CN114989060A - Preparation method of brivaracetam - Google Patents
Preparation method of brivaracetam Download PDFInfo
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- CN114989060A CN114989060A CN202110380195.7A CN202110380195A CN114989060A CN 114989060 A CN114989060 A CN 114989060A CN 202110380195 A CN202110380195 A CN 202110380195A CN 114989060 A CN114989060 A CN 114989060A
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- brivaracetam
- organic solvent
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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 22
- 229960002161 brivaracetam Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 13
- 230000009471 action Effects 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- HNNJFUDLLWOVKZ-UHFFFAOYSA-N 2-aminobutanamide Chemical compound CCC(N)C(N)=O HNNJFUDLLWOVKZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 13
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- NVTUTJMZAZZKAZ-ZCFIWIBFSA-N (4r)-4-propyloxolan-2-one Chemical compound CCC[C@H]1COC(=O)C1 NVTUTJMZAZZKAZ-ZCFIWIBFSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 2
- YHWCPXVTRSHPNY-UHFFFAOYSA-N butan-1-olate;titanium(4+) Chemical compound [Ti+4].CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-] YHWCPXVTRSHPNY-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- VLCDUOXHFNUCKK-UHFFFAOYSA-N N,N'-Dimethylthiourea Chemical compound CNC(=S)NC VLCDUOXHFNUCKK-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- GUPWNYUKYICHQX-UHFFFAOYSA-N carbonobromidic acid Chemical compound OC(Br)=O GUPWNYUKYICHQX-UHFFFAOYSA-N 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of brivaracetam, which comprises the following steps: 1) reacting R-4-propyl dihydrofuran-2-ketone of a compound in a formula I with L-2-aminobutanamide of a compound in a formula II to obtain an intermediate III; 2) reacting the intermediate III with a brominating reagent to obtain an intermediate IV; 3) and (4) closing the ring of the intermediate IV under the action of alkali to obtain the brivaracetam. The method has simple synthesis steps and high yield, provides a new route for the synthesis of brivaracetam, and has strong industrial application prospect.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of (2S) -2- [ (4R) -2-oxo-4-propyl-pyrrolidine-1-yl ] butanamide.
Background
Brivaracetam is a novel antiepileptic drug released by UCB company, and the compound contains two chiral centers, so that the synthesis difficulty is high, and the specific chemical structure is as follows:
the prior art reports various preparation method patents, the original patent CN1208319C is hydrogenated and reduced to obtain 4-propyl racemate, and finally the target configuration is obtained through chiral separation. The method has low efficiency, high separation cost and poor industrial production feasibility.
The CN106748950B patent discloses that racemic carboxylic acid and R-methylbenzylamine are salified in isopropanol, refined and dissociated to obtain optically pure carboxylic acid, and finally brivaracetam is obtained under the action of a condensing agent. Through the resolution of chemical reagent, the atom utilization rate is low, the yield is low, salifying, refining in the resolution process, and reevolving can greatly increase the difficulty of the post-treatment step, and meanwhile, partial products can be racemized through the condensation reaction of amino acid.
The CN111848483A patent discloses asymmetric reduction of an olefin intermediate under the action of a chiral rhodium catalyst to obtain brivaracetam. However, the chiral catalyst cannot be obtained commercially, so that the preparation cost is high, and the optical purity of the product cannot meet the requirement of medicinal grade.
CN106279074B discloses a method for preparing (R) -4-propyl-dihydrofuran-2-one, and synthesizing brivaracetam from the chiral material. However, the route is too long, which greatly increases the production cost, and in addition, the isomers after aminolysis are not controlled in the ideal range, and the requirements of API on the isomers are not met.
CN108503573B discloses a method for preparing brivaracetam by ring-opening (R) -4-propyl-dihydrofuran-2-ketone as a starting material under the action of a brominating agent to obtain bromocarboxylic acid, condensing with L-2-aminobutanamide to obtain a bromo intermediate, and finally closing the ring under the action of alkali. The TMSBr has certain risks in the using process, and in addition, racemization is easy to occur in amino acid condensation.
CN111196771A discloses a method for preparing brivaracetam by directly ring-opening (R) -4-propyl-dihydrofuran-2-one and L-2-aminobutanamide to obtain a hydroxyl intermediate, and then dehydrating under the action of stoichiometric sulfuric acid. The method needs to use stoichiometric concentrated sulfuric acid to dehydrate and close the ring, so that racemization of amino acid can be caused, hydrolysis of amide can be caused, and the quality of a finished product is greatly influenced.
Aiming at the defects of the existing preparation method, the invention aims to provide a novel method for preparing brivaracetam, and brivaracetam with optical purity meeting API requirements can be obtained by the method without chiral preparative chromatography. The preparation method has the advantages of easily obtained starting materials, simple synthesis steps, higher yield and stronger industrial application prospect.
Disclosure of Invention
The invention mainly aims to provide a preparation method of brivaracetam, which comprises the following steps:
1) reacting the compound R-4-propyl dihydrofuran-2-ketone in the formula I with the compound L-2-aminobutanamide in the formula II to obtain an intermediate III;
2) reacting the intermediate III with a brominating agent to obtain an intermediate IV;
3) and (4) closing the ring of the intermediate IV under the action of alkali to obtain the brivaracetam.
Further, step 1) is carried out under catalysis of a lewis acid, which is tetraisopropyl titanate, tetrabutyl titanate, or tetraethyl titanate, preferably tetraisopropyl titanate.
Further, the molar ratio of the compound R-4-propyldihydrofuran-2-one in the formula I in the step 1) to the Lewis acid is 1: 1.2-1: 2.5; preferably 1: 2.0.
Further, step 1) is carried out in an organic solvent, wherein the organic solvent is 2-methyltetrahydrofuran, tetrahydrofuran or toluene; tetrahydrofuran is preferred.
Further, in the step 1), the mass volume ratio of the R-4-propyldihydrofuran-2-ketone to the organic solvent is 1: 5-1: 10 kg/L; the mass-to-volume ratio is preferably 1:5 kg/L.
Further, the brominating reagent in the step 2) is dibromosulfoxide, phosphorus tribromide or NBS.
Further, the step 2) is carried out in an organic solvent, wherein the organic solvent is tetrahydrofuran and dichloromethane.
Further, the reaction temperature in the step 2) is 0-10 ℃, and the reaction time is 6-16 hours.
Further, the alkali in the step 3) is inorganic alkali, preferably potassium hydroxide and sodium hydroxide.
Further, step 3) is carried out in an organic solvent, wherein the organic solvent is dichloromethane, tetrahydrofuran or chloroform.
The invention has the advantages of providing a new method for preparing brivaracetam, having simple synthesis steps and higher yield, providing a new route for brivaracetam synthesis, and having stronger industrial application prospect.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the present invention is not limited thereto, and any equivalent replacement in the field made in accordance with the present disclosure is included in the scope of the present invention.
EXAMPLE 1 preparation of Compound III
Adding compound I (50g) and compound II (79.7g) into a three-neck flask, replacing with nitrogen, adding anhydrous tetrahydrofuran (250ml), stirring, dropwise adding tetraisopropyl titanate (222g), keeping the reaction temperature not higher than 20 ℃, stirring overnight at room temperature, performing TLC spot plate to obtain a TLC spot plate with almost no compound I residue, adding ethyl acetate (500ml), 6N hydrochloric acid (100ml), stirring for layering, extracting the water layer twice with a mixed solvent of ethyl acetate and isopropanol (200ml X2, v/v ═ 10/1), combining the organic phases, washing with saturated saline solution (100ml), drying the organic phase with anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate under reduced pressure to dryness to obtain a pale yellow solid, adding isopropanol (180ml) into the solid, heating for dissolution and clarification, dropwise adding methyl tert-butyl ether (1350ml), naturally cooling the solution to room temperature for about 4h, then cooling to about 5 ℃ in an ice water bath, carrying out suction filtration after one hour, and drying a filter cake at 40 ℃ under reduced pressure to obtain a white solid III with the yield of 74.4%.
EXAMPLE 2 preparation of Compound IV
Adding the compound III (1.0g) and anhydrous THF (10ml) into a three-neck flask, cooling by an ice bath, dropwise adding dibromosulfoxide (1.3g), reacting for 6 hours at 5-10 ℃ after dropwise adding, concentrating the reaction solution under reduced pressure to dryness, adding ethyl acetate (20ml) and water (20ml) into the solid residue, stirring and layering, extracting the water phase twice with ethyl acetate (10ml x2), combining the organic phases, washing with saturated saline solution (10ml), concentrating the organic phase to obtain a light yellow solid, adding isopropyl ether (20ml), pulping, performing suction filtration, and drying at 40 ℃ to obtain an off-white solid IV with the yield of 71%.
EXAMPLE 3 preparation of Compound IV
Adding the compound III (2g) and dichloromethane (10ml) into a single-neck bottle, stirring uniformly, adding dimethylthiourea (0.7g) and NBS (2.3g), stirring at 10 ℃ for 16h, directly concentrating a TLC (thin layer chromatography) plate with a little raw material residue, stirring the mixture with silica gel, passing the mixture through a column, and collecting a target component to obtain a light yellow solid IV with the yield of 43%.
Example 4 preparation of brivaracetam
Compound III (10g), methylene chloride (100ml) was added to a single-neck flask, stirring was turned on, the temperature was reduced to-20 ℃ and KOH (2.5g) powder was added, the temperature was maintained and the reaction was carried out for 3 hours, and little starting material remained by TLC. Adding dichloromethane (100ml) and water (50ml), stirring for layering, washing an organic phase with saturated salt solution (20ml), concentrating the organic phase at 35 ℃ under reduced pressure until the organic phase is dried to obtain an off-white solid, adding isopropyl ether (50ml), pulping at room temperature for 2h, filtering to obtain a crude product of brivaracetam, adding methyl tert-butyl ether (40ml) into the crude product, heating for dissolving, cooling for crystallization, performing suction filtration, washing a filter cake with a little methyl tert-butyl ether, and drying at 40 ℃ under reduced pressure to obtain the brivaracetam white solid with the yield of 52.5%, the purity of 99.88% and the optical purity of 99.94%.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds of the present application and the methods of making the same without departing from the spirit or scope of the application, and therefore, the scope of the invention encompasses all modifications and variations that may be made to the present application so long as they are within the scope of the claims and their equivalents.
Claims (10)
1. A preparation method of brivaracetam, which comprises the following steps:
1) reacting the compound R-4-propyl dihydrofuran-2-ketone in the formula I with the compound L-2-aminobutanamide in the formula II to obtain an intermediate III;
2) reacting the intermediate III with a brominating agent to obtain an intermediate IV;
3) and (4) closing the ring of the intermediate IV under the action of alkali to obtain the brivaracetam.
2. The method according to claim 1, wherein step 1) is carried out under catalysis of a lewis acid, which is tetraisopropyl titanate, tetrabutyl titanate, or tetraethyl titanate; tetraisopropyl titanate is preferred.
3. The preparation method of claim 1, wherein the molar ratio of the compound of formula I R-4-propyldihydrofuran-2-one to the Lewis acid in the step 1) is 1: 1.2-1: 2.5; preferably 1: 2.0.
4. The method according to claim 1, wherein step 1) is carried out in an organic solvent, which is 2-methyltetrahydrofuran, tetrahydrofuran or toluene; tetrahydrofuran is preferred.
5. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound R-4-propyldihydrofuran-2-one of the formula I in the step 1) to the organic solvent is 1: 5-1: 10 kg/L; the mass-to-volume ratio is preferably 1:5 kg/L.
6. The method according to claim 1, wherein the brominating reagent in step 2) is dibromosulfoxide, phosphorus tribromide, or NBS.
7. The method according to claim 1, wherein the step 2) is carried out in an organic solvent, and the organic solvent is tetrahydrofuran or dichloromethane.
8. The preparation method according to claim 1, wherein the reaction temperature in the step 2) is 0 ℃ to 10 ℃ and the reaction time is 6 to 16 hours.
9. The process according to claim 1, wherein the base in the step 3) is an inorganic base; potassium hydroxide and sodium hydroxide are preferred.
10. The method according to claim 1, wherein the step 3) is performed in an organic solvent, and the organic solvent is dichloromethane, tetrahydrofuran or chloroform.
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| CN202110380195.7A CN114989060A (en) | 2021-04-09 | 2021-04-09 | Preparation method of brivaracetam |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116573992A (en) * | 2023-07-14 | 2023-08-11 | 瑞博(苏州)制药有限公司 | Non-classical solid phase synthesis carrier and preparation method and application thereof |
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| CN111196771A (en) * | 2018-11-16 | 2020-05-26 | 浙江京新药业股份有限公司 | Compound, preparation method thereof and application thereof in preparation of brivaracetam |
| WO2020148787A1 (en) * | 2019-01-17 | 2020-07-23 | Clininvent Research Pvt. Ltd. | Enantioselective synthesis of brivaracetam and intermediates thereof |
| CN112521325A (en) * | 2019-09-19 | 2021-03-19 | 北京万全德众医药生物技术有限公司 | Novel preparation method of brivaracetam |
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2021
- 2021-04-09 CN CN202110380195.7A patent/CN114989060A/en not_active Withdrawn
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| CN108503573A (en) * | 2017-02-24 | 2018-09-07 | 北京艾百诺医药股份有限公司 | A kind of new preparation method of Bu Waxitan |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116573992A (en) * | 2023-07-14 | 2023-08-11 | 瑞博(苏州)制药有限公司 | Non-classical solid phase synthesis carrier and preparation method and application thereof |
| CN116573992B (en) * | 2023-07-14 | 2023-09-29 | 瑞博(苏州)制药有限公司 | Non-classical solid phase synthesis carrier and preparation method and application thereof |
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