CN104817518A - Optimized chlormezanone synthesis method - Google Patents
Optimized chlormezanone synthesis method Download PDFInfo
- Publication number
- CN104817518A CN104817518A CN201410485798.3A CN201410485798A CN104817518A CN 104817518 A CN104817518 A CN 104817518A CN 201410485798 A CN201410485798 A CN 201410485798A CN 104817518 A CN104817518 A CN 104817518A
- Authority
- CN
- China
- Prior art keywords
- chlormezanone
- toluene
- crude product
- reaction
- methylamine
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to the field of medicinal chemistry, and specifically relates to an optimized chlormezanone synthesis method. The method provided by the invention comprises the following steps: (1) in a toluene solvent, p-chlorobenzaldehyde and methylamine are subjected to a reaction under the catalysis of a catalyst, such that p-chlorobenzylidene methylamine is produced; (2) p-chlorobenzylidene methylamine and 3-mercaptopropionic acid are subjected to a condensation dehydration reaction in toluene, such that a cyclized compound is obtained; (3) the cyclized compound is oxidized in an acidic potassium permanganate water solution, such that a chlormezanone crude product is produced; and (4) the chlormezanone crude product is re-crystallized with anhydrous ethanol, such that a white crystalline powdery solid which is a chlormezanone refined product is obtained. The method provided by the invention has the advantages of low cost, high yield, high finished product purity, and simple operation.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of preparation method of chlormezanone.
Background technology
Chlormezanone, chemical name is: 3-methyl-2-2-(4-chloro-phenyl-) first hydrogen-3-4H-1,3-thiazine-4-ketone-1,1-dioxide, molecular formula: C11H12CINO3S, molecular weight: 273.7399, former name: chlomezanone, structural formula:
Chlormezanone is stress, fear, moderate anxiety, confirmed fatigue and the agitation insomnia etc. that caused by anxiety, excitement and some disease; Its mechanism of action may be suppress Subcortex cynapse reflection; Site of action mainly at positions such as thalamus, basal ganglia, cerebral limbic system, formatio reticularis mesencephalis, on vegetative nerve without impact; Also without adrenolytic and cholinolytic effect, the recycle system is had no significant effect; The restraining effect of this product to single synapses reflection of spinal cord is very little, obvious to multiple synapses reflection restraining effect, thus presents central myorelaxant effects; The emotional state not having the moderate anxiety of Consciousness degree obstacle can be improved.
The synthetic route of current chlormezanone only has one: in benzene solvent, and 4-chloro-benzaldehyde and the reaction of methylamine reflux dewatering, after reaction terminates, add 3-thiohydracrylic acid, continue dehydration reaction, reaction terminates to reclaim benzene, concentrated solution is oxidized in sulfuric acid and potassium permanganate solution, generates chlormezanone.The method use toxic solvents benzene, be not easy to operation; 4-chloro-benzaldehyde and methylamine be reflux dewatering reaction in benzene, and the reaction times is very long, low conversion rate, and side reaction is many; In the oxidation reaction, with the potassium permanganate solution of sulfuric acid, destroy serious to product structure, productive rate is low, and by product is many, and quality product is bad.
Therefore, the synthetic method of Low-cost, high yield, highly purified chlormezanone becomes current one needs.
Summary of the invention
The object of the invention is in view of the foregoing defects the prior art has, the chlormezanone synthetic method of a kind of low cost, high yield, highly purified optimization is provided.
The inventive method comprises the step of following order:
(1) 4-chloro-benzaldehyde is added to fills in the container of toluene, under whipped state, add catalyzer, below 20 DEG C, pass into dry methylamine gas.After ventilation terminates, react 3 hours below 20 DEG C, after reaction terminates, suction filtration, reclaim under reduced pressure toluene, to completely, obtains p-chlorobenzal base methylamine crude product;
(2) in the container that water trap is housed, p-chlorobenzal base methylamine and 3-thiohydracrylic acid in toluene solvent, back flow reaction 5 hours, the water generated in reaction process separates through water trap, after reaction terminates, is down to normal temperature, add a certain amount of water, under whipped state, adjust pH value to alkalescence with ammoniacal liquor, separate aqueous phase, wash organic phase again with water once, separate aqueous phase, reclaim under reduced pressure toluene, to completely, obtains cyclocomplex crude product;
(3) in the potassium permanganate solution of Glacial acetic acid, slowly drip cyclocomplex, temperature controls below 20 DEG C, after dropwising, stir 3 hours under normal temperature, then use the potassium permanganate that bisulfite sodium reduction unreacted is complete, add chloroform extraction, organic phase washed with water is washed till neutrality, recycling design is to complete, add dehydrated alcohol, under agitation crystallization, obtain chlormezanone crude product;
(4) chlormezanone crude product and gac are added in dehydrated alcohol, reflux 1 hour, suction filtration gac, filtrate decrease temperature crystalline, suction filtration, dry, obtain chlormezanone highly finished product.
Chlormezanone synthetic method of the present invention, synthetic route is shown below:
The present invention is solvent with toluene, and avoiding with benzene is the toxicity of solvent, brings conveniently to operation; With catalyzer, reduce reaction conditions, just obtain high conversion at normal temperatures; Use the potassium permanganate solution of Glacial acetic acid, cyclocomplex is oxidized under comparatively gentle condition, improves yield; Refine with dehydrated alcohol, obtaining finished product purity is 99.3%.
Specific implementation method
Below in conjunction with specific experiment example, the present invention is described in further detail.
Embodiment 1:
(1) 4-chloro-benzaldehyde 50g is added to fills in the 1000ml there-necked flask of 250g toluene, under whipped state, add catalyzer 10 grams, pass into dry methylamine gas at 20 ~ 30 DEG C and be about 20g.After ventilation terminates, 20 ~ 30 DEG C of reactions 3 hours, after reaction terminates, suction filtration, reclaim under reduced pressure toluene is to complete, and obtain p-chlorobenzal base methylamine crude product 60g, content 83%, yield is 92%;
(2) in the 1000ml there-necked flask that water trap is housed, toluene 400g is added, p-chlorobenzal base methylamine crude product 60g and 3-thiohydracrylic acid 42g, back flow reaction 5 hours, the water generated in reaction process separates through water trap, after reaction terminates, be down to normal temperature, add the water of 300g, under whipped state, adjust pH value to alkalescence with ammoniacal liquor, separate aqueous phase, then wash organic phase with water once, separate aqueous phase, reclaim under reduced pressure toluene, to completely, obtains cyclocomplex crude product 80g, content 87%, yield is 89%;
(3) in the there-necked flask of 2000ml, add Glacial acetic acid 240g, deionized water 1000g, potassium permanganate 80g, after stirring and dissolving, slowly drips cyclocomplex, temperature controls below 20 DEG C, after dropwising, stir 3 hours under normal temperature, then with the potassium permanganate that sodium bisulfite 75g reduction unreacted is complete, add chloroform 800g to extract, organic phase washed with water is washed till neutrality, and recycling design, to completely, adds dehydrated alcohol 160g, under agitation crystallization, obtain chlormezanone crude product 68g, content 95%, yield is 83%;
(4) in the there-necked flask of 500ml, add chlormezanone crude product 68g and gac 5g dehydrated alcohol 200g, reflux 1 hour, suction filtration gac, filtrate decrease temperature crystalline, suction filtration, dry, obtain chlormezanone highly finished product 58g, purity 99.3%, yield is 85%.
Claims (5)
1. the chlormezanone synthetic method optimized, is characterized in that the step comprising following order:
(1) 4-chloro-benzaldehyde is added to fills in the container of toluene, under whipped state, add catalyzer, below 20 DEG C, pass into dry methylamine gas.After ventilation terminates, react 3 hours below 20 DEG C, after reaction terminates, suction filtration, reclaim under reduced pressure toluene, to completely, obtains p-chlorobenzal base methylamine crude product;
(2) in the container that water trap is housed, p-chlorobenzal base methylamine and 3-thiohydracrylic acid in toluene solvent, back flow reaction 5 hours, the water generated in reaction process separates through water trap, after reaction terminates, is down to normal temperature, add a certain amount of water, under whipped state, adjust pH value to alkalescence with ammoniacal liquor, separate aqueous phase, wash organic phase again with water once, separate aqueous phase, reclaim under reduced pressure toluene, to completely, obtains cyclocomplex crude product;
(3) in the potassium permanganate solution of Glacial acetic acid, slowly drip cyclocomplex, temperature controls below 20 DEG C, after dropwising, stir 3 hours under normal temperature, then use the potassium permanganate that bisulfite sodium reduction unreacted is complete, add chloroform extraction, organic phase washed with water is washed till neutrality, recycling design is to complete, add dehydrated alcohol, under agitation crystallization, obtain chlormezanone crude product;
(4) chlormezanone crude product and gac are added in dehydrated alcohol, reflux 1 hour, suction filtration gac, filtrate decrease temperature crystalline, suction filtration, dry, obtain chlormezanone highly finished product.
2. according to claim 1, in step (1), it is characterized in that: solvent is toluene, react under the catalysis of catalyzer, react between less than 20 DEG C.
3. according to claim 1, in step (2), it is characterized in that: dehydrated solvent is toluene; After reaction terminates, wash reaction solution with the aqueous solution of ammonia.
4. according to claim 1, in step (3), it is characterized in that: the acid that the acid potassium permanganate aqueous solution is selected is Glacial acetic acid; After reaction terminates, use chloroform extraction.
5. according to claim 1, in step (4), it is characterized in that: refining solvent selects dehydrated alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410485798.3A CN104817518A (en) | 2014-09-23 | 2014-09-23 | Optimized chlormezanone synthesis method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410485798.3A CN104817518A (en) | 2014-09-23 | 2014-09-23 | Optimized chlormezanone synthesis method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104817518A true CN104817518A (en) | 2015-08-05 |
Family
ID=53728019
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410485798.3A Pending CN104817518A (en) | 2014-09-23 | 2014-09-23 | Optimized chlormezanone synthesis method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104817518A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114044762A (en) * | 2021-11-24 | 2022-02-15 | 广州隽沐生物科技股份有限公司 | Preparation method of chlormezanone intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB815203A (en) * | 1956-07-20 | 1959-06-17 | Sterling Drug Inc | Substituted-4-metathiazanones |
| US3082209A (en) * | 1958-11-28 | 1963-03-19 | Sterling Drug Inc | 4-metathiazanone derivatives and their preparation |
-
2014
- 2014-09-23 CN CN201410485798.3A patent/CN104817518A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB815203A (en) * | 1956-07-20 | 1959-06-17 | Sterling Drug Inc | Substituted-4-metathiazanones |
| US3082209A (en) * | 1958-11-28 | 1963-03-19 | Sterling Drug Inc | 4-metathiazanone derivatives and their preparation |
Non-Patent Citations (2)
| Title |
|---|
| ALEXANDER R. SURREY ET AL.: "Central Nervous System Depressants. The Preparation of Some 2-Aryl-4-metathiazanones", 《J. AM. CHEM. SOC.》 * |
| ELIZABETH M. SMITH ET AL.: "T-type calcium channel blockers: spiro-piperidine azetidines and azetidinones-optimization，design and synthesis", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114044762A (en) * | 2021-11-24 | 2022-02-15 | 广州隽沐生物科技股份有限公司 | Preparation method of chlormezanone intermediate |
| CN114044762B (en) * | 2021-11-24 | 2023-07-18 | 广州隽沐生物科技股份有限公司 | Preparation method of chlormezanone intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107848999A (en) | For the method for the acid composition for preparing purifying | |
| CN103435564A (en) | Preparation method of tebuconazole | |
| CN105061414B (en) | One kettle way prepares Brexpiprazole | |
| CN105254544A (en) | Preparing method for bisphenol S | |
| BR112019011367B1 (en) | HMF PRODUCTION PROCESS | |
| US8680329B2 (en) | Process for preparation of α-ketoglutaric acid | |
| WO2016112814A1 (en) | Caprolactam preparation method | |
| CN103664923B (en) | The preparation method of Nifuratel | |
| CN108752415A (en) | A kind of Finasteride chiral impurity（5 β-Finasterides）Synthesis and purification process | |
| US8754256B2 (en) | Process for preparation of L-Arginine α-ketoglutarate 1:1 and 2:1 | |
| CN104086619B (en) | The preparation method of danazol | |
| CN105820042A (en) | Production technology of p-hydroxy benzaldehyde and production system thereof | |
| CN104817518A (en) | Optimized chlormezanone synthesis method | |
| CN111116692A (en) | Synthesis method of high-purity selamectin | |
| CN103980481B (en) | The preparation method of watermiscible vitamin E | |
| US20170158729A1 (en) | Method of synthesizing 25-hydroxy cholesterol | |
| CN104876812B (en) | Process for preparing sertraline hydrochloride intermediates and impurities | |
| EP3207016B1 (en) | Method for producing specific alpha,beta-unsaturated aldehydes by rearrangement process | |
| CN106966980A (en) | The preparation method of high-purity Eptazocine intermediate | |
| CN103739502B (en) | A kind of separation and purification technique of ambroxol alkali | |
| CN108203385B (en) | Method for preparing 3- (4-fluoro-2-nitrophenyl) acetone | |
| CN114685410B (en) | Preparation method of butylphthalide | |
| CN109535179B (en) | Improved 6-APA extraction method | |
| CN109400489B (en) | Preparation method of meclofenoxate hydrochloride | |
| CN101613355B (en) | Method for synthesizing pyrano-coumarin derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150805 |