCN), purity 97.6%, yield 94.6%;
Compound 3d nuclear magnetic data:
1h NMR (CDCl
3, 400MHz, δ ppm): 3.06 – 3.10 (m, 2H, CH
2), 3.43 – 3.63 (m, 2H, CH
2), 4.95 (s, 1H, CH), 7.28 – 7.54 (m, 4H, ArH), MS (ESI ,+ve): m/z:159.1[M+H]
+.
Example 1-2: in encloses container, add compound 3c(78.1g, 0.5mol), methyl alcohol (0.7L) and Raney's nickel catalyst (12g); with after air in the hydrogen exchange container; continue to pass into hydrogen (1MPa), 25-30 degree stirring reaction 8 hours, the complete stopped reaction of HPLC detection reaction; filtering recovering catalyst; reaction solution is through concentrating under reduced pressure, and residuum is the 73.95g solid chemical compound, is compound 3d; purity 94.4%, yield 93.5%; Can be directly used in next step reaction without being further purified.
Compound 3d nuclear magnetic data:
1h NMR (CDCl
3, 400MHz, δ ppm): 3.06 – 3.10 (m, 2H, CH
2), 3.43 – 3.63 (m, 2H, CH
2), 4.95 (s, 1H, CH), 7.28 – 7.54 (m, 4H, ArH).
MS(ESI,+ve):m/z:159.1[M+H]
+。
Example 1-3: by compound 3c(78.1g, 0.5mol) join in 1000mL ethanol, add in batches sodium borohydride (19g, 0.5mol), 30-40 degree stirring reaction 16 hours, system becomes clarification.The complete stopped reaction of HPLC detection reaction, organic solvent is removed in underpressure distillation, and residuum dissolves with methylene dichloride, the saturated common salt water washing, the concentrating under reduced pressure desolventizing, obtain 76.0g white solid compound, is compound 3d, yield 96.1%, purity 94.2%.
Compound 3d nuclear magnetic data:
1h NMR (CDCl
3, 400MHz, δ ppm): 3.06 – 3.10 (m, 2H, CH
2), 3.43 – 3.63 (m, 2H, CH
2), 4.95 (s, 1H, CH), 7.28 – 7.54 (m, 4H, ArH), MS (ESI ,+ve): m/z:159.1[M+H]
+.
The synthetic R-type tetrahydroisoquinoline methane amide (compound 14) of embodiment 2
Route is as follows:
Example 2-1: utilize Nitrile hydratase (rhodococcus erythropolis TA37, Rhodococcus erythropolis TA37, purchased from U.S. ATCC strain library) to prepare compound 14
Add compound 3d(158mg, 100mmol in reactor) and Tris-HCl damping fluid (10mL, 0.1mM, pH8.5, containing 1mM DTT), solubility promoter methyl alcohol (0.2mL), stir, reaction system adds Nitrile hydratase (10mg at 25 ℃ of temperature, rhodococcus erythropolis TA37, Rhodococcus erythropolis TA37, purchased from U.S. ATCC strain library) start and react, reaction system stirs and carries out at 25 ℃ of temperature, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 24 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 123.5mg through second alcohol and water recrystallization, and compound 14, yield 70.1%, ee value 91.3%.
Compound 14 nuclear magnetic datas:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]
+。
Example 2-2: in reactor, add compound 3d(39.55mg, 25mmol) and Tris-HCl damping fluid (10mL, 0.1mM, pH9.5, containing 1mM DTT), solubility promoter ethanol (0.1mL), stir, reaction system adds Nitrile hydratase (10mg at 37 ℃ of temperature, rhodococcus erythropolis TA37, Rhodococcus erythropolis TA37, from U.S. ATCC strain library) start and react, reaction system stirs and carries out at 37 ℃ of temperature, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 10 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 39.2mg through second alcohol and water recrystallization, and compound 14, yield 89.1%, ee value 96.5%.
Compound 14 nuclear magnetic datas:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]
+。
Example 2-3: in reactor, add compound 3d(39.55mg, 25mmol) and Tris-HCl damping fluid (10mL, 0.1mM, pH9.5, containing 1mM DTT), solubility promoter DMSO(0.1mL), stir, reaction system adds Nitrile hydratase (10mg at 18 ℃ of temperature, rhodococcus erythropolis TA37, Rhodococcus erythropolis TA37, from U.S. ATCC strain library) start and react, reaction system stirs and carries out at 18 ℃ of temperature, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 16 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 37.7mg through second alcohol and water recrystallization, and compound 14, yield 85.6%, ee value 99.1%.
Compound 14 nuclear magnetic datas:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]
+。
Example 2-4: in reactor, add compound 3d(158mg, 100mmol) with Tris-HCl damping fluid (10mL, 0.1mM, pH10, containing 1mM DTT), solubility promoter methyl alcohol (0.2mL), stir, reaction system adds Nitrile hydratase (10mg at 25 ℃ of temperature, thermophilic Shi Shi bacillus SC-J05-1, thermophilic Bacillus smithii strain SC-J05-1, purchased from U.S. ATCC strain library) start and react, reaction system stirs and carries out at 25 ℃ of temperature, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 28 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 146.4mg through second alcohol and water recrystallization, and compound 14, yield 83.1%, ee value 90.4%.
Compound 14 nuclear magnetic datas:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).MS(ESI,+ve):m/z:177.1[M+H]
+。
Example 2-5: in reactor, add compound 3d(39.55mg, 25mmol) with Tris-HCl damping fluid (10mL, 0.1mM, pH9.5, containing 1mM DTT), solubility promoter ethanol (0.1mL), stir, reaction system adds Nitrile hydratase (10mg at 37 ℃ of temperature, thermophilic Shi Shi bacillus SC-J05-1, thermophilic Bacillus smithii strain SC-J05-1, purchased from U.S. ATCC strain library) start and react, reaction system stirs and carries out at 37 ℃ of temperature, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 12 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 41.2mg through second alcohol and water recrystallization, and compound 14, yield 93.5%, ee value 96.2%.
Compound 14 nuclear magnetic datas:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]
+。
Example 2-6: in reactor, add compound 3d(39.55mg, 25mmol) with Tris-HCl damping fluid (10mL, 0.1mM, pH8.5, containing 1mM DTT), solubility promoter DMSO(0.1mL), stir, reaction system adds Nitrile hydratase (10mg under temperature 45 C, thermophilic Shi Shi bacillus SC-J05-1, thermophilic Bacillus smithii strain SC-J05-1, purchased from U.S. ATCC strain library) start and react, reaction system stirs and carries out under temperature 45 C, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 16 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 40.79mg through second alcohol and water recrystallization, and compound 14, yield 92.6%, ee value 89.1%.
Compound 14 nuclear magnetic datas:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]
+。
Example 2-7: in reactor, add compound 3d(158mg, 100mmol) and Tris-HCl damping fluid (10mL, 0.1mM, pH10, containing 1mM DTT), solubility promoter methyl alcohol (0.2mL), stir, reaction system adds Nitrile hydratase (10mg at 25 ℃ of temperature, thermophilic Selective medium JCM3095, Pseudonocardia thermophila JCM3095, purchased from U.S. ATCC strain library) start and react, reaction system stirs and carries out at 25 ℃ of temperature, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 28 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 120.7mg through second alcohol and water recrystallization, and compound 14, yield 68.5%, ee value 81.8%.
Compound 14 nuclear magnetic datas: 1H NMR (CDCl3,400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]+。
Example 2-8: in reactor, add compound 3d(39.55mg, 25mmol) and Tris-HCl damping fluid (10mL, 0.1mM, pH9.5, containing 1mM DTT), solubility promoter ethanol (0.1mL), stir, reaction system adds Nitrile hydratase (10mg at 37 ℃ of temperature, thermophilic Selective medium JCM3095, Pseudonocardia thermophila JCM3095, purchased from U.S. ATCC strain library) start and react, reaction system stirs and carries out at 37 ℃ of temperature, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 10 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 36.64mg through second alcohol and water recrystallization, and compound 14, yield 83.2%, ee value 96.4%.
Compound 14 nuclear magnetic datas: 1H NMR (CDCl3,400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]+。
Example 2-9: in reactor, add compound 3d(39.55mg, 25mmol) and Tris-HCl damping fluid (10mL, 0.1mM, pH8.5, containing 1mM DTT), solubility promoter DMSO(0.1mL), stir, reaction system adds Nitrile hydratase (10mg under temperature 45 C, thermophilic Selective medium JCM3095, Pseudonocardia thermophila JCM3095, purchased from U.S. ATCC strain library) start and react, reaction system stirs and carries out under temperature 45 C, HPLC monitoring reaction process.Stopped reaction when reaction carries out that transformation efficiency was greater than 99% in 16 hours, salt acid for adjusting pH value the centrifugal zymoprotein that goes.Through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, and filter cake obtains white solid product 40.2mg through second alcohol and water recrystallization, i.e. formula (10) compound, yield 91.2%, ee value 99.0%.
Compound 14 nuclear magnetic datas: 1H NMR (CDCl3,400MHz, δ ppm): 2.03 (brs, 1H), (2.63-2.70 m, 1H), 2.74-2.81 (m, 1H), (2.98 t, J=5.9Hz, 2H), 4.34 (s, 1H), 6.97 (brs, 2H), (7.00-7.02 m, 1H), 7.09-7.11 (m, 2H), 7.40-7.44 (m, 1H).
MS(ESI,+ve):m/z:177.1[M+H]+。
Embodiment 3 takes following route synthetic compound 16
In reactor, add compound 14(4.4g, 25mmol, 1eq.), triethylamine (3.78g, 5.22mL, 37.5mmol, 1.5eq.), methylene dichloride (124mL), ice bath is cooled to 0 ℃.Drip Benzoyl chloride (3.86g, 27.47mmol, 1.1eq.) under stirring in this mixture, keep 0 ℃ of temperature.Dropwise, in 20-25 ℃ of stirring reaction 6-8 hour.HPLC follows the tracks of and reacts completely.Water (16mL) cancellation is reacted and is continued and stirs 30 minutes.Separate organic layer and use respectively saturated sodium carbonate solution, 0.5NHCl solution and salt solution washing, anhydrous sodium sulfate drying, the concentrating under reduced pressure desolventizing, the residuum ethyl alcohol recrystallization, obtain compound 16(6.59g, yield 96%, purity 99%, 99.2%ee).
The nuclear magnetic data of compound 16 is as follows:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.97-3.09 (m, 2H), 3.89-4.02 (m, 2H), 5.95 (s, 1H), 7.08 (brs, 2H), 7.40-7.51 (m, 3H), 7.56-7.64 (m, 2H), 7.78-7.98 (m, 4H).
MS(ESI,+ve):m/z:281.1[M+H]
+。
Embodiment 4 takes following route synthetic compound 17
In encloses container, add compound 16(5.6g, 20mmol) and anhydrous methanol (200mL) and containing ruthenium 5% catalyzer Ru/C(0.5g), after the interior air of hydrogen exchange container, pass into hydrogen (3Mpa), be warming up to 90-95 ℃, stirring reaction 16-18 hour, detection reaction is complete, filtering recovering catalyst.Reaction solution is through concentrating under reduced pressure, and residuum obtains the 4.58g faint yellow solid through ethanol/normal hexane (volume ratio 1:3) recrystallization, is compound 17, yield 86%, and fusing point 125-127 ℃, the ee value is greater than 99%.
The nuclear magnetic data of compound 17 is as follows:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.68-2.76 (m, 1H), 2.88-3.01 (m, 3H), (3.17-3.47 m, 1H), 3.89-4.21 (m, 1H), 4.90-5.15 (m, 1H), (6.91-7.17 m, 2H), 7.56-7.64 (m, 3H), 7.72-8.01 (m, 4H).
MS(ESI,+ve):m/z:267.1[M+H]
+。
Embodiment 5 synthetic compounds 19
Example 5-1: by compound 17(2.7g, 10mmol), toluene (30mL) and 50% sodium hydroxide solution (1.84g, 23mmol) add in reactor, stir, drip chloroacetyl chloride (1.4g in this reaction mixture, 12mmol), dropwise rear stirring at room reaction 3 hours, the HPLC detection reaction is complete.Add benzyltriethylammoinium chloride (22.7mg, 0.1mmol) in reaction mixture, be heated to 80 ℃, reaction 1-2 hour, the HPLC detection reaction is complete.Remove by filter insolubles; toluene layer is successively after water and saturated common salt water washing; anhydrous magnesium sulfate drying; decompression is removed solvent and is obtained crude product; crude product is obtained to the left-handed benzoyl praziquantel of sterling solid 2.73g with the dehydrated alcohol recrystallization, and compound 19, yield 89%; fusing point 128-130 ℃, the ee value is greater than 99%.
The nuclear magnetic data of compound 19 is as follows:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.49-2.53 (m, 1H, CH
2), 2.74-2.70 (m, 1H, CH
2), 2.88-2.78 (m, 2H, CH
2), 3.26 (d, 1H, CH
2), 4.21 (d, 1H, CH
2), 4.37 (dd, 1H, CH
2), 4.82-4.76 (m, 1H, CH
2), 4.97 (dd, 1H, CH), 7.12 (d, 2H, Ar-H), 7.26-7.19 (m, 3H, Ar-H), 7.32 (d, 2H, Ar-H), 7.68 (d, 2H, Ar-H).MS(ESI,+ve):m/z:307.1[M+H]
+。
Example 5-2: by compound 17(2.7g, 10mmol), ethyl acetate (30mL) and potassium tert.-butoxide (2.58g, 23mmol) add in reactor, stir, drip chloroacetyl chloride (1.4g in this reaction mixture, 12mmol), dropwise rear stirring at room reaction 3 hours, the HPLC detection reaction is complete.Add benzyltriethylammoinium chloride (22.7mg, 0.1mmol) in reaction mixture, be heated to back flow reaction 4-5 hour, the HPLC detection reaction is complete.Remove by filter insolubles; ethyl acetate layer is successively after water and saturated common salt water washing; anhydrous magnesium sulfate drying; decompression is removed solvent and is obtained crude product; crude product is obtained to the left-handed benzoyl praziquantel of sterling solid 2.39g with the dehydrated alcohol recrystallization, and compound 19, yield 78%; fusing point 128-130 ℃, the ee value is greater than 99%.
The nuclear magnetic data of compound 19 is as follows:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.49-2.53 (m, 1H, CH
2), 2.74-2.70 (m, 1H, CH
2), 2.88-2.78 (m, 2H, CH
2), 3.26 (d, 1H, CH
2), 4.21 (d, 1H, CH
2), 4.37 (dd, 1H, CH
2), 4.82-4.76 (m, 1H, CH
2), 4.97 (dd, 1H, CH), 7.12 (d, 2H, Ar-H), 7.26-7.19 (m, 3H, Ar-H), 7.32 (d, 2H, Ar-H), 7.68 (d, 2H, Ar-H).MS(ESI,+ve):m/z:307.1[M+H]
+。
Example 5-3: by compound 17(5.4g, 20mmol), ethylene dichloride (50mL) and Anhydrous potassium carbonate (6.5g, 46mmol) add in reactor, stir, drip chloroacetyl chloride (2.8g in this reaction mixture, 24mmol), dropwise post-heating 40-45 ℃ of stirring reaction 5-6 hour, the HPLC detection reaction is complete.Add benzyltriethylammoinium chloride (45.4mg, 0.2mmol) in reaction mixture, be heated to back flow reaction 10-12 hour, the HPLC detection reaction is complete.Remove by filter insolubles; the ethylene dichloride layer is successively after water and saturated common salt water washing; anhydrous magnesium sulfate drying; decompression is removed solvent and is obtained crude product; crude product is obtained to the left-handed benzoyl praziquantel of sterling solid 4.9g with the dehydrated alcohol recrystallization, and compound 19, yield 80%; fusing point 128-130 ℃, the ee value is greater than 99%.
The nuclear magnetic data of compound 19 is as follows:
1h NMR (CDCl
3, 400MHz, δ ppm): 2.49-2.53 (m, 1H, CH
2), 2.74-2.70 (m, 1H, CH
2), 2.88-2.78 (m, 2H, CH
2), 3.26 (d, 1H, CH
2), 4.21 (d, 1H, CH
2), 4.37 (dd, 1H, CH
2), 4.82-4.76 (m, 1H, CH
2), 4.97 (dd, 1H, CH), 7.12 (d, 2H, Ar-H), 7.26-7.19 (m, 3H, Ar-H), 7.32 (d, 2H, Ar-H), 7.68 (d, 2H, Ar-H).MS(ESI,+ve):m/z:307.1[M+H]
+。
The synthetic left-handed praziquantel (compound 12) of embodiment 6
(a) synthetic route is as follows:
Synthesizing of example 6-1 intermediate R-(-)-praziquantel amine (R-(-)-PZQA)
In reactor, add compound 19(15.32g, 50mmol, 1equiv.), phosphoric acid (80mL), in 120 ℃ of lower stirring reactions 3 hours, it is complete that HPLC follows the tracks of detection reaction.Mixture is poured into after being cooled to 0 ℃ in trash ice water (300mL), and water 10% sodium hydroxide is regulated pH value to 12.Methylene dichloride for water layer (3X50mL) extraction.Merge organic layer, drying, concentrated, residuum obtains the 8.9g faint yellow solid with the toluene recrystallization and is intermediate R-(-)-praziquantel amine, yield 88.1%, 123 ℃ of fusing point 122 –, 99.1%ee.
Intermediate R-(-)-praziquantel amine nuclear magnetic data:
1h NMR (CDCl
3, 400MHz, δ ppm): 1.76 (bs, 1H), 2.64 – 3.02 (m, 4H), 3.49 (d, J=17.6,1H), 3.61 (d, 1H), 3.67 (ddd, 1H), 4.69 – 4.85 (m, 2H), 7.04 – 7.20 (m, 4H).
MS(ESI,+ve):m/z:203.1[M+H]
+。
Synthesizing of example 6-2 intermediate R-(-)-praziquantel amine
In reactor, add compound 19(15.32g, 50mmol, 1equiv.), ethanol (130mL), hydrochloric acid (1M, 600mL), be heated to reflux, stirring reaction 28-30 hour, it is complete that HPLC follows the tracks of detection reaction.Mixture is cooled to 0 ℃, and after ethyl acetate (3x50mL) extraction, water 10% sodium hydroxide is regulated pH value to 12, methylene dichloride for water layer (3X50mL) extraction.Merge organic layer and wash with salt solution, anhydrous sodium sulfate drying, concentrated, residuum obtains the 9.4g faint yellow solid with the toluene recrystallization and is intermediate R-(-)-praziquantel amine, yield 93%, 123 ℃ of fusing point 122 –, 99.4%ee.
Intermediate R-(-)-praziquantel amine nuclear magnetic data:
1h NMR (CDCl
3, 400MHz, δ ppm): 1.76 (bs, 1H), 2.64 – 3.02 (m, 4H), 3.49 (d, J=17.6,1H), 3.61 (d, 1H), 3.67 (ddd, 1H), 4.69 – 4.85 (m, 2H), 7.04 – 7.20 (m, 4H).
MS(ESI,+ve):m/z:203.1[M+H]
+。
Synthesizing of the left-handed praziquantel of example 6-3
In reactor, add intermediate R-(-)-praziquantel amine (5.05g, 25mmol, 1eq.), triethylamine (3.78g, 5.22mL, 37.5mmol, 1.5eq.), methylene dichloride (124mL), ice bath is cooled to 0 ℃.Drip hexanaphthene formyl chloride (4.05g, 3.69mL, 27.47mmol, 1.1eq.) under stirring in this mixture, keep 0 ℃ of temperature.Dropwise, in 20-25 ℃ of stirring reaction 16 hours.HPLC follows the tracks of and reacts completely.Water (16mL) cancellation is reacted and is continued and stirs 30 minutes.Separate organic layer and use respectively saturated sodium carbonate solution, 0.5N HCl solution and salt solution washing, anhydrous sodium sulfate drying, concentrating under reduced pressure desolventizing, acetone for residuum/normal hexane mixed solution (55mL, 1/1, v/v) recrystallization, obtain the 7.42g clear crystal and be the left-handed praziquantel of sterling, yield 95%, purity 99.2%, ee99.2%, fusing point 113-115 ℃.
Left-handed praziquantel nuclear magnetic data:
1h NMR (DMSO-d
6, 400MHz, δ ppm): 1.21-1.96 (m, 10H, 5xCH
2), 2.45-2.50 (m, 1H, CH), 2.78-3.05 (m, 4H, CH
2), 4.10 (d, 1H, CH
2), 4.48 (d, 1H, CH
2), 4.79-4.85 (m, 2H, CH
2), 5.20 (d, 1H, CH), 7.12-7.30 (m, 4H, Ar-H).
MS(ESI,+ve):m/z:313.1[M+H]
+。
Above-described embodiment is only explanation technical conceive of the present invention and characteristics, and its purpose is to allow the person skilled in the art can understand content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences that spirit is done according to the present invention change or modify, within all should being encompassed in protection scope of the present invention.
Claims (10)
1. the method for a synthetic left-handed praziquantel, it is characterized in that: the method is taked following synthetic route:
In above formula, described Nitrile hydratase comprises: the Nitrile hydratase that comes from Arabidopis thaliana, come from the Nitrile hydratase of Gramineae, Cruciferae or Musaceae plant, come from the Nitrile hydratase of the fungi of sickle-like bacteria, aspergillus or mould, and come from that Bao Man is motionless, the Nitrile hydratase of the bacterium of comamonas, Cray Bai Shi, pseudomonas, Nocardia bacteria and rhodococcus.
2. the method for synthetic left-handed praziquantel according to claim 1, it is characterized in that: described Nitrile hydratase is rhodococcus erythropolis TA37, thermophilic Shi Shi bacillus SC-J05-1 or thermophilic Selective medium JCM3095.
3. the method for synthetic left-handed praziquantel according to claim 1, it is characterized in that: in step (2), make the racemic modification of compound 3d in the damping fluid and solubility promoter of pH7～11, under the effect of Nitrile hydratase, at 10～50 ℃ of temperature, reaction generates described compound 14.
4. the method for synthetic left-handed praziquantel according to claim 3, it is characterized in that: the specific implementation process of step (2) is: in reactor, add compound 3d, damping fluid, solubility promoter, stir, make reaction system add Nitrile hydratase at 10～50 ℃ of temperature, start reaction, reaction system stirs and carries out at 10～50 ℃ of temperature, HPLC monitoring reaction process, stopped reaction while to transformation efficiency, being more than or equal to 99%, salt acid for adjusting pH value the centrifugal zymoprotein that goes, through concentrating under reduced pressure, anhydrate, residuum adds acetone to separate out solid filtering, filter cake obtains white solid product through second alcohol and water recrystallization, be compound 14.
5. according to the method for the described synthetic left-handed praziquantel of claim 3 or 4, it is characterized in that: described damping fluid is the Tris-HCl damping fluid, and described solubility promoter is one or more the combination be selected from methyl alcohol, ethanol and dimethyl sulfoxide (DMSO).
6. according to the synthetic method of claim 4 or 5 described left-handed praziquantel, it is characterized in that: the temperature of step (2) reaction is 20～40 ℃.
7. according to the synthetic method of claim 4 or 5 described left-handed praziquantel, it is characterized in that: in step (2), described Nitrile hydratase add 1%～10% of quality that quality is described compound 3d.
8. the synthetic method of left-handed praziquantel according to claim 1, it is characterized in that: in step (3): in reactor, add compound 14, triethylamine, methylene dichloride, ice bath is cooled to 0 ℃～2 ℃, drip Benzoyl chloride under stirring in this mixture, keep 0 ℃～2 ℃ of temperature, dropwise, in 20～25 ℃ of lower stirring reactions 6～8 hours, HPLC follows the tracks of reaction process, after reacting completely, water cancellation reaction, and continue to stir 30～40 minutes, separate organic layer, through washing, dry, the concentrating under reduced pressure desolventizing, the residuum ethyl alcohol recrystallization, obtain compound 16.
9. the synthetic method of left-handed praziquantel according to claim 1, it is characterized in that: in step (4): in encloses container, add compound 16 and anhydrous methanol and ruthenium-containing catalyst Ru/C, after the interior air of hydrogen exchange container, pass into hydrogen, be warming up to 90～95 ℃, stirring reaction 16～18 hours, detection reaction is complete, filtering recovering catalyst, reaction solution is through concentrating under reduced pressure, and residuum obtains faint yellow solid through ethanol and the normal hexane mixed solvent recrystallization that 1:2～4 form by volume, is compound 17.
10. the synthetic method of left-handed praziquantel according to claim 1, it is characterized in that: in step (5): compound 17, organic solvent and alkaline solution are added in reactor, stir, drip chloroacetyl chloride in this reaction mixture, after dropwising, stirring at room reaction 3～4 hours, the HPLC detection reaction is complete, directly carries out next step reaction; In step (6): in the reaction mixture of step (5), add benzyltriethylammoinium chloride, be heated to 75 ℃～85 ℃, react 1～2 hour, the HPLC detection reaction is complete, remove by filter insolubles, organic solvent layer is successively through washing, after drying, decompression is removed solvent and is obtained crude product, and crude product is obtained to compound 19 with the dehydrated alcohol recrystallization;
Step (7) minute following two steps are carried out:
1., make compound 19 under phosphoric acid or hydrochloric acid effect, reaction generates intermediate R-(-)-praziquantel amine;
R-(-)-praziquantel amine
2., make intermediate R-(-)-praziquantel amine and hexanaphthene formyl chloride in solvent, triethylamine exists reaction at 20～25 ℃ of lower and temperature to generate described left-handed praziquantel.
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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 |
| CN103539796A (en) * | 2013-10-25 | 2014-01-29 | 田雷 | Preparation method of levo praziquantel as well as intermediate thereof |
| WO2015055126A1 (en) * | 2013-10-17 | 2015-04-23 | 苏州同力生物医药有限公司 | Crystalline levopraziquantel, and preparation method and application thereof |
| CN105237532A (en) * | 2014-12-05 | 2016-01-13 | 苏州同力生物医药有限公司 | L-praziquantel synthesizing method and midbody thereof |
| CN107151245A (en) * | 2016-03-04 | 2017-09-12 | 苏州同力生物医药有限公司 | A kind of preparation method of levo-praziquantel |
| US9802934B2 (en) | 2013-10-17 | 2017-10-31 | Tongli Biomedical Co., Ltd. | Process for the synthesis of (R)-praziquantel |
| TWI650313B (en) * | 2017-09-08 | 2019-02-11 | 財團法人國家衛生研究院 | Heterocyclic compounds and use thereof |
| US10597378B2 (en) | 2017-09-08 | 2020-03-24 | National Health Research Institutes | Tetrahydroisoquinolines for use as MOR/NOP dual agonists |
| WO2022171150A1 (en) * | 2021-02-09 | 2022-08-18 | Tongli Biomedical Co., Ltd. | Methods and pharmaceutical composition for treating diseases |
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| CN103421007B (en) * | 2013-08-27 | 2016-01-20 | 绍兴民生医药有限公司 | A kind of preparation method of levo-praziquantel |
| CN103421007A (en) * | 2013-08-27 | 2013-12-04 | 绍兴民生医药有限公司 | Preparation method for levo-praziquantel |
| US9802934B2 (en) | 2013-10-17 | 2017-10-31 | Tongli Biomedical Co., Ltd. | Process for the synthesis of (R)-praziquantel |
| WO2015055126A1 (en) * | 2013-10-17 | 2015-04-23 | 苏州同力生物医药有限公司 | Crystalline levopraziquantel, and preparation method and application thereof |
| US9657017B2 (en) | 2013-10-17 | 2017-05-23 | Tongli Biomedical Co., Ltd. | Crystal form of (R)-praziquantel and preparation method and application thereof |
| CN103539796B (en) * | 2013-10-25 | 2015-05-20 | 田雷 | Preparation method of levo praziquantel as well as intermediate thereof |
| CN103539796A (en) * | 2013-10-25 | 2014-01-29 | 田雷 | Preparation method of levo praziquantel as well as intermediate thereof |
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| CN107151245B (en) * | 2016-03-04 | 2019-04-05 | 苏州同力生物医药有限公司 | A kind of preparation method of levo-praziquantel |
| TWI650313B (en) * | 2017-09-08 | 2019-02-11 | 財團法人國家衛生研究院 | Heterocyclic compounds and use thereof |
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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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