CN113943240A - Novel preparation method of brivaracetam - Google Patents
Novel preparation method of brivaracetam Download PDFInfo
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- CN113943240A CN113943240A CN202010678583.9A CN202010678583A CN113943240A CN 113943240 A CN113943240 A CN 113943240A CN 202010678583 A CN202010678583 A CN 202010678583A CN 113943240 A CN113943240 A CN 113943240A
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- brivaracetam
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- 229960002161 brivaracetam Drugs 0.000 title claims abstract description 34
- 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 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 229940125782 compound 2 Drugs 0.000 claims description 8
- 238000007142 ring opening reaction Methods 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000000926 separation method Methods 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 206010015037 epilepsy Diseases 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 229910006124 SOCl2 Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000001314 paroxysmal effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 108010005730 R-SNARE Proteins Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108010052164 Sodium Channels Proteins 0.000 description 1
- 102000018674 Sodium Channels Human genes 0.000 description 1
- 102000002215 Synaptobrevin Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- -1 comprises two steps Chemical compound 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of brivaracetam, which takes (R) -4-propyl dihydro-2 (3H) -ketone which is purchased from the market as a raw material to synthesize the brivaracetam in two steps under certain conditions. The preparation method provided by the invention can directly obtain the high-optical-purity brivaracetam without adopting a chiral preparation chromatographic column separation step. The method has the advantages of high yield, simple and convenient post-treatment, low production cost and suitability for industrial production.
Description
Technical Field
The invention relates to a novel preparation method of brivaracetam.
Background
Epilepsy, commonly known as epilepsy, is a disease of paroxysmal motor, sensation, consciousness, mental and autonomic nerve dysfunction caused by paroxysmal abnormal discharge of neuron groups in the brain due to various reasons. The total prevalence rate of domestic epilepsy is 7.0%, the annual incidence rate is 28.8/10 ten thousand, and the prevalence rate of active epilepsy with seizures within 1 year is 4.6%. The Brivaracetam is a sitan derivative, is a novel high-affinity synaptobrevin 2A ligand, can inhibit a neuron voltage-dependent sodium channel, and plays a role in resisting epilepsy. Brivaracetam is a 3 rd generation antiepileptic drug developed by belgium time ratio (UCB) corporation.
The chemical name of the Buvalsartan is (2S) -2- [ (4R) -2-oxo-4-propyltrahydro-1H-pyrrol-1-yl ] butanamide.
Structural formula of it
The brivaracetam can be prepared in various ways, and is mainly prepared by the following two methods:
the method comprises the following steps: using racemic 4-propyl-dihydrofuran-2-ketone as raw material, making ring-opening reaction, acyl chlorination reaction, finally making ring-closing reaction with BRT-2 to obtain BRT and its diastereoisomer mixture: (J.Med.Chem.,2004,47,530）。
The target molecule is obtained only by silica gel column separation and purification and chiral resolution, and the method has high production cost and poor industrial feasibility.
The second method comprises the following steps: the (R) -4-propyl-dihydrofuran-2-ketone is used as a raw material, and the steps of ring opening, halogenation, condensation, ring closing and the like are carried out to prepare the brivaracetam (WO 2018152950).
In this method, the target compound cannot be obtained in high purity because the starting material is not completely reacted during the ring opening and the target compound is not obtained until the final product is obtained.
Therefore, it is necessary to find a synthetic route of the brivaracetam, which has the advantages of few steps, high yield, simple post-treatment, high purity and suitability for industrial production. .
Disclosure of Invention
Aiming at the defects of the prior art, the technical scheme of the invention is to provide a novel method for synthesizing the brivaracetam. The preparation method provided by the invention can directly obtain the high-optical-purity brivaracetam without adopting a chiral preparation chromatographic column separation step. The method has the advantages of high yield, simple and convenient post-treatment, low production cost and suitability for industrial production.
The invention provides a preparation method of brivaracetam, which takes (R) -4-propyl dihydro-2 (3H) -ketone (compound 3) which is purchased from the market as a raw material to synthesize the brivaracetam (compound 5) through two steps of ring opening and ring closing.
The synthetic route is as follows:
the step of synthesizing the brivaracetam mainly comprises two steps, and the brivaracetam is prepared by the following synthetic route: the first step is that (R) -4-propyl dihydro-2 (3H) -ketone (compound 3) generates ring-opening reaction under certain conditions to generate compound 2, and the second step generates compound 2 to generate target compound, namely the brivaracetam 1.
In the first step of the synthesis of the brivaracetam, a ring-opening reagent is thionyl chloride.
In the first step of synthesizing the brivaracetam, the catalyst is N, N-Dimethylformamide (DMF), N-dimethylaniline or pyridine, and the like, and the N, N-dimethylformamide is preferred.
In the second step of synthesizing the brivaracetam, the catalyst is N, N-Dimethylformamide (DMF), N-dimethylaniline or pyridine, and the like, and the N, N-dimethylformamide is preferred.
In the first step of synthesizing the brivaracetam, the feeding ratio is 1:1 to 1:3, and the like, and preferably 1: 2.
The method according to claim 1, wherein the reaction temperature in the first step of the synthesis of the brivaracetam is 20-150%oC, preferably 110oC。
The process according to claim 1, wherein in the second step of the synthesis of bravaracetam, the basic agent is KOH, NaOH, triethylamine or the like, preferably KOH.
The method according to claim 1, wherein in the second step of the synthesis of the brivaracetam, the preferable reaction temperature is-20 to 50%oC, preferably-10oC。
The preparation method provided by the invention has the advantages of few steps, suitability for industrial production, no need of chiral high-pressure liquid phase preparation column resolution, simple post-treatment and high purity. The total impurity of the brivaracetam is less than 0.5 percent, the single impurity is less than 0.1 percent, the grade of raw material medicine (API) is achieved, and the brivaracetam is suitable for industrial production.
Detailed Description
The following examples further illustrate the present invention without, however, limiting the scope of the invention thereto. The experimental methods in the following examples, which do not indicate specific conditions, were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
The preparation method of the Buvartan comprises the following process steps
(1) Adding SOCl2(566.4 mL, 7.8076 mol) and 3.0L of toluene were charged in a 5L three-necked flask, and stirring was started, 10 mL of DMF was added dropwise, and the mixture was stirred for 30 min. Compound 3 (500.0 g, 3.9038 mol) was weighed out and added dropwise to the system, and after completion of the addition, the reaction was carried out under heating reflux for 6 hours. The reaction is complete at 60oConcentration under C gave 541.2g of a tan liquid (Compound 2) in 82% yield
(2) S-2-aminobutanamide (532.5 g, 3.8417 moL) and KOH (269.4 g, 4.8021moL) were dissolved in dichloromethane (3L) and added to a 5L one-neck flask with stirring turned on. In the range of-10 to 0oUnder the condition of C, measuring the compound 2(541.2g, 3.2014 moL) and dropwise adding into the system, and after dropwise adding is finished, 0-10oC, reacting for 12 hours. After the reaction is finished, dropwise adding saturated ammonium chloride solution (1.5L), carrying out suction filtration, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate for 2 hours, and concentrating to obtain crude product 530.1g of brown oily product of Buvalsartan, wherein the yield is 78.0%.
(3) Adding a crude product of the brivaracetam (530.1g, 2.4971mol) and 1.06 mL of ethyl acetate into a 10L three-neck flask, stirring, heating to reflux, dissolving, adding 4.24L of methyl tert-butyl ether for crystallization, performing crystallization for four hours in an ice water bath, performing suction filtration, collecting 425.7g of a white solid, wherein the total yield is 80.3%, the total impurities are detected by HPLC (high performance liquid chromatography) and 0.06% of the maximum single impurities, and the optical impurities are 0.07%.
Example 2
(1) Adding SOCl2(849.6 mL, 11.7114 mol) and 3.0L of toluene were charged in a 5L three-necked flask, and stirring was started, 10 mL of DMF was added dropwise, and the mixture was stirred for 30 min. Compound 3 (500.0 g, 3.9038 mol) was weighed out and added dropwise to the system, and after completion of the addition, the reaction was carried out under heating reflux for 5 hours. The reaction is complete at 60oConcentration under CAfter the condensation, 587.3g of a tan liquid (Compound 2) was obtained in 89.0% yield.
(2) S-2-aminobutanamide (577.8 g, 4.1689 moL) and NaOH (208.5 g, 5.2112moL) were dissolved in dichloromethane (3L) and added to a 5L one-neck flask with stirring turned on. In the range of-10 to 0oUnder the condition of C, measuring the compound 2(587.3g, 3.4741 moL) and dropwise adding into the system, and after dropwise adding is finished, 0-10oC, reacting for 12 hours. After the reaction is finished, dropwise adding saturated ammonium chloride solution (1.5L), carrying out suction filtration, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate for 2 hours, and concentrating to obtain 553.1g of brown oily crude product of the brivaracetam, wherein the yield is 75.0%.
(3) Adding crude product of brivaracetam (553.1g, 2.6056 mol) and 1.16 mL of ethyl acetate into a 10L three-neck flask, stirring, heating to reflux, dissolving, adding 4.64L of methyl tert-butyl ether for crystallization, performing crystallization for four hours in an ice water bath, performing suction filtration, collecting 459.1g of white solid, wherein the total yield is 83.0%, total impurities are detected by HPLC (high performance liquid chromatography) to be 0.39%, the maximum single impurities is 0.07%, and optical impurities are 0.08%.
1H NMR(400MHz, CDCl3): 0.83-0.91 (m, 6H), 1.26-1.34 (m, 2H), 1.31-1.45 (m, 2H), 1.67-1.72 (m, 1H), 2.59 (dd, 1H, JA =16.8 Hz, JB = 8.4 Hz), 3.03 (dd, 1H, JA =9.6 Hz, JB = 7.2 Hz), 3.49 (dd, 1H, JA =9.6 Hz, JB = 8.4 Hz), 4.45 (dd, 1H, JA =8.4 Hz, JB = 7.2 Hz), 5.30(s, br, 1H), 6.20 (s, br, 1H) 。
Claims (7)
1. A preparation method of the brivaracetam is characterized by comprising the following steps: the preparation method is prepared by the following synthetic route: the first step is that (R) -4-propyl dihydro-2 (3H) -ketone (compound 3) generates ring-opening reaction under certain conditions to generate compound 2, and the second step generates compound 2 to generate target compound, namely the brivaracetam 1.
2. The process according to claim 1, wherein in the first step of the synthesis of brivaracetam, the ring-opening reagent is thionyl chloride.
3. The process according to claim 1, wherein in the first step of the synthesis of bravaracetam the catalyst is N, N-Dimethylformamide (DMF), N-dimethylaniline or pyridine, etc., preferably N, N-dimethylformamide.
4. The process according to claim 1, wherein the first step of the synthesis of bravaracetam is carried out in a feed ratio of 1:1 to 1:3, etc., preferably 1: 2.
5. The method according to claim 1, wherein the reaction temperature in the first step of the synthesis of the brivaracetam is 20-150%oC, preferably 110oC。
6. The process according to claim 1, wherein in the second step of the synthesis of bravaracetam, the basic agent is KOH, NaOH, triethylamine or the like, preferably KOH.
7. The method according to claim 1, wherein in the second step of the synthesis of the brivaracetam, the preferable reaction temperature is-20 to 50%oC, preferably-10oC。
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| Application Number | Priority Date | Filing Date | Title |
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| CN202010678583.9A CN113943240A (en) | 2020-07-15 | 2020-07-15 | Novel preparation method of brivaracetam |
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| CN202010678583.9A CN113943240A (en) | 2020-07-15 | 2020-07-15 | Novel preparation method of brivaracetam |
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| CN113943240A true CN113943240A (en) | 2022-01-18 |
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- 2020-07-15 CN CN202010678583.9A patent/CN113943240A/en active Pending
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