CN106866663A - A kind of process of praziquantel synthesis - Google Patents
A kind of process of praziquantel synthesis Download PDFInfo
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- CN106866663A CN106866663A CN201710152220.XA CN201710152220A CN106866663A CN 106866663 A CN106866663 A CN 106866663A CN 201710152220 A CN201710152220 A CN 201710152220A CN 106866663 A CN106866663 A CN 106866663A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract
The present invention provides a kind of process of praziquantel synthesis, and β phenyl ethylamines are put into a kettle., and dichloromethane carries out acylation reaction；Stirring cooling, acylation reaction temperature is to less than 0 35 DEG C；Lower pair of reaction solution temperature control is added dropwise chloracetyl chloride and liquid caustic soda, during dropwise addition, control acylation reaction pH value 6 12, insulated and stirred after completion of dropwise addition, layering.The present invention uses one kettle way, and process costs are low, and operating method is simply controllable, and environmental safety is good, product quality stabilization.
Description
Technical field
The present invention relates to a kind of technique for synthesizing praziquantel, belong to medicine and its intermediate technical field.
Background technology
Praziquantel is broad-spectrum anti-parasite medicine, all highly effective to the main snail fever of human body, from 1980 in moral
State takes the lead in after listing, soon as the choice drug for the treatment of snail fever and various parasitic diseases in the world.Praziquantel is asked
Generation is an important breakthrough of parasitic disease treatment, and at present, it has turned into the anti parasitic disease medicine being most widely used in the world
Thing.
Existing synthesis praziquantel technique productions high cost, complex process, yield is low, pollution is big, operate relative risk, the three wastes
The restriction of the factor such as serious is discharged, price is relatively expensive.
The content of the invention
Goal of the invention：In order to overcome above shortcomings in the prior art, it is an object of the invention to provide a kind of technique
Low cost, reaction condition is gentle, and operating method is simply controllable, it is to avoid the use of a large amount of toxic reagents, and environmental safety is good, produces
Quality stabilization, products obtained therefrom meets the synthesis technique of the praziquantel of medicinal requirements.
Technical scheme：A kind of process of praziquantel synthesis, comprises the following steps：
1）β phenyl ethylamines are put into a kettle., and dichloromethane carries out acylation reaction；Stirring cooling, acylation reaction temperature to 0-35
Below DEG C；Lower pair of reaction solution temperature control is added dropwise chloracetyl chloride and liquid caustic soda, during dropwise addition, controls acylation reaction pH value 6-12, is added dropwise
Insulated and stirred after end, layering, obtains intermediate 1；
2）Amino substance will be added in the dichloromethane solution of intermediate 1；Insulation reaction 2.0 hours, carries out condensation reaction, control
Temperature in system, setting-up point is no more than 60-120 DEG C；Vacuum distillation recovery amino substance is extremely steamed without cut and obtains intermediate 2；
3）Intermediate 2, and dichloromethane are put into a kettle., carry out ring-closure reaction；Keep cyclization reaction temperature in reaction bulb
Less than 10-30 DEG C is added dropwise the concentrated sulfuric acid and carries out ring-closure reaction；Obtain intermediate 3；
4）Dropping liquid adjusting PH with base=6-12 in upper step reaction solution；Stirring is cooled to 10-30 DEG C, double drops in this temperature, pH value range
Plus cyclohexanecarbonyl chloride and liquid caustic soda, carry out secondary acylation, insulated and stirred 1.0-3.0 hours；Centrifugation, layering, organic layer is concentrated under reduced pressure
To dry, acetone solution is added, crystallization of then lowering the temperature, centrifugation obtains light brown crude product.
Preferably, preferred 10-20 DEG C of described acylation reaction temperature.
Preferably, the preferred 7-8 of acylation reaction pH.
Preferably, preferred 60-70 DEG C of condensation temp.
Preferably, preferred 10-30 DEG C of ring-closure reaction temperature.
Preferably, the secondary preferred 1.0-2.0h of acylated soaking time.
Preferably, in step 1.2, described organic solvent is the one kind in acetone, methyl alcohol, ethanol, toluene；It is the most excellent
Select acetone.
Preferably, in step 1.2, preferably 3.0 times amounts of times amount of organic solvent.
Preferably, in step 1.2, preferably -5~5 DEG C of recrystallization temperature.
Beneficial effect：
Compared with prior art, the present invention has the advantages that：
1）The present invention prepares praziquantel, yield of praziquantel obtained by the inventive method easy to operate using one kettle way
Height, can reach 60-75%；
2）Reaction condition is gentle, and operating method is simply controllable, it is to avoid the use of a large amount of toxic reagents, and environmental safety is good, produces
Quality stabilization；And suitable for industrialized production, economic worth higher can be created.
Specific embodiment
With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention
Rather than limitation the scope of the present invention.
The present invention is described in further detail by Examples below, but is not limit the scope of the invention.
Embodiment 1：
1.1 put into β phenyl ethylamines 12.g in a kettle.（0.1mol）, dichloromethane 120g, stirring be cooled to less than 0-5 DEG C.Instead
Answer lower pair of hydraulic control temperature that chloracetyl chloride 11.3g is added dropwise（0.1mol）And liquid caustic soda 13.3g（0.1mol）, control ph 6 during dropwise addition,
Insulated and stirred after completion of dropwise addition, layering, obtains praziquantel intermediate 1.
1.2 will add amino substance 10.5g in BK-1 dichloromethane solutions（0.1mol）.Insulation reaction 2.0 hours, control
Temperature is extremely steamed without cut no more than 60 DEG C of vacuum distillations recovery amino substances and obtains praziquantel intermediate 2 in making.
1.3 put into praziquantel intermediate 2, and dichloromethane 120g in a kettle., keep 10-15 DEG C of temperature in reaction bulb
Concentrated sulfuric acid 10.0g is below added dropwise（0.1mol）Carry out ring-closure reaction.Obtain praziquantel intermediate 3.
Dropping liquid adjusting PH with base=6 in reaction solution are walked on 1.4.Stirring is cooled to 10-15 DEG C, double in this temperature, pH value range
Cyclohexanecarbonyl chloride 14.7 is added dropwise（0.1mol）And liquid caustic soda 13.3g（0.1mol）, insulated and stirred 1.0 hours.Centrifugation, layering is organic
Layer is concentrated under reduced pressure into dry, adds acetone 60g dissolving, crystallization of then lowering the temperature, centrifugation to obtain light brown crude product 50.0g, yield：60-
65%。
Embodiment 2：
1.1 put into β phenyl ethylamines 12.g in a kettle.（0.1mol）, dichloromethane 120g, stirring be cooled to less than 0-10 DEG C.Instead
Answer lower pair of hydraulic control temperature that chloracetyl chloride 17.0g is added dropwise（0.15mol）And liquid caustic soda 14.6g（0.11mol）, control ph during dropwise addition
7, insulated and stirred after completion of dropwise addition, layering obtains praziquantel intermediate 1.
1.2 will add amino substance 21.0g in BK-1 dichloromethane solutions（0.2mol）.Insulation reaction 2.0 hours, control
Temperature is extremely steamed without cut no more than 60 DEG C of vacuum distillations recovery amino substances and obtains praziquantel intermediate 2 in making.
1.3 put into praziquantel intermediate 2, and dichloromethane 120g in a kettle., keep 10-20 DEG C of temperature in reaction bulb
Concentrated sulfuric acid 10.0g is below added dropwise（0.1mol）Carry out ring-closure reaction.Obtain praziquantel intermediate 3.
Dropping liquid adjusting PH with base=6 in reaction solution are walked on 1.4.Stirring is cooled to 0-5 DEG C, double drops in this temperature, pH value range
Plus cyclohexanecarbonyl chloride 14.7（0.1mol）And liquid caustic soda 13.3g（0.1mol）, insulated and stirred 1.0 hours.Centrifugation, layering, organic layer
It is concentrated under reduced pressure into dry, adds acetone 60g dissolving, crystallization of then lowering the temperature, centrifugation to obtain light brown crude product 42g, yield：50-55%.
Embodiment 3：
1.1 put into β phenyl ethylamines 12.g in a kettle.（0.1mol）, dichloromethane 120g, stirring be cooled to less than 10-20 DEG C.
Lower pair of reaction solution temperature control is added dropwise chloracetyl chloride 17.0g（0.15mol）And liquid caustic soda 14.6g（0.11mol）, pH is controlled during dropwise addition
Value 7, insulated and stirred after completion of dropwise addition, layering obtains praziquantel intermediate 1.
1.2 will add amino substance 10.5g in BK-1 dichloromethane solutions（0.1mol）.Insulation reaction 2.0 hours, control
Temperature is extremely steamed without cut no more than 100 DEG C of vacuum distillations recovery amino substances and obtains praziquantel intermediate 2 in making.
1.3 put into praziquantel intermediate 2, and dichloromethane 120g in a kettle., keep 10-20 DEG C of temperature in reaction bulb
Concentrated sulfuric acid 10.0g is below added dropwise（0.1mol）Carry out ring-closure reaction.Obtain praziquantel intermediate 3.
Dropping liquid adjusting PH with base=6 in reaction solution are walked on 1.4.Stirring is cooled to 0-5 DEG C, double drops in this temperature, pH value range
Plus cyclohexanecarbonyl chloride 14.7（0.1mol）And liquid caustic soda 13.3g（0.1mol）, insulated and stirred 1.0 hours.Centrifugation, layering, organic layer
It is concentrated under reduced pressure into dry, adds acetone 80g dissolving, crystallization of then lowering the temperature, centrifugation to obtain light brown crude product 45g, yield：50-60%.
Embodiment 5：
Praziquantel is refined：To acetone 150g, activated carbon 1.5g and praziquantel crude product 50g is added in reactor, 30 DEG C are warming up to, protected
After temperature is decolourized, -10-0 DEG C, insulated and stirred crystallization 2 hours are cooled to；Suction filtration, is dried to obtain praziquantel 43.0g, yield：80-
85%。
Example 6：
Praziquantel is refined：To acetone 200g, activated carbon 1.5g and praziquantel crude product 50g is added in reactor, 50 DEG C are warming up to, protected
After temperature is decolourized, -10-0 DEG C, insulated and stirred crystallization 2 hours are cooled to；Suction filtration, is dried to obtain praziquantel 40g, yield：80-85%.
Example 7：
Praziquantel is refined：To acetone 250g, activated carbon 1.5g and praziquantel crude product 50g is added in reactor, 50 DEG C are warming up to, protected
After temperature is decolourized, 0-10 DEG C, insulated and stirred crystallization 2 hours are cooled to；Suction filtration, is dried to obtain praziquantel 35.0g；Yield：70-75%.
Claims (10)
1. the process that a kind of praziquantel synthesizes, it is characterised in that：Comprise the following steps：
(1) the preparation of praziquantel crude product：
1）β phenyl ethylamines are put into a kettle., and dichloromethane carries out acylation reaction；Stirring cooling, acylation reaction temperature to 0-35
Below DEG C；Lower pair of reaction solution temperature control is added dropwise chloracetyl chloride and liquid caustic soda, during dropwise addition, controls acylation reaction pH value 6-12, is added dropwise
Insulated and stirred after end, layering, obtains intermediate 1；
2）Amino substance will be added in the dichloromethane solution of intermediate 1；Insulation reaction 2.0 hours, carries out condensation reaction, control
Temperature in system, setting-up point is no more than 60-120 DEG C；Vacuum distillation recovery amino substance is extremely steamed without cut and obtains intermediate 2；
3）Intermediate 2, and dichloromethane are put into a kettle., carry out ring-closure reaction；Keep cyclization reaction temperature in reaction bulb
Less than 10-30 DEG C is added dropwise the concentrated sulfuric acid and carries out ring-closure reaction, obtains intermediate 3；
4）Dropping liquid adjusting PH with base=6-12 in upper step reaction solution；Stirring is cooled to 10-30 DEG C, double drops in this temperature, pH value range
Plus cyclohexanecarbonyl chloride and liquid caustic soda, carry out secondary acylation, insulated and stirred 1.0-3.0 hours；Centrifugation, layering, organic layer is concentrated under reduced pressure
To dry, acetone solution is added, crystallization of then lowering the temperature, centrifugation obtains light brown crude product；
(2) praziquantel is refined：Organic solvent, activated carbon and praziquantel crude product dry product are measured to adding 3-5 times in reactor, is risen
Temperature is incubated after decolourizing to 30-60 DEG C, cooling crystallization to -10~15 DEG C, insulated and stirred crystallization 2 hours；Suction filtration, is dried to obtain pyrrole
Quinoline ketone fine work.
2. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：Described acylation reaction temperature
It is preferred that 10-20 DEG C.
3. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：The preferred 7-8 of acylation reaction pH.
4. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：The preferred 60-70 of condensation temp
℃。
5. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：Ring-closure reaction temperature is preferred
10-30℃。
6. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：Secondary acylated soaking time is excellent
Select 1.0-2.0h.
7. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：In step 1.2, described has
Machine solvent is the one kind in acetone, methyl alcohol, ethanol, toluene.
8. the process that a kind of praziquantel as claimed in claim 7 synthesizes, it is characterised in that：Described organic solvent is preferred
Acetone.
9. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：In step 1.2, organic solvent
Times amount preferably 3.0 times amount.
10. the process that a kind of praziquantel as claimed in claim 1 synthesizes, it is characterised in that：In step 1.2, crystallization temperature
Preferably -5~5 DEG C of degree.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201710152220.XA CN106866663A (en) | 2017-03-15 | 2017-03-15 | A kind of process of praziquantel synthesis |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201710152220.XA CN106866663A (en) | 2017-03-15 | 2017-03-15 | A kind of process of praziquantel synthesis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336885A (en) * | 2018-11-16 | 2019-02-15 | 周口师范学院 | A kind of preparation method of praziquantel |
| CN111072656A (en) * | 2019-12-31 | 2020-04-28 | 江苏诚信药业有限公司 | Synthetic method of praziquantel |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103739601A (en) * | 2013-12-12 | 2014-04-23 | 江苏诚信制药有限公司 | Method for preparing praziquantel |
| WO2016127350A1 (en) * | 2015-02-12 | 2016-08-18 | 浙江海正药业股份有限公司 | Preparation method for praziquantel and intermediate compounds thereof |
-
2017
- 2017-03-15 CN CN201710152220.XA patent/CN106866663A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103739601A (en) * | 2013-12-12 | 2014-04-23 | 江苏诚信制药有限公司 | Method for preparing praziquantel |
| WO2016127350A1 (en) * | 2015-02-12 | 2016-08-18 | 浙江海正药业股份有限公司 | Preparation method for praziquantel and intermediate compounds thereof |
Non-Patent Citations (1)
| Title |
|---|
| CHOONG SUP KIM ET AL: "Formation of Pyrazinoisoquinoline Ring System by the Tandem Amidoalkylation and N-Acyliminium Ion Cyclization: An Efficient Synthesis of Praziquantel", 《TETRAHEDRON》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109336885A (en) * | 2018-11-16 | 2019-02-15 | 周口师范学院 | A kind of preparation method of praziquantel |
| CN109336885B (en) * | 2018-11-16 | 2021-04-13 | 周口师范学院 | Preparation method of praziquantel |
| CN111072656A (en) * | 2019-12-31 | 2020-04-28 | 江苏诚信药业有限公司 | Synthetic method of praziquantel |
| WO2021135891A1 (en) * | 2019-12-31 | 2021-07-08 | 江苏诚信药业有限公司 | Praziquantel synthesis method |
| CN111072656B (en) * | 2019-12-31 | 2022-11-25 | 江苏诚信药业有限公司 | Praziquantel synthesis method |
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Application publication date: 20170620 |