CN106431980A - Synthesis method of pyrimethamine drug intermediate p-chlorobenzonitrile - Google Patents
Synthesis method of pyrimethamine drug intermediate p-chlorobenzonitrile Download PDFInfo
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- CN106431980A CN106431980A CN201610817126.7A CN201610817126A CN106431980A CN 106431980 A CN106431980 A CN 106431980A CN 201610817126 A CN201610817126 A CN 201610817126A CN 106431980 A CN106431980 A CN 106431980A
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- Prior art keywords
- pyrimethamine
- benzyl chloride
- mass fraction
- solution
- synthetic method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
Abstract
A synthesis method of a pyrimethamine drug intermediate p-chlorobenzonitrile includes the following steps that1.3 mol of p-chlorobenzyl chloride and 0.56 mol of stannous chloride are added to a reaction container provided with a mixer, a thermometer, a reflux condenser and a dropping funnel, the stirring speed is controlled to be 130-160 rpm, the solution temperature rises to 90-95 DEG C, 1.5-1.7 mol of cyanamide is slowly added, the dropwise adding time is controlled to be 1-2 hours, stirring reaction continues for 4-5 hours, the solution temperature is reduced to 10-15 DEG C, 230 ml of sodium chloride solution is added, a water layer is removed, an oil layer is washed with a salt solution, acetonitrile washing is performed, reduced pressure distillation is performed, a fraction recrystallizes in ethyl acetate to obtain the crystal p-chlorobenzonitrile, wherein the mass fraction of the sodium chloride solution in the step is 15-20%, and the salt solution in the step is any one of potassium bromide and sodium nitrate.
Description
Technical field
The present invention relates to a kind of synthetic method to benzyl chloride nitrile for pyrimethamine pharmaceutical intermediate.
Background technology
Pyrimethamine has inhibitory action to the Exoerythrocytic Stage of some malignant malarias and Plasmodium vivax, the inhibitory action to erythrocytic stage
It is only limitted to immature schizont phase, the division of trophozoite can be suppressed.Blood-stage Plasmodium can not be using appearance in environment
Folic acid, and must voluntarily synthesize, pyrimethamine is the inhibitor of dihyrofolate reductase, makes dihydrofoilic acid can not be reduced to tetrahydrochysene
Folic acid, and then affect the biosynthesis of purine and pyrimidine nucleotide, so that nucleic acid synthesis is reduced, make nuclear division and malaria
The breeding of protozoon is suppressed.Plasmodial DNA synthesis occurs mainly in the trophozoite stage, synthesizes very few in the schizont phase, therefore
Pyrimethamine mainly acts on the plasmodium carrying out schizogony, then invalid to full schizont.In intestines after oral
Road absorbs relatively slow but completely, in 6 hours, PC reaches peak, and its anti-folic acid acts on sustainable more than 48 hours.Main point
It is distributed in the organ such as red, leucocyte and lung, liver,kidney,spleen.This product can pass through placenta, slowly discharges through kidney.5～7 days after medication
The original shape thing that inside there are about 10%～20% is discharged from urinate, sustainable more than 30 days.This product also can be discharged by milk.T1/2 β is
80～100 hours.When PC is 10～100mg/L, schizont in the blood of plasmodium falciparum sensitive strain can be suppressed.To benzyl chloride
As pyrimethamine pharmaceutical intermediate, its synthetic method quality, for improving pharmaceutical synthesis product quality, reduces accessory substance and contains nitrile
Measurer has Important Economic meaning.
Content of the invention
It is an object of the invention to provide a kind of synthetic method to benzyl chloride nitrile for pyrimethamine pharmaceutical intermediate, including as follows
Step：
I (), in the reaction vessel being provided with agitator, thermometer, reflux condenser, dropping funel, adds to benzyl chloride
(2) 1.3mol, stannous chloride 0.56mol, control mixing speed in 130 160rpm, raise solution temperature to 90--95 DEG C, delay
Slow addition cyanamide (3) 1.5 1.7mol, time for adding controls in 1 2h, continues stirring reaction 4 5h, reduces solution temperature extremely
10--15 DEG C, add sodium chloride solution 230ml, branch vibration layer, oil reservoir brine, acetonitrile washs, vacuum distillation, cut
Ethyl acetate recrystallizes, obtains crystal to benzyl chloride nitrile (1)；
Wherein, the sodium chloride solution mass fraction described in step (i) is 15 20%, and the salting liquid described in step (i) is
Any one in KBr, sodium nitrate, the acetonitrile mass fraction described in step (i) is 75 80%, subtracting described in step (i)
Pressure residing for pressure distillation is 1.7 1.8kPa, and the ethyl acetate mass fraction described in step (i) is 90 95%.
Whole course of reaction can use following reaction equation to represent：
The invention has the advantages that：Decrease the intermediate link of reaction, reduce reaction temperature and reaction time, improve anti-
Answer yield.
