CN101805292A - Pyrazolines compound as well as application and preparation method thereof - Google Patents
Pyrazolines compound as well as application and preparation method thereof Download PDFInfo
- Publication number
- CN101805292A CN101805292A CN 201010156628 CN201010156628A CN101805292A CN 101805292 A CN101805292 A CN 101805292A CN 201010156628 CN201010156628 CN 201010156628 CN 201010156628 A CN201010156628 A CN 201010156628A CN 101805292 A CN101805292 A CN 101805292A
- Authority
- CN
- China
- Prior art keywords
- edaravone
- preparation
- compound
- propylene glycol
- sodium pyrosulfite
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- -1 Pyrazolines compound Chemical class 0.000 title 1
- QELUYTUMUWHWMC-UHFFFAOYSA-N edaravone Chemical compound O=C1CC(C)=NN1C1=CC=CC=C1 QELUYTUMUWHWMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229950009041 edaravone Drugs 0.000 claims abstract description 24
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 13
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims abstract description 10
- 235000010262 sodium metabisulphite Nutrition 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000012535 impurity Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- 239000007788 liquid Substances 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000013558 reference substance Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 1
- 238000001914 filtration Methods 0.000 abstract description 2
- 238000004007 reversed phase HPLC Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 150000001793 charged compounds Chemical class 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- FXXMNCZOYVUJEE-UHFFFAOYSA-N C1(=CC=CC=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O Chemical compound C1(=CC=CC=C1)N1N=CCC1=O.CC1(CC(C(=O)O)=CC=C1)C(=O)O FXXMNCZOYVUJEE-UHFFFAOYSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 150000003219 pyrazolines Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a compound having a structure as shown in a specification as well as a preparation method and application thereof. The preparation method comprises the steps of: reacting edaravone, sodium pyrosulfite and 1,2-propylene glycol; placing the solution of the reaction under an environment with the temperature of 35-55 DEG C for 96-168 hours and filtering for later use; and separating the edaravone solution by using a reversed phase high performance liquid chromatography method for preparing 4-(1-hydroxy-2-sulfo-propane-2-yl)-3-methyl-1-phenyl-2-pyrazoline-5-ketone. The compound can be used a comparison product of edaravone impurities and is convenient for controlling edaravone and the content of the edaravone in relevant preparations.
Description
Invention field
The present invention relates to 4-(1-hydroxyl-2-sulfonic group-propane-2-yl)-3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one and its production and use.
Background technology
3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one, popular name: Edaravone, be the cerebral infarction medication, belong to free radical scavenging formulation neuroprotective, its structural formula is suc as formula shown in the I:
Formula I
As clinical commonly used drug, Edaravone because the existence of high temperature process such as sterilization, might produce impurity and causes drug quality decline in its production, storage, use.
Domestic report to related substance in the Edaravone Injection mostly is reaction raw materials etheric acid second vinegar and phenylhydrazine, but the reflection Edaravone Injection is had an effect by Edaravone and auxiliary material and is produced related substance research and reports seldom, and above-mentioned Edaravone and auxiliary material are had an effect and the preparation method that produces related substance also rarely has report.
Summary of the invention
One of purpose of the present invention provides a kind of new compound of following structure: 4-(1-hydroxyl-2-sulfonic group-propane-2-yl)-3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one.Below be referred to as compd A.
Formula II
Chemical name is: 4-(1-hydroxyl-2-sulfonic group-propane-2-yl)-3-methyl isophthalic acid-phenyl-2-pyrazolin-5-one.
Two of purpose of the present invention provides a kind of method for preparing above compound, for achieving the above object, adopts following preparation separating technology:
At first, take by weighing Edaravone, Sodium Pyrosulfite, 1 respectively, 2-propylene glycol, three's mass ratio are 1～5: 1～5: 10～50, place open container.
Above-mentioned raw materials adds solvent and is mixed with (pH=4～7) solution or suspension liquid, and solvent can be water or organic solvent.
This solution or uncovered the placing under 35～55 ℃ of envrionment temperatures of suspension liquid were stirred 96～168 hours, be cooled to the room temperature after-filtration, filtrate for later use.
Utilize reversed-phase liquid chromatography side that above-mentioned solution is separated again, the preparation compd A.
Final compd A is analyzed its purity with HPLC, and adopts MS, NMR to prove conclusively its structure.
Edaravone, Sodium Pyrosulfite, 1,2-propylene glycol, three's mass ratio preferred 1～2: 1～2: 10～20.
Edaravone, Sodium Pyrosulfite, 1,2-propylene glycol, three's mass ratio further preferred 1: 1: 10.
Edaravone is complete synthesis cerebral apoplexy neuroprotective, owing to there is high temperature process such as high-temperature sterilization, may produces compd A in its preparation and causes downgrade in preparation and the storage.The present invention adopts reversed-phased high performace liquid chromatographic that compd A has been carried out separating preparation, this method is simple, the recovery rate height, and product purity reaches (HPLC) more than 90%, can be used as Edaravone impurity reference substance, be convenient to the amount of the compd A of control ratio Edaravone and related preparations.
The finished product carry out structure with nucleus magnetic resonance, mass spectrum and identify attached data declaration.
1, LC-MS (ESI (+)) molecular ion peak (M+1), m/z is 313;
LC-MS (ESI (-)) molecular ion peak (M-1), m/z are 311;
2、NMR(DMSO-d
6)
Embodiment:
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
Embodiment 1
Take by weighing Edaravone 4g, Sodium Pyrosulfite 5g, 1 respectively, 2-propylene glycol 50g, water 50mL place open container.
Place 50 ℃ of oil bath heated and stirred with this suspension liquid is uncovered, take out after 96 hours, put and be chilled to room temperature, filter filtrate for later use.
Adopt anti-phase medium pressure liguid chromatograph that above-claimed cpd A solution is separated, prepare compd A 103mg, yield 1.4%.
Embodiment 2
Take by weighing Edaravone 100mg, Sodium Pyrosulfite 50mg, 1 respectively, 2-propylene glycol 500mg, DMSO 1mL place open container.
Place 40 ℃ of oil bath heated and stirred with this solution is uncovered, take out after 168 hours, put and be chilled to room temperature, filter filtrate for later use.
Adopt rp-hplc that above-claimed cpd A solution is separated, prepare compd A 5mg, yield 2.7%.
Claims (10)
1. new compound has following structure:
2. method for preparing the described compound of claim 1, this method comprises: Edaravone, Sodium Pyrosulfite, 1, the 2-propylene glycol reacts.
3. preparation method according to claim 2 is characterized in that described raw material is added solution or the suspension liquid that solvent is mixed with pH=4～7.
4. preparation method according to claim 3 is characterized in that solvent can be water or organic solvent.
5. preparation method according to claim 2 is characterized in that Edaravone, Sodium Pyrosulfite, 1, and 2-propylene glycol, three's mass ratio are 1～5: 1～5: 10～50.
6. preparation method according to claim 2 is characterized in that Edaravone, Sodium Pyrosulfite, 1, and 2-propylene glycol, three's mass ratio are 1～2: 1～2: 10～20.
7. preparation method according to claim 2 is characterized in that Edaravone, Sodium Pyrosulfite, 1, and 2-propylene glycol, three's mass ratio are 1: 1: 10.
8. preparation method according to claim 2 is characterized in that temperature of reaction is 35～55 ℃.
9. preparation method according to claim 2 is characterized in that the reaction times is 96～168 hours.
10. the application of the described compound of claim 1 in preparation Edaravone impurity reference substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010156628 CN101805292B (en) | 2010-04-27 | 2010-04-27 | Pyrazolines compound as well as application and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010156628 CN101805292B (en) | 2010-04-27 | 2010-04-27 | Pyrazolines compound as well as application and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101805292A true CN101805292A (en) | 2010-08-18 |
| CN101805292B CN101805292B (en) | 2012-01-25 |
Family
ID=42607262
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010156628 Active CN101805292B (en) | 2010-04-27 | 2010-04-27 | Pyrazolines compound as well as application and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101805292B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102140080A (en) * | 2011-01-24 | 2011-08-03 | 江苏先声药物研究有限公司 | Method for synthesizing sulfoacid organic compounds in one step |
| CN102336710A (en) * | 2011-07-11 | 2012-02-01 | 宁波大学 | Method for synthesizing edaravone derivative |
| CN105646530A (en) * | 2014-12-03 | 2016-06-08 | 江苏先声药业有限公司 | Phenyl pyrazole compound, preparation method and application thereof |
| CN106167465A (en) * | 2016-07-06 | 2016-11-30 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of Edaravone dimer impurity compound and preparation method thereof |
| CN106316957A (en) * | 2015-06-15 | 2017-01-11 | 江苏正大丰海制药有限公司 | Edaravone impurity intermediate, preparation method and application thereof |
| CN108072710A (en) * | 2016-11-14 | 2018-05-25 | 江苏正大丰海制药有限公司 | A kind of Edaravone Sodium Chloride Injections Related Substances detection method |
| WO2022037537A1 (en) * | 2020-08-17 | 2022-02-24 | 先声药业有限公司 | Stable pharmaceutical composition |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1449754A (en) * | 2003-04-16 | 2003-10-22 | 浙江震元制药有限公司 | Edaravone medicine composition and preparation thereof |
| CN101288650A (en) * | 2008-06-04 | 2008-10-22 | 江苏先声药物研究有限公司 | Edaravone lyophilized preparation and preparation technique thereof |
-
2010
- 2010-04-27 CN CN 201010156628 patent/CN101805292B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1449754A (en) * | 2003-04-16 | 2003-10-22 | 浙江震元制药有限公司 | Edaravone medicine composition and preparation thereof |
| CN101288650A (en) * | 2008-06-04 | 2008-10-22 | 江苏先声药物研究有限公司 | Edaravone lyophilized preparation and preparation technique thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《西南军医》 20071031 宋丽等 色谱法检测药物杂质的研究进展 第9卷, 第5期 2 * |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102140080A (en) * | 2011-01-24 | 2011-08-03 | 江苏先声药物研究有限公司 | Method for synthesizing sulfoacid organic compounds in one step |
| CN102140080B (en) * | 2011-01-24 | 2013-05-22 | 江苏先声药物研究有限公司 | Method for synthesizing sulfoacid organic compounds in one step |
| CN102336710A (en) * | 2011-07-11 | 2012-02-01 | 宁波大学 | Method for synthesizing edaravone derivative |
| CN102336710B (en) * | 2011-07-11 | 2014-03-12 | 宁波大学 | Method for synthesizing edaravone derivative |
| CN105646530A (en) * | 2014-12-03 | 2016-06-08 | 江苏先声药业有限公司 | Phenyl pyrazole compound, preparation method and application thereof |
| CN105646530B (en) * | 2014-12-03 | 2020-05-12 | 南京先声东元制药有限公司 | Phenylpyrazole compound and preparation method and application thereof |
| CN106316957A (en) * | 2015-06-15 | 2017-01-11 | 江苏正大丰海制药有限公司 | Edaravone impurity intermediate, preparation method and application thereof |
| CN106316957B (en) * | 2015-06-15 | 2018-12-28 | 江苏正大丰海制药有限公司 | A kind of intermediate of impurity phenylhydrazine and its preparation method and application |
| CN106167465A (en) * | 2016-07-06 | 2016-11-30 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of Edaravone dimer impurity compound and preparation method thereof |
| CN106167465B (en) * | 2016-07-06 | 2018-06-22 | 扬子江药业集团江苏海慈生物药业有限公司 | A kind of Edaravone dimer impurity compound and preparation method thereof |
| CN108072710A (en) * | 2016-11-14 | 2018-05-25 | 江苏正大丰海制药有限公司 | A kind of Edaravone Sodium Chloride Injections Related Substances detection method |
| WO2022037537A1 (en) * | 2020-08-17 | 2022-02-24 | 先声药业有限公司 | Stable pharmaceutical composition |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101805292B (en) | 2012-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101805292B (en) | Pyrazolines compound as well as application and preparation method thereof | |
| CN108026030B (en) | Preparation method of deuterated compound | |
| CN102558182B (en) | Ertapenem sodium crystal form E and preparation method thereof | |
| CN103570622B (en) | Preparation method of celecoxib | |
| CN105175340A (en) | Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal | |
| CN104098512A (en) | Edaravone derivative, and preparation method, detection method and application thereof | |
| CN105254569A (en) | Preparation method of ornidazole injection impurity 1-(3-chloro-propenyl)-2-methyl-5-nitroimidazole | |
| CN102391259B (en) | Nifuratel compound and preparation method thereof | |
| CN110128385B (en) | Quercetin derivative chemically modified by lauroyl chloride and synthetic method thereof | |
| CN104557674B (en) | The preparation method of the hydroxy piperidines of one kind (S) N Boc 3 | |
| CN104961787B (en) | Synthetic method of cordycepin | |
| WO2021218275A1 (en) | Method for synthesizing and refining 4-fluorobenzoylacetonitrile | |
| CN105646530B (en) | Phenylpyrazole compound and preparation method and application thereof | |
| CN103059098B (en) | Preparation method of dutasteride | |
| CN105001197B (en) | A kind of Egelieting derivatives I and preparation method and application | |
| CN104177294A (en) | Preparation method of celecoxib | |
| CN113045583B (en) | Preparation method of pinoxaden metabolite | |
| CN108101911A (en) | A kind of synthesis technology of sitagliptin intermediate | |
| CN113135862A (en) | Synthetic method of 6-fluoro-3-hydroxypyrazine-2-carboxylic acid | |
| CN112125889A (en) | Preparation method of 7-bromo-2- (1-methyl-1H-pyrazol-4-yl) quinoxaline | |
| CN108912018B (en) | Preparation method and application of impurity compound in key intermediate for synthesizing sulpiride | |
| CN104356126A (en) | Preparation method of arotinolol hydrochloride | |
| CN104387332B (en) | A kind of method of synthetic aroma enzyme inhibitors | |
| CN108530361A (en) | A kind of synthesis technology of 5- [2- (3,5- Dimethoxyphenyls) ethyl] -1H- pyrazoles -3- amine | |
| CN110117251B (en) | Preparation method of 4, 5-dichloro-2-hydroxypyridine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: BODA PHARMACEUTICAL CO., LTD., JILIN PROVINCE Effective date: 20130327 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20130327 Address after: 210042 Xuanwu Avenue, Jiangsu, Nanjing, No. 699 -18 Patentee after: JIANGSU SIMCERE PHARMACEUTICAL R & D Co.,Ltd. Patentee after: JILIN BODA PHARMACEUTICAL Co.,Ltd. Address before: 210042 Xuanwu Avenue, Jiangsu, Nanjing, No. 699 -18 Patentee before: JIANGSU SIMCERE PHARMACEUTICAL R & D Co.,Ltd. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160725 Address after: 210042 Xuanwu District, Xuanwu District, Jiangsu, Nanjing No. 699 -18 Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Patentee after: JILIN BODA PHARMACEUTICAL Co.,Ltd. Address before: 210042 Xuanwu Avenue, Jiangsu, Nanjing, No. 699 -18 Patentee before: JIANGSU SIMCERE PHARMACEUTICAL R & D Co.,Ltd. Patentee before: Jilin Boda Pharmaceutical Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Co-patentee after: Jilin Boda pharmaceutical Limited by Share Ltd. Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Co-patentee before: Jilin Boda Pharmaceutical Co.,Ltd. Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20180921 Address after: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Co-patentee after: Jilin Boda pharmaceutical Limited by Share Ltd. Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Co-patentee after: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Co-patentee before: Jilin Boda pharmaceutical Limited by Share Ltd. Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| CP01 | Change in the name or title of a patent holder | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 210042 -18, Xuanwu Avenue, Xuanwu District, Jiangsu, Nanjing, 699 Co-patentee after: Jilin Boda pharmaceutical Limited by Share Ltd. Patentee after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Co-patentee after: SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 -18, Xuanwu Avenue, Xuanwu District, Jiangsu, Nanjing, 699 Co-patentee before: Jilin Boda pharmaceutical Limited by Share Ltd. Patentee before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Co-patentee before: NANJING SIMCERE DONGYUAN PHARMACEUTICA Co.,Ltd. |