CN106397375A - Synthesis method of furpromide drug intermediate 2-furanacrylic acid - Google Patents
Synthesis method of furpromide drug intermediate 2-furanacrylic acid Download PDFInfo
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- CN106397375A CN106397375A CN201610824139.7A CN201610824139A CN106397375A CN 106397375 A CN106397375 A CN 106397375A CN 201610824139 A CN201610824139 A CN 201610824139A CN 106397375 A CN106397375 A CN 106397375A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A synthesis method of a furpromide drug intermediate 2-furanacrylic acid includes the steps of adding 3.1 mol of 2-furan chloromethanol solution (2), 3.6-3.9 mol of propanedioic acid solution (3) and 300 ml of nitroethane into a reactor provided with a stirrer and a reflux condenser, controlling a stirring speed at 130-170 rpm, increasing the solution temperature to 70-75 DEG C, performing refluxing for 5-8 hours, decreasing the solution temperature to 8-13 DEG C, adding 310 ml of sodium bromide solution and 200 ml of potassium bisulfite solution, reacting for 90-120 minutes, standing for 3-6 hours, separating out solids, filtering, conducting saline solution washing, methylbenzene washing and ethanediamine washing and dehydration by a dehydrating agent and recrystallizing in propionitrile so as to obtain a crystal, namely the 2-furanacrylic acid.
Description
Technical field
The present invention relates to a kind of synthetic method of furapromide pharmaceutical intermediate 2- furylacrylic acid.
Background technology
Furapromide indication is to be mainly used in schistosomiasis japanica it can also be used to fasciolopsiasis buski, and this product is nitrofuran
Class non-antimony agent is administered orally antischistosomal, has the glycometabolic effect of interference schistosomicide so as to body flesh and sucker defunctionalization, with
Blood flow enters liver and besieged disappearance.There is special antipyretic effect to Patients With Acute Schistosomiasis, but alone curative effect is poor.Mouthful
Clothes absorb rapid, and mainly in intestinal absorption, after entering liver, major part is metabolized rapidly, and metabolite and original shape medicine are by urinating row
Let out, the metabolite such as yellow furapromide can be detected in urine within 15 minutes, 4～6 hours excretions at most, are arranged in 12 hours urine
Let out totally.To the heart, liver no obvious damage in therapeutic dose, untoward reaction mainly has the gastrointestinal tract disease such as inappetence, Nausea and vomiting
Shape.Occasionally have blood in stool and the reaction such as sural spasm, small number of patients may occur in which mental disorder, shows as hypomnesis, emotion is lost
Often, dystropy etc., recovers normal after drug withdrawal.2- furylacrylic acid as furapromide pharmaceutical intermediate, its synthetic method
Quality, for improving pharmaceutical synthesis product quality, reduces by-products content and has Important Economic meaning.
Content of the invention
It is an object of the invention to provide a kind of synthetic method of furapromide pharmaceutical intermediate 2- furylacrylic acid, including
Following steps：
I (), in the reaction vessel being provided with agitator, reflux condenser, adds 2- furan chloromethane alcoholic solution (2)
3.1mol, malonic acid solution (3) 3.6 3.9mol, nitroethane 300ml, control mixing speed 130 170rpm, raise molten
To 70--75 DEG C, flow back liquid temp 5 8h, reduces solution temperature to 8--13 DEG C, adds 310ml sodium bromide solution, 200ml is sub-
Potassium hydrogen sulfate solution, reacts 90 120min, stands 3 6h, separates out solid, filters, brine, and toluene washs, second two
Amine washs, and dehydrant is dehydrated, and recrystallization in propionitrile obtains crystal 2- furylacrylic acid (1)；Wherein, the 2- furan described in step (i)
Chloromethane alcoholic solution mass fraction of muttering is 70 76%, and the malonic acid liquid quality fraction described in step (i) is 80 87%, step
I the nitroethane mass fraction described in () is 60 66%, the sodium bromide solution mass fraction described in step (i) is 30
35%, the Potassium acid sulfite liquid quality fraction described in step (i) is 40 45%, and the saline solution described in step (i) is bromination
Any one in ammonium, potassium iodide, the toluene mass fraction described in step (i) is 70 75%, the ethylenediamine described in step (i)
Mass fraction is 85 90%, and the dehydrant described in step (i) is activated alumina, any one in natrium carbonicum calcinatum, step
Suddenly the propionitrile mass fraction described in (i) is 91 98%.
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 response 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 of furapromide pharmaceutical intermediate 2- furylacrylic acid
Example 1：
In the reaction vessel being provided with agitator, reflux condenser, addition mass fraction is 70%2- furan chloromethane alcohol
Solution (2) 3.1mol, mass fraction is 80% malonic acid solution (3) 3.6mol, and mass fraction is 60% nitroethane 300ml,
Control mixing speed 130rpm, raise solution temperature to 70 DEG C, flow back 5h, reduce solution temperature to 8 DEG C, add 310ml mass
Fraction is 30% sodium bromide solution, and 200ml mass fraction is 40% bisulfite potassium solution, reacts 90min, stands 3h, separates out
Solid, filters, and ammonium bromide solution washs, and mass fraction is 70% toluene washing, and mass fraction is 85% ethylenediamine washing, activity
Alumina dehydration, is recrystallization in 91% propionitrile in mass fraction, obtains crystal 2- furylacrylic acid 355.07g, yield 83%.
