CN1288886A - Felodipine producing technology - Google Patents
Felodipine producing technology Download PDFInfo
- Publication number
- CN1288886A CN1288886A CN 99120908 CN99120908A CN1288886A CN 1288886 A CN1288886 A CN 1288886A CN 99120908 CN99120908 CN 99120908 CN 99120908 A CN99120908 A CN 99120908A CN 1288886 A CN1288886 A CN 1288886A
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- Prior art keywords
- felodipine
- chlorination
- radiation
- reaction
- toluene
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a new chemical synthesis process of felodipine-calcium antagonist for extensively curing angiocardiopathy. As compared with traditional technological process sand invented new synthesis process can obviously raise synthetic yield, its product composition is purer, and its production cost is relatively reduced.
Description
The present invention relates to a kind of chemical synthesis process of medicine for cardiovascular system, be specifically related to the novel process of the chemosynthesis of felodipine.
The felodipine product is a kind of calcium antagonist of novel therapeutic cardiovascular disorder, clinical application is extensive, because this medical instrument has the arteriole of inhibition unstriated muscle to change the theca cell outflow, selectivity expansion arteriole, but there is not this effect for vein, so do not cause postural hypotension, and will be much larger than to action of the heart for the effect of arteriole unstriated muscle, especially effective to cardiovascular diseases and congestive heart failure that heart function sustains damage.In view of this unique pharmacology of felodipine and minimum side effect, since this medicine listing, more than 20 country is widely used in the treatment high blood pressure disease in the world.
At present, domestic Lip river Horizon manufacturer nothing but still, according to the prior art data, consult the skill water data that Sweden Astra company in 1988 delivers, the said firm utilizes toluene chemosynthesis felodipine technology, and the chemosynthesis time is long, complete sets of Techniques equipment manufacturing cost height, energy consumption is big, and yield is lower, is a kind of common felodipine production technique.
The present invention uses for reference the advantage of its technology, in the chlorination process, use metal Fe to make catalyzer, in the nitration reaction process, use ultrasonic wave to make catalyzer, obtain highly purified felodipine with high yield, technology is better than Astra company felodipine production technique, through international online retrieval, world patent, United States Patent (USP), U.S. chemical abstract, Chinese patent and four kinds of domestic professional digests, all do not send out sight than the effective patent documentation of aforesaid method simple economy, the present invention has filled up the blank of domestic and international this respect.
The object of the present invention is to provide a kind of felodipine chemosynthesis novel process, with shortening, reduce production costs, and yield improves relatively when this method makes the whole production technical process.
The quality standard of main supplementary material: toluene: water white transparency or little yellow liquid, content 〉=95% liquefied ammonia: yellow-green colour oily liquid, chlorine 〉=99.5%, moisture content≤0.06%NaOH: content 〉=30%, technical grade methyl acetoacetate: colourless or weak yellow liquid, content 〉=97% ammoniacal liquor: content 〉=25% ethanol: industrial one-level, content 〉=95.5% yellow soda ash: white crystalline powder, 〉=99.2% sulfuric acid: technical grade, 〉=95% tetracol phenixin: technical grade, 〉=90%
Chemical reaction and technical process: toluene-→ substitution reaction → nitration reaction → cyclization backflow → felodipine
Main consumption of raw and auxiliary materials volume: toluene 3000Kg liquid chlorine 45000KgNaOH 12000Kg etheric acid second fat 55200Kg
Production instance:
1. chlorination: toluene is dropped in the reaction tower, make catalyzer with Fe and feed chlorine, controlled temperature is at-5～0 ℃, and reaction promptly gets dichloro-toluene.
2. nitration reaction: in the nitration reaction jar, dichloro-toluene is heated to 135～140 ℃, feed nitric acid vapor, controlled temperature was ventilated 5 hours at 135～140 ℃, used power to carry out radiation greater than the ultrasonic wave of 20MHz simultaneously, every radiation in 1 hour 10～15 minutes, be cooled to 18～20 ℃, filter, promptly get orthodichlorobenzene base Nitromethane 99Min..
3. chlorination reaction: in the chlorination reaction still, orthodichlorobenzene base Nitromethane 99Min. is dissolved among 2% the NaOH, be cooled to 5～8 ℃, potassium permanganate, magnesium sulfate heptahydrate be dissolved among 2% the NaOH, be cooled to 3～5 ℃, stir two liquid are mixed, left standstill 15 minutes, stir the mixed solution that adds sulfuric acid and methyl alcohol, filtration, washing promptly get orthodichlorobenzene formaldehyde.
4. cyclization refluxes: add orthodichlorobenzene formaldehyde, methyl aceto acetate, ethanol, 2/3 ammoniacal liquor in the ring-closure reaction jar, slowly refluxing added 1/3 remaining ammoniacal liquor 1 hour the time, refluxed 4 hours again, and crystallisation by cooling filters, small amount of ethanol wash the felodipine crude product.The ethanol that crude product is added 7 times of amounts is warmed up to 60 ℃ of thermosols 1 hour, filtered while hot, and filtrate is left standstill, and crystallisation by cooling, filtration drying promptly get makes with extra care felodipine.Its quality standard meets Chinese Pharmacopoeia latest edition standard.
Precaution: 1, chlorine system severe toxicity, choke damp, must be careful during operation, band smoke mask (No. 3 toxin filter apparatuss) is prepared some weak ammonias and is done first aid process.2, pipeline must seal, with anti-leak.As closing total valve in case generation leaks in time to wear a mask, cut off source of the gas, remake and deal carefully with.
Claims (1)
- The invention is characterized in: raw material toluene is made felodipine through chloro, nitrated, chlorination, cyclization back flow reaction.According to claims: the invention is characterized in that nitration reaction uses metallic iron to make catalyzer, chlorination uses ultrasonic wave to make catalyzer, and yield of radiation is 50MHz, and the time was every radiation in 1 hour 10 minutes.According to claims: the crude product felodipine adds 99.5% ethanol of 7 times of amounts, is warmed up to 60 ℃, and thermosol 1.2 hours filters, and leaves standstill crystallization, must make with extra care felodipine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99120908 CN1288886A (en) | 1999-09-21 | 1999-09-21 | Felodipine producing technology |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99120908 CN1288886A (en) | 1999-09-21 | 1999-09-21 | Felodipine producing technology |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1288886A true CN1288886A (en) | 2001-03-28 |
Family
ID=5281710
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99120908 Pending CN1288886A (en) | 1999-09-21 | 1999-09-21 | Felodipine producing technology |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1288886A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012142927A1 (en) * | 2011-04-18 | 2012-10-26 | 合肥贝霓医药科技有限公司 | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
-
1999
- 1999-09-21 CN CN 99120908 patent/CN1288886A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012142927A1 (en) * | 2011-04-18 | 2012-10-26 | 合肥贝霓医药科技有限公司 | Method for purification of calcium channel blockers of dihydropyridine type and preparation of nanoparticles thereof |
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| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |