CN114213306A - Preparation method of brivaracetam acid impurity - Google Patents
Preparation method of brivaracetam acid impurity Download PDFInfo
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- CN114213306A CN114213306A CN202111682165.8A CN202111682165A CN114213306A CN 114213306 A CN114213306 A CN 114213306A CN 202111682165 A CN202111682165 A CN 202111682165A CN 114213306 A CN114213306 A CN 114213306A
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- 239000012535 impurity Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- LTDAHGXWZNKFNP-BDAKNGLRSA-N (2s)-2-[(4r)-2-oxo-4-propylpyrrolidin-1-yl]butanoic acid Chemical compound CCC[C@H]1CN([C@@H](CC)C(O)=O)C(=O)C1 LTDAHGXWZNKFNP-BDAKNGLRSA-N 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 238000006482 condensation reaction Methods 0.000 claims abstract description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 19
- QWCKQJZIFLGMSD-VKHMYHEASA-N L-alpha-aminobutyric acid Chemical compound CC[C@H](N)C(O)=O QWCKQJZIFLGMSD-VKHMYHEASA-N 0.000 claims abstract description 13
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 28
- 239000012074 organic phase Substances 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000002425 crystallisation Methods 0.000 claims description 23
- 230000008025 crystallization Effects 0.000 claims description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000002904 solvent Substances 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 150000007514 bases Chemical class 0.000 claims description 12
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 11
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 11
- 229940011051 isopropyl acetate Drugs 0.000 claims description 11
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 239000002808 molecular sieve Substances 0.000 claims description 10
- 239000003444 phase transfer catalyst Substances 0.000 claims description 10
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 10
- 230000007935 neutral effect Effects 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000002516 radical scavenger Substances 0.000 claims description 2
- -1 (S) -2-aminobutyric acid ester Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000000463 material Substances 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 20
- 238000001035 drying Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 11
- 229960002161 brivaracetam Drugs 0.000 description 10
- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000002274 desiccant Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 239000012670 alkaline solution Substances 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 3
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 230000006340 racemization Effects 0.000 description 3
- MIYUTMZDGYBCOY-ZCFIWIBFSA-N (3r)-3-(iodomethyl)hexanoic acid Chemical compound CCC[C@@H](CI)CC(O)=O MIYUTMZDGYBCOY-ZCFIWIBFSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- HDBMIDJFXOYCGK-DFWYDOINSA-N (2s)-2-aminobutanamide;hydrochloride Chemical compound Cl.CC[C@H](N)C(N)=O HDBMIDJFXOYCGK-DFWYDOINSA-N 0.000 description 1
- NCBVCRLVTCSQAG-ZCFIWIBFSA-N (4r)-4-propylpyrrolidin-2-one Chemical compound CCC[C@H]1CNC(=O)C1 NCBVCRLVTCSQAG-ZCFIWIBFSA-N 0.000 description 1
- 101000584505 Homo sapiens Synaptic vesicle glycoprotein 2A Proteins 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102100030701 Synaptic vesicle glycoprotein 2A Human genes 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 208000028326 generalized seizure Diseases 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- AHAQQEGUPULIOZ-WCCKRBBISA-N methyl (2s)-2-aminobutanoate;hydrochloride Chemical compound Cl.CC[C@H](N)C(=O)OC AHAQQEGUPULIOZ-WCCKRBBISA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000005554 pickling Methods 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- JYPZPJQJIKUEMF-RGMNGODLSA-N propan-2-yl (2S)-2-aminobutanoate hydrochloride Chemical compound Cl.CC[C@H](N)C(=O)OC(C)C JYPZPJQJIKUEMF-RGMNGODLSA-N 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000003977 synaptic function Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a brivaracetam acid impurity, which comprises the following steps: s1) carrying out condensation reaction on the compound shown in the formula (2) and (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) to obtain a compound shown in the formula (4); s2) hydrolyzing the compound shown in the formula (4) under alkaline conditions to obtain the impurity of the bravaracetam acid shown in the formula (1). Compared with the prior art, the method has the advantages of simple synthesis process flow, mild reaction conditions, easily obtained required materials, high sample yield and purity, and capability of obtaining the target product without chiral column resolution.
Description
Technical Field
The invention belongs to the technical field of medical biology, and particularly relates to a preparation method of a bravaracetam acid impurity.
Background
The Brivaracetam (Brivaracetam), the chemical name of which is (S) -2- [ (R) -2-oxo-4-propylpyrrolidin-1-yl ] butanamide, is a third-generation antiepileptic drug developed by Belgium Shikoku pharmaceutical company, and exerts an antiepileptic effect by selectively and reversibly binding with central synaptosomal protein SV2A to influence synaptic function. The composition is marketed in Europe and the United states at 1 month, 14 days and 2 months, 18 days of 2016, and can be used for adjuvant treatment of partial seizure in patients with epilepsy in adolescents and adults 16 years old and older, with or without secondary generalized seizure. FDA-supplemented new drug application approval was obtained in 2017, 9, month 15 and could be used as monotherapy for focal seizures in epileptic patients over 16 years of age. The original research company makes import registration application in China in 2017, 3 and 6 months.
The main route of bravaracetam is:
(R) -4-propyl-2-pyrrolidone is subjected to ring opening under the action of iodotrimethylsilane to obtain (R) -3-iodomethylhexanoic acid, and the (R) -3-iodomethylhexanoic acid is subjected to acylation and then reacts with (S) -2-aminobutanamide hydrochloride to obtain the brivaracetam. Since the last step is a reaction under strongly alkaline conditions, small amounts of hydrolysis impurities may be produced. The hydrolyzed impurities have the following structure:
the standard research of impurities in the process of drug development is an important link, and the impurities are controlled within a safe and reasonable limit range, and a certain amount of standard substances are required for establishing quality standards. Based on this, for impurities in the brivaracetam: the preparation of (S) -2- [ (R) -2-oxo-4-propyl pyrrolidine-1-yl ] butyric acid has important significance, and the preparation method can be used for quality research such as qualitative and quantitative analysis of impurities in the synthesis of the brivaracetam, thereby being beneficial to improving the quality of the brivaracetam and providing important guiding significance for reducing the medication risk of the brivaracetam.
In order to develop the technical research and quality research of the brivaracetam and improve the medication safety of the brivaracetam, researchers need to obtain a sufficient amount of impurity reference substances firstly. In the research process, the impurity exists in a trace amount by adopting the synthesis method of the literature, the dosage of alkali is difficult to control due to strong acidity of the acyl chloride, racemization is easy to occur in the synthesis process by adopting dichloromethane as a solvent, the impurity reference substance with enough quantity is difficult to obtain by separating reaction liquid, the amount of the impurity cannot be increased by changing the reaction condition of the literature, and racemization is easy to occur when the impurity is prepared by directly hydrolyzing the Buvalacetam. At present, the synthesis routes of the brivaracetam are reported in the market, but the synthesis methods of the impurities are less reported. The inventor finds that acetonitrile is used as a solvent, and the reaction is not easy to racemize, so that the invention prepares the impurity of the bravaracetam acid on the basis of a bravaracetam synthesis route, reduces racemization by adopting a method of firstly condensing acyl chloride and (S) -2-aminobutyric acid ester hydrochloride in acetonitrile and then hydrolyzing, and lays a foundation for the mass preparation of the impurity of the bravaracetam acid and the effective control and tamping of the quality of a raw material medicament.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a method for preparing high-purity impurity of bravaracetam acid.
The invention provides a preparation method of a brivaracetam acid impurity, which comprises the following steps:
s1) carrying out condensation reaction on the compound shown in the formula (2) and (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) to obtain a compound shown in the formula (4);
s2) hydrolyzing the compound shown in the formula (4) under alkaline conditions to obtain the impurity of the bravaracetam acid shown in the formula (1);
wherein, X is Br or Cl, and R is C1-C3 alkyl.
Preferably, the condensation reaction in step S1) is performed in the presence of a basic compound and a molecular sieve water removal agent;
the alkaline compound is selected from one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide and sodium carbonate;
the molar ratio of the basic compound to (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) is (1-6): 1.
preferably, the condensation reaction in step S1) is performed in the presence of a phase transfer catalyst;
the phase transfer catalyst is selected from polyethylene glycol;
the mass of the phase transfer catalyst is 30-60% of that of the compound represented by the formula (2).
Preferably, the condensation reaction in step S1) is performed in an organic solvent; the organic solvent is selected from one or more of dichloromethane, acetonitrile, tetrahydrofuran and isopropyl acetate.
Preferably, the molar ratio of the compound shown in the formula (2) to the (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) is 1: (1-2);
the condensation reaction temperature is-10 ℃ to 10 ℃.
Preferably, after the condensation reaction in step S1), the reaction solution is washed with water and acid, concentrated, and crystallized by adding a crystallization solvent to obtain the compound represented by formula (4); the crystallization solvent is selected from one or more of ethyl acetate, isopropanol, isopropyl ether, petroleum ether and isopropyl acetate.
Preferably, the alkaline condition in step S2) is provided by one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate.
Preferably, the basic conditions are provided by basic compounds; the molar ratio of the compound represented by the formula (4) to the basic compound is 1: (2-3).
Preferably, the hydrolysis is carried out in methanol and/or water; the hydrolysis temperature is 0-50 ℃.
Preferably, after hydrolysis, adjusting the pH value of the reaction solution to be neutral, extracting with an organic solvent, separating an organic phase, concentrating, adding a crystallization solvent, stirring and crystallizing to obtain the impurity of the brivaracetam acid shown in the formula (1); the crystallization solvent is selected from one or more of ethyl acetate, isopropanol, isopropyl ether, petroleum ether and isopropyl acetate.
The invention provides a preparation method of a brivaracetam acid impurity, which comprises the following steps: s1) carrying out condensation reaction on the compound shown in the formula (2) and (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) to obtain a compound shown in the formula (4); s2) hydrolyzing the compound shown in the formula (4) under alkaline conditions to obtain the impurity of the bravaracetam acid shown in the formula (1). Compared with the prior art, the method has the advantages of simple synthesis process flow, mild reaction conditions, easily obtained required materials, high sample yield and purity, and capability of obtaining the target product without chiral column resolution.
Drawings
FIG. 1 is a high performance liquid chromatogram of Compound 1 obtained in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of Compound 1 obtained in example 1 of the present invention;
FIG. 3 is a mass spectrum of Compound 1 obtained in example 1 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a preparation method of a brivaracetam acid impurity, which comprises the following steps: s1) carrying out condensation reaction on the compound shown in the formula (2) and (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) to obtain a compound shown in the formula (4); s2) hydrolyzing the compound shown in the formula (4) under alkaline conditions to obtain the impurity of the bravaracetam acid shown in the formula (1);
wherein X is Br or Cl, preferably Cl; r is C1-C3 alkyl, preferably methyl, ethyl or isopropyl.
Carrying out condensation reaction on a compound shown as a formula (2) and (S) -2-aminobutyric acid ester hydrochloride shown as a formula (3); the molar ratio of the compound represented by the formula (2) to the (S) -2-aminobutyric acid ester hydrochloride represented by the formula (3) is preferably 1: (1-2), more preferably 1: (1-1.5), and more preferably 1: (1-1.2); the condensation reaction is preferably carried out in an organic solvent; the organic solvent is preferably one or more of dichloromethane, acetonitrile, tetrahydrofuran and isopropyl acetate, most preferably acetonitrile; the concentration of the compound represented by the formula (2) in the condensation reaction system is preferably 0.1-1 mol/L, more preferably 0.3-0.8 mol/L, and still more preferably 0.3-0.5 mol/L; the condensation reaction is preferably carried out in the presence of a basic compound and a molecular sieve water scavenger; the molar ratio of the basic compound to the (S) -2-aminobutyric acid ester hydrochloride represented by the formula (3) is preferably (1-6): 1, more preferably (2-6): 1, and preferably (3-5): 1, most preferably 4: 1; the alkaline compound is preferably one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide and sodium carbonate; the preferable proportion of the molecular sieve water removing agent to the organic solvent is (1-10) g: 100mL, more preferably (2-8) g: 100mL, more preferably (4-6) g: 100mL, most preferably 5 g: 100 mL; the molecular sieve water removing agent is preferably a 4A molecular sieve; the condensation reaction is also preferably carried out in the presence of a phase transfer catalyst; the proportion of the phase transfer catalyst to the organic solvent is preferably (1-10) g: 100mL, more preferably (2-8) g: 100mL, more preferably (4-6) g: 100mL, most preferably (4-5) g: 100 mL; the phase transfer catalyst is preferably polyethylene glycol, more preferably polyethylene glycol 400; the temperature of the condensation reaction is preferably-10 ℃ to 10 ℃, and more preferably-5 ℃ to 5 ℃; in the invention, the step preferably comprises the steps of mixing an alkaline compound, a molecular sieve water removal agent and an organic solvent, cooling to the reaction temperature, adding a phase transfer catalyst and (S) -2-aminobutyric acid ester hydrochloride shown in a formula (3), continuously stirring, adding a compound shown in a formula (2), and stirring for condensation reaction; the continuous stirring time is preferably 0.5-2 h, more preferably 0.8-1.2 h, and still more preferably 1 h.
After the condensation reaction is finished, preferably washing and pickling the reaction solution, concentrating, adding a crystallization solvent for crystallization to obtain a compound shown in the formula (4); in the present invention, it is preferable that the reaction solution is diluted with an organic solvent and then washed with water; the organic solvent is preferably one or more of dichloromethane, acetonitrile, tetrahydrofuran and isopropyl acetate; after washing, collecting an organic phase and washing with acid; the acid washing is preferably carried out by using 1N hydrochloric acid; acid washing, collecting organic phase, adding desiccant, drying, filtering, and concentrating; the drying agent is preferably anhydrous sodium sulfate; in the invention, preferably, after concentrating until a large amount of solid is precipitated, adding a crystallization solvent for crystallization; the crystallization solvent is preferably one or more of ethyl acetate, isopropanol, isopropyl ether, petroleum ether and isopropyl acetate; in the examples provided by the present invention, a mixed solution of ethyl acetate and isopropyl ether is preferably used; the volume ratio of the ethyl acetate to the isopropyl ether is preferably 1: (1-3), more preferably 1: (1.5-2.5), most preferably 1: 2; after crystallization, filtration and drying, the compound shown in the formula (4) can be obtained.
Hydrolyzing a compound represented by the formula (4) under alkaline conditions; the basic conditions are preferably provided by basic compounds; the alkaline compound is preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate; the molar ratio of the compound represented by the formula (4) to the basic compound is 1: (2-3), preferably 1: (2-2.8), preferably 1: (2.3-2.5); the hydrolysis is preferably carried out in methanol and/or water, more preferably in a mixture of methanol and water; the volume ratio of the methanol to the water is preferably (1-5): 1, more preferably (2-4): 1, more preferably 3: 1; the hydrolysis temperature is preferably 0 ℃ to 50 ℃, more preferably 10 ℃ to 40 ℃, and further preferably 20 ℃ to 30 ℃.
After hydrolysis, preferably adjusting the pH value of the reaction solution to be neutral, extracting with an organic solvent, separating an organic phase, concentrating, adding a crystallization solvent, stirring and crystallizing to obtain the impurity of the brivaracetam acid shown in the formula (1); in the present invention, it is preferable to adjust the pH of the reaction solution to neutral with an aqueous alkaline solution; the alkaline solution is preferably a sodium hydroxide solution and/or a potassium hydroxide solution; the concentration of the alkaline solution is preferably 1N; the organic solvent is preferably one or more of dichloromethane, acetonitrile, tetrahydrofuran and isopropyl acetate; after separating the organic phase, preferably adding a drying agent, drying, filtering and concentrating; the drying agent is preferably anhydrous sodium sulfate; after concentration, adding a crystallization solvent for crystallization; the crystallization solvent is preferably one or more of ethyl acetate, isopropanol, isopropyl ether, petroleum ether and isopropyl acetate; after crystallization, filtering and drying, the impurity of the brivaracetam acid shown in the formula (1) can be obtained.
The method has the advantages of simple synthesis process flow, mild reaction conditions, easily obtained required materials, high sample yield and purity, and capability of obtaining the target product without chiral column resolution.
In order to further illustrate the present invention, the following will describe in detail the preparation method of a bravaracetam acid impurity provided by the present invention with reference to examples.
The reagents used in the following examples are all commercially available.
The reaction scheme in the examples is as follows:
example 1
Step 1: 9.78g of potassium hydroxide (0.175mol), 5.0g of 4A molecular sieve and 100ml of acetonitrile are added into a reaction flask, and the temperature is reduced to-5 ℃ to 5 ℃ under stirring.
Adding 4.0g of PEG400 and 6.7g (0.0436mol) of (S) -2-aminobutyric acid methyl ester hydrochloride into the system, continuing stirring for 1h, keeping the temperature at-5 ℃, dropwise adding 210.0 g (0.0364mol, refer to CN107216276A example) of the compound, stirring for 3-4 h after dropwise adding is finished, and monitoring the reaction process by TLC until the compound 2 is completely consumed. Adding 200ml of dichloromethane, washing the reaction solution once, collecting an organic phase, washing the organic phase once with 1N hydrochloric acid 200m1, collecting the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase until a large amount of solid is separated out, adding ethyl acetate-isopropyl ether for crystallization (the volume ratio is 1:2), filtering and drying to obtain 6.2g of a compound 4, wherein the yield is as follows: 74.8 percent.
Step 2: adding 6.0g of compound 4, 30ml of methanol and 10ml of purified water into a reaction bottle, adding 2.5g of lithium hydroxide monohydrate at the temperature of 20-30 ℃, continuously stirring for reaction for 3-5 hours, and monitoring the reaction process by TLC until the compound 4 is completely consumed. Adjusting the reaction liquid to be neutral by using 1N sodium hydroxide, extracting by using dichloromethane, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, adding 50ml of isopropyl ether, stirring, crystallizing, filtering, and drying to obtain 2.8g of a compound 1, wherein the yield is as follows: 49.7 percent.
Example 2
Step 1: 9.78g of potassium hydroxide (0.175mol), 5.0g of 4A molecular sieve and 100ml of acetonitrile are added into a reaction flask, and the temperature is reduced to-5 ℃ to 5 ℃ under stirring.
Adding 4.0g of PEG400 and 7.3g (0.0436mol) of (S) -2-ethyl aminobutyric acid hydrochloride into the system, continuing stirring for 1h, keeping the temperature at-5 ℃, dropwise adding 210.0 g (0.0364mol, refer to CN107216276A example) of the compound, stirring for 3-4 h after the dropwise adding is finished, and monitoring the reaction process by TLC until the compound 2 is completely consumed. Adding 200ml of dichloromethane, washing the reaction solution once, collecting an organic phase, washing the organic phase once with 1N hydrochloric acid 200m1, collecting the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase until a large amount of solid is separated out, adding ethyl acetate-isopropyl ether (the volume ratio is 1:2) for crystallization, filtering, and drying to obtain 6.45g of a compound 4, wherein the yield is as follows: 73.4 percent.
Step 2: adding 6.0g of compound 4, 30ml of methanol and 10ml of purified water into a reaction bottle, adding 2.4g of lithium hydroxide monohydrate at the temperature of 20-30 ℃, continuously stirring for reaction for 3-5 hours, and monitoring the reaction process by TLC until the compound 4 is completely consumed. Adjusting the reaction liquid to be neutral by using 1N sodium hydroxide, extracting by using dichloromethane, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, adding 50ml of isopropyl ether, stirring, crystallizing, filtering, and drying to obtain 2.6g of a compound 1, wherein the yield is as follows: 49.0 percent.
Example 3
Step 1: 9.78g of potassium hydroxide (0.175mol), 5.0g of 4A molecular sieve and 100ml of acetonitrile are added into a reaction flask, and the temperature is reduced to-5 ℃ to 5 ℃ under stirring.
Adding 4.0g of PEG400 and 9.4g (0.0436mol) of (S) -2-amino-butyric acid isopropyl ester hydrochloride into the system, continuing stirring for 1h, keeping the temperature between 5 ℃ below zero and 5 ℃, dropwise adding 210.0 g (0.0364mol, refer to CN107216276A example) of the compound, stirring for 3-4 h after dropwise adding, and monitoring the reaction process by TLC until the compound 2 is completely consumed. Adding 200ml of dichloromethane, washing the reaction solution once, collecting an organic phase, washing the organic phase once with 1N hydrochloric acid 200m1, collecting the organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the organic phase until a large amount of solid is separated out, adding ethyl acetate-isopropyl ether for crystallization, filtering, and drying to obtain 7.0g of a compound 4, wherein the yield is as follows: 75.3 percent.
Step 2: adding 6.0g of compound 4, 30ml of methanol and 10ml of purified water into a reaction bottle, adding 2.25g of lithium hydroxide monohydrate at the temperature of 20-30 ℃, continuously stirring for reaction for 3-5 hours, and monitoring the reaction process by TLC until the compound 4 is completely consumed. Adjusting the reaction liquid to be neutral by using 1N sodium hydroxide, extracting by using dichloromethane, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering, concentrating the organic phase under reduced pressure, adding 50ml of isopropyl ether, stirring, crystallizing, filtering, and drying to obtain 2.35g of a compound 1, wherein the yield is as follows: 46.9 percent.
The results of detecting the compound 1 obtained in examples 1 to 3 by liquid chromatography are shown in Table 2 and FIG. 1. FIG. 1 is a high performance liquid chromatogram of Compound 1 obtained in example 1.
The detection conditions are as follows:
a chromatographic column: octadecylsilane bonded silica gel column (YMC 18,150X 4.6mm, 3 μm); wavelength: 210 nm; mobile phase A: 0.1% phosphoric acid solution (adjusted to pH 5.5 with 1mol/L sodium hydroxide solution); mobile phase B: acetonitrile; flow rate: 1.0 ml/min; column temperature: gradient elution was carried out at 40 ℃ and the procedure is shown in Table 1.
TABLE 1 gradient elution procedure
| Time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 95 | 5 |
| 30 | 65 | 35 |
| 32 | 0 | 100 |
| 37 | 0 | 100 |
| 37.1 | 95 | 5 |
| 50 | 95 | 5 |
TABLE 2 liquid chromatography test results
| Purity (%) | |
| Example 1 | 99.597 |
| Example 2 | 99.332 |
| Example 3 | 99.101 |
The results show that the impurity yield of the bravaracetam acid is up to 49.7%, the purity of the bravaracetam acid is up to more than 99.5%, and the sample yield and the purity of the bravaracetam acid are both high.
The compound 1 obtained in example 1 was analyzed by nuclear magnetic resonance, and its nuclear magnetic resonance hydrogen spectrum was shown in fig. 2.
The compound 1 obtained in example 1 was analyzed by mass spectrometry, and the mass spectrum thereof was shown in fig. 2.
Claims (10)
1. A preparation method of a bravaracetam acid impurity is characterized by comprising the following steps:
s1) carrying out condensation reaction on the compound shown in the formula (2) and (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) to obtain a compound shown in the formula (4);
s2) hydrolyzing the compound shown in the formula (4) under alkaline conditions to obtain the impurity of the bravaracetam acid shown in the formula (1);
wherein, X is Br or Cl, and R is C1-C3 alkyl.
2. The method according to claim 1, wherein the condensation reaction in step S1) is carried out in the presence of a basic compound and a molecular sieve water scavenger;
the alkaline compound is selected from one or more of potassium hydroxide, sodium hydroxide, lithium hydroxide and sodium carbonate;
the molar ratio of the basic compound to (S) -2-aminobutyric acid ester hydrochloride shown in the formula (3) is (1-6): 1.
3. the method according to claim 1, wherein the condensation reaction in step S1) is carried out in the presence of a phase transfer catalyst;
the phase transfer catalyst is selected from polyethylene glycol;
the mass of the phase transfer catalyst is 30-60% of that of the compound represented by the formula (2).
4. The method according to claim 1, wherein the condensation reaction in step S1) is carried out in an organic solvent; the organic solvent is selected from one or more of dichloromethane, acetonitrile, tetrahydrofuran and isopropyl acetate.
5. The production method according to claim 1, wherein the molar ratio of the compound represented by the formula (2) to the hydrochloride of (S) -2-aminobutyric acid ester represented by the formula (3) is 1: (1-2);
the condensation reaction temperature is-10 ℃ to 10 ℃.
6. The preparation method according to claim 1, wherein after the condensation reaction in step S1), the reaction solution is washed with water and acid, concentrated, and crystallized by adding a crystallization solvent to obtain the compound represented by formula (4); the crystallization solvent is selected from one or more of ethyl acetate, isopropanol, isopropyl ether, petroleum ether and isopropyl acetate.
7. The method as claimed in claim 1, wherein the basic condition in step S2) is provided by one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium carbonate.
8. The method of claim 1, wherein the basic conditions are provided by a basic compound; the molar ratio of the compound represented by the formula (4) to the basic compound is 1: (2-3).
9. The method of claim 1, wherein the hydrolysis is carried out in methanol and/or water; the hydrolysis temperature is 0-50 ℃.
10. The preparation method according to claim 1, characterized in that, after hydrolysis, the pH value of the reaction solution is adjusted to be neutral, the reaction solution is extracted by an organic solvent, the organic phase is separated, and after concentration, a crystallization solvent is added, and stirred for crystallization, so as to obtain the impurity of the bravaracetam acid shown in the formula (1); the crystallization solvent is selected from one or more of ethyl acetate, isopropanol, isopropyl ether, petroleum ether and isopropyl acetate.
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| CN115557873A (en) * | 2022-10-19 | 2023-01-03 | 浙江美诺华药物化学有限公司 | Synthesis method of methyl esterification impurity of brivaracetam |
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| AU2009221177A1 (en) * | 2008-03-03 | 2009-09-11 | Ucb Biopharma Sprl | Pharmaceutical solutions, process of preparation and therapeutic uses |
| CN107216276A (en) * | 2017-06-29 | 2017-09-29 | 爱斯特（成都）生物制药股份有限公司 | A kind of new Bu Waxitan synthetic method |
| CN111170920A (en) * | 2018-11-12 | 2020-05-19 | 浙江京新药业股份有限公司 | Method for removing genotoxicity warning intermediate from brivaracetam |
| CN111170881A (en) * | 2018-11-09 | 2020-05-19 | 上海医药集团股份有限公司 | Preparation method of brivaracetam intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2009221177A1 (en) * | 2008-03-03 | 2009-09-11 | Ucb Biopharma Sprl | Pharmaceutical solutions, process of preparation and therapeutic uses |
| CN107216276A (en) * | 2017-06-29 | 2017-09-29 | 爱斯特（成都）生物制药股份有限公司 | A kind of new Bu Waxitan synthetic method |
| CN111170881A (en) * | 2018-11-09 | 2020-05-19 | 上海医药集团股份有限公司 | Preparation method of brivaracetam intermediate |
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