CN113880744A - Chiral resolution method of brivaracetam - Google Patents
Chiral resolution method of brivaracetam Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- stirring
- chiral resolution
- brivaracetam
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Abstract
The invention relates to a chiral resolution method of brivaracetam, which 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 method can separate the brivaracetam from diastereoisomers easily and conveniently, thereby preparing the 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.
Claims (9)
1. A chiral resolution method of brivaracetam is characterized by comprising 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.
2. The chiral resolution method of claim 1, wherein 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; the mass ratio of the volume of the solvent used to the compound of formula 2 is 10-25: 1.
3. The chiral resolution process of claim 2, wherein the solvent in step 1) is selected from the group consisting of toluene; the mass ratio of the volume of the solvent used to the compound of formula 2 is 15-20: 1.
4. The chiral resolution method of claim 1, wherein the D-tartaric acid is used in the step 1) in a molar ratio of 0.5-2:1 relative to the compound of formula 2;
and/or the reaction temperature is 15-100 ℃.
5. The chiral resolution process of claim 1, wherein step 1) is carried out as follows: mixing the compound shown in the formula 2 with a solvent, heating and stirring until the system is clear, then adding D-tartaric acid, keeping the temperature and stirring, cooling and crystallizing, filtering and washing.
6. The chiral resolution process of claim 1, wherein the base in step 2) is sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or a combination thereof; the mass molar ratio of the alkali to the compound shown in the formula 3 is 0.5-3: 1;
and/or the reaction temperature is 0-100 ℃.
7. The chiral resolution process of claim 1, wherein the base liberation of step 2) is performed as follows: uniformly stirring the compound of the formula 3 and water, adding a sodium hydroxide solution, adjusting the pH value to 6-7, adding isopropyl acetate, stirring 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.
8. The chiral resolution method of claim 1, wherein the base in step 3) is selected from one or a combination of potassium tert-butoxide, sodium methoxide, sodium hydroxide and potassium hydroxide; the reaction temperature is 10-50 ℃;
and/or the reaction time is 2-10 h.
9. The chiral resolution method of claim 8, wherein the reaction temperature in step 3) is 20-30 ℃;
and/or the reaction time is 4-6 h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010626080.7A CN113880744A (en) | 2020-07-02 | 2020-07-02 | Chiral resolution method of brivaracetam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010626080.7A CN113880744A (en) | 2020-07-02 | 2020-07-02 | Chiral resolution method of brivaracetam |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113880744A true CN113880744A (en) | 2022-01-04 |
Family
ID=79012295
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010626080.7A Pending CN113880744A (en) | 2020-07-02 | 2020-07-02 | Chiral resolution method of brivaracetam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113880744A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115010640A (en) * | 2022-07-13 | 2022-09-06 | 苏州诚和医药化学有限公司 | Preparation process of brivaracetam |
| CN115806519A (en) * | 2022-12-22 | 2023-03-17 | 浙江普洛家园药业有限公司 | Method for splitting intermediate of brivaracetam and application of intermediate |
-
2020
- 2020-07-02 CN CN202010626080.7A patent/CN113880744A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115010640A (en) * | 2022-07-13 | 2022-09-06 | 苏州诚和医药化学有限公司 | Preparation process of brivaracetam |
| CN115806519A (en) * | 2022-12-22 | 2023-03-17 | 浙江普洛家园药业有限公司 | Method for splitting intermediate of brivaracetam and application of intermediate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112739683B (en) | Preparation method of brivaracetam and intermediate thereof | |
| CZ295477B6 (en) | Process for preparing tolterodine | |
| EP3395788A1 (en) | Compound having chiral spirobiindane skeleton and preparation method therefor | |
| CN113880744A (en) | Chiral resolution method of brivaracetam | |
| JP2005507900A (en) | Citalopram manufacturing method | |
| CN1293653A (en) | Process for cis-selective catalytic hydrogenation of sub cyclohexylidenamines | |
| KR20010112223A (en) | Process for the Resolution of Tramadol | |
| FR3101348A1 (en) | PROCESS FOR THE PREPARATION OF (15α, 16α, 17β) -OESTRA-1,3,5 (10) -TRIENE-3,15,16,17-TETROL (OESTETROL) AND INTERMEDIARIES OF THE SAID PROCESS | |
| CN111689869A (en) | Preparation method of L-phenylephrine hydrochloride | |
| CN114989061A (en) | Preparation method of brivaracetam | |
| WO2014184756A2 (en) | Process for the preparation of arformoterol or salt thereof | |
| JPH08291106A (en) | Production of optically active 2-propyloctanoic acid | |
| CN113045468A (en) | Preparation method of brivaracetam intermediate | |
| WO2005023763A1 (en) | Process for the preparation of pure levetiracetam | |
| EP3247697B1 (en) | Process for the racemization of enantiomerically enriched 1-aminoindane | |
| CN115385818B (en) | Paracetamol impurity and preparation method thereof | |
| CN113264839B (en) | Method for preparing levo-terbutaline by using chiral prosthetic group | |
| EP3068746B1 (en) | Process for the preparation of enantiomerically pure 1-aminoindan | |
| CN114804989B (en) | Purification method and racemization recycling of rivastigmine key chiral intermediate | |
| CN109180496B (en) | Method for synthesizing cinacalcet by using chemical-enzymatic method | |
| CN112194655B (en) | Preparation method of engelizin | |
| WO2023248154A1 (en) | Process for the preparation of viloxazine hydrochloride | |
| WO2023001299A1 (en) | Crystal form of compound represented by formula i, and preparation therefor and application thereof | |
| CA2611035C (en) | Stereoselective hydrogenation process for preparing cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-methoxy-5,6,7,8-tetrahydronaphthalene hydrochloride | |
| CN101522189A (en) | Polymorphic form of duloxetine hydrochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |