CN106854202A - A kind of new method for preparing high-purity asthma drug Pranlukast - Google Patents
A kind of new method for preparing high-purity asthma drug Pranlukast Download PDFInfo
- Publication number
- CN106854202A CN106854202A CN201611102738.4A CN201611102738A CN106854202A CN 106854202 A CN106854202 A CN 106854202A CN 201611102738 A CN201611102738 A CN 201611102738A CN 106854202 A CN106854202 A CN 106854202A
- Authority
- CN
- China
- Prior art keywords
- pranlukast
- purity
- new method
- asthma drug
- base
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of new method for preparing high-purity asthma drug Pranlukast, it is related to medicine technical field of organic synthesis, it is reaction raw materials with the chromene hydrochlorides of 8 amino, 4 oxo, 2 tetrazolium, 5 base 4H 1, first neutralized with alkaline matter and salt-forming reaction generation intermediate, there is amidation process in gained intermediate, that is, Pranlukast is obtained in non-polar solven with to benzene butyl phenyl ether formyl chloride.Whole process of the present invention is simple, clean, it is easy to control, so as to get crude product purity be that, up to more than 99%, and can reach more than 99.9% after primary purification.
Description
Technical field：
The present invention relates to medicine technical field of organic synthesis, and in particular to a kind of high-purity asthma drug Pranlukast of preparing
New method.
Background technology：
Pranlukast is developed by Japanese little Ye companies, only Selective depression leukotriene receptor, to arachidonic acid metabolic
Enzyme almost without influence, while to acetylcholine, serotonin etc. also without antagonism, spy answered in clinical practice type asthma and
Other kinds of bronchial astehma has good therapeutic effect.
The method for commercially producing Pranlukast for generally using both at home and abroad at present mainly has two kinds：First method be with
3 '-(4- (4- benzene butoxy) Ammonium benzoate) -2 '-hydroxy acetophenones (PBHA) are raw material, in polar solvent, in the presence of highly basic
There is ester ketone condensation reaction, then closed loop generation Pranlukast in acid condition with tetrachloro iminazole acid ethyl ester；Second method is
With 8- amino -4- oxo -2- tetrazolium -5- base -4H-1 chromenes hydrochloride starting, in the presence of acid binding agent with to benzene butyl phenyl ether
There is amidation process in formyl chloride, so as to Pranlukast is obtained.
First method is needed with the polar solvent and substantial amounts of highly basic of a large amount of and difficult recovery, and production process produces big
Amount waste liquid, waste residue and waste water, and because material is constantly in highly basic, the Pranlukast crude product for obtaining is caused under highly basic closed loop conditions
Content is very low to can be only achieved more than 99.5%, it is necessary to repeatedly purify；Second method has the same problem of the above method, due to
Contain hydrochloric acid in AOTH, need, first with acid binding agent and hydrochloric acid, to make amino separate out in course of reaction, could be sent out with acyl chlorides
Raw amidation process, in course of reaction constantly the hydrogen chloride of production still need acid binding agent remove in time can just make reaction continue into
OK, crude product purity only 80-85%, not only needs repeatedly purification, cumbersome, and cost is very high.
The content of the invention：
The technical problems to be solved by the invention are to provide a kind of simple to operate, preparation high-purity that three wastes yield is few
The new method of asthma drug Pranlukast.
The technical problems to be solved by the invention are realized using following technical scheme：
A kind of new method for preparing high-purity asthma drug Pranlukast, with 8- amino -4- oxo -2- tetrazolium -5- bases -4H-1
Chromene hydrochloride is reaction raw materials, and first neutralized with alkaline matter and salt-forming reaction generation intermediate, gained intermediate exists
There is amidation process with to benzene butyl phenyl ether formyl chloride in non-polar solven, that is, Pranlukast is obtained.
The alkaline matter is inorganic base or organic base.
The inorganic base is selected from the one kind in NaOH, ammoniacal liquor.
The organic base is selected from the one kind in pyridine, triethylamine.
The non-polar solven is selected from dichloromethane, dichloroethanes, tetrahydrofuran, N,N-dimethylformamide, dimethyl
One kind in sulfoxide.
By taking triethylamine as an example, reaction scheme is as follows：
Reaction principle：The mesh of 8- amino -4- oxos -2- tetrazoliums -5- bases -4H-1 chromenes hydrochloride and triethylamine react
, on the one hand it is using the semicarbazide hydrochloride in triethylamine neutralization reaction raw material mix, by amino separate out；On the other hand it is
Tetrazole is converted into triethylamine salt in making reaction raw materials structure by triethylamine.So gained intermediate with to benzene butyl phenyl ether
Formyl chloride occur amidation process when, react generation sal-ammoniac can in time with triethylamine in and generate triethylamine hydrochloride, with
Play a part of acid binding agent.
The beneficial effects of the invention are as follows：The present invention utilizes 8- amino -4- oxo -2- tetrazolium -5- base -4H-1- chromenes
The faintly acid of tetrazole radical in hydrochloride (AOTH), different from organic acid in other inventions and amino into salt, with triethylamine therewith into
Salt, makes amino separate out, during triethylamine salt and the acyl chloride reaction of AOTH prepare Pranlukast, reacts the chlorination of generation
Ammonia in time with triethylamine in and generation triethylamine hydrochloride, the triethylamine of intramolecular plays a part of acid binding agent, whole process letter
It is single, it is clean, it is easy to control, so as to get crude product purity be up to more than 99%, and be can reach after primary purification 99.9% with
On.
Specific embodiment：
In order that technological means, creation characteristic, reached purpose and effect that the present invention is realized are easy to understand, tie below
Specific embodiment is closed, the present invention is expanded on further.
Embodiment 1
8- amino -4- oxo -2- tetrazolium -5- base -4H-1 chromene hydrochlorides 80g is dissolved in 500ml dichloromethane,
65g triethylamines are added dropwise, rear back flow reaction 2h is dripped off, dichloromethane is reclaimed, residue is obtained final product in stirring 30min, suction filtration at 0 DEG C
Intermediate 8- amino -4- oxos -2- returns azoles -5- base -4H-1- chromene list triethylamine salts 93g.
8- amino -4- oxos -2- return azoles -5- base -4H-1- chromene list triethylamine salts 67g, to benzene butyl phenyl ether formyl
In chlorine 60g 1000ml reaction bulbs of the input equipped with 700ml dichloromethane, after stirring temperature rising reflux 6h, dichloromethane is reclaimed, to surplus
5% buck 1200ml is added in excess, is stirred, plus a little activated carbon decolorizing, freeze crystallization and obtain Pranlukast sodium salt, then will
In gained Pranlukast sodium salt input 500ml ethanol, 500ml water is added, stirring is lower with salt acid for adjusting pH to 6.8-7.2, repetition measurement
After constant, filtering, pure water for several times, obtains white solid wet product, and drying obtains 99g products, and HPLC detections purity is
99.92%.
Embodiment 2
8- amino -4- oxo -2- tetrazolium -5- base -4H-1 chromene hydrochlorides 80g is dissolved in 500ml dichloromethane,
50g pyridines are added dropwise, rear back flow reaction 2h is dripped off, dichloromethane is reclaimed, residue is in stirring 30min, suction filtration, in obtaining final product at 0 DEG C
Mesosome 8- amino -4- oxos -2- returns azoles -5- base -4H-1- chromene list pyridiniujms 86g.
8- amino -4- oxos -2- return azoles -5- base -4H-1- chromene list pyridiniujms 62g, to benzene butyl phenyl ether formyl chloride
In 60g 1000ml reaction bulbs of the input equipped with 700ml dichloromethane, after stirring temperature rising reflux 6h, dichloromethane is reclaimed, to residue
5% buck 1200ml is added in thing, is stirred, plus a little activated carbon decolorizing, freezing crystallization obtains Pranlukast sodium salt, then by institute
Obtain in Pranlukast sodium salt input 500ml ethanol, add 500ml water, stirring is lower to use salt acid for adjusting pH to 6.8-7.2, and repetition measurement is not
After change, filtering, pure water for several times, obtains white solid wet product, and drying obtains 97g products, and HPLC detections purity is
99.93%.
General principle of the invention and principal character and advantages of the present invention has been shown and described above.The technology of the industry
Personnel it should be appreciated that the present invention is not limited to the above embodiments, simply explanation described in above-described embodiment and specification this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appending claims and its
Equivalent thereof.
Claims (5)
1. a kind of new method for preparing high-purity asthma drug Pranlukast, it is characterised in that：With 8- amino -4- oxo -2- tetrazoliums -
5- base -4H-1 chromenes hydrochloride is reaction raw materials, first neutralized with alkaline matter and salt-forming reaction generation intermediate, gained
There is amidation process in intermediate, that is, Pranlukast is obtained in non-polar solven with to benzene butyl phenyl ether formyl chloride.
2. it is according to claim 1 prepare high-purity asthma drug Pranlukast new method, it is characterised in that：The alkalescence
Material is inorganic base or organic base.
3. it is according to claim 2 prepare high-purity asthma drug Pranlukast new method, it is characterised in that：It is described inorganic
Alkali is selected from the one kind in NaOH, ammoniacal liquor.
4. it is according to claim 2 prepare high-purity asthma drug Pranlukast new method, it is characterised in that：It is described organic
Alkali is selected from the one kind in pyridine, triethylamine.
5. it is according to claim 1 prepare high-purity asthma drug Pranlukast new method, it is characterised in that：The non-pole
Property solvent be selected from dichloromethane, dichloroethanes, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide (DMSO) in one kind.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611102738.4A CN106854202B (en) | 2016-12-05 | 2016-12-05 | Novel method for preparing pranlukast high-purity asthma medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611102738.4A CN106854202B (en) | 2016-12-05 | 2016-12-05 | Novel method for preparing pranlukast high-purity asthma medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106854202A true CN106854202A (en) | 2017-06-16 |
| CN106854202B CN106854202B (en) | 2020-11-13 |
Family
ID=59127013
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611102738.4A Active CN106854202B (en) | 2016-12-05 | 2016-12-05 | Novel method for preparing pranlukast high-purity asthma medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106854202B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110938052A (en) * | 2018-09-21 | 2020-03-31 | 重庆圣华曦药业股份有限公司 | Industrial preparation method of intermediate of pranlukast as anti-asthma drug |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995032199A1 (en) * | 1994-05-21 | 1995-11-30 | Smithkline Beecham Plc | Process for preparing benzopyran compounds |
| JP2006348032A (en) * | 2005-06-11 | 2006-12-28 | Estecpharma Co Ltd | Method for producing pranlukast or its hydrate, and intermediate for synthesizing the same |
| JP2008163026A (en) * | 2006-12-26 | 2008-07-17 | Cadila Pharmaceuticals Ltd | Improved method for producing 8-nitro-2-(1h-tetrazol-5-yl)-4h-1-benzopyran-4-one from 8-nitro-2-cyano-4h-1-benzopyran-4-one and converting resultant product into hydrochloride salt of 8-amino-2-(1h-tetrazol-5-yl)-4h-1-benzopyran-4-one |
| KR20080107545A (en) * | 2007-06-07 | 2008-12-11 | (주)팜스웰바이오 | Preparation method of pranlukast or pharmaceutically acceptable salts thereof |
| CN101560208A (en) * | 2009-05-31 | 2009-10-21 | 安徽阿幸食品有限公司 | Preparation method of pranlukast |
| WO2010002075A1 (en) * | 2008-07-02 | 2010-01-07 | Pharmacostech Co., Ltd. | Methods for preparing amide derivatives |
-
2016
- 2016-12-05 CN CN201611102738.4A patent/CN106854202B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995032199A1 (en) * | 1994-05-21 | 1995-11-30 | Smithkline Beecham Plc | Process for preparing benzopyran compounds |
| JP2006348032A (en) * | 2005-06-11 | 2006-12-28 | Estecpharma Co Ltd | Method for producing pranlukast or its hydrate, and intermediate for synthesizing the same |
| JP2008163026A (en) * | 2006-12-26 | 2008-07-17 | Cadila Pharmaceuticals Ltd | Improved method for producing 8-nitro-2-(1h-tetrazol-5-yl)-4h-1-benzopyran-4-one from 8-nitro-2-cyano-4h-1-benzopyran-4-one and converting resultant product into hydrochloride salt of 8-amino-2-(1h-tetrazol-5-yl)-4h-1-benzopyran-4-one |
| KR20080107545A (en) * | 2007-06-07 | 2008-12-11 | (주)팜스웰바이오 | Preparation method of pranlukast or pharmaceutically acceptable salts thereof |
| WO2010002075A1 (en) * | 2008-07-02 | 2010-01-07 | Pharmacostech Co., Ltd. | Methods for preparing amide derivatives |
| CN101560208A (en) * | 2009-05-31 | 2009-10-21 | 安徽阿幸食品有限公司 | Preparation method of pranlukast |
Non-Patent Citations (1)
| Title |
|---|
| HISAO NAKAI，等: "New Potent Antagonists of Leukotrienes C4 and D4. 1. Synthesis and Structure-Activity Relationships", 《J. MED. CHEM.》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110938052A (en) * | 2018-09-21 | 2020-03-31 | 重庆圣华曦药业股份有限公司 | Industrial preparation method of intermediate of pranlukast as anti-asthma drug |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106854202B (en) | 2020-11-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103524440B (en) | The preparation method of gout therapertics Lesinurad and Lesinurad intermediate | |
| CN106699570B (en) | Synthesis method of (2-chloro-5-iodophenyl) (4-fluorophenyl) ketone | |
| CN103772278A (en) | Important tetrahydroisoquinoline derivative midbody and synthesis method thereof | |
| CN105175348A (en) | Preparation method for lesinurad | |
| CN101735029B (en) | Synthesis method of hellebore aldehyde | |
| CN106854202A (en) | A kind of new method for preparing high-purity asthma drug Pranlukast | |
| CN105037236A (en) | Ribociclib intermediate and preparation method thereof | |
| CN103130810A (en) | Synthesis method of pyrrolo[1,5-c] quinazoline compounds | |
| CN112939893B (en) | Synthesis method of 4- (4-aminophenyl) -3-morpholinone | |
| CN106892932A (en) | A kind of preparation method of non_steroidal anti_inflammatory drug Lornoxicam | |
| CN105884746A (en) | Synthesizing method of flumatinib | |
| CN102206182B (en) | Method for synthesizing Rimonabant hydrochloride | |
| CN104557763A (en) | Method for synthesizing 2-isopropyl-4-(methylaminomethyl)thiazole | |
| CN104163798A (en) | Synthesis method of 3-amino-8-trifluoromethyl quinoline | |
| CN105061375A (en) | Method for preparing 3-isochromanone | |
| CN103772310A (en) | Method for synthesizing rivaroxaban midbody | |
| CN103804221A (en) | Preparation method of 4-(4-amino phenyl)-3-morpholone and intermediate of 4-(4-amino phenyl)-3-morpholone | |
| CN104003887A (en) | Preparation method of bromhexine hydrochloride | |
| CN105622520A (en) | New intermediate of non-small-cell lung carcinoma treating drug Ceritinib, and preparation method thereof | |
| CN104311469A (en) | Synthetic method of substituted indole-3-acetic acid | |
| CN105037369B (en) | A kind of synthetic method of pyrazolo [5,1 a] Carbox amide of iso-indoles 3 | |
| CN104788474B (en) | A kind of synthetic method of triazole benzo buprofezin condensed hetero ring | |
| CN103524530A (en) | Prasugrel hydrobromide and preparation method thereof | |
| CN107056781A (en) | A kind of synthetic method of the formaldoxime of (E) 5 methyl 1H pyrrolo-es [2,3 b] pyridine 3 | |
| CN106045931A (en) | Preparation method of 5-phenyl-1-(4-methoxy phenyl)-1H-tetrazole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |