CN108689968B - Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam - Google Patents
Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam Download PDFInfo
- Publication number
- CN108689968B CN108689968B CN201810610090.4A CN201810610090A CN108689968B CN 108689968 B CN108689968 B CN 108689968B CN 201810610090 A CN201810610090 A CN 201810610090A CN 108689968 B CN108689968 B CN 108689968B
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- organic solvent
- preparation
- sodium
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings 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
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present application provides a compound of formula IV and a compound of formula V and methods for their preparation. The application also provides a synthesis method of the compound shown in the formula IV and the compound shown in the formula V for synthesizing the brivaracetam. The method disclosed by the application has the advantages that the raw materials are easy to obtain and low in price, and the high-optical-purity brivaracetam can be prepared.
Description
The present application is a divisional application filed on 2015, 5 and 25, with application number 201510271449.6, entitled "a compound and a preparation method and application thereof in synthesis of bravaracetam".
Technical Field
The application relates to the field of drug synthesis, in particular to two compounds, a preparation method thereof and application thereof in synthesis of brivaracetam. The application also relates to a method for synthesizing the brivaracetam.
Background
Epilepsy is a common disease of the nervous system, the morbidity of people is 0.6-1.1%, and 60-70% of patients still have the seizure when taking anti-epilepsy drugs, so that a part of patients stop drug treatment by themselves. At present, more than 600 million epileptics exist in China, 65-70 million new epileptics are developed every year, and about 25 percent of patients are intractable epileptics. Although the current diagnosis and treatment of epilepsy has advanced greatly, the number of intractable epilepsy patients is increasing. Broadly refractory epilepsy refers to epilepsy and epileptic syndromes that cannot be terminated or have been clinically proven refractory using current standard treatment with antiepileptic drugs (AEDs).
Brivaracetam (Brivaracetam) is a novel high-affinity synaptobrevin 2A ligand, can inhibit a neuron voltage-dependent sodium channel, and is used for treating refractory partial epileptic seizures. The clinical trials of the phase II and the phase III of the brivaracetam have better curative effect. The incidence of major adverse events of bravaracetam was similar to that of the placebo group, all mild to moderate fatigue, headache, nasopharyngitis, nausea, somnolence and dizziness. No patient discontinued treatment due to adverse events. The results show that the brivaracetam tablets are effective and well-tolerated in adjuvant therapy of patients with refractory partial seizure epilepsy of 16-65 years old. In general, the Buvalacetam is a third-generation antiepileptic drug with very good prospect after levetiracetam.
So far, no domestic patent on the synthesis of the brivaracetam is reported. There are also few foreign related patents reported, such as patents US 6,784,197, US 7,629,474, US 8,957,226, US 8,338,621, US 8,076,493 and related patents reporting the synthesis of brivaracetam, wherein US 6,784,197, US 7,629,474 report the following synthetic routes:
US 8,957,226 (examples 1,3) and US 8,338,621 (examples 4,11) report the following synthetic routes:
kenda et al (Journal of Medicinal Chemistry,2004,47,530) reported the following synthetic routes:
the chiral center of the n-propyl group on the butyrolactam is not constructed by the above routes, but the optically pure bravaracetam is obtained in the final product by a chiral high performance liquid purification method, and the raw materials are not economically utilized.
Therefore, there is a need for a simple and cost-effective process for the preparation of brivaracetam, to obtain brivaracetam of high optical purity.
Disclosure of Invention
The application aims to provide a compound in a general formula I and a preparation method thereof.
It is a further object of the present application to provide the use of a compound of formula I for the synthesis of brivaracetam of formula VII.
It is a further object of the present application to provide a process for the synthesis of bravaracetam of formula VII.
In one aspect, the present application provides a compound having the structure of formula I:
wherein R is C1-20A hydrocarbyl group.
Wherein, the term "C1-20Hydrocarbyl "comprising C1-20Alkyl radical, C1-20Alkenyl radical, C1-20Alkynyl groups, aryl groups, and the like, aryl groups can include phenyl, benzyl, or other aryl groups. Preferably, C1-20The hydrocarbyl group is methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, t-butyl, or benzyl.
Furthermore, it will be understood by those skilled in the art that the compound of formula I requires only the n-propyl group at the 4-position in the (R) configuration, and there is no particular requirement for the configuration of the ester group at the 3-position, and thus the ester group at the 3-position may be in either the (R) or (S) configuration, or the ester group at the 3-position may be in both the (R) and (S) configurations.
In another aspect, the present application provides a process for preparing a compound of formula I, said process comprising the step of preparing a compound of formula I from a compound of formula II:
wherein R is C1-20A hydrocarbyl group.
It will be appreciated by those skilled in the art that the compound of formula I may be prepared from the compound of formula II by ring opening methods known in the art, such as by reacting the compound of formula II with an ethyl metal reagent.
In one embodiment, the compound of formula I may be prepared by reacting a compound of formula II with an ethyl metal reagent in an aprotic organic solvent at a temperature of-78 ℃ to 200 ℃, wherein the molar equivalents of the ethyl metal reagent used may be between 1 and 5, preferably the ethyl metal reagent may be selected from one or more of ethyl magnesium bromide, ethyl magnesium chloride, diethyl zinc, ethyl lithium and diethyl lead, more preferably the ethyl metal reagent may be used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride, and the molar equivalents of cuprous iodide, cuprous cyanide or anhydrous zinc chloride used in the reaction may be between 0.01 and 2; preferably, the aprotic organic solvent may be selected from one or more of Tetrahydrofuran (THF), methyltetrahydrofuran, toluene, dichloromethane, diethyl ether and methyl tert-butyl ether.
In yet another aspect, the present application provides the use of a compound of formula I as described above for the synthesis of brivaracetam of formula VII
In one embodiment, a compound of formula III may be synthesized from a compound of formula I, followed by the design synthesis of the formula VII, Buvalsartan,
wherein R is C1-20A hydrocarbyl group.
In one embodiment, the compound of formula I may be subjected to a de-esterification reaction in a mixture of a water-soluble high boiling organic solvent and water at a temperature in the range of 50 ℃ to 200 ℃ under the action of a salt or base to give a compound of formula III, wherein the salt or base is used in a molar equivalent of between 0.01 and 10; preferably, the salt is selected from one or more of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and lithium bromide, the base is selected from one or more of lithium hydroxide, potassium hydroxide or sodium hydroxide, and the water-soluble high boiling point organic solvent is selected from one or more of N-methylpyrrolidone, N-dimethylformamide, dimethylsulfoxide, sulfolane and 4-methyl-2-pentanol;
or, if R contains unsaturated part, the compound of formula I is firstly subjected to metal catalysis to remove R group, and then is subjected to decarboxylation reaction at the temperature of 25-200 ℃ to obtain the compound of formula III; preferably, the deacidification reaction is carried out in one or more selected from the group consisting of toluene, methyl t-butyl ether, N-methylpyrrolidone, N-dimethylformamide and dimethylsulfoxide.
With respect to metal catalysis, those skilled in the art will appreciate that this can be done by metal catalysis methods known in the art, and the catalyst can be a metal catalyst such as Pd, Pt, Ni, palladium triphenylphosphine, etc., and specific methods can be referred to Protective Groups in Organic Synthesis, Third edition, theodora w.greene, peter g.m.wuts,1999, John Wiley & Sons, inc., chapter 5, etc.
In other aspects, the present application provides a method of synthesizing bravaracetam of formula VII, comprising the steps of:
wherein R is C1-20The hydrocarbon group, preferably,r is methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, tert-butyl or benzyl, more preferably R is ethyl; r1 is H or C1-20A hydrocarbyl group, preferably R1 is methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, tert-butyl or benzyl, more preferably R1 is ethyl; and X is chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy or p-nitrobenzenesulfonyloxy, preferably X is bromo.
Wherein R, R1 or X can be appropriately selected by those skilled in the art according to the type of reaction involved in the process. For example, R may be any C that does not affect decarboxylation1-20A hydrocarbyl group; r1 may be any C capable of forming a ring-opened ester1-6Alkyl, which depends on the alcohol used for the ring-opening reaction; and X may be any leaving group such as chloro, bromo, iodo, mesyloxy or p-toluenesulfonyloxy.
In some embodiments, R may be methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, tert-butyl, or benzyl.
In some embodiments, R and R1 may be ethyl groups and X may be bromine.
It will also be understood by those skilled in the art that, based on the synthetic routes described above, those skilled in the art are fully enabled to obtain the desired product by appropriate selection of starting materials and synthetic methods known in the art, based on their common technical knowledge and routine technical means.
In one embodiment, the reaction conditions for each reaction step may be:
preparing a compound of formula I from a compound of formula II:
reacting a compound of formula II with an ethyl metal reagent in an aprotic organic solvent at a temperature of-78 ℃ to 200 ℃ to produce a compound of formula I, wherein the molar equivalent of the ethyl metal reagent used may be between 1 and 5; preferably, the ethyl metal reagent may be selected from one or more of ethyl magnesium bromide, ethyl magnesium chloride, diethyl zinc, ethyl lithium and diethyl lead; more preferably, the ethyl metal reagent may be used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride, the molar equivalent of cuprous iodide, cuprous cyanide or anhydrous zinc chloride used in the reaction being between 0.01 and 2; preferably, the aprotic organic solvent may be selected from one or more of Tetrahydrofuran (THF), methyltetrahydrofuran, toluene, dichloromethane, diethyl ether and methyl tert-butyl ether;
preparing a compound of formula III from a compound of formula I:
subjecting the compound of formula I to a de-esterification reaction in a mixture of a water-soluble high boiling organic solvent and water at a temperature in the range of 50 ℃ to 200 ℃ under the action of a salt or a base to obtain a compound of formula III, wherein the salt or the base is used in a molar equivalent of between 0.01 and 10; preferably, the salt is selected from one or more of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and lithium bromide, the base is selected from one or more of lithium hydroxide, potassium hydroxide or sodium hydroxide, and the water-soluble high boiling point organic solvent is selected from one or more of N-methylpyrrolidone, N-dimethylformamide, dimethylsulfoxide, sulfolane and 4-methyl-2-pentanol;
or, if R contains an unsaturated moiety, subjecting the compound of formula I to a metal catalyzed removal of the R group followed by decarboxylation at a temperature in the range of 25 ℃ to 200 ℃ to give the compound of formula III, preferably the deacidification is carried out in one or more selected from the group consisting of toluene, methyl tert-butyl ether, N-methylpyrrolidone, N-dimethylformamide and dimethyl sulfoxide;
preparing a compound of formula IV from a compound of formula III:
subjecting the compound of formula III to a ring-opening reaction with iodotrimethylsilane, bromotrimethylsilane, hydrobromic acid, hydrochloric acid or hydroiodic acid in an organic solvent 1 to obtain a compound of formula IV,
or, hydrolyzing the compound of formula III under alkaline conditions for ring opening, and then reacting with methanesulfonyl chloride, p-toluenesulfonyl chloride, or p-nitrobenzenesulfonyl chloride in organic solvent 1 to obtain a compound of formula IV; preferably, the organic solvent 1 is selected from the group consisting of N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, and cyclic compoundsButyl sulfone, methylene chloride, acetonitrile or C1-20One or more of alkyl alcohols, the alkaline conditions for hydrolytic ring opening being achieved by the addition of sodium hydroxide, potassium hydroxide, lithium hydroxide;
preparing a compound of formula V from a compound of formula IV:
reacting a compound of formula IV with (S) -2-amino-butanamide or a salt thereof in an organic solvent 2 at a temperature of 25 ℃ to 200 ℃ under basic conditions formed by a basic compound to prepare a compound of formula V, wherein the molar equivalent of the basic compound used is between 1 and 5, and the molar equivalent of the (S) -2-aminobutanamide or a salt thereof used is between 0.5 and 5; preferably, the basic compound is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide or sodium bis (trimethylsilyl) amide, and the organic solvent 2 is selected from one or more of N-methylpyrrolidone, N-dimethylformamide, dimethylsulfoxide, sulfolane;
preparing a compound of formula VII from a compound of formula V:
in an organic solvent 3, ring closing the compound of formula V at a temperature of 25 ℃ to 200 ℃ to obtain a compound of formula VII; preferably, the ring closure reaction is carried out under the action of an amide bond promoter selected from HOBt or 2-hydroxypyridine, and the organic solvent 3 is selected from one or more of toluene, methyl isobutyl ketone, xylene or chlorobenzene.
In a specific exemplary embodiment, the method may include the steps of:
wherein R is C1-20Hydrocarbyl, preferably R is ethyl.
In the above or other embodiments, the compound of formula II may be a commercially available product, such as the product of ultrayue chemical catalog No. SP-13711.
In the above or other embodiments, the compound of formula II may also be prepared by:
wherein R is C1-20A hydrocarbyl group, wherein the reaction temperature is 0 ℃ to 100 ℃, the molar equivalent of the base is between 1 and 3, and the molar equivalent of the compound 2 is between 1 and 3; preferably, the base is selected from one or more of sodium metal and potassium metal, more preferably, the sodium metal is sodium methoxide, sodium ethoxide or sodium tert-butoxide, and the potassium metal is potassium tert-butoxide; the organic solvent 4 is selected from one or more of ethanol, methanol, propanol and isopropanol.
Compared with the prior art, the method for synthesizing the brivaracetam has the following advantages:
1. the raw materials are easy to obtain and the price is low.
2. The intermediate and the product are easy to separate and purify, even the intermediate and the product do not need to be purified, the intermediate and the product can be directly subjected to a series reaction to be used for preparing the brivaracetam and similar compounds in the next step, and the operation is simple.
3. The chiral center of the n-propyl group on the butyrolactam is constructed at the beginning, so that the high-optical-purity brivaracetam can be obtained; 98% ee of the initial raw material, and 98% ee of the brivaracetam prepared by multi-step reaction, and the optical purity of the whole reaction process is kept.
4. The total reaction yield of the preparation of the brivaracetam by the method can reach the level equivalent to or even higher than that of the prior art, the synthesis method avoids chiral isomers which are difficult to separate, the total yield of the brivaracetam prepared by the compound of the formula I reaches up to 30 percent, and the yield is expected to be further improved by condition optimization. The total yield of the synthesis method for obtaining the brivaracetam by using chiral HPLC (high performance liquid chromatography) purification reported in the prior literature is about 15-20%, and isomers cannot be recovered.
Detailed Description
Embodiments of the present application are described below by way of examples, and it should be appreciated by those skilled in the art that these specific examples merely illustrate selected embodiments for achieving the purposes of the present application and are not intended to limit the technical solutions. Modifications of the technical solutions of the present application in combination with the prior art are obvious from the teachings of the present application and fall within the protection scope of the present application.
The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
Among them, the chemical agents used in the following examples are all commercially available chemical agents.
In an exemplary embodiment of the invention, brivaracetam is synthesized using the following route:
in the above synthetic schemes, the selection of R as ethyl, X as bromo and R1 as ethyl is exemplified. R may also be selected from any other group defined above, and those skilled in the art may make changes to the above synthetic routes, such as changing specific reaction conditions or adjusting the synthetic route of one or more steps, etc., as needed, and such changes are within the scope of the present application without departing from the spirit of the present invention.
EXAMPLE 1 preparation of Compound 3
Sodium methoxide (2.05g, 38mmol) was added to 80mL of anhydrous ethanol to dissolve completely. The reaction flask was placed in an ice-water bath and diethyl malonate was added. Stirring at this temperature for 10 minutes, allowing the system to warm to room temperature, slowly adding (R) -epichlorohydrin (ee 98%) (2.7mL, 35mmol) (purchased from Annaiji chemical) to the reaction system, reacting for 18 hours under reflux, stopping the reaction, cooling the system to room temperature, spin-drying the solvent, adding 100mL of water, and extracting with 100mL of ethyl acetate for 3 times. And (3) combining organic phases, drying the organic phases by using anhydrous sodium sulfate, filtering the mixture after the drying is finished, and spin-drying the filtrate to obtain a compound 3, and obtaining a colorless liquid by reduced pressure distillation with the yield of 55%. Compound 3 chiral HPLC (ee 98%)
The nuclear magnetic data for compound 3 are as follows:1H NMR(400MHz,CDCl3):4.33(1H,dd),4.23(2H,q),4.16(1H,d),2.73-2.75(1H,m),2.05(1H,dd),1.35(1H,t),1.28(3H,t)。
EXAMPLE 2 preparation of Compound 4
CuI (9.5g, 50mol) was added to 100mL of dry THF, the flask was placed in a low temperature reaction bath at-30 deg.C, a solution of ethyl Grignard reagent in THF (1.0M, 300mL, 300mmol) was added to the flask, stirring was carried out for 1 hour, and a solution of compound 3(20g, 117mmol) in dry THF, as prepared in example 1, was added dropwise to the flask. After the addition was complete, the mixture was stirred at this temperature for 30 minutes and then slowly warmed to-15 ℃. Quenching the reaction with saturated ammonium chloride, adding 1L of water, extracting with 1L of ethyl acetate for three times, combining organic phases, drying over anhydrous sodium sulfate, drying, filtering, and concentrating the filtrate to obtain a crude compound 4.
Nuclear magnetic data for purified compound 4 obtained by column chromatography (polarity of developing solvent: petroleum ether/ethyl acetate 10/1) was as follows:1H NMR(400MHz,CDCl3)4.52(1H,dd),4.27(2H,q),3.92(1H,dd),3.23(1H,d),2.96-3.03(1H,m),1.49-1.56(2H,m),1.27-1.35(5H,m),0.95(3H,t)。
the specific optical rotation of the purified compound 4 obtained by column chromatography purification (polarity of developing solvent: petroleum ether/ethyl acetate: 10/1) is [ α ]]23 D＝+22.6(C＝10,CHCl3)
EXAMPLE 3 preparation of Compound 5
The crude compound 4 (117 mmol) prepared as described in example 2 was added DMSO/H2O (400mL/20mL), LiCl (14.7g, 350mmol) was added to the reaction flask. The system is after 18h reaction at 140 ℃, poured into 400mL water, extracted three times with 400mL ethyl acetate, the organic phases are combined, washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated to obtain crude product, and the crude product is distilled under reduced pressure to obtain compound 5, colorless liquid, and the total yield of the two steps is 50 percent in the example 2
The nuclear magnetic data for compound 5 are as follows:1H NMR(400MHz,CDCl3)4.42(1H,dd),3.92(1H,dd),2.52-2.65(2H,m),2.18(1H,dd),1.40-1.47(2H,m),1.40-1.47(2H,m),1.27-1.39(2H,m),0.94(3H,t)。
compound (I)5 has a specific optical rotation of [ α ]]23 D＝+3.9(C＝10,CHCl3)
EXAMPLE 4 preparation of Compound 6
TMSBr (3.1mL, 24mmol) was added under ice-water bath conditions to a solution of compound 5(1.1g, 7.8mmol), prepared as in example 3, and 2.5mL of absolute ethanol in 40mL of dichloromethane, and the system was reacted at room temperature overnight. To the system was added a sodium thiosulfate solution, 50mL of water was added, the system was extracted three times with ethyl acetate (50mL × 3), the organic phases were combined, washed once with 20mL of a saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (polarity of developing solvent: petroleum ether/ethyl acetate ═ 20/1) to give compound 6 as a colorless liquid, yield 87%.
The nuclear magnetic data for compound 6 are as follows:1H NMR(400MHz,CDCl3)4.16(q,2H),3.58(dd,1H),3.55(dd,1H),2.51(dd,1H),2.36(dd,1H),2.15-2.30(m,1H),1.25-1.51(m,7H),0.94(t,3H)。
the specific optical rotation of the compound 6 is [ α ]]23 D＝-3.8(C＝10,CHCl3)
EXAMPLE 5 preparation of Compound 8
Compound 7(S) -2-aminobutanamide hydrochloride (5.8g, 24.5mmol) (available from Beijing coupling technology Co., Ltd.), Compound 6(2.83g, 20.4mmol) prepared as in example 4, sodium carbonate (7.78g, 73.4mmol) and sodium iodide (1.83g, 12.2mmol) were added to 60mL of DMF solution and reacted at 90 ℃ for 18 h. The reaction was stopped, and 100mL of water and 50mL of ethyl acetate were added to the reaction mixture to separate the layers. The organic phase was removed, the aqueous phase was extracted twice with ethyl acetate (50mL × 2), the organic phases were combined, washed once with 20mL saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated and purified by column chromatography (eluent polarity DCM/MeOH/TEA ═ 100/1/1) to give compound 8 as an egg yellow liquid in 40% yield.
The nuclear magnetic data for compound 8 is as follows:1H NMR(400MHz,CDCl3)7.03(brs,1H),5.86(brs,1H),4.13(q,2H),2.96(t,1H),2.54(dd,1H),2.33(dd,1H),1.78-2.10(m,1H),1.56-1.75(m,2H),1.24-1.48(m,7H),0.85-1.03(m,6H)。
practice ofEXAMPLE 6 preparation of Compound 9 Buvalracetam
Compound 8(120mg, 0.46mmol), HOBt (63mg, 0.46mmol) prepared as in example 5 was added to 1mL of toluene. The system is heated to 90 ℃ to react for 3 h. The reaction was stopped, and 50mL of a saturated aqueous sodium bicarbonate solution and 50mL of ethyl acetate were added to the reaction mixture to separate the layers. The organic phase was removed, the aqueous phase was extracted twice with ethyl acetate (50mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent polar EtOAc/TEA ═ 100/1) to give a white solid, i.e. bravaracetam, yield 41%, chiral HPLC 98% ee.
The brooacetam nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)6.42(brs,1H),5.69(brs,1H),4.46(dd,1H),3.50(dd,1H),3.05(dd,1H),2.57(dd,1H),2.25-2.40(m,1H),2.05(dd,1H),1.78-1.99(m,1H),1.54-1.75(m,1H),1.25-1.48(m,4H),0.80-0.95(m,6H)。
EXAMPLE 7 preparation of the Compound 9 Buvalracetam
Compound 8(435mg, 1.73mmol), 2-hydroxypyridine (82mg, 0.86mmol) prepared as in example 5 was added to 4mL of toluene. The system is heated to 90 ℃ to react for 3 h. The reaction was stopped, and 50mL of a saturated aqueous sodium bicarbonate solution and 50mL of ethyl acetate were added to the reaction mixture to separate the layers. The organic phase was removed, the aqueous phase was extracted twice with ethyl acetate (50mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent polarity PE/EtOAc/TEA ═ 50/50/1) to give a white solid, i.e. bravaracetam, yield 58%, chiral HPLC 98% ee.
The brooacetam nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)6.42(brs,1H),5.69(brs,1H),4.46(dd,1H),3.50(dd,1H),3.05(dd,1H),2.57(dd,1H),2.25-2.40(m,1H),2.05(dd,1H),1.78-1.99(m,1H),1.54-1.75(m,1H),1.25-1.48(m,4H),0.80-0.95(m,6H)。
EXAMPLE 8 preparation of Compound 9 Buvalracetam
Compound 7(S) -2-aminobutanamide hydrochloride (4.35g, 31.5mmol) (available from Beijing coupling technology Co., Ltd.), Compound 6(5.0g, 21.0mmol) prepared as in example 4, sodium carbonate (8.9g, 84.0mmol) and sodium iodide (1.57g, 10.5mmol) were added to 50mL of DMF solution and reacted at 90 ℃ for 18 h. The reaction was stopped, and 100mL of water and 50mL of ethyl acetate were added to the reaction mixture to separate the layers. The organic phase was taken out, the aqueous phase was extracted twice with ethyl acetate (50 mL. times.2), the organic phases were combined, washed once with 20mL of saturated NaCl solution, dried over anhydrous sodium sulfate, filtered, spun-dried, dissolved in 50mL of toluene, and reacted for 5h at 90 ℃ with 2-hydroxypyridine (1.0g, 10.5 mmol). 100mL of a saturated aqueous sodium bicarbonate solution and 100mL of ethyl acetate were added to the reaction mixture, and the layers were separated. The organic phase was removed, the aqueous phase was extracted twice with ethyl acetate (100mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent polarity PE/EtOAc/TEA ═ 50/50/1) to give a white solid, i.e. bravaracetam, yield 50%, chiral HPLC 98% ee.
The brooacetam nuclear magnetic data are as follows:1H NMR(400MHz,CDCl3)6.42(brs,1H),5.69(brs,1H),4.46(dd,1H),3.50(dd,1H),3.05(dd,1H),2.57(dd,1H),2.25-2.40(m,1H),2.05(dd,1H),1.78-1.99(m,1H),1.54-1.75(m,1H),1.25-1.48(m,4H),0.80-0.95(m,6H)。
this application is intended to cover any variations, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.
Claims (27)
1. A compound having the structure of formula IV:
r1 is H or C1-20A hydrocarbyl group, and X is chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy, or p-nitrobenzenesulfonyloxy.
2. The compound of claim 1, wherein R1 is H, methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, t-butyl, or benzyl, and X is chloro, bromo, or iodo.
3. The compound of claim 1, wherein R1 is H, methyl, or ethyl, and X is chloro, bromo, or iodo.
4. A compound having the structure of formula V:
r1 is H or C1-20A hydrocarbyl group.
5. The compound of claim 4, wherein R1 is H, methyl, ethyl, propyl, allyl, n-butyl, isobutyl, isopropyl, n-pentyl, n-hexyl, t-butyl, or benzyl.
6. The compound of claim 4, wherein R1 is H, methyl, or ethyl.
7. A process for the preparation of a compound according to any one of claims 1 to 3, comprising the steps of:
wherein R1 is hydrogen or C1-20A hydrocarbyl group; and X is chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy or p-nitrobenzenesulfonyloxy.
8. The process of claim 7, wherein the compound of formula III is subjected to a ring opening reaction with trimethyliodosilane, trimethylbromosilane, hydrobromic acid, hydrochloric acid or hydroiodic acid in an organic solvent to provide the compound of formula IV; or
The compound of formula III is hydrolytically opened under basic conditions and then reacted with methanesulfonyl chloride, p-toluenesulfonyl chloride, or p-nitrobenzenesulfonyl chloride in an organic solvent to give the compound of formula IV.
9. The process of claim 8, wherein the organic solvent used in the preparation of the compound of formula IV is selected from N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, sulfolane, dichloromethane, acetonitrile or C1-20One or more of a hydrocarbon alcohol.
10. The process of claim 8, wherein the basic conditions for hydrolytic ring opening are achieved by addition of sodium hydroxide, potassium hydroxide or lithium hydroxide.
11. A process for the preparation of a compound according to any one of claims 4 to 6, comprising the steps of:
wherein R1 is hydrogen or C1-20A hydrocarbyl group; and X is chloro, bromo, iodo, methanesulfonyloxy, p-toluenesulfonyloxy or p-nitrobenzenesulfonyloxy.
12. The process according to claim 11, wherein the compound of formula V is prepared by reacting a compound of formula IV with (S) -2-amino-butyramide or a salt thereof in an organic solvent at a temperature of from 25 ℃ to 200 ℃ under basic conditions formed by a basic compound, wherein the molar equivalent of the basic compound used is between 1 and 5, and the molar equivalent of the (S) -2-amino-butyramide or a salt thereof used is between 0.5 and 5.
13. The process according to claim 12, wherein the organic solvent used in the preparation of the compound of formula V is selected from one or more of N-methylpyrrolidone, N-dimethylformamide, dimethylsulfoxide, sulfolane.
14. The method of claim 12, wherein the basic compound is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, or sodium bis (trimethylsilyl) amide.
15. A process for preparing the compound of formula VII, bwacitam, from the compound of formula III, wherein said process comprises:
(1) preparing a compound of formula IV as claimed in any one of claims 1 to 3 from a compound of formula III:
subjecting the compound of formula III to a ring-opening reaction with iodotrimethylsilane, bromotrimethylsilane, hydrobromic acid, hydrochloric acid or hydroiodic acid in an organic solvent to obtain a compound of formula IV; or
Hydrolyzing the compound of formula III for ring opening under an alkaline condition, and then reacting the compound of formula III with methanesulfonyl chloride, p-toluenesulfonyl chloride or p-nitrobenzenesulfonyl chloride in an organic solvent to obtain a compound of formula IV;
(2) preparing a compound of formula V according to any one of claims 4-6 from a compound of formula IV and (S) -2-aminobutanamide or a salt thereof in an organic solvent under basic conditions,
reacting a compound of formula IV with (S) -2-amino-butanamide or a salt thereof in an organic solvent at a temperature of 25 ℃ to 200 ℃ under basic conditions formed by a basic compound to produce a compound of formula V, wherein the molar equivalent of the basic compound used is between 1 and 5, and the molar equivalent of the (S) -2-amino-butanamide or a salt thereof used is between 0.5 and 5;
(3) subjecting a compound of formula V to a ring closure reaction to produce a compound of formula VII:
(iii) ring closing the compound of formula V in an organic solvent at a temperature of 25 ℃ to 200 ℃ to obtain the compound of formula VII.
16. The process of claim 15, wherein the organic solvent used in the preparation of the compound of formula IV is selected from N-methylpyrrolidone, N-dimethylformamide, dimethyl sulfoxide, sulfolane, dichloromethane, acetonitrile or C1-20One or more of a hydrocarbon alcohol.
17. The process of claim 15, wherein the basic conditions for hydrolytic ring opening are achieved by addition of sodium hydroxide, potassium hydroxide or lithium hydroxide.
18. The process according to claim 15, wherein the organic solvent used in the preparation of the compound of formula V is selected from one or more of N-methylpyrrolidone, N-dimethylformamide, dimethylsulfoxide, sulfolane.
19. The method of claim 15, wherein the basic compound is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, or sodium bis (trimethylsilyl) amide.
20. The process according to claim 15, wherein the ring closure reaction is carried out under the action of an amide bond promoter selected from HOBt or 2-hydroxypyridine and the organic solvent used in the preparation of the compound of formula VII is selected from one or more of toluene, methyl isobutyl ketone, xylene or chlorobenzene.
21. A process for the preparation of the compound of formula VII, bwaitant, from the compound of formula IV according to any one of claims 1-3, wherein the process comprises:
(1) preparing a compound of formula V according to any one of claims 4-6 from a compound of formula IV and (S) -2-aminobutanamide or a salt thereof in an organic solvent under basic conditions,
reacting a compound of formula IV with (S) -2-amino-butanamide or a salt thereof in an organic solvent at a temperature of from 25 ℃ to 200 ℃ under basic conditions formed by a basic compound to prepare a compound of formula V, wherein the molar equivalent of the basic compound used is between 1 and 5, the molar equivalent of the (S) -2-amino-butanamide or a salt thereof used is between 0.5 and 5,
(2) subjecting a compound of formula V to a ring closure reaction to produce a compound of formula VII:
(iii) ring closing the compound of formula V in an organic solvent at a temperature of 25 ℃ to 200 ℃ to obtain the compound of formula VII.
22. The process according to claim 21, wherein the organic solvent used in the preparation of the compound of formula V is selected from one or more of N-methylpyrrolidone, N-dimethylformamide, dimethylsulfoxide, sulfolane.
23. The method of claim 21, wherein the basic compound is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, or sodium bis (trimethylsilyl) amide.
24. A process according to claim 21, wherein the ring closure reaction is carried out under the action of an amide bond promoter selected from HOBt or 2-hydroxypyridine and the organic solvent used in the preparation of the compound of formula VII is selected from one or more of toluene, methyl isobutyl ketone, xylene or chlorobenzene.
25. A process for the preparation of the compound of formula VII, bravaracetam, from the compound of formula V according to any one of claims 4-6:
wherein R1 is hydrogen or C1-20A hydrocarbyl group.
26. The method of claim 25, wherein the method comprises: subjecting a compound of formula V to a ring closure reaction to produce a compound of formula VII:
(iii) ring closing the compound of formula V in an organic solvent at a temperature of 25 ℃ to 200 ℃ to obtain the compound of formula VII.
27. The process of claim 26, wherein the ring closure reaction is carried out under the action of an amide bond promoter selected from HOBt or 2-hydroxypyridine and the organic solvent used in the preparation of the compound of formula VII is selected from one or more of toluene, methyl isobutyl ketone, xylene or chlorobenzene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810610090.4A CN108689968B (en) | 2015-05-25 | 2015-05-25 | Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810610090.4A CN108689968B (en) | 2015-05-25 | 2015-05-25 | Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam |
| CN201510271449.6A CN106279074B (en) | 2015-05-25 | 2015-05-25 | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510271449.6A Division CN106279074B (en) | 2015-05-25 | 2015-05-25 | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108689968A CN108689968A (en) | 2018-10-23 |
| CN108689968B true CN108689968B (en) | 2020-09-15 |
Family
ID=57634428
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810610090.4A Active CN108689968B (en) | 2015-05-25 | 2015-05-25 | Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam |
| CN201510271449.6A Active CN106279074B (en) | 2015-05-25 | 2015-05-25 | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510271449.6A Active CN106279074B (en) | 2015-05-25 | 2015-05-25 | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN108689968B (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432030B (en) * | 2015-10-10 | 2019-06-25 | 苏州鹏旭医药科技有限公司 | A kind of preparation method of Bu Waxitan |
| CN106748748B (en) * | 2015-11-10 | 2021-08-24 | 成都国为生物医药有限公司 | Preparation method and intermediate of brivaracetam |
| CN105646319B (en) * | 2015-12-30 | 2018-05-18 | 佛山市隆信医药科技有限公司 | A kind of preparation method of Bu Waxitan |
| CN106748950B (en) * | 2017-01-13 | 2019-09-03 | 成都美域高制药有限公司 | A kind of preparation method of Bu Waxitan and its intermediate |
| CN108947883A (en) * | 2017-05-25 | 2018-12-07 | 北京万全德众医药生物技术有限公司 | The preparation of Bu Waxitan |
| CN109593055B (en) * | 2017-09-30 | 2022-04-26 | 上海医药工业研究院 | Preparation method of brivaracetam isomer (2S, 4S) |
| CN107604018A (en) * | 2017-10-17 | 2018-01-19 | 重庆迪维斯生物科技有限公司 | A kind of preparation method of Bu Waxitan intermediates |
| CN108530402B (en) * | 2018-04-10 | 2020-06-26 | 浙江工业大学 | Preparation method of (R) -3-propyl-gamma-butyrolactone |
| CN108929289B (en) * | 2018-06-19 | 2022-01-04 | 上海博氏医药科技有限公司 | Intermediate compound for preparing brivaracetam and preparation method and application thereof |
| CN110615744B (en) * | 2018-06-20 | 2023-01-06 | 上海朴颐化学科技有限公司 | Buvalracetam intermediate and preparation method thereof |
| JP7117796B2 (en) * | 2018-06-22 | 2022-08-15 | 福建▲海▼西新▲薬▼▲創▼制有限公司 | its use in the synthesis of compounds and intermediates and drug substances of Brivaracetam |
| CN110357790A (en) * | 2018-07-26 | 2019-10-22 | 福建海西新药创制有限公司 | Compound and its purposes in synthesis Bu Waxitan bulk pharmaceutical chemicals |
| CN111170920A (en) * | 2018-11-12 | 2020-05-19 | 浙江京新药业股份有限公司 | Method for removing genotoxicity warning intermediate from brivaracetam |
| CN109932442A (en) * | 2019-03-04 | 2019-06-25 | 成都美域高制药有限公司 | A kind of detection method of Bu Waxitan isomers |
| CN112062740B (en) * | 2020-09-24 | 2022-11-04 | 深圳市华先医药科技有限公司 | Synthesis method of (R) -4-propyl dihydrofuran-2-ketone |
| CN115466233A (en) * | 2022-09-28 | 2022-12-13 | 合肥立方制药股份有限公司 | Synthetic method of brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone |
| CN115557873A (en) * | 2022-10-19 | 2023-01-03 | 浙江美诺华药物化学有限公司 | Synthesis method of methyl esterification impurity of brivaracetam |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1404469A (en) * | 2000-02-23 | 2003-03-19 | Ucb公司 | 2-Oxo-1-pyrrolidine derivatives, processes for preparing them and their uses |
| CN101821228A (en) * | 2007-08-10 | 2010-09-01 | 韩国科学技术院 | Novel method for preparing pregabalin |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2530398T3 (en) * | 2005-09-15 | 2015-03-02 | Ucb Pharma Sa | 4-substituted pyrrolidin-2-ones and their use |
| US8338621B2 (en) * | 2005-12-21 | 2012-12-25 | Ucb S.A. | Process for the preparation of 2-oxo-1-pyrrolidine derivatives |
| KR100915671B1 (en) * | 2007-08-14 | 2009-09-04 | 한국과학기술원 | ENANTIOSELECTIVE SYNTHESIS OF SUBSTITUTED γ-BUTYROLACTONES |
-
2015
- 2015-05-25 CN CN201810610090.4A patent/CN108689968B/en active Active
- 2015-05-25 CN CN201510271449.6A patent/CN106279074B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1404469A (en) * | 2000-02-23 | 2003-03-19 | Ucb公司 | 2-Oxo-1-pyrrolidine derivatives, processes for preparing them and their uses |
| CN101821228A (en) * | 2007-08-10 | 2010-09-01 | 韩国科学技术院 | Novel method for preparing pregabalin |
Non-Patent Citations (2)
| Title |
|---|
| Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic Activity;Benoit M. Kenda，等;《J.Med.Chem.》;20031225;第47卷;第536页图1、第538页左栏、第545页右栏最后一段到第546页左栏第一段 * |
| Enantiomerically Pure Synthesis of β-Substitutedγ-Butyrolactones: A Key Intermediate to ConciseSynthesis of Pregabalin;Taedong Ok，等;《J.Org.Chem.》;20070823;第2卷;第7392页右栏表2 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106279074A (en) | 2017-01-04 |
| CN106279074B (en) | 2018-06-26 |
| CN108689968A (en) | 2018-10-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108689968B (en) | Two compounds, preparation method thereof and application thereof in synthesis of brivaracetam | |
| JP6872500B2 (en) | How to make bribalacetam | |
| WO2017201846A1 (en) | Preparation method of antibacterial oxazolidinone medicine and intermediate thereof | |
| CN104557572B (en) | Levalbuterol intermediate and levalbuterol hydrochloride synthesis method | |
| TWI579259B (en) | Method of preparing (1r,2s)-2-(3,4-difluorophenyl)-3-r substituted-cyclopropylamine | |
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| JP5301431B2 (en) | Process for producing chiral cyclic β-aminocarboxamide | |
| TWI629261B (en) | Preparation method of bovasacetam | |
| TW201726593A (en) | Method for producing optically active 2-(2-fluorobiphenyl-4-yl) propanoic acid | |
| CN110128439B (en) | Oxaspiro compound and synthesis and resolution method thereof | |
| CN105646285B (en) | One kind dimension Lactel sieve intermediate and its preparation method and application | |
| JP2007230963A (en) | Method for producing 2,4-disubstituted pyridine | |
| CN103980120A (en) | Synthesis method of D,L-danshensu isopropyl ester | |
| JP2001510174A (en) | Process for preparing aminoarylacetylene | |
| CN102344431A (en) | Method for preparing nebivolol hydrochloride | |
| CN112479967B (en) | Biliverdin compound, and preparation method and application thereof | |
| CN104693090A (en) | Silodosin and preparation methods for intermediates thereof | |
| KR101686087B1 (en) | Process for Production of Optically Active Indoline Derivatives or Salts Thereof | |
| CN109988070B (en) | Intermediate of trans-1-hydroxy-1- (trifluoromethyl) -3-aminocyclobutane hydrochloride, preparation method and application | |
| CN107365312A (en) | A kind of new method for preparing Oclacitinib | |
| CN103755657A (en) | Preparation method of rivaroxaban intermediate | |
| WO2013146987A1 (en) | Rhodium catalyst and method for producing amine compound | |
| CN105523964A (en) | Preparation method of anti-heart-failure drug intermediate | |
| KR101164424B1 (en) | Manufacturing method for donepezil HCl | |
| JP3272340B2 (en) | Method for producing 1-[(cyclopent-3-en-1-yl) methyl] -5-ethyl-6- (3,5-dimethylbenzoyl) -2,4-pyrimidinedione |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20181023 Assignee: CHENGDA PHARMACEUTICALS Co.,Ltd. Assignor: SUZHOU PENGXU PHARMATECH Co.,Ltd. Contract record no.: X2021980001583 Denomination of invention: Two compounds, their preparation methods and their application in the synthesis of buvasetam Granted publication date: 20200915 License type: Common License Record date: 20210311 |