CN110483324A - The preparation method of safinamide impurity - Google Patents
The preparation method of safinamide impurity Download PDFInfo
- Publication number
- CN110483324A CN110483324A CN201910855024.8A CN201910855024A CN110483324A CN 110483324 A CN110483324 A CN 110483324A CN 201910855024 A CN201910855024 A CN 201910855024A CN 110483324 A CN110483324 A CN 110483324A
- Authority
- CN
- China
- Prior art keywords
- safinamide
- impurity
- preparation
- ethyl
- ethyl acetate
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of safinamide impurity, the described method comprises the following steps: step S10, and D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, condensing agent, alkali are stirred in a solvent, reacted；Water is added after reaction and is extracted with ethyl acetate with ethyl acetate, water phase by step S20, and organic phase drying is concentrated to get safinamide impurity.Compared with the existing technology, the present invention can provide convenience for the impurity analysis and research of safinamide bulk pharmaceutical chemicals and its preparation, provide detection method and judgment basis for the production of safinamide and drug safety.
Description
Technical field
The present invention relates to the production of safinamide and drug safety detection technique field more particularly to a kind of safinamide are miscellaneous
The preparation method of matter.
Background technique
Parkinson's disease (Parkinson&apos；S disease, PD) be to tremble, splinting, bradykinesia, posture step
The motor symptoms such as state exception are the common person in middle and old age's nerve retrograde affection of one kind of main clinical manifestation.China over-65s people
Group's PD totality illness rate is 1 700,/10 ten thousand, and increases with the age and increase, and brings heavy burden to family and society.It passes
System theory, which thinks that PD physiological pathology mechanism is mainly damaged with nigral dopaminergic neuron, causes dopamine mediator in corpus straitum insufficient, second
Phatidylcholine function is relatively dominant related, and there are also new research shows that non-dopaminergic nerve transmitter, such as excessively living
The glutamine transaminage of change and the occurrence and development of PD are closely related.Exogenous supplement dopamine inhibits internal DOPA amine degradation
It is clinical common treatment PD means, PD motor symptoms can be effectively relieved in levodopa and its compound preparation, and clinical application is extensive.But
The long-term or large dosage of use of levodopa can generate fluctuation motor symptoms, such as " on-off phenomenon ", even result in " levodopa
It is related " dyskinesia generation.Therefore, middle and advanced stage PD patient often takes treated with combined medication, i.e., on the basis of levodopa, adds use
Dopamine-receptor stimulant (dopamine agonists, DAs), monoamine oxidase B (monoamine oxidase B, MAO-
B) inhibitor, selective catechol-O-methyltransferase (catecholO-methyltransferase, COMT) inhibitor
Or amantadine.Combination therapy can effectively delay PD disease progression again and can be reduced levodopa dosage, reduce left-handed more
Bar adverse reaction occurrence risk.
Safinamide (trade name: Xadago) is a kind of novel MAO-B inhibitor, can be reduced dopamine caused by MAO-B
Degradation and reuptake improve intracerebral dopamine concentration, improve PD clinical symptoms.Safinamide praises nation (Zambon) collection by Italy
Group and Newron drugmaker R & D Cooperation, 2 months 2015 in the granted listing of European Union, acquisition U.S. FDA on March 21st, 2017 batch
Standard, this is that the U.S. is first granted for treating the new chemical entities of PD during the last ten years.With traditional MAO-B inhibitor Si Laiji
Blue, Rasagiline difference, safinamide has higher selectivity to MAO-B, and reversible action, safe range are wider.
The impurity contained in drug is the principal element for influencing pharmaceutical purity, and the impurity of limitation is had more than as contained in drug,
It is possible to change physicochemical constant, appearance character generates variation, and influences the stability of drug；Impurity, which increases, also necessarily makes medicine
The content of object is relatively low or active reduction, toxic side effect dramatically increase.Therefore, the determination of foreign matter of drug is control pharmaceutical purity, is mentioned
One very important link of high drug quality.
Summary of the invention
It is a primary object of the present invention to propose a kind of preparation method of safinamide impurity, it is intended to be safinamide raw material
The impurity analysis of medicine and its preparation and research provide convenience, provide detection method for the production of safinamide and drug safety and sentence
Determine foundation.
To achieve the above object, the present invention proposes a kind of preparation method of safinamide impurity, and the method includes following
Step:
Step S10 stirs D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, condensing agent, alkali in a solvent
It mixes, react；
Water is added after reaction and is extracted with ethyl acetate with ethyl acetate, water phase by step S20, and organic phase drying is dense
Contracting obtains safinamide impurity.
The further technical solution of the present invention is that the condensing agent includes I-hydroxybenzotriazole, 1- ethyl-(3- diformazan
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 2-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester or 2- tetramethylurea hexafluoro
One or more of phosphate.
The further technical solution of the present invention is that the alkali includes n,N-diisopropylethylamine, triethylamine or tri-n-butylamine
One of.
The further technical solution of the present invention is that the solvent includes one of acetonitrile, DMF or methylene chloride.
The further technical solution of the present invention is that the condensing agent includes I-hydroxybenzotriazole, 1- ethyl-(3- diformazan
Base aminopropyl) phosphinylidyne diimmonium salt hydrochlorate, the alkali is n,N-diisopropylethylamine, and the solvent is DMF, third ammonia of D-
Amide hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, I-hydroxybenzotriazole, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne
Diimmonium salt hydrochlorate, n,N-diisopropylethylamine mass ratio be 2:1:1.5:3:5, the quality of the DMF is D- alanimamides
40-100 times of hydrochloride.
The further technical solution of the present invention is that the mixing time in the step S10 is 2-16 hours.
The beneficial effects of the present invention are: the preparation method of safinamide impurity of the present invention will be through the above technical solutions, first will
D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, condensing agent, alkali are stirred in a solvent, are reacted, after reaction plus
Enter water and be extracted with ethyl acetate with ethyl acetate, water phase, organic phase drying is concentrated to get safinamide impurity, can be husky fragrant acyl
The impurity analysis and research of amine bulk pharmaceutical chemicals and its preparation provide convenience, provide detection side for the production and drug safety of safinamide
Method and judgment basis.
Detailed description of the invention
Fig. 1 is the flow diagram of the preparation method preferred embodiment of safinamide impurity of the present invention；
Fig. 2 is the synthetic route of safinamide impurity in the preparation method preferred embodiment of safinamide impurity of the present invention
Figure；
Fig. 3 is the chemical structural formula of safinamide impurity in the preparation method preferred embodiment of safinamide impurity of the present invention
Figure.
Specific embodiment
It should be appreciated that the specific embodiments described herein are merely illustrative of the present invention, it is not intended to limit the present invention.
Preferred embodiment of the invention is described in further detail below.
Fig. 1 to Fig. 3 is please referred to, the present invention proposes a kind of preparation method of safinamide impurity, wherein Fig. 1 is the present invention
The flow diagram of the preparation method preferred embodiment of safinamide impurity；Fig. 2 is the preparation side of safinamide impurity of the present invention
The synthetic route chart of safinamide impurity in method preferred embodiment；Fig. 3 is that the preparation method of safinamide impurity of the present invention is preferable
The chemical structural formula figure of safinamide impurity in embodiment.
As shown in Figure 1 to Figure 3, in the present embodiment, method includes the following steps:
Step S10 stirs D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, condensing agent, alkali in a solvent
It mixes, react.
Wherein, the condensing agent includes I-hydroxybenzotriazole, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine
Hydrochloride, 2-N, N, N', one or more of N'- tetramethylurea hexafluorophosphoric acid ester or 2- tetramethylurea hexafluorophosphoric acid ester,
The alkali includes one of n,N-diisopropylethylamine, triethylamine or tri-n-butylamine, the solvent include acetonitrile, DMF or
One of person's methylene chloride.
The mixing time is 2-16 hours, such as 2 hours or 9 hours or 16 hours.
For example, as an implementation, the condensing agent includes I-hydroxybenzotriazole, 1- ethyl-(3- dimethylamino
Base propyl) phosphinylidyne diimmonium salt hydrochlorate, the alkali is n,N-diisopropylethylamine, and the solvent is DMF, wherein the D- third
Aminoacyl amine hydrochlorate, 4- (3- fluorine benzyloxy) benzoic acid, I-hydroxybenzotriazole, 1- ethyl-(3- dimethylaminopropyl) carbon
Acyl diimmonium salt hydrochlorate, n,N-diisopropylethylamine mass ratio be 2:1:1.5:3:5, the quality of the DMF is D- alanyl
40-100 times of amine hydrochlorate.
Water is added after reaction and is extracted with ethyl acetate with ethyl acetate, water phase by step S20, and organic phase drying is dense
Contracting obtains safinamide impurity.
Specifically, in the present embodiment, first by D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, 1- hydroxy benzenes
And triazole, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and n,N-diisopropylethylamine in mass ratio 2:
1:1.5:3:5 is stirred at room temperature 2 hours to 16 hours in solvent DMF (40-100 times of D- alanimamides hydrochloric acid salt quality), instead
Water is added after answering and ethyl acetate, water phase are extracted with ethyl acetate, organic phase drying is concentrated to get the safinamide impurity.
In the present embodiment, enforceable material quality can be from 0.1 gram to 100 gram.
The beneficial effect of the preparation method of safinamide impurity of the present invention is: the preparation method of safinamide impurity of the present invention
Through the above technical solutions, in a solvent by D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, condensing agent, alkali first
Water is added after reaction and is extracted with ethyl acetate with ethyl acetate, water phase for stirring, reaction, and organic phase drying is concentrated to get
Safinamide impurity can provide convenience for the impurity analysis and research of safinamide bulk pharmaceutical chemicals and its preparation, be safinamide
Production and drug safety provide detection method and judgment basis.
The above is only a preferred embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalent structure or equivalent flow shift made by bright specification and accompanying drawing content is applied directly or indirectly in other relevant skills
Art field, is included within the scope of the present invention.
Claims (6)
1. a kind of preparation method of safinamide impurity, which is characterized in that the described method comprises the following steps:
D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, condensing agent, alkali are stirred in a solvent, are anti-by step S10
It answers；
Water is added after reaction and is extracted with ethyl acetate with ethyl acetate, water phase by step S20, and organic phase drying is concentrated to give
To safinamide impurity.
2. the preparation method of safinamide impurity according to claim 1, which is characterized in that the condensing agent includes 1- hydroxyl
Base benzotriazole, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, 2-N, N, N', N'- tetramethylurea hexafluoro
One or more of phosphate or 2- tetramethylurea hexafluorophosphoric acid ester.
3. the preparation method of safinamide impurity according to claim 2, which is characterized in that the alkali includes N, and N- bis- is different
One of propylethylamine, triethylamine or tri-n-butylamine.
4. the preparation method of safinamide impurity according to claim 3, which is characterized in that the solvent include acetonitrile,
One of DMF or methylene chloride.
5. the preparation method of safinamide impurity according to claim 4, which is characterized in that the condensing agent includes 1- hydroxyl
Base benzotriazole, 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, the alkali are N, N- diisopropyl second
Amine, the solvent are DMF, the D- alanimamides hydrochloride, 4- (3- fluorine benzyloxy) benzoic acid, I-hydroxybenzotriazole, 1-
Ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate, n,N-diisopropylethylamine mass ratio be 2:1:1.5:3:
5, the quality of the DMF is 40-100 times of D- alanimamides hydrochloride.
6. the preparation method of safinamide impurity according to claim 5, which is characterized in that stirring in the step S10
Mixing the time is 2-16 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910855024.8A CN110483324A (en) | 2019-09-10 | 2019-09-10 | The preparation method of safinamide impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910855024.8A CN110483324A (en) | 2019-09-10 | 2019-09-10 | The preparation method of safinamide impurity |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110483324A true CN110483324A (en) | 2019-11-22 |
Family
ID=68557285
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910855024.8A Pending CN110483324A (en) | 2019-09-10 | 2019-09-10 | The preparation method of safinamide impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110483324A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113024407A (en) * | 2019-12-24 | 2021-06-25 | 上海科胜药物研发有限公司 | Salfinamide nitrite impurity compound and preparation method thereof |
| CN113390986A (en) * | 2021-05-31 | 2021-09-14 | 河北国龙制药有限公司 | Method for detecting genotoxic impurities in salfinamide mesylate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1659135A (en) * | 2002-06-12 | 2005-08-24 | 弗·哈夫曼-拉罗切有限公司 | Fluorobenzamides suitable for the treatment of alzheimer's disease or senile dementia |
-
2019
- 2019-09-10 CN CN201910855024.8A patent/CN110483324A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1659135A (en) * | 2002-06-12 | 2005-08-24 | 弗·哈夫曼-拉罗切有限公司 | Fluorobenzamides suitable for the treatment of alzheimer's disease or senile dementia |
Non-Patent Citations (2)
| Title |
|---|
| LIANG ZOU ET AL.: "Identification, characterization, and quantification of impurities of safinamide mesilate: process-related impurities and degradation products", 《JOURNAL OF AOAC INTERNATIONAL》, vol. 100, no. 4, 1 July 2017 (2017-07-01), pages 1029 - 1037 * |
| 刘鹰翔等: "《药物合成反应》", vol. 1, 31 August 2017, 中国中医药出版社, pages: 133 - 135 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113024407A (en) * | 2019-12-24 | 2021-06-25 | 上海科胜药物研发有限公司 | Salfinamide nitrite impurity compound and preparation method thereof |
| CN113390986A (en) * | 2021-05-31 | 2021-09-14 | 河北国龙制药有限公司 | Method for detecting genotoxic impurities in salfinamide mesylate |
| CN113390986B (en) * | 2021-05-31 | 2022-04-08 | 河北国龙制药有限公司 | Method for detecting genotoxic impurities in salfinamide mesylate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Jubrias et al. | Large energetic adaptations of elderly muscle to resistance and endurance training | |
| CN110483324A (en) | The preparation method of safinamide impurity | |
| CN1195743C (en) | Dihydro-1,3,5-triazine amine derivatives and their therapeutic uses | |
| Oyer et al. | A1c control in a primary care setting: self-titrating an insulin analog pre-mix (INITIATEplus Trial) | |
| CN100497337C (en) | Folacin dimethylbiguanide and process for production thereof | |
| Chemburkar et al. | Chemistry of thyroxine: an historical perspective and recent progress on its synthesis | |
| CN107922420A (en) | The therapeutic compound and composition of obstacle are used for treating human communication disorders and medicine | |
| Egawa et al. | Redox-controlled proton gating in bovine cytochrome c oxidase | |
| US20230241024A1 (en) | Methods of treating metabolic disorders | |
| Odin et al. | Continuous dopaminergic stimulation achieved by duodenal levodopa infusion | |
| CN102344950B (en) | A kind of method of the acetylize metabolite for detecting SSAT substrate | |
| CN103319399B (en) | The preparation method of Egelieting intermediate R-3-amino piperidine dihydrochloride | |
| CA2750074A1 (en) | Use of cardiotrophin-1 for the treatment of metabolic diseases | |
| CN104230770B (en) | The application of styryl sulfone compound, its preparation method as well as neuroprotective agent | |
| CN108703946B (en) | A kind of transdermal absorption formulation for treating diabete peripheral herve pain | |
| CN105832724A (en) | Use of indolol in preparation of anti-depression drugs | |
| Lesmana et al. | Ethionamide Alters Thyroid Receptor Gene Expression in Rats' Muscle | |
| CN1579377A (en) | Use of Rhizoma-Curcumae-Longae element in preparing medicine for treating lung disease | |
| CN104530011B (en) | A kind of itrile group diamantane tetrazotized zole compound, Preparation Method And The Use | |
| KR100395338B1 (en) | Chrysin Derivatives and their Composition for Anti-Diabete | |
| US20230054551A1 (en) | Oral pharmaceutical composition and method for delivering nitric oxide to a patient's circulatory system or brain | |
| CN102119137A (en) | Methods of sythesizing cinacalcet hydrochloride | |
| US20240130675A1 (en) | Methods for Treating Autism Spectrum Disorder | |
| CN100486960C (en) | Biguanide derivative and preparing method thereof | |
| CN106674192A (en) | Preparation method for degraded trelagliptin impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20191122 |
|
| RJ01 | Rejection of invention patent application after publication |