Example 2：
In the reaction vessel being provided with agitator, reflux condenser, addition mass fraction is 73%2- furan chloromethane alcohol
Solution (2) 3.1mol, mass fraction is 82% malonic acid solution (3) 3.8mol, and mass fraction is 63% nitroethane 300ml,
Control mixing speed 140rpm, raise solution temperature to 72 DEG C, flow back 6h, reduce solution temperature to 10 DEG C, add 310ml mass
Fraction is 32% sodium bromide solution, and 200ml mass fraction is 42% bisulfite potassium solution, reacts 110min, stands 5h, separates out
Solid, filters, and liquor kalii iodide washs, and mass fraction is 72% toluene washing, and mass fraction is 87% ethylenediamine washing, anhydrous
Sodium carbonate is dehydrated, and is recrystallization in 97% propionitrile in mass fraction, obtains crystal 2- furylacrylic acid 367.91g, yield 86%.
Example 3：
In the reaction vessel being provided with agitator, reflux condenser, addition mass fraction is 76%2- furan chloromethane alcohol
Solution (2) 3.1mol, mass fraction is 87% malonic acid solution (3) 3.9mol, and mass fraction is 66% nitroethane 300ml,
Control mixing speed 170rpm, raise solution temperature to 75 DEG C, flow back 8h, reduce solution temperature to 13 DEG C, add 310ml mass
Fraction is 35% sodium bromide solution, and 200ml mass fraction is 45% bisulfite potassium solution, reacts 120min, stands 6h, separates out
Solid, filters, and ammonium bromide solution washs, and mass fraction is 75% toluene washing, and mass fraction is 90% ethylenediamine washing, activity
Alumina dehydration, is recrystallization in 98% propionitrile in mass fraction, obtains crystal 2- furylacrylic acid 389.30g, yield 91%.
Claims (5)
1. a kind of synthetic method of furapromide pharmaceutical intermediate 2- furylacrylic acid is it is characterised in that comprise the steps：
I (), in the reaction vessel being provided with agitator, reflux condenser, adds 2- furan chloromethane alcoholic solution (2) 3.1mol, malonic acid
Solution (3) 3.6 3.9mol, nitroethane 300ml, control mixing speed 130 170rpm, rising solution temperature to 70--75
DEG C, flow back 5 8h, reduces solution temperature to 8--13 DEG C, addition 310ml sodium bromide solution, 200ml bisulfite potassium solution, instead
Answer 90 120min, stand 3 6h, separate out solid, filter, brine, toluene washs, ethylenediamine washs, dehydrant takes off
Water, recrystallization in propionitrile, obtain crystal 2- furylacrylic acid (1)；Wherein, the 2- furan chloromethane alcoholic solution matter described in step (i)
Amount fraction is 70 76%, and the malonic acid liquid quality fraction described in step (i) is 80 87%, the nitro described in step (i)
Ethane mass fraction is 60 66%, and the sodium bromide solution mass fraction described in step (i) is 30 35%, and step (i) is described
Potassium acid sulfite liquid quality fraction be 40 45%, the saline solution described in step (i) is ammonium bromide, any in potassium iodide
A kind of.
2. a kind of synthetic method of furapromide pharmaceutical intermediate 2- furylacrylic acid according to claim 1, its feature exists
In the toluene mass fraction described in step (i) is 70 75%.
3. a kind of synthetic method of furapromide pharmaceutical intermediate 2- furylacrylic acid according to claim 1, its feature exists
In the ethylenediamine mass fraction described in step (i) is 85 90%.
4. a kind of synthetic method of furapromide pharmaceutical intermediate 2- furylacrylic acid according to claim 1, its feature exists
In, the dehydrant described in step (i) be activated alumina, any one in natrium carbonicum calcinatum.
5. a kind of synthetic method of furapromide pharmaceutical intermediate 2- furylacrylic acid according to claim 1, its feature exists
In the propionitrile mass fraction described in step (i) is 91 98%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2016102195A AU2016102195A4 (en) | 2015-12-23 | 2016-12-23 | Furan propylamine drug intermediates 2-furan acrylic acid synthesis method |
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|---|---|---|---|
| CN201510981741.7A CN105439996A (en) | 2015-12-23 | 2015-12-23 | Synthesis method of furapromide drug intermediate 2-furfuracrylic acid |
| CN2015109817417 | 2015-12-23 |
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| CN201610824139.7A Pending CN106397375A (en) | 2015-12-23 | 2016-09-17 | Synthesis method of furpromide drug intermediate 2-furanacrylic acid |
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Application publication date: 20170215 |