CN113880744A - A kind of chiral separation method of brivaracetam - Google Patents
A kind of chiral separation method of brivaracetam Download PDFInfo
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- CN113880744A CN113880744A CN202010626080.7A CN202010626080A CN113880744A CN 113880744 A CN113880744 A CN 113880744A CN 202010626080 A CN202010626080 A CN 202010626080A CN 113880744 A CN113880744 A CN 113880744A
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- brivaracetam
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- MSYKRHVOOPPJKU-BDAKNGLRSA-N brivaracetam Chemical compound CCC[C@H]1CN([C@@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-BDAKNGLRSA-N 0.000 title claims abstract description 40
- 229960002161 brivaracetam Drugs 0.000 title claims abstract description 39
- 238000000926 separation method Methods 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 90
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000002360 preparation method Methods 0.000 claims abstract description 21
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 15
- 229960001270 d- tartaric acid Drugs 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 14
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000003756 stirring Methods 0.000 claims description 96
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 65
- 238000001816 cooling Methods 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 239000007787 solid Substances 0.000 claims description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 22
- 229940011051 isopropyl acetate Drugs 0.000 claims description 22
- 238000005406 washing Methods 0.000 claims description 21
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000000967 suction filtration Methods 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 8
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 2
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 claims 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- 238000004321 preservation Methods 0.000 claims 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims 1
- 238000010792 warming Methods 0.000 claims 1
- 239000013078 crystal Substances 0.000 abstract description 8
- 238000006345 epimerization reaction Methods 0.000 abstract description 3
- 239000001294 propane Substances 0.000 abstract 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 20
- 238000010438 heat treatment Methods 0.000 description 19
- 230000005496 eutectics Effects 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000001035 drying Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- -1 (R) -2-oxo-4-propyl pyrrolidine-1-yl Chemical group 0.000 description 5
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 5
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 5
- 238000009776 industrial production Methods 0.000 description 5
- 235000011090 malic acid Nutrition 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- BJEPYKJPYRNKOW-UWTATZPHSA-N (R)-malic acid Chemical compound OC(=O)[C@H](O)CC(O)=O BJEPYKJPYRNKOW-UWTATZPHSA-N 0.000 description 2
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 2
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 2
- 229930182847 D-glutamic acid Natural products 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 229940116298 l- malic acid Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MSYKRHVOOPPJKU-RKDXNWHRSA-N (2r)-2-[(4r)-2-oxo-4-propylpyrrolidin-1-yl]butanamide Chemical compound CCC[C@H]1CN([C@H](CC)C(N)=O)C(=O)C1 MSYKRHVOOPPJKU-RKDXNWHRSA-N 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001037 epileptic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000010829 isocratic elution Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011593 sulfur Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种布瓦西坦的手性拆分方法，包括以下步骤：1)在溶剂中，式2化合物(R,S)‑2‑((R)‑2‑氧代‑4‑丙基吡咯烷‑1‑基)丁酰胺与D‑酒石酸共晶得到式3化合物；2)式3化合物经碱游离得到式1化合物；3)步骤1)中另一非对映异构体式4化合物在碱的作用下差向异构化得到式2化合物，继续用于式1化合物的制备。该方法能够操作简便地将布瓦西坦与非对映异构体分离，从而制得高纯度的布瓦西坦。 The present invention relates to a kind of chiral resolution method of brivaracetam, comprising the following steps: 1) in a solvent, formula 2 compound (R,S)-2-((R)-2-oxo-4-propane pyrrolidin-1-yl) butyramide and D-tartaric acid co-crystal to obtain the compound of formula 3; 2) the compound of formula 3 is freed by base to obtain the compound of formula 1; 3) another diastereomer compound of formula 4 in step 1) The compound of formula 2 is obtained by epimerization under the action of a base, which is continued to be used for the preparation of the compound of formula 1. The method can be easily operated to separate brivaracetam from diastereomers, thereby preparing high-purity brivaracetam. 
Description
Technical Field
The invention belongs to the field of chemical drugs, and relates to a chiral resolution method of brivaracetam, in particular to a chiral resolution method of brivaracetam and diastereoisomer (R) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butanamide.
Background
Brivaracetam (English name: brivaracetam), chemical name is: (S) -2- ((R) -2-oxo-4-propylpyrrolidin-1-yl) butanamide, a third-generation antiepileptic drug developed by UCB of Belgium, is mainly used for clinically treating partial seizure type epileptics aged 16 years and above, and is accompanied or not accompanied by adjuvant therapy of secondary generalized seizures. The structural formula of the brivaracetam is shown as the following formula 1:
in the preparation process of the brivaracetam, the key technology and difficulty for preparing the brivaracetam are how to separate the brivaracetam from the diastereoisomer with high yield, which is simple and convenient to operate, because the brivaracetam and the diastereoisomer 4 of the brivaracetam have similar physicochemical properties.
The separation and purification methods reported in the literature are only carried out by means of column chromatography: (see WO2005028435) which employs chiral stationary phase chiralpak AD20um, in the form of n-heptane: ethanol 45:55 as mobile phase. Although the method can separate the brivaracetam from the non-corresponding isomer with high yield, the operation of separating by adopting column chromatography is complex, the cost is higher, and the method is only suitable for small-scale preparation in a laboratory and is not beneficial to industrial production.
Therefore, the method for chiral resolution of the brivaracetam, which has the advantages of high yield, high product purity, simple operation and easy industrial production, is urgently needed in the field.
Disclosure of Invention
In order to overcome the problems of complex operation and high cost of the existing chiral resolution method of the brivaracetam, the inventor develops a simple process by adopting a more economical conventional chemical process for industrial production, and the brivaracetam is separated from diastereoisomers by adopting a mode of eutectic crystal of a compound (R, S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butanamide shown in a formula 2 and D-tartaric acid. Specifically, the present invention adopts the following technical solutions.
A chiral resolution method of brivaracetam comprises the following steps:
1) in a solvent, the compound (R, S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butyramide shown in the formula 2 is eutectic with D-tartaric acid to obtain a compound shown in a formula 3;
2) dissociating the compound shown in the formula 3 by using alkali to obtain a compound shown in a formula 1;
3) epimerizing the other diastereomer compound of formula 4 in step 1) under the action of a base to obtain a compound of formula 2, and continuing to use the compound of formula 1 for preparation of the compound of formula 1.
The solvent is not limited in kind, and is an organic solvent conventionally used in the art, such as paraffin, olefin, alcohol, aldehyde, amine, ester, ether, ketone, aromatic hydrocarbon, hydrogenated hydrocarbon, terpene hydrocarbon, halogenated hydrocarbon, heterocyclic compound, nitrogen-containing compound, sulfur-containing compound, and the like.
Preferably, the solvent in step 1) is one or a mixture of two or more selected from toluene, ethyl acetate, isopropyl acetate, acetonitrile, acetone, isopropanol, methyl tert-butyl ether, n-heptane, methanol, ethanol and dichloromethane, and the preferred solvent is toluene; the mass ratio of the volume of the solvent used to the compound of formula 2 is 10-25:1, preferably 15-20: 1.
Preferably, the D-tartaric acid is used in the step 1) in a molar ratio of 0.5 to 2:1, preferably 0.5 to 0.6:1, relative to the compound of formula 2.
The reaction temperature in step 1) is 15 to 100 ℃ and preferably 20 to 50 ℃. Specifically, the method comprises the following steps: heating the compound shown in the formula 2 and a solvent to 40-45 ℃, stirring until the system is clear, then adding D-tartaric acid, keeping the temperature and stirring for 30min, cooling to 35-40 ℃, stirring for crystallization for 1h, cooling to 20-25 ℃, stirring for 4h, performing suction filtration and washing to obtain a white-like solid.
The base is a base conventionally used in the art.
Preferably, the free base in step 2) is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or a combination thereof, further preferably sodium hydroxide; the mass molar ratio of the alkali to the compound shown in the formula 3 is 0.5-3: 1; preferably 1-2.5: 1; the reaction temperature is 0 to 100 ℃ and preferably 20 to 50 ℃.
The alkali liberation of step 2) is carried out in particular as follows: stirring the compound of formula 3 and water uniformly, adding sodium hydroxide solution at 20-30 ℃, adjusting the pH value to 6-7, adding isopropyl acetate, stirring at 40 ℃ until the solid is completely dissolved, and separating liquid; and (3) adding saturated saline solution into the organic phase for washing, and concentrating and drying the organic phase under reduced pressure to obtain a crude product of the Buvalracetam.
Preferably, in the epimerization in the step 3), the base is selected from one or a combination of sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium hydroxide and potassium hydroxide, and sodium tert-butoxide is further preferred; the reaction temperature has very obvious influence on the yield, and is 10-50 ℃, preferably 20-30 ℃; the reaction time is 2-10h, and the preferable reaction time is 4-6 h.
The post-treatment process of the step 1), the step 2) and the step 3) can further comprise a recrystallization step, and the operation can be carried out according to a conventional recrystallization method in the field.
Compared with the prior art, the D-tartaric acid is adopted as a resolution reagent in the step 1), the bravaracetam is separated from diastereomers by separating out a eutectic compound from a solvent after forming the eutectic compound with the D-tartaric acid, and the separated eutectic compound is dissociated in alkali liquor to prepare the bravaracetam, so that the separation and purification mode avoids column chromatography operation with high cost.
After the resolution process of step 1), in order to reuse the remaining diastereomer, i.e. the compound of formula 4 (R) -2- ((R) -2-oxo-4-propylpyrrolidin-1-yl) butanamide, the diastereomer was changed into the initial starting compound of formula 2 again by the above treatment by epimerization of the compound of formula 4, and the subsequent separation and purification was continued. The cyclic reaction achieves the aim of reducing the production cost.
The preparation and separation of the technical scheme can obtain the brivaracetam with high yield and high purity, and the application of the cyclic reaction avoids resource waste and improves atom economy. The whole process route is very simple, the production cost is greatly reduced, and the method is suitable for industrial production.
Detailed Description
Herein, the term "compound of formula x" is sometimes expressed as "compound of formula x" or "compound x", which means the same meaning, as can be understood by those skilled in the art.
The invention is further illustrated by the following examples. It is to be understood that these examples are for illustrative purposes only and are not limiting upon the present invention. Various changes or modifications thereof, which may occur to those skilled in the art based on the teachings of the present invention, are within the scope of the present invention.
The addition amount, content and concentration of various substances are referred to herein, wherein the percentage refers to the mass percentage unless otherwise specified.
In the examples herein, if no specific description is made about the reaction temperature or the operation temperature, the temperature is usually referred to as room temperature (15 to 30 ℃).
Reagent: the organic solvents and the like used in the examples of the present invention are all industrial grade and used directly. The reagents were purchased from Shanghai element chemical Co., Ltd.
Polarimeters are of the type: rudolph Autopol V;
nuclear magnetic resonance apparatus type: bruker affinity HD 600MHz, Bruker affinity III 400 MHz;
mass spectrometer (liquid mass spectrometry (LCMS)), type: agilent 6120B, detector DAD.
HPLC assay conditions for compounds of formula 1: a chromatographic column: CHIRALPAK AD-H4.6 mm 5 μm; column temperature: 20 ℃; detection wavelength: 205 nm; mobile phase: n-hexane: isocratic elution with isopropanol 90: 10; operating time: 35 min; sample introduction amount: 20 mu l of the mixture; flow rate: 1.0 ml/min.
EXAMPLE 1 preparation of the Compound of formula 3
Adding 2.56L of toluene and 2128 g (0.603mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is clear, adding 47.97g (0.320mol) of D-tartaric acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring until solid is separated out, continuing stirring for crystallization for 1h, cooling to 20-25 ℃, stirring for 4h, filtering, and washing a filter cake with about 256ml of toluene to obtain a white-like solid.
Transferring the solid to a 5L jacketed reaction bottle, adding 2.30L of toluene, heating to 95-100 ℃, keeping the temperature and stirring for 30min, cooling to 60-70 ℃, stirring to separate out the solid, keeping the temperature and stirring for 1h, cooling to 40 ℃, stirring for 1h, continuously cooling to 20-25 ℃, stirring for 4h, performing suction filtration, washing a filter cake with about 256ml of toluene, and drying to constant weight at 50-60 ℃ (the vacuum degree is more than or equal to 0.095MPa), thereby obtaining 92.0g of the compound shown in the formula 3, the yield is 42.1%, and the de value is 99.7%.
EXAMPLE 2 preparation of the Compound of formula 1
Adding 184ml of water and 92.0g (0.254mol) of a compound of formula 3 into a 1L three-necked bottle, uniformly stirring, dripping sodium hydroxide solution (82 ml of water and 23.37g of sodium hydroxide) at 20-30 ℃, detecting the pH value of a system at 6-7 by using a precise pH test paper, stopping dripping, adding 276ml of isopropyl acetate, stirring below 40 ℃ until the solid is completely dissolved, and separating liquid; and adding 46ml of saturated saline solution into the organic phase, washing once, concentrating and drying the organic phase under reduced pressure to obtain a crude product of the brivaracetam.
Transferring the crude product into a 100ml flask, adding 69ml isopropyl acetate, heating to reflux, stirring to dissolve, slowly cooling to 30 ℃ (1-1.5h), stirring at constant temperature for 0.5h, cooling to 0-5 ℃, stirring at constant temperature for 1h, filtering, washing filter cake with 30ml isopropyl acetate, drying at 50-60 ℃ (vacuum degree not less than 0.095MPa) to constant weight to obtain 49.5g of the compound of formula 1, total yield 38.7%, HPLC purity 99.9%, melting point 76.8-77.9 ℃, and alpha]D 20-62.0°(c＝1.0g/100mL，MeOH)。
The 1H-NMR spectrum of the compound of formula 1 has the following characteristics, consistent with the 1H-NMR spectrum data disclosed for bravaracetam:
1H NMR(400MHz，DMSO)δ：1H NMR(400MHz,DMSO)δ：7.36(1H,s),7.03(1H,s),4.25(3H,m),3.47–3.28(1H,m),3.11(1H,dd,J 9.4,7.2),2.38(1H,dd,J 16.1,8.5),2.29–2.16(1H,m),1.98(1H,dd,J 16.1,8.0),1.77(1H,dd,J 13.6,7.2),1.63–1.50(1H,m),1.41–1.20(4H,m),0.88(3H,t,J 7.1),0.77(3H,t,J 7.3).
EXAMPLE 3 preparation of the Compound of formula 2
Adding 52.7g of the compound shown in the formula 4 and 472ml of isopropanol into a 1L single-mouth bottle, stirring at room temperature until the compound is dissolved, adding 9.72g of sodium tert-butoxide solid, stirring at 20-30 ℃ for reaction for 4 hours, sampling, adjusting the pH to 6-7 by using 2N hydrochloric acid, detecting by HPLC (high performance liquid chromatography), stopping the reaction, and concentrating the dry reaction solution under reduced pressure at 45 ℃. Adding 378ml of isopropyl acetate and 95ml of 15% sodium chloride aqueous solution, stirring until dissolved, adjusting the pH to 6-7 with concentrated hydrochloric acid, washing the organic layer once with 48ml of 15% sodium chloride aqueous solution, and rotary-evaporating at 45-50 ℃ to obtain a white solid.
Transferring the solid into a 250ml reaction bottle, adding 130ml of isopropyl acetate, heating and refluxing, stirring to dissolve, slowly cooling (0.5 ℃/min) to 50 ℃, keeping the temperature and stirring for 1h, continuously cooling to 0-5 ℃, keeping the temperature and stirring for 1 h. Filtering, washing the filter cake with 86ml isopropyl acetate, drying at 50-60 deg.C to constant weight to obtain 47.6g of compound of formula 2, yield 90.3%, and HPLC purity 99.7%.
EXAMPLE 4 preparation of the Compound of formula 3
Adding 1.28L of toluene and 2128 g (0.603mol) of compound into a 2.5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is dissolved, adding 47.97g (0.320mol) of D-tartaric acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring until solid is separated out, continuing stirring for crystallization for 1h, cooling to 20-25 ℃, stirring for 4h, performing suction filtration, and washing a filter cake with about 256ml of toluene to obtain a white-like solid.
And transferring the solid to a 5L jacketed reaction bottle, adding 2.30L of toluene, heating to 95-100 ℃, keeping the temperature and stirring for 30min, cooling to 60-70 ℃, stirring to separate out the solid, keeping the temperature and stirring for 1h, cooling to 40 ℃, stirring for 1h, continuously cooling to 20-25 ℃, stirring for 4h, performing suction filtration, washing a filter cake by using about 256ml of toluene, and drying at 50-60 ℃ to constant weight to obtain 95.0g of the compound shown in the formula 3, wherein the yield is 43.5% and the de value is 98.9%.
EXAMPLE 5 preparation of the Compound of formula 1
Adding 184ml of water and 92.0g (0.254mol) of a compound of formula 3 into a 1L three-necked bottle, uniformly stirring, dropwise adding a sodium carbonate solution (100 ml of water and 31.0g of sodium carbonate) at 20-30 ℃, detecting the pH value of a system at 6-7 by using a precision pH test paper, stopping dropwise adding, adding 400ml of isopropyl acetate, stirring below 40 ℃ until the solid is completely dissolved, and separating liquid; and adding 46ml of saturated saline solution into the organic phase, washing once, concentrating and drying the organic phase under reduced pressure to obtain a crude product of the brivaracetam.
Transferring the crude product into a 100ml flask, adding 70ml of isopropyl acetate, heating to reflux, stirring to dissolve, slowly cooling to 30 ℃ (1-1.5h), stirring at constant temperature for 0.5h, cooling to 0-5 ℃, stirring at constant temperature for 1h, performing suction filtration, washing a filter cake with 30ml of isopropyl acetate, drying to constant weight at 50-60 ℃ (vacuum degree is more than or equal to 0.095MPa), and obtaining 48.3g of the compound of formula 1, wherein the total yield is 37.8%, the HPLC purity is 99.9%, and the melting point is 76.8-78.0 DEG C
EXAMPLE 6 preparation of the Compound of formula 2
Adding 52.7g of the compound shown in the formula 4 and 472ml of isopropanol into a 1L single-mouth bottle, stirring at room temperature until the compound is dissolved, adding 4.05g of sodium hydroxide solid, stirring at 30-40 ℃ for reaction for 4 hours, sampling, adjusting the pH to 6-7 by using 2N hydrochloric acid, detecting by HPLC (high performance liquid chromatography), stopping the reaction, and concentrating the dry reaction solution under reduced pressure at 45 ℃. Adding 378ml of isopropyl acetate and 95ml of 15% sodium chloride aqueous solution, stirring until dissolved, adjusting the pH to 6-7 with concentrated hydrochloric acid, washing the organic layer once with 48ml of 15% sodium chloride aqueous solution, and rotary-evaporating at 45-50 ℃ to obtain a white solid.
Transferring the solid into a 250ml reaction bottle, adding 130ml of isopropyl acetate, heating and refluxing, stirring to dissolve, slowly cooling (0.5 ℃/min) to 50 ℃, keeping the temperature and stirring for 1h, continuously cooling to 0-5 ℃, keeping the temperature and stirring for 1 h. Suction filtration, filter cake washing with 86ml isopropyl acetate, 50-60 deg.C drying to constant weight, get formula 2 compound 46.2g, yield 87.6%, HPLC purity 99.5%.
EXAMPLE 7 preparation of the Compound of formula 3
Adding 2.56L of toluene and 2128 g (0.603mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is dissolved, adding 89.6g (0.422mol) of D-tartaric acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring until solid is separated out, continuing stirring for crystallization for 1h, cooling to 20-25 ℃, stirring for 4h, performing suction filtration, and washing a filter cake with about 256ml of toluene to obtain a white-like solid.
And (2) transferring the solid to a 5L jacketed reaction bottle, adding 2.30L of toluene, heating to 95-100 ℃, keeping the temperature and stirring for 30min, cooling to 60-70 ℃, stirring to separate out the solid, keeping the temperature and stirring for 1h, cooling to 40 ℃, stirring for 1h, continuously cooling to 20-25 ℃, stirring for 4h, performing suction filtration, washing a filter cake with about 256ml of toluene, and drying at 50-60 ℃ to constant weight to obtain 96.6g of the compound shown in the formula 3, wherein the yield is 44.2% and the de value is 97.1%.
EXAMPLE 8 preparation of the Compound of formula 1
Adding 184ml of water and 92g (0.254mol) of a compound of formula 3 into a 1L three-necked bottle, uniformly stirring, dropwise adding an aqueous solution of potassium carbonate (100 ml of water and 40.4g) at 20-30 ℃, detecting the pH value of a system at 6-7 by using a precise pH test paper, stopping dropwise adding, adding 276ml of isopropyl acetate, stirring below 40 ℃ until the solid is completely dissolved, and separating; and adding 46ml of saturated saline solution into the organic phase, washing once, concentrating and drying the organic phase under reduced pressure to obtain a crude product of the brivaracetam.
Transferring the crude product into a 100ml flask, adding 70ml of isopropyl acetate, heating to reflux, stirring to dissolve, slowly cooling to 30 ℃ (1-1.5h), keeping the temperature and stirring for 0.5h, cooling to 0-5 ℃, keeping the temperature and stirring for 1h, performing suction filtration, washing a filter cake by using 30ml of isopropyl acetate, and drying to constant weight at 50-60 ℃ (the vacuum degree is more than or equal to 0.095MPa) to obtain 48.1g of the compound of the formula 1, wherein the total yield is 37.6%, the HPLC purity is 99.8%, and the melting point is 76.8-77.9 ℃.
EXAMPLE 9 preparation of the Compound of formula 2
Adding 52.7g of the compound shown in the formula 4 and 470ml of isopropanol into a 1L single-neck bottle, stirring at room temperature until the compound is dissolved, adding 11.3g of potassium tert-butoxide solid, stirring at 20-30 ℃ for reaction for 4h, sampling, adjusting the pH to 6-7 by using 2N hydrochloric acid, detecting by HPLC (high performance liquid chromatography), stopping the reaction, and concentrating the dry reaction solution under reduced pressure at 45 ℃. Adding 378ml of isopropyl acetate and 95ml of 15% sodium chloride aqueous solution, stirring until dissolved, adjusting the pH to 6-7 with concentrated hydrochloric acid, washing the organic layer once with 48ml of 15% sodium chloride aqueous solution, and rotary-evaporating at 45-50 ℃ to obtain a white solid.
Transferring the solid into a 250ml reaction bottle, adding 130ml of isopropyl acetate, heating and refluxing, stirring to dissolve, slowly cooling (0.5 ℃/min) to 50 ℃, keeping the temperature and stirring for 1h, continuously cooling to 0-5 ℃, keeping the temperature and stirring for 1 h. Suction filtration, filter cake washing with 86ml isopropyl acetate, 50-60 deg.C drying to constant weight, get formula 2 compound 46.9g, yield 89.0%, HPLC purity 99.7%.
To further demonstrate the excellent effects of the present invention, the following comparative examples are provided. In comparative examples, brivaracetam cannot form eutectic compounds with common organic acids such as malic acid, mandelic acid, glutamic acid, and the like. The method adopts the D-tartaric acid as a resolution reagent, can prepare the eutectic compound of the brivaracetam and the D-tartaric acid, has higher yield and purity, and is suitable for large-scale industrial production.
Comparative example 1 preparation of a Co-crystal Compound of Buvalracetam
Adding 400ml of toluene and 220.0 g (0.0942mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is clear, adding 6.7g (0.0499mol) of D-malic acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring for 1h, cooling to 10-15 ℃, stirring for 24h, and no solid is separated out from the reaction liquid, so that the eutectic compound of the brivaracetam and the D-malic acid is not obtained.
Comparative example 2 preparation of eutectic crystals of brivaracetam
Adding 400ml of toluene and 220.0 g (0.0942mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is clear, adding 6.7g (0.0499mol) of L-malic acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring for 1h, cooling to 10-15 ℃, stirring for 24h, and no solid is separated out from the reaction liquid, so that the eutectic compound of the brivaracetam and the L-malic acid is not obtained.
Comparative example 3 preparation of eutectic crystals of brivaracetam
Adding 400ml of toluene and 220.0 g (0.0942mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is clear, adding 7.6g (0.0499mol) of D-mandelic acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring for 1h, cooling to 10-15 ℃, stirring for 24h, and no solid is separated out from the reaction solution, so that the eutectic compound of the brivaracetam and the D-mandelic acid is not obtained.
Comparative example 4 preparation of eutectic crystals of brivaracetam
Adding 400ml of toluene and 220.0 g (0.0942mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is clear, adding 7.6g (0.0499mol) of L-mandelic acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring for 1h, cooling to 10-15 ℃, stirring for 24h, and no solid is separated out from the reaction solution, so that the eutectic compound of the brivaracetam and the L-mandelic acid is not obtained.
Comparative example 5 preparation of eutectic crystals of brivaracetam
Adding 400ml of toluene and 220.0 g (0.0942mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is clear, adding 7.3g (0.0499mol) of D-glutamic acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring for 1h, cooling to 10-15 ℃, stirring for 24h, and no solid is separated out from the reaction liquid, so that the eutectic compound of the brivaracetam and the D-glutamic acid is not obtained.
Comparative example 6 preparation of eutectic crystals of brivaracetam
Adding 400ml of toluene and 220.0 g (0.0942mol) of compound into a 5L jacketed reaction bottle, heating to 40-45 ℃, stirring until the system is clear, adding 7.3g (0.0499mol) of L-glutamic acid, keeping the temperature at 40-45 ℃, stirring for 30min, cooling to 35-40 ℃, stirring for 1h, cooling to 10-15 ℃, stirring for 24h, and no solid is separated out from the reaction liquid, so that the eutectic compound of the brivaracetam and the L-glutamic acid is not obtained.
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| CN116217522A (en) * | 2023-02-22 | 2023-06-06 | 广东莱佛士制药技术有限公司 | Chiral purification method of key intermediate of GLP-1 receptor agonist |
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