CN106432082A - Preparation method of edaravone impurity standard product - Google Patents
Preparation method of edaravone impurity standard product Download PDFInfo
- Publication number
- CN106432082A CN106432082A CN201610887644.6A CN201610887644A CN106432082A CN 106432082 A CN106432082 A CN 106432082A CN 201610887644 A CN201610887644 A CN 201610887644A CN 106432082 A CN106432082 A CN 106432082A
- Authority
- CN
- China
- Prior art keywords
- preparation
- edaravone
- impurity
- pyrazoles
- phenyl
- 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
- 0 *C(CC1=O)=NN1c1ccccc1 Chemical compound *C(CC1=O)=NN1c1ccccc1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of edaravone impurity standard product; the preparation takes edaravone as raw material, and performs catalytic oxidation and purification, so as to obtain 4, 4-bi(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-radical)-3-methyl-1-phenyl-1H-pyrazol-5(4H)-ketone pure product; the pure product content is marked by regular analysis method. The impurity preparation method provided by the invention is easy to obtain raw material, simple and fast in technique, and short in preparation cycle; the marked product content is more than 99.0%. The edaravone provided by the invention can be used as the impurity standard product, and applied to qualitative and quantitative study and detection of edaravone raw materials and the impurities of its preparations.
Description
First, technical field
The present invention relates to a kind of preparation method of impurity of the drug standard substance, specifically a kind of impurity phenylhydrazine standard
The preparation method of product, belongs to pharmaceutical technology field.
2nd, background technology
Edaravone (Edaravone), chemical entitled 3-methyl-1-phenyl-2-pyrazolin-5-one, is a kind of cranial nerve
Protective agent, by Mitsubishi, Pharmaceutical Co., Ltd develops, and its injection is in June calendar year 2001 in Japan's listing (trade name：Specification：30mg/20ml、15mg/10ml、10mg/5ml).It is clinically used for acute cerebral infarction is treated, improves acute brain
Nervous symptoms caused by infarction, recover self care ability, mitigate the paralysis of daily routines obstacle and cerebral infarction acute attack.
Edaravone raw material medicine can produce trimer impurity in building-up process：4,4- pair (5- hydroxy-3-methyl -1- phenyl -
1H- pyrazoles -4- base) -3- methyl isophthalic acid-phenyl -1H- pyrazoles -5 (4H) -one, shown in its structure such as formula (I).The impurity is in crude drug
Significantly can generate in production process.For major impurity in edaravone raw material medicine and its injection.
Synthesis currently, with respect to the impurity and content scaling method have no report.In view of the impurity is to controlling Edaravone
Product quality is most important, and the preparation method of its standard substance that can use as those skilled in the art and quality determining method
Still not available, therefore the acquisition of the contamination levels product has important meaning to effective control edaravone raw material and its tablet quality
Justice.
3rd, content of the invention
The present invention is intended to provide a kind of impurity phenylhydrazine standard substance 4,4- pair (5- hydroxy-3-methyl -1- phenyl -
1H- pyrazoles -4- base) -3- methyl isophthalic acid-phenyl -1H- pyrazoles -5 (4H) -one preparation method, this method have technique simple and direct, system
The advantage of standby cycle is short, through demarcating product content height.
The preparation method of impurity phenylhydrazine standard substance of the present invention, comprises the steps：
1st, aoxidize
Chloroform and Edaravone are put into successively in reaction bulb, after stirring and dissolving, manganese dioxide is put into, prior to 30-
40 DEG C of ultrasound 10-20min, then at 60-65 DEG C be stirred at reflux reaction 4-6h, reaction terminate rear reacting liquor while hot filtration, filtrate in
30-40 DEG C is evaporated to dry, obtains impurity crude product；
The present invention using Edaravone be general commercially available commercial synthesis product, its No. CAS be 89-25-8.
In step 1, Edaravone is 1g with the mass volume ratio of chloroform:15-30ml；Edaravone and manganese dioxide
Mol ratio be 1:1-3.
2nd, refine
Dehydrated alcohol being added in impurity crude product, is stirred at reflux dissolving, plus activated carbon in 75-80 DEG C, continues backflow
10min, filtered while hot, filtrate is cooled to 0-10 DEG C, stirring and crystallizing 3-4h, filter, filter cake absolute ethanol washing, solid in
40-50 DEG C of drying under reduced pressure 6-8h, obtains double (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- the base) -3- of impurity sterling i.e. 4,4-
Methyl isophthalic acid-phenyl -1H- pyrazoles -5 (4H) -one, is white powder.
Impurity crude product described in step 2 is 1g with the mass volume ratio of dehydrated alcohol:10-20ml；Impurity crude product and activity
The mass ratio of charcoal is 10:0.2-0.5.
Synthetic route of the present invention is as follows：
Double (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- the base) -3- methyl isophthalic acid-phenyl-of 4,4- obtained in the present invention
The cubage method of 1H- pyrazoles -5 (4H) -one is as follows：
Content (%)=(100.0% loss on drying % residue on ignition %) × chromatographic purity
Loss on drying is used for measuring in sample volatile impurity (such as：Residual solvent) or low boiling impurity is (such as：Moisture)
Content, analysis method is as follows：
Take this product 1g, totally 2 parts, put in the constant temperature vacuum drying apparatus added with phosphorus pentoxide, according to dry weightless mensuration (in
2015 editions four general rules of state's pharmacopeia<0831>) 60 DEG C of drying under reduced pressure, to constant weight, calculate less loss weight respectively and account for the hundred of sample total amount
Divide ratio, take the meansigma methodss of 2 results.
Residue on ignition is used for measuring in sample inorganic impurity (such as：Inorganic salt) or can not carbide (such as：Metal) content,
Analysis method is as follows：
This product 1g is taken, totally 2 parts, according to residue on ignition algoscopy (2015 editions four general rules of Chinese Pharmacopoeia<0841>) determine, point
Not Ji Suan level of residue account for the percentage ratio of sample total amount, take the meansigma methodss of 2 results.
Chromatographic purity is used for analyzing the ratio that main composition in sample accounts for detection total organic matter, and analysis method is as follows：
HPLC method
Chromatographic column：Luna C18 (150mm × 4.6mm, 5 μm)
Wavelength：240nm (UV detector)
Column temperature：40℃
Mobile phase：Acetum (1 → 100)-methanol (40:60)
Flow velocity：1.0ml/min
Solvent：Mobile phase
Sample size：20μl
HPLC chromatogram in figure, after deducting solvent peak, (main peak area accounts for Zong Feng to calculate main peak content by areas of peak normalization method
The percentage ratio of area).It is calculated as follows chromatographic purity：
Chromatographic purity=main peak content %/100%
As stated above, demarcate 4,4- obtained in the present invention double (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- base) -
3- methyl isophthalic acid-phenyl -1H- pyrazoles -5 (4H) -one content, demarcates content and is all higher than 99.0%.
Double (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- the base) -3- methyl isophthalic acids-phenyl -1H- pyrrole of the 4,4- of the present invention
Azoles -5 (4H) -one preparation technology is simple and direct, synthesis cycle is short, raw materials used be easy to get, synthesize low cost, be both suitable for laboratory and close in a small amount
Become, it can also be used to large-scale production.
Double (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- the base) -3- methyl isophthalic acids-phenyl -1H- pyrrole of the 4,4- of the present invention
Azoles -5 (4H) -one content scaling method is conventional method of analysis, and appointed condition is not high, easily realizes.
Double (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- the base) -3- methyl of 4,4- for being prepared using the inventive method -
The demarcation content of 1- phenyl -1H- pyrazoles -5 (4H) -one is all higher than 99.0%, can be applied to Edaravone as contamination levels product
The qualitative and quantitative study and detection of raw material and its preparation impurity, has to effective control edaravone raw material and its quality of the pharmaceutical preparations
Positive progressive meaning.
4th, illustrate
Fig. 1 is double (5-hydroxy-3-methyl-1-phenyl-1H-pyrazoles-4-base)-3-methyl isophthalic acids-benzene of 4, as can be seen from Figure 1, chromatographic purity is 0.9959. to 4-in embodiment 1Base-1H-pyrazoles-5 (4H)-one purity detecting chromatogram.
Fig. 2 is double (5-hydroxy-3-methyl-1-phenyl-1H-pyrazoles-4-base)-3-methyl isophthalic acids-benzene of 4, as can be seen from Figure 1, chromatographic purity is 0.9952. to 4-in embodiment 2Base-1H-pyrazoles-5 (4H)-one purity detecting chromatogram.
Fig. 3 is double (5-hydroxy-3-methyl-1-phenyl-1H-pyrazoles-4-base)-3-methyl isophthalic acids-benzene of 4, as can be seen from Figure 1, chromatographic purity is 0.9961. to 4-in embodiment 3Base-1H-pyrazoles-5 (4H)-one purity detecting chromatogram.
5th, specific embodiment
Following preferable examples of the present invention will be described, it will be appreciated that preferred embodiment described herein is only used for
The bright and explanation present invention, is not intended to limit the present invention.
Embodiment 1：
1st, chloroform 150ml and Edaravone 10g (57.4mmol) is put into successively in reaction bulb, after stirring and dissolving,
Manganese dioxide 5g (57.5mmol) is put into, and prior to 30-40 DEG C of ultrasound 10min, 4h is stirred at reflux then at 60-65 DEG C；Reaction terminates
Reacting liquor while hot is filtered afterwards, and filtrate is concentrated to dryness in 30-40 DEG C of decompression (vacuum >=0.08MPa), obtains impurity crude product 8.9g, is received
Rate 89.7%.
2nd, dehydrated alcohol 100ml being added in 8.9g impurity crude product, is stirred at reflux dissolving, plus activated carbon in 75-80 DEG C
0.2g, continuation backflow 10min, filtered while hot, filtrate is cooled to 0-10 DEG C, stirring and crystallizing 3h, filters, and filter cake is washed with dehydrated alcohol
Wash, solid dries 6h in 40-50 DEG C of decompression (vacuum >=0.08MPa), obtain the double (5- hydroxy-3-methyl -1- phenyl -1H- of 4,4-
Pyrazoles -4- base) -3- methyl isophthalic acid-phenyl -1H- pyrazoles -5 (4H) -one sterling 7.5g, yield 84.3%.
Elementary analysiss are C30H26N6O3
| Analysis project | C (%) | H (%) | N (%) |
| Theoretical value | 69.48 | 5.24 | 16.17 |
| Measured value | 69.27 | 5.13 | 16.29 |
TOF-MS[M+H]+：519.3(Mol·Wt:518.57)
IR(KBr)ν(cm-1)：3298,3064,2914,2790,1712,1627,1594,1570,1498,1457,1457,
1358,754,689
1HNMR(DMSO-d6)δ(ppm)：11.52 (brs, 1H, OH), 10.21 (s, 1H, OH), 7.88 (d, 2H, Ar-H),
7.69 (d, 4H, Ar-H), 7.43 (d, 6H, Ar-H), 7.19 (m, 3H, Ar-H), 2.14 (s, 9H, CH3)
13CNMR(DMSO-d6)δ(ppm)：172.8,161.2 (2C), 149.0 (3C), 138.3 (2C), 137.0,128.8
(6C) 125.0 (2C), 124.2,119.2 (2C), 118.1 (4C), 98.9 (2C), 54.1,16.1 (2C), 12.6
Content calibration result：
Embodiment 2：
1st, chloroform 300ml and Edaravone 20g (114.8mmol) is put into successively in reaction bulb, after stirring and dissolving,
Manganese dioxide 15g (172.5mmol) is put into, and prior to 30-40 DEG C of ultrasound 10min, 6h is stirred at reflux then at 60-65 DEG C；Reaction knot
After bundle, reacting liquor while hot is filtered, and filtrate is concentrated to dryness in 30-40 DEG C of decompression (vacuum >=0.08MPa), obtains impurity crude product
18.5g, yield 93.2%.
2nd, dehydrated alcohol 350ml being added in 18.5g impurity crude product, is stirred at reflux dissolving, plus activated carbon in 75-80 DEG C
0.5g, continuation backflow 10min, filtered while hot, filtrate is cooled to 0-10 DEG C, stirring and crystallizing 4h, filters, and filter cake is suitable with dehydrated alcohol
Amount washing, solid dries 8h in 40-50 DEG C of decompression (vacuum >=0.08MPa), obtains the double (5- hydroxy-3-methyl -1- benzene of 4,4-
Base -1H- pyrazoles -4- base) -3- methyl isophthalic acid-phenyl -1H- pyrazoles -5 (4H) -one sterling 16.7g, yield 90.3%.
Content calibration result：
Embodiment 3：
1st, put into chloroform 400ml and Edaravone 50g (287mmol) in reaction bulb successively, after stirring and dissolving, throw
Entering manganese dioxide 75g (863mmol), prior to 30-40 DEG C of ultrasound 10min, 8h is stirred at reflux then at 60-65 DEG C；After reaction terminates
Reacting liquor while hot is filtered, and filtrate is concentrated to dryness in 30-40 DEG C of decompression (vacuum >=0.08MPa), obtains impurity crude product 47.3g,
Yield 95.3%.
2nd, dehydrated alcohol 700ml being added in 47.3g impurity crude product, is stirred at reflux dissolving, plus activated carbon in 75-80 DEG C
4.5g, continuation backflow 10min, filtered while hot, filtrate is cooled to 0-10 DEG C, stirring and crystallizing 4h, filters, and filter cake is suitable with dehydrated alcohol
Amount washing, solid dries 8h in 40-50 DEG C of decompression (vacuum >=0.08MPa), obtains the double (5- hydroxy-3-methyl -1- benzene of 4,4-
Base -1H- pyrazoles -4- base) -3- methyl isophthalic acid-phenyl -1H- pyrazoles -5 (4H) -one sterling 43.1g, yield 91.1%.
Content calibration result：
Unless otherwise defined, used in the present invention all professional terms and term are familiar with one skilled in the art
Meaning consistent.Additionally, any method similar or impartial to described content and material are all can be applicable in the inventive method.
Claims (5)
1. a kind of preparation method of impurity phenylhydrazine standard substance, it is characterised in that comprise the steps：
(1) aoxidize
Chloroform and Edaravone are put into successively in reaction bulb, after stirring and dissolving, manganese dioxide is put into, prior to 30-40 DEG C
Ultrasonic 10-20min, is stirred at reflux reaction 4-6h then at 60-65 DEG C, and reaction terminates the filtration of rear reacting liquor while hot, and filtrate is in 30-40
DEG C it is evaporated to dry, obtains impurity crude product；
(2) refine
Dehydrated alcohol being added in impurity crude product, is stirred at reflux dissolving, plus activated carbon in 75-80 DEG C, continues backflow 10min, take advantage of
Heat filtering, filtrate is cooled to 0-10 DEG C, stirring and crystallizing 3-4h, filters, filter cake absolute ethanol washing, and solid subtracts in 40-50 DEG C
Dry 6-8h is pressed dry, obtains double (5- hydroxy-3-methyl -1- phenyl -1H- pyrazoles -4- the base) -3- methyl isophthalic acids-benzene of impurity sterling i.e. 4,4-
Base -1H- pyrazoles -5 (4H) -one, is white powder.
2. preparation method according to claim 1, it is characterised in that：
In step (1), Edaravone is 1g with the mass volume ratio of chloroform:15-30ml.
3. preparation method according to claim 1, it is characterised in that：
In step (1), Edaravone is 1 with the mol ratio of manganese dioxide:1-3.
4. preparation method according to claim 1, it is characterised in that：
Impurity crude product described in step (2) is 1g with the mass volume ratio of dehydrated alcohol:10-20ml.
5. preparation method according to claim 1, it is characterised in that：
In step (2), impurity crude product is 10 with the mass ratio of activated carbon:0.2-0.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610887644.6A CN106432082B (en) | 2016-10-11 | 2016-10-11 | A kind of preparation method of impurity phenylhydrazine standard items |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610887644.6A CN106432082B (en) | 2016-10-11 | 2016-10-11 | A kind of preparation method of impurity phenylhydrazine standard items |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106432082A true CN106432082A (en) | 2017-02-22 |
| CN106432082B CN106432082B (en) | 2018-07-10 |
Family
ID=58174783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610887644.6A Active CN106432082B (en) | 2016-10-11 | 2016-10-11 | A kind of preparation method of impurity phenylhydrazine standard items |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106432082B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098860A (en) * | 2017-05-23 | 2017-08-29 | 安徽天洋药业有限公司 | A kind of preparation method of Edaravone about material |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL148478B2 (en) * | 1987-05-18 | 1989-10-31 | Method of obtaining derivatives of 2-pyrazolin-5-one | |
| JP2008001607A (en) * | 2006-06-20 | 2008-01-10 | Mitsubishi Pharma Corp | Aqueous solution agent containing pyrazolone compound |
| CN102180833A (en) * | 2010-07-29 | 2011-09-14 | 南京长澳医药科技有限公司 | Preparation method and detection method for edaravone dimer and tautomer thereof |
-
2016
- 2016-10-11 CN CN201610887644.6A patent/CN106432082B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL148478B2 (en) * | 1987-05-18 | 1989-10-31 | Method of obtaining derivatives of 2-pyrazolin-5-one | |
| JP2008001607A (en) * | 2006-06-20 | 2008-01-10 | Mitsubishi Pharma Corp | Aqueous solution agent containing pyrazolone compound |
| CN102180833A (en) * | 2010-07-29 | 2011-09-14 | 南京长澳医药科技有限公司 | Preparation method and detection method for edaravone dimer and tautomer thereof |
Non-Patent Citations (5)
| Title |
|---|
| 《 HETEROCYCLIC COMMUNICATIONS》 * |
| 《ACTA CHEMICA SCANDINAVICA》 * |
| 《INDIAN JOURNAL OF CHEMISTRY, SECTION B: ORGANIC CHEMISTRY INCLUDING MEDICINAL CHEMISTRY》 * |
| 《J. PRAKT. CHEM.》 * |
| 《TETRAHEDRON LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107098860A (en) * | 2017-05-23 | 2017-08-29 | 安徽天洋药业有限公司 | A kind of preparation method of Edaravone about material |
| CN107098860B (en) * | 2017-05-23 | 2019-08-16 | 安徽天洋药业有限公司 | A kind of preparation method of the Edaravone in relation to substance |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106432082B (en) | 2018-07-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101671314B (en) | Uloric crystal and preparation method thereof | |
| CN101155814B (en) | Crystals of morphinan derivative and process for producing the same | |
| CN103159797A (en) | Fosaprepitant dimeglumine crystal form compound | |
| CN106995397B (en) | R-amisulpride medicinal salt, preparation method, crystal form and application thereof | |
| CN104860939A (en) | Cinchona alkaloids compound and preparation method thereof | |
| CN105085373A (en) | Purification method for Apremilast products | |
| CN103570621B (en) | Preparation method of (-)-huperzine A | |
| CN106831804A (en) | The method that ion exchange and silica gel column chromatography separation prepare Stephania tetrandra first, B prime | |
| CN102020635A (en) | Preparation method of hydrochloride Fasudil hemihydrate | |
| CN106432082A (en) | Preparation method of edaravone impurity standard product | |
| CN106478524B (en) | A kind of preparation method of ambroxol hydrochloride impurity standard items | |
| CN105968042B (en) | A kind of preparation method of Miglitol | |
| CN108586355A (en) | A kind of process for purification of olaparib | |
| CN112110961A (en) | Preparation method of impurities in calcium gluconate | |
| CN111718344A (en) | Tadalafil refining method | |
| CN102775424A (en) | Preparation method for levofloxacin impurity | |
| CN110117255A (en) | A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof | |
| CN109776372A (en) | Related substance of vildagliptin and preparation method thereof | |
| CN104072491A (en) | Azilsartan derivative compound and preparation method and application thereof | |
| CN103265457A (en) | (R)-4-amino phenethyl-(2-hydroxy-2-phenylethyl)-tert-butyl carbamate synthesis method | |
| CN104072433A (en) | Hydrolysable impurity compound of valsartan and preparation method, detection method and use thereof | |
| CN103601708A (en) | Preparation method of prostaglandin medicine impurity | |
| CN109293682A (en) | A kind of support method is for cloth impurity and preparation method thereof | |
| CN109879800B (en) | Preparation process of bepotastine drug intermediate | |
| CN107089942B (en) | The preparation method of tegafur, gimeracil and oteracil potassium impurity B CB |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |