CN113030283A - Rasagiline genotoxic impurity compound and preparation method and application thereof - Google Patents
Rasagiline genotoxic impurity compound and preparation method and application thereof Download PDFInfo
- Publication number
- CN113030283A CN113030283A CN201911354999.9A CN201911354999A CN113030283A CN 113030283 A CN113030283 A CN 113030283A CN 201911354999 A CN201911354999 A CN 201911354999A CN 113030283 A CN113030283 A CN 113030283A
- Authority
- CN
- China
- Prior art keywords
- formula
- rasagiline
- xii
- xiii
- compound
- 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
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
- C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
- C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
- G01N2030/062—Preparation extracting sample from raw material
Abstract
The invention discloses rasagiline genotoxic impurity compounds shown in formulas XI, XII and XIII, a preparation method of the compounds and application of the compounds as genotoxic impurity reference substances in quality inspection of rasagiline intermediates and finished products.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to rasagiline genotoxic impurity compounds, a preparation method and application thereof.
Background
Rasagiline, represented by structural formula I and having the chemical name R- (+) -N-propargyl-1-aminoindan mesylate, is a second generation of selective, irreversible monoamine oxidase-B (MAO-B) inhibitor, commonly developed by Teva and Lundbeck, useful for the treatment of Parkinson's Disease (PD). The drug was first approved for marketing in israel in 1 month of 2005, either as first line drug for the early treatment of Parkinson's Disease (PD), alone or in combination with levodopa for the treatment of moderate, severe parkinson's disease, under the trade name Azilect, and subsequently approved for marketing in europe in the european union in 2 months of 2005 and had obtained an FDA approvable letter. In addition, the medicine is currently in clinical treatment for treating senile dementia (AD), depression, and attention deficit hyperactivity disorder. At present, the medicine is not on the market at home.
Parkinson's Disease (PD) is a degenerative disease of the nervous system, which is common in the middle-aged and elderly, and the diseased part is the part of the human brain called midbrain. The substantia nigra neurons, synthesize a neurotransmitter called dopamine, the nerve fibers of which project into other areas of the brain, such as the striatum, and regulate the motor function of the brain. When these substantia nigra neurons degenerate and die to more than 80%, dopamine, a neurotransmitter in the brain, is reduced to the point where it fails to maintain normal function in the regulatory nervous system, and symptoms of parkinson's disease occur. As a novel, potent, second-generation selective, irreversible monoamine oxidase-B (MAO-B) inhibitor, rasagiline has similar pharmacological effects to the first-generation selective, irreversible monoamine oxidase inhibitor selegiline, which is currently used for the treatment of parkinson's disease and senile dementia, and transdermal agents thereof have been used for the treatment of depression, but has stronger inhibitory effects on MAO-B in vivo, and does not produce side effects such as elevation of blood pressure, increase in heart rate, sleep disorders and excitement caused by selegiline metabolism because the metabolism of the drug is different from selegiline. Evidence exists in a laboratory animal model to show that the medicine can avoid apoptosis of nerve cells caused by Parkinson's disease. Clinical research results show that the rasagiline mesylate has good tolerance and safety and light side effect no matter used alone or used together with other medicines, and common side effects comprise headache, nausea and the like; the most common side effects on long-term treatment are infection, accidental injury, nausea, and arthralgia.
Combining with the valsartan event in 2018, genotoxic impurities such as N-Nitrosodimethylamine (NDMA) and the like are found in the valsartan bulk drug, and then genotoxic impurities such as N-Nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA) and the like are successively exposed. Identification and investigation of process impurities in the bulk drugs, particularly identification and risk control of genotoxic impurities, become important work affecting the quality of the bulk drugs.
Disclosure of Invention
Route I is one of the common processes for the preparation of rasagiline, in which route the starting material 3-chloropropyne of formula VI contains impurities of formulae VIII, IX and X, which in process route I can be derived from intermediates of formula V, to give suspected genotoxic impurities of formulae XI, XII and XIII, and thus the process route is at risk of the presence of suspected genotoxic impurities of formulae XI, XII and XIII. Predicted by CASE Ultra software (version 1.7.0.5) from Multicase, the possibility of the compounds of formulae XI, XII and XIII being genotoxic impurities was equal to or greater than 50% in three models GT1_ BMUT, GT _ EXPERT and PHARM _ BMUT. If the content of the genotoxic impurity exceeds an acceptable limit (calculated by TTC, the content is 1500ppm), the genotoxic impurity brings the risk of teratogenicity, carcinogenesis and mutagenesis to patients taking the medicine, so the genotoxic impurity is prepared and used as a reference substance to monitor the content of the rasagiline and is controlled by a technological means, the quality of the rasagiline can be effectively controlled, and the safety and the effectiveness of the clinical use of the rasagiline are ensured.
Route I:
the prepared compound shown in the formula XI is structurally characterized by quantitative nuclear magnetic resonance (Q NMR) and mass spectrum (ESI-MS), and the detection results are respectively shown in figure 1 and figure 2. The quantitative nuclear magnetic resonance hydrogen spectrum is analyzed, the content is 84.6 percent, and the hydrogen spectrum is attributed as follows:
1H NMR(400MHz,d6-DMSO)δ1.70-1.77(m,1H),2.23-2.31(m,1H),2.68-2.76(m,1H),2.86-2.92(m,1H),3.39(s,2H),4.13(t,J＝6.8Hz,1H),5.33(d,J＝0.8Hz,1H),5.60(d,J＝1.6Hz,1H),7.15-7.21(m,3H),7.32-7.36(m,1H)；
the mass spectral characteristics of this impurity compound are described below:
mass Spectrometry (ESI-MS) gives [ M + H [ ]]+Isotopic peaks at 208.2 and 210.15, consistent with the theoretical molecular weight of 207.70 for impurity XI; gives an ion peak of 117.2, differs from the theoretical molecular weight of 207.70 by 90.5, and is [207.7-90.5 ]]+The fragment ion peak of amine.
Based on the above data, the inventors determined that the compound has the structure shown in formula XI:
the compound of formula XII obtained by the preparation was structurally characterized by quantitative nuclear magnetic resonance (Q NMR) and mass spectrometry (ESI-MS), and the results of the detection are shown in fig. 3 and fig. 4, respectively. The quantitative nuclear magnetic resonance hydrogen spectrum is analyzed, the content is 89.3 percent, and the hydrogen spectrum attribution is as follows:
1H NMR(400MHz,d6-DMSO)δ1.69-1.77(m,1H),2.24-2.32(m,1H),2.67-2.75(m,1H),2.87-2.94(m,1H),3.39(dd,J＝6.0Hz,2.0Hz,2H),4.10(t,J＝6.8Hz,1H),5.99(dd,J＝13.2Hz,6.0Hz,1H),6.31(dt,J＝7.2Hz,1.6Hz,1H),7.14-7.21(m,3H),7.31-7.36(m,1H)；
the mass spectral characteristics of this impurity compound are described below:
mass Spectrometry (ESI-MS) gives [ M + H [ ]]+The isotopic peaks of 208.15 and 210.10 correspond to the theoretical molecular weight of 207.70 for the structure of impurity XII; gives an ion peak of 117.2, differs from the theoretical molecular weight of 207.70 by 90.5, and is [207.7-90.5 ]]+The fragment ion peak of amine.
Based on the above data, the inventors determined that the compound has the structure shown in formula XII:
the prepared compound represented by the formula XIII is structurally characterized by quantitative nuclear magnetic resonance (Q NMR) and mass spectrometry (ESI-MS), and the detection results are shown in FIG. 5 and FIG. 6, respectively. The quantitative nuclear magnetic resonance hydrogen spectrum is analyzed, the content is 88.4 percent, and the hydrogen spectrum attribution is as follows:
1H NMR(400MHz,d6-DMSO)δ1.67-1.72(m,1H),2.23-2.50(m,1H),2.66-2.74(m,1H),2.86-2.92(m,1H),3.24(td,J＝6.8Hz,1.6Hz,2H),4.09(t,J＝6.8Hz,1H),6.03(m,1H),6.37(dt,J＝13.2Hz,1.6Hz,1H),7.12-7.21(m,3H),7.31-7.36(m,1H)；
the mass spectral characteristics of this impurity compound are described below:
mass Spectrometry (ESI-MS) gives [ M + H [ ]]+The isotopic peaks, 208.15 and 210.10, correspond to the theoretical molecular weight of 207.70 for the structure of impurity XIII; gives an ion peak of 117.2, differs from the theoretical molecular weight of 207.70 by 90.5, and is [207.7-90.5 ]]+The fragment ion peak of amine.
Based on the above data, the inventors determined that the compound has the structure shown in formula XIII:
in a second aspect, the present invention also relates to a process for the preparation of compounds of formula XI, formula XII and formula XIII, comprising the steps of:
reacting (R) -2, 3-dihydro-1H-indene-1-amine with 2, 3-dichloro-1-propene, cis-1, 3-dichloro-1-propene or trans-1, 3-dichloro-1-propene in acetonitrile at 60 ℃ in the presence of sodium bicarbonate, and separating to obtain the compounds shown in the formulas XI, XII and XIII.
The use of the compounds shown as impurities XI, XII and XIII according to the invention as controls for genotoxic impurities in the quality testing of rasagiline intermediates and finished products.
The invention also provides a method for controlling the quality of rasagiline intermediates and finished products, characterized in that: impurities XI, XII and XIII were used as controls for genotoxic impurities. A preferred quality control method comprises the steps of: weighing a proper amount of impurity XI compound (or XII or XIII compound), and dissolving in a diluent to prepare an impurity reference substance solution with a proper concentration; then, the rasagiline intermediate and the impurity XI compound (XII or XIII compound) contained in the final sample were investigated qualitatively or quantitatively by LCMS-ESI.
The compounds shown as impurities XI, XII and XIII discovered according to the invention have important application significance in the process development, quality research and analytical method development of rasagiline. In addition, the impurities XI, XII and XIII compounds found in the present invention allow easier and more intuitive quality control of rasagiline intermediates and final products. In addition, the preparation method of the impurity compounds XI, XII and XIII has low process cost, easy control and easy acquisition of raw materials; and the obtained product has stable quality and high yield.
The invention has the beneficial effects that: the invention discovers compounds XI, XII and XIII with genotoxic impurities, and if the content of the genotoxic impurities exceeds an acceptable limit, the compounds bring risks of teratogenicity, carcinogenesis and mutagenesis to patients taking the compounds, so the genotoxic impurities are prepared and used as reference substances to monitor the content of rasagiline and are controlled by technological means, the quality of the rasagiline can be effectively controlled, and the safety and the effectiveness of the clinical use of the rasagiline are ensured.
Drawings
FIG. 1 shows a QNMR spectrum of a compound represented by formula XI.
FIG. 2 ESI-MS spectra of compounds of formula XI.
FIG. 3 shows a QNMR spectrum of a compound represented by the formula XII.
FIG. 4 shows ESI-MS spectra of compounds of formula XII.
FIG. 5 shows a QNMR spectrum of a compound represented by the formula XIII.
FIG. 6 ESI-MS spectra of compounds represented by formula XIII.
Detailed Description
Example 1
Preparation of a compound of formula XI:
adding 2.0g of (R) -2, 3-dihydro-1H-indene-1-amine shown in the formula V into 46mL of acetonitrile, adding 1.7g of 2, 3-dichloro-1-propylene shown in the formula VIII and 1.1g of sodium bicarbonate, stirring at 60 ℃ for 18 hours, monitoring the reaction process through LC-MS analysis, filtering the reaction solution after the reaction is finished, washing with 2mL of acetonitrile, concentrating the filtrate under reduced pressure to dryness, adding 8mL of toluene and 4mL of water, adjusting the pH to 2.5-3.0 by using 10% sulfuric acid, stirring, separating, and extracting the toluene phase twice by using 4mL of water when the pH is controlled to be 2.5-3.0; the aqueous phases were combined, the pH was adjusted to 7.5-8.0 with 15% aqueous sodium hydroxide solution, the mixture was extracted three times with 4mL of toluene, the organic phase was concentrated and evaporated to dryness to give 1.6g of a brownish red oil, and silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) was carried out to give 2.1g of a pale yellow oil as the target impurity compound XI (content: 84.6%) in a yield of 82%.
Example 2
Preparation of a compound of formula XII:
adding 2.0g of (R) -2, 3-dihydro-1H-indene-1-amine shown in the formula V into 46mL of acetonitrile, adding 1.7g of cis-1, 3-dichloro-1-propylene shown in the formula IX and 1.1g of sodium bicarbonate, stirring at 60 ℃ for 18 hours, monitoring the reaction progress through LC-MS analysis, filtering the reaction liquid after the reaction is finished, washing with 2mL of acetonitrile, decompressing and concentrating the filtrate to dryness, adding 8mL of toluene and 4mL of water, adjusting the pH to 2.5-3.0 by using 10% sulfuric acid, stirring, separating liquid, and extracting the toluene phase twice by using 4mL of water when the pH is controlled to be 2.5-3.0; the aqueous phases were combined, the pH was adjusted to 7.5-8.0 with 15% aqueous sodium hydroxide solution, three times of extraction with 4mL of toluene, the organic phase was concentrated and evaporated to dryness to give 2.0g of a brownish red oil, and 2.0g of a pale yellow oil was obtained by silica gel column chromatography (petroleum ether: ethyl acetate: 20:1) as the target impurity compound XII (content 89.3%) in 78% yield.
Example 3
Preparation of a compound of formula XIII:
adding 2.0g of (R) -2, 3-dihydro-1H-indene-1-amine shown in the formula V into 46mL of acetonitrile, adding 1.7g of trans-1, 3-dichloro-1-propylene shown in the formula X and 1.1g of sodium bicarbonate, stirring at 60 ℃ for 18 hours, monitoring the reaction progress through LC-MS analysis, filtering the reaction liquid after the reaction is finished, washing with 2mL of acetonitrile, decompressing and concentrating the filtrate to dryness, adding 8mL of toluene and 4mL of water, adjusting the pH to 2.5-3.0 by using 10% sulfuric acid, stirring, separating liquid, and extracting the toluene phase twice by using 4mL of water when the pH is controlled to be 2.5-3.0; the aqueous phases were combined, the pH was adjusted to 7.5-8.0 with 15% aqueous sodium hydroxide, three times of extraction were performed with 4mL of toluene, the organic phase was concentrated and evaporated to dryness to give 1.4g of a brownish red oil, and 2.4g of a pale yellow oil was obtained by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) as the target impurity compound XIII (content 88.4%), with a yield of 94%.
Example 4
This example illustrates the use of compounds of formula XI, formula XII and formula XIII as controls for genotoxic impurities in the quality testing of rasagiline intermediates and preparations.
Chromatographic conditions are as follows:
the instrument comprises the following steps: LCMS-02-1309(Agilent 1260HPLC chromatograph APCI/MS detector)
A chromatographic column: agilent, Poroshell 120EC-C18,2.7 μm, 50 × 3.0mm (SPZ-18082)
Mobile phase A: 0.1% aqueous trifluoroacetic acid solution, 1mL trifluoroacetic acid diluted to 1L with deionized water
Mobile phase B: 0.1% trifluoroacetic acid in acetonitrile, 1mL trifluoroacetic acid diluted to 1L with acetonitrile
The diluent acetonitrile and water are 1:1
Sample preparation
Blank solution: acetonitrile and water 1:1
Impurity stock solution: accurately weighing 25mg of impurities into a 10mL volumetric flask, dissolving the impurities with acetonitrile, fixing the volume, and uniformly mixing (2.5 mg/mL); 20. mu.L of the solution was accurately transferred to a 10mL volumetric flask, diluted to a constant volume and mixed (5. mu.g/mL).
System adaptation solution: accurately transferring 1000. mu.L of the solution into a 10mL volumetric flask, diluting the solution to a constant volume, and uniformly mixing. (500ng/mL)
System adaptation solution: accurately transferring 1000 mu L of the system adaptive solution into a 10mL volumetric flask, diluting the solution to a constant volume by using a diluent, and uniformly mixing. (50ng/mL)
LOQ solution: 250 mul of the systematic adaptive solution is accurately transferred and added with 500 mul of the diluent and mixed evenly. (16.7 ng/mL).
LOD solution: accurately transferring 1000 mu L of the system adaptive solution into a 10mL volumetric flask, diluting the solution to a constant volume by using a diluent, and uniformly mixing. (5 ng/mL).
Linear solution: 50% System Adaptation solution 500. mu.L of impurity stock solution was transferred to a 10mL volumetric flask and the volume was fixed with diluent. (25ng/mL)
80% System Adaptation solution 800. mu.L of impurity stock solution was transferred to a 10mL volumetric flask and the volume was fixed with diluent. (40ng/mL)
100% System Adaptation solution 1000. mu.L of impurity stock solution was transferred to a 10mL volumetric flask and the volume was fixed with diluent. (50ng/mL)
120% System Adaptation solution 1200. mu.L of impurity stock solution was transferred to a 10mL volumetric flask and the volume was fixed with diluent. (60ng/mL)
150% System Adaptation solution 1500. mu.L of impurity stock solution was transferred to a 10mL volumetric flask and the volume was fixed with diluent. (75ng/mL)
200% System Adaptation solution 2000. mu.L of impurity stock solution was transferred to a 10mL volumetric flask and the volume was fixed with diluent. (100ng/mL)
Recovery rate solution: accurately weighing 10mg of sample in a 100mL volumetric flask, and then adding a system adaptive solution to the constant volume. Two portions were prepared in parallel. (0.1mg/mL)
Test solution: accurately weighing 10mg of the sample in a 100mL volumetric flask, and then diluting the solution to a constant volume. Two portions were prepared in parallel. (0.1mg/mL)
Program control solution: and (3) same system adaptive solution.
Impurities XI, XII and XIII compounds as genotoxic impurity controls the quality check results for the synthesis of rasagiline intermediates and final products according to scheme I are as follows:
the results show that the process of the route I has good control on impurities XI, XII and XIII in the rasagiline intermediate and the finished product, and can ensure the quality of rasagiline, thereby ensuring the safety and effectiveness of rasagiline in clinical use.
Claims (4)
1. Use of compounds of formula XI, formula XII and formula XIII as genotoxic impurity controls in the quality testing of rasagiline intermediates and finished products. .
2. A process for the preparation of compounds of formula XI, formula XII and formula XIII comprising the steps of:
reacting (R) -2, 3-dihydro-1H-indene-1-amine with 2, 3-dichloro-1-propene, cis-1, 3-dichloro-1-propene or trans-1, 3-dichloro-1-propene in acetonitrile at 60 ℃ in the presence of sodium bicarbonate, and separating to obtain the compounds shown in the formulas XI, XII and XIII.
3. A method for controlling the quality of rasagiline intermediates and end products, characterized by: a compound of formula XI, formula XII or formula XIII was used as a control for genotoxic impurities.
4. The method of claim 3, comprising the steps of:
weighing a proper amount of impurity XI compound (or XII or XIII compound), and dissolving in a diluent to prepare an impurity reference substance solution with a proper concentration; then, the rasagiline intermediate and the impurity XI compound (XII or XIII compound) contained in the final sample were investigated qualitatively or quantitatively by LCMS-ESI.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911354999.9A CN113030283A (en) | 2019-12-25 | 2019-12-25 | Rasagiline genotoxic impurity compound and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911354999.9A CN113030283A (en) | 2019-12-25 | 2019-12-25 | Rasagiline genotoxic impurity compound and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113030283A true CN113030283A (en) | 2021-06-25 |
Family
ID=76458044
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911354999.9A Pending CN113030283A (en) | 2019-12-25 | 2019-12-25 | Rasagiline genotoxic impurity compound and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113030283A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113884603A (en) * | 2021-11-17 | 2022-01-04 | 常州市第四制药厂有限公司 | Method for determining content of genotoxic impurities in rasagiline mesylate by liquid chromatography-mass spectrometry |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7572834B1 (en) * | 2005-12-06 | 2009-08-11 | Teva Pharmaceutical Industries, Ltd. | Rasagiline formulations and processes for their preparation |
| US20110155626A1 (en) * | 2009-11-26 | 2011-06-30 | Usv Limited | Process for preparation of rasagiline and salts thereof |
| CN102464589A (en) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | Preparation methods of rasagiline, mesylate thereof and intermediate of rasagiline |
-
2019
- 2019-12-25 CN CN201911354999.9A patent/CN113030283A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7572834B1 (en) * | 2005-12-06 | 2009-08-11 | Teva Pharmaceutical Industries, Ltd. | Rasagiline formulations and processes for their preparation |
| US20110155626A1 (en) * | 2009-11-26 | 2011-06-30 | Usv Limited | Process for preparation of rasagiline and salts thereof |
| CN102464589A (en) * | 2010-11-17 | 2012-05-23 | 凯瑞斯德生化(苏州)有限公司 | Preparation methods of rasagiline, mesylate thereof and intermediate of rasagiline |
Non-Patent Citations (1)
| Title |
|---|
| 李磊;张雪梅;王玉成;: "抗帕金森新药雷莎吉兰盐酸盐合成的改进", 徐州师范大学学报(自然科学版), no. 02 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113884603A (en) * | 2021-11-17 | 2022-01-04 | 常州市第四制药厂有限公司 | Method for determining content of genotoxic impurities in rasagiline mesylate by liquid chromatography-mass spectrometry |
| CN113884603B (en) * | 2021-11-17 | 2024-02-13 | 常州市第四制药厂有限公司 | Method for determining content of genotoxic impurities in rasagiline mesylate by liquid chromatography-mass spectrometry |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6852215B2 (en) | Voglibose Impurity I Hydrochloride Preparation Method | |
| US20120095105A1 (en) | Inhibitors of cognitive decline | |
| CN102595884A (en) | Inhibitors of cognitive decline | |
| CN113030283A (en) | Rasagiline genotoxic impurity compound and preparation method and application thereof | |
| González et al. | Efficient access to the Iboga skeleton: Optimized procedure to obtain voacangine from Voacanga africana root bark | |
| CN110922361A (en) | Etomidate oxidation impurity and preparation method thereof | |
| CN103864646B (en) | The impurity preparation of rasagiline mesilate and the method for analysis | |
| CN103458885A (en) | Isolated compounds from turmeric oil and methods of use | |
| CN110927279A (en) | Method for separating imidapril hydrochloride related substances | |
| US20140196523A1 (en) | 5,6,7,8-tetrahydro-6-[n,n-bis[(2-thienyl)ethyl]] amino-1-naphthol, and preparing method and use thereof | |
| CN113045456A (en) | New rasagiline impurity compound and preparation method and application thereof | |
| CN105254612A (en) | Lipoic acid impurity, preparation method of lipoic acid impurity and application of lipoic acid impurity | |
| CN101932549A (en) | Improved process for preparing cinacalcet hydrochloride | |
| CN110749692B (en) | Separation and detection method of L-glutamic acid diethyl ester hydrochloride and optical isomer thereof | |
| Chung et al. | Simple and sensitive liquid chromatographic method with fluorimetric detection for the analysis of gabapentin in human plasma | |
| CN103910674A (en) | Reference compounds for flupirtine maleate analysis | |
| CN101936959B (en) | High performance liquid chromatography (HPLC) for fast separating and analyzing zafirlukast and isomers thereof | |
| CN104072491A (en) | Azilsartan derivative compound and preparation method and application thereof | |
| CN112213407B (en) | Detection method of levoornidazole related substances | |
| CN113024405A (en) | Novel lacosamide impurity and preparation method and application thereof | |
| CN105974000A (en) | Use of 7-benzoyl-1,3-dihydroindole-2-one in nepafenac stability quality control | |
| CN106589007B (en) | Cis- Quzhazhigan and preparation method thereof and detection method | |
| CN111077247A (en) | Detection method of plant extract or preparation thereof | |
| CN110790705A (en) | Hydroxychloroquine derivative and preparation method and application thereof | |
| CN103553942A (en) | Preparation method of phenylephrine hydrochloride 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 |