Specific embodiment
With reference to being embodied as example, the invention will be further described：
A kind of synthetic method to benzyl chloride nitrile for pyrimethamine pharmaceutical intermediate
Example 1：
In the reaction vessel being provided with agitator, thermometer, reflux condenser, dropping funel, add to benzyl chloride (2)
1.3mol, stannous chloride 0.56mol, control mixing speed in 130rpm, raise solution temperature to 90 DEG C, are slowly added to cyanamide
(3) 1.5mol, time for adding controls in 1h, continues stirring reaction 4h, reduces solution temperature to 10 DEG C, and addition mass fraction is
15% sodium chloride solution 230ml, branch vibration layer, oil reservoir is washed with potassium bromide solution, and mass fraction is 75% acetonitrile washing,
1.7kPa vacuum distillation, cut is to recrystallize in 90% ethyl acetate in mass fraction, obtains crystal to benzyl chloride nitrile 165.98g, receives
Rate 84%.
Example 2：
In the reaction vessel being provided with agitator, thermometer, reflux condenser, dropping funel, add to benzyl chloride (2)
1.3mol, stannous chloride 0.56mol, control mixing speed in 140rpm, raise solution temperature to 92v, are slowly added to cyanamide (3)
1.6mol, time for adding controls in 1h, continues stirring reaction 4h, reduces solution temperature to 13 DEG C, adds mass fraction to be 17%
Sodium chloride solution 230ml, branch vibration layer, oil reservoir is washed with sodium nitrate solution, and mass fraction is 77% acetonitrile washing, and 1.7kPa subtracts
Pressure distillation, cut is to recrystallize in 92% ethyl acetate in mass fraction, obtains crystal to benzyl chloride nitrile 171.91g, yield 87%.
Example 3：
In the reaction vessel being provided with agitator, thermometer, reflux condenser, dropping funel, add to benzyl chloride (2)
1.3mol, stannous chloride 0.56mol, control mixing speed in 160rpm, raise solution temperature to 95 DEG C, are slowly added to cyanamide
(3) 1.7mol, time for adding controls in 2h, continues stirring reaction 5h, reduces solution temperature to 15 DEG C, and addition mass fraction is
20% sodium chloride solution 230ml, branch vibration layer, oil reservoir is washed with potassium bromide solution, and mass fraction is 80% acetonitrile washing,
1.8kPa vacuum distillation, cut is to recrystallize in 95% ethyl acetate in mass fraction, obtains crystal to benzyl chloride nitrile 179.82g, receives
Rate 91%.
Claims (4)
1. a kind of pyrimethamine pharmaceutical intermediate to the synthetic method of benzyl chloride nitrile it is characterised in that comprising the steps：I () exists
It is provided with the reaction vessel of agitator, thermometer, reflux condenser, dropping funel, add to benzyl chloride (2) 1.3mol, chlorination
Stannous 0.56mol, control mixing speed in 130 160rpm, raise solution temperature to 90--95 DEG C, are slowly added to cyanamide (3)
1.5 1.7mol, time for adding controls in 1 2h, continues stirring reaction 4 5h, reduces solution temperature to 10--15 DEG C, adds
Sodium chloride solution 230ml, branch vibration layer, oil reservoir brine, acetonitrile washs, vacuum distillation, and cut is in ethyl acetate
Recrystallization, obtains crystal to benzyl chloride nitrile (1)；Wherein, the sodium chloride solution mass fraction described in step (i) is 15 20%, step
I the salting liquid described in () is KBr, any one in sodium nitrate.
2. according to claim 1 a kind of pyrimethamine pharmaceutical intermediate to the synthetic method of benzyl chloride nitrile it is characterised in that step
Suddenly the acetonitrile mass fraction described in (i) is 75 80%.
3. according to claim 1 a kind of pyrimethamine pharmaceutical intermediate to the synthetic method of benzyl chloride nitrile it is characterised in that step
Suddenly pressure residing for the vacuum distillation described in (i) is 1.7 1.8kPa.
4. according to claim 1 a kind of pyrimethamine pharmaceutical intermediate to the synthetic method of benzyl chloride nitrile it is characterised in that step
Suddenly the ethyl acetate mass fraction described in (i) is 90 95%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2016102261A AU2016102261A4 (en) | 2015-12-24 | 2016-12-23 | Pyrimethamine drug intermediates chloro benzonitrile synthesis method |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015109959140 | 2015-12-24 | ||
| CN201510995914.0A CN105439900A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of pyrimethamine drug intermediate p-chlorobenzonitrile |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106431980A true CN106431980A (en) | 2017-02-22 |
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510995914.0A Pending CN105439900A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of pyrimethamine drug intermediate p-chlorobenzonitrile |
| CN201610817126.7A Pending CN106431980A (en) | 2015-12-24 | 2016-09-12 | Synthesis method of pyrimethamine drug intermediate p-chlorobenzonitrile |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510995914.0A Pending CN105439900A (en) | 2015-12-24 | 2015-12-24 | Synthesis method of pyrimethamine drug intermediate p-chlorobenzonitrile |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN105439900A (en) |
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2015
- 2015-12-24 CN CN201510995914.0A patent/CN105439900A/en active Pending
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2016
- 2016-09-12 CN CN201610817126.7A patent/CN106431980A/en active Pending
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| Publication number | Publication date |
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| CN105439900A (en) | 2016-03-30 |
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| PB01 | Publication | ||
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| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170222 |