CN113024405A - Novel lacosamide impurity and preparation method and application thereof - Google Patents
Novel lacosamide impurity and preparation method and application thereof Download PDFInfo
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- CN113024405A CN113024405A CN201911352131.5A CN201911352131A CN113024405A CN 113024405 A CN113024405 A CN 113024405A CN 201911352131 A CN201911352131 A CN 201911352131A CN 113024405 A CN113024405 A CN 113024405A
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- impurity
- compound
- lacosamide
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- 239000012535 impurity Substances 0.000 title claims abstract description 32
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 title claims abstract description 28
- 229960002623 lacosamide Drugs 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000013558 reference substance Substances 0.000 claims abstract description 11
- 239000000543 intermediate Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims 1
- 238000007689 inspection Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000011550 stock solution Substances 0.000 description 16
- 239000003814 drug Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 4
- 229940007550 benzyl acetate Drugs 0.000 description 4
- 238000007865 diluting Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 239000012088 reference solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 208000034308 Grand mal convulsion Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 238000012946 outsourcing Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000012372 quality testing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- 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
Abstract
The invention discloses a compound shown as a formula (I), and also discloses a preparation method of the compound and application of the compound as an impurity reference substance in quality inspection of lacosamide intermediates and finished products.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method and application of lacosamide impurity compounds.
Background
The chemical name of lacosamide is 2-acetamido-N-benzyl-3- (benzylamino) propionamide, and the chemical structural formula is as follows:
lacosamide (Lacosamide) is a drug approved by UCB for treating epilepsy and neuropathic pain after development of University of Houston (USA), and Lacosamide tablets (Lacosamide) approved by UCB company in European Union of 2008.08.29 are marketed for adjuvant treatment of partial epileptic seizures of patients with or without secondary grand mal seizures 16 years old and older. 2008.10.28 U.S. FDA approved lacosamide is marketed as an adjuvant drug in combination with other drugs for partial seizures.
The research on impurities is an important content in the research and development process of the medicine, is directly related to the quality control and the medication safety of the medicine, and can ensure the quality and the safety of the product by controlling the impurities in the medicine product. The impurities of the drug mainly originate from the by-products in the synthesis process and the degradation of the drug. At present, related process impurities and degradation impurities are rarely reported, but the invention aims at the impurities which are generated in the processes of preparation, storage and use of lacosamide and can influence the product quality, and has important significance for controlling the product quality.
Disclosure of Invention
The invention provides a preparation method of lacosamide impurity compound and an impurity reference substance used as lacosamide intermediate and finished product, which can effectively control the quality of lacosamide, thereby ensuring the safety and effectiveness of the clinical use of lacosamide, wherein the impurity compound is the compound of formula (I).
The impurity compound is generated in the preparation process of lacosamide.
The chemical name of the compound of the formula (I) is 2- (acetamido) -N- (benzyl acetate) -2-acrylamide, and the hydrogen spectrum is as follows:
1H NMR(400MHz,d6-DMSO)δ1.82-1.88(s,3H),2.28-2.41(m,1H),2.65-2.80(m, 2H),3.28-3.31(m,1H),3.61-3.71(s,1H),4.19-4.33(m,2H),4.35-4.44(m,1H),7.15-7.35(m, 10H),7.91-8.04(d,1H),8.42-8.51(t,1H)；Mass:326.2[M+H].
the invention also relates to the preparation of the impurity compound, which comprises the step of reacting the compound of formula 1 with the compound of formula 2 in a solvent to obtain the compound of formula (I), wherein the solvent is water, methanol, ethanol and a mixture thereof, preferably water, and the dosage of the compound of formula 2 is 3.0eq-10.0eq, preferably 5.0 eq.
The invention has the beneficial effects that: the invention discovers a novel impurity compound shown as the formula (I), and if the content of the impurity exceeds an acceptable limit, the impurity brings danger to a patient taking the medicine, so that the impurity is prepared and used as a reference substance to monitor the content of lacosamide and is controlled by a technological means, the quality of the lacosamide can be effectively controlled, and the safety and the effectiveness of the clinical use of the lacosamide are ensured.
FIG. 1: of formula (I)1H-NMR chart
FIG. 2 is a drawing: ESI-MS diagram of formula (I)
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
To further illustrate the present invention, specific embodiments of the present invention are described below with reference to examples. It is noted that the following description is only intended to further illustrate the features and advantages of the present invention, and not to limit the scope of the claims of the present invention.
Example 1:
adding 0.5g of 2- (acetamido) -N- (benzyl acetate) -2-acrylamide, 5mL of water and 1.25g of benzylamine into a 100mL three-neck flask, stirring to dissolve, stirring at the temperature of 15-25 ℃ for reaction for 20-26 hours, adding water and ethyl acetate, stirring for layering, extracting an aqueous phase with ethyl acetate, combining ethyl acetate phases, drying and concentrating to obtain a solid, pulping the solid with methyl tert-butyl ether, and drying at the temperature of 50 ℃ to obtain 0.59g of solid with the yield of 78.7%.
Example 2:
adding 0.5g of 2- (acetamido) -N- (benzyl acetate) -2-acrylamide, 5mL of methanol and 0.74g of benzylamine into a 100mL three-neck flask, stirring to dissolve, stirring at the temperature of 25-35 ℃ for reaction for 20-26 hours, adding water and ethyl acetate, stirring for layering, extracting an aqueous phase with ethyl acetate, combining ethyl acetate phases, drying and concentrating to obtain a solid, pulping the solid with methyl tert-butyl ether, and drying at the temperature of 50 ℃ to obtain 0.35g of solid with the yield of 46.7%.
Example 3:
adding 0.5g of 2- (acetamido) -N- (benzyl acetate) -2-acrylamide, 5mL of ethanol and 2.5g of benzylamine into a 100mL three-neck flask, stirring to dissolve, stirring at 15-25 ℃ for reaction for 20-26 hours, adding water and ethyl acetate, stirring for layering, extracting an aqueous phase with ethyl acetate, combining ethyl acetate phases, drying and concentrating to obtain a solid, pulping the solid with methyl tert-butyl ether, and drying at 50 ℃ to obtain 0.41g of solid with the yield of 54.7%
Example 4:
this example illustrates the use of the compound of formula (I) as a reference for impurities in the quality testing of lacosamide intermediates and finished products.
Chromatographic conditions are as follows:
1.1.2 reagents and standards
Phosphoric acid: chromatographic purity supplier: CNW CAS:7664-38-2
Methanol: chromatographic purity supplier: merck
Acetonitrile: chromatographic purity supplier: merck
Water: purified water
SC-3372-IMP41: company self-made or outsourcing
1.1.3 solution preparation
Diluting liquid: acetonitrile: water 1:9 (% V/V)
Blank solution: diluent liquid
SC-3372-IMP41 stock solution 1: 30mg of SC-3372-IMP34 reference substance is accurately weighed, precisely weighed in a 100mL volumetric flask, dissolved by diluent, fixed to a scale, and uniformly mixed (0.3 mg/mL).
SC-3372-IMP41 stock solution 2: accurately transferring 5.0mL of SC-3372-IMP34 stock solution into a volumetric flask of 100mL, dissolving the solution with diluent, fixing the volume to the scale, and uniformly mixing (15 mu g/mL).
SC-3372 stock solution 1: 30mg of SC-3372-CRUDE reference substance is accurately weighed, precisely weighed in a 100mL volumetric flask, dissolved by a diluent, and fixed to a scale, and uniformly mixed (0.3 mg/mL).
SC-3372 stock solution 2: accurately transferring the SC-3372-CRUDE stock solution into a volumetric flask with 5.0mL to 100mL, dissolving by using a diluent, fixing the volume to a scale, and uniformly mixing (15 mu g/mL).
Resolution solution: weighing 30mg of SC-3372 reference substance, precisely weighing the reference substance in a 100mL volumetric flask, transferring 3.0mL of SC-3372-D stock solution 2, transferring 3.0mL of SC-3372-IMP34 stock solution 2, transferring 3.0mL of SC-3372-IMP31 stock solution 2 in the volumetric flask, dissolving the reference substance in a diluent, diluting the reference substance to a scale, and uniformly mixing. (SC-3372:0.3 mg/mL SC-3372-D: 0.45. mu.g/mL, SC-3372-IMP34: 0.45. mu.g/mL, SC-3372-IMP41: 0.45. mu.g/mL).
Sensitivity solution: transferring 1.0mL of SC-3372 stock solution 2 into a 100mL volumetric flask, transferring 1.0mL of SC-3372-D stock solution 2, transferring 1.0mL of SC-3372-IMP34 stock solution 2, transferring 1.0mL of SC-3372-IMP31 stock solution 2 into the volumetric flask, diluting with a diluent, fixing the volume to a scale, and mixing uniformly (SC-3372: 0.15. mu.g/mL of SC-3372-D: 0.15. mu.g/mL, SC-3372-IMP34: 0.15. mu.g/mL, SC-3372-IMP31: 0.15. mu.g/mL).
Impurity standard solution: transferring 2.0mLSC-3372 stock solution 2 into a 100mL volumetric flask, then transferring 3.0IMP41 stock solution 2 into the volumetric flask respectively, fixing the volume of the diluent to the scale, and mixing uniformly. (SC-3372: 0.30. mu.g/mL, SC-3372-IMP41: 0.45. mu.g/mL).
Reference solution: transferring 1.0mL of SC-3372 stock solution 1 into a 100mL volumetric flask, diluting the solution to a constant volume to a scale, and mixing uniformly. (SC-3372: 3. mu.g/mL).
Test solution: prepare a test solution with a test concentration of 0.3mg/mL (for example, 30mg of the test sample is weighed, precisely weighed in a 100mL volumetric flask, dissolved and diluted to the scale with a diluent, and mixed well).
System applicability solution: as with the reference solution.
Program control solution: as with the reference solution.
Impurity (I) compound as an impurity control the quality inspection results for lacosamide intermediates and finished products were as follows:
| batch number | Impurity (I) Compound |
| SC-3372-D-1450-010-26 | Not detected out |
| SC-3372-D-1450-011-25 | Not detected out |
| SC-3372-D-1450-012-25 | Not detected out |
| SC-3372-CRUDE-1450-017-06 | Not detected out |
| SC-3372-CRUDE-1450-018-06 | Not detected out |
| SC-3372-CRUDE-1450-019-05 | Not detected out |
| SC-3372-1450-020-19 | Not detected out |
| SC-3372-1450-021-19 | Not detected out |
| SC-3372-1450-022-19 | Not detected out |
The result shows that the route process has good control on impurities (I) in lacosamide intermediates and finished products, and can ensure the quality of lacosamide, thereby ensuring the safety and effectiveness of the clinical use of the lacosamide.
Claims (7)
1. The invention reports a lacosamide impurity, a compound shown as a formula (I),
2. a process according to claim 1 for the preparation of lacosamide impurity compound, which comprises reacting a compound of formula 1 with a compound of formula 2 in a solvent to obtain a compound of formula (I)
3. The reaction temperature as set forth in claim 2 is 15 to 35 ℃.
4. The solvent as set forth in claim 2 is: water, methanol, ethanol or mixtures thereof, preferably the solvent is water.
5. The method of claim 2: the number of reaction equivalents of the compound of formula 2 is 3.0eq to 10.0eq, preferably 5 eq.
6. A method for controlling the quality of lacosamide intermediates and finished products, characterized by: the compound shown in the formula (I) is used as an impurity reference substance.
7. The method of claim 6, comprising the steps of:
weighing a proper amount of impurity (I) compound, and dissolving the impurity (I) compound in a diluent to prepare an impurity reference substance solution with a proper concentration; the impurity (I) compounds contained in the lacosamide intermediate and finished product samples were then investigated qualitatively or quantitatively by HPLC.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819269A (en) * | 2021-09-16 | 2023-03-21 | 北京新康哌森医药科技有限公司 | Lacosamide alkali degradation impurity and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3520930A (en) * | 1964-12-31 | 1970-07-21 | Merck & Co Inc | Lower alkoxy-amino-benzylamines |
| US7041667B1 (en) * | 1998-12-23 | 2006-05-09 | Pfizer, Inc. | CCR5 modulators |
| CN105800610A (en) * | 2016-03-31 | 2016-07-27 | 神华集团有限责任公司 | Preparing method for coal-based briquette active carbon without binding agent |
| CN106255513A (en) * | 2013-12-27 | 2016-12-21 | 酵活有限公司 | For drug conjugates containing sulfonamide connection system |
| CN107441766A (en) * | 2016-06-01 | 2017-12-08 | 中国科学院上海有机化学研究所 | A kind of extracts composition, extraction system and its application |
| CN109010301A (en) * | 2018-09-05 | 2018-12-18 | 上海上药第生化药业有限公司 | A kind of lacosamide crystal form II tablet and its preparation method and application |
| CN110320291A (en) * | 2019-06-21 | 2019-10-11 | 山东省药学科学院 | A kind of method of HPLC standard measure detection lacosamide injection liquid hold-up |
-
2019
- 2019-12-25 CN CN201911352131.5A patent/CN113024405A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3520930A (en) * | 1964-12-31 | 1970-07-21 | Merck & Co Inc | Lower alkoxy-amino-benzylamines |
| US7041667B1 (en) * | 1998-12-23 | 2006-05-09 | Pfizer, Inc. | CCR5 modulators |
| CN106255513A (en) * | 2013-12-27 | 2016-12-21 | 酵活有限公司 | For drug conjugates containing sulfonamide connection system |
| CN105800610A (en) * | 2016-03-31 | 2016-07-27 | 神华集团有限责任公司 | Preparing method for coal-based briquette active carbon without binding agent |
| CN107441766A (en) * | 2016-06-01 | 2017-12-08 | 中国科学院上海有机化学研究所 | A kind of extracts composition, extraction system and its application |
| CN109010301A (en) * | 2018-09-05 | 2018-12-18 | 上海上药第生化药业有限公司 | A kind of lacosamide crystal form II tablet and its preparation method and application |
| CN110320291A (en) * | 2019-06-21 | 2019-10-11 | 山东省药学科学院 | A kind of method of HPLC standard measure detection lacosamide injection liquid hold-up |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819269A (en) * | 2021-09-16 | 2023-03-21 | 北京新康哌森医药科技有限公司 | Lacosamide alkali degradation impurity and preparation method and application thereof |
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