CN115466233A - Synthetic method of brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone - Google Patents

Synthetic method of brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone Download PDF

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CN115466233A
CN115466233A CN202211190213.6A CN202211190213A CN115466233A CN 115466233 A CN115466233 A CN 115466233A CN 202211190213 A CN202211190213 A CN 202211190213A CN 115466233 A CN115466233 A CN 115466233A
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dihydrofuran
propyl
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季俊虬
李斌
潘浩然
闻振
蒋敏燕
刘亚会
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Hefei Lifeon Pharmaceutical Co ltd
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    • 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
    • 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
    • C07B2200/09—Geometrical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention provides a synthesis method of a (R) -4-propyl-dihydrofuran-2-ketone intermediate of brivaracetam, which can take malonic diester as a starting material to react with R-epichlorohydrin, then carry out hydrolysis, then carry out ring opening reaction in the presence of an ethyl metal reagent, and obtain a target intermediate after decarboxylation.

Description

Synthetic method of brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of a brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone.
Background
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. (R) -4-propyl-dihydrofuran-2-ketone is used as an important drug intermediate of the brivaracetam, and the research on the synthetic method of the brivaracetam has important significance for the industrial synthesis of the brivaracetam.
To date, various synthetic routes to (R) -4-propyl-dihydrofuran-2-one have been reported in the prior art, for example:
published patent CN113336726A discloses the following synthetic route:
Figure BDA0003869023070000011
published patent CN113717132A discloses the following synthetic route:
Figure BDA0003869023070000021
published patent CN112939900A discloses the following synthetic route:
Figure BDA0003869023070000022
the published patent CN112521352A discloses the following synthetic route:
Figure BDA0003869023070000023
published patent CN112062740A discloses the following synthetic route:
Figure BDA0003869023070000024
published patent CN112521351A and published Journal of Medicinal Chemistry,2004, 47, 530 disclose the following synthetic routes:
Figure BDA0003869023070000025
published patent CN109852644A discloses the following synthetic route:
Figure BDA0003869023070000026
published patent CN111548329A discloses the following synthetic route:
Figure BDA0003869023070000031
publication CN111349007A discloses the following synthetic route:
Figure BDA0003869023070000032
published patents CN111333598A and CN108530402A disclose the following synthetic routes:
Figure BDA0003869023070000033
the published patents IN201931002041A, WO2020148787A1 disclose the following synthetic routes:
Figure BDA0003869023070000034
publication WO2019242692A1 discloses the following synthetic route:
Figure BDA0003869023070000035
the published patent WO2020168510A1 discloses the following synthetic route:
Figure BDA0003869023070000036
published patents CN110790731A and CN110790730A disclose the following synthetic routes:
Figure BDA0003869023070000041
published patent CN109553595A discloses the following synthetic route:
Figure BDA0003869023070000042
published patent CN110357839A discloses the following synthetic route:
Figure BDA0003869023070000043
published patent CN109134406A discloses the following synthetic route:
Figure BDA0003869023070000044
the published patent CN109535107A discloses the following synthetic route:
Figure BDA0003869023070000051
published patent CN108929289A discloses the following synthetic route:
Figure BDA0003869023070000052
published patent CN108203419A discloses the following synthetic route:
Figure BDA0003869023070000053
published patents CN107827845A and CN107652254A disclose the following synthetic routes:
Figure BDA0003869023070000054
published patent CN107827844A discloses the following synthetic route:
Figure BDA0003869023070000055
published patent CN107663185A discloses the following synthetic route:
Figure BDA0003869023070000056
the following synthetic routes are disclosed in the published patents CN106279074A, WO2016191435A1, CN105646319A, and published Organic Process Research & Development,2016, 20 (9), 1566-1575:
Figure BDA0003869023070000061
by taking the disclosed synthetic method into account, the defects of harsh reaction conditions, large impurities in the reaction process, need of repeated splitting in the later period and the like exist generally, and the high-yield and high-purity (R) -4-propyl-dihydrofuran-2-one Buvaracetam intermediate is difficult to obtain.
Disclosure of Invention
Based on the technical problems in the background art, the invention provides a synthesis method of a brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone, which comprises the steps of taking malonic diester as an initial material, reacting with R-epichlorohydrin, hydrolyzing, carrying out ring-opening reaction in the presence of an ethyl metal reagent, and decarboxylating to obtain a target intermediate.
The invention provides a synthesis method of a brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone, which comprises the following steps:
carrying out ring-opening reaction on a compound shown as a formula II and an ethyl metal reagent to obtain a compound shown as a formula III;
Figure BDA0003869023070000071
compared with the prior art that the compound shown as the formula IV is used as a substrate to carry out a ring-opening reaction with an ethyl metal reagent, when the compound shown as the formula II is used as the substrate, carboxyl contained in the compound consumes a part of the ethyl metal reagent, but the product yield of the ring-opening reaction is improved, and the chiral product with a high ee value is obtained; in the prior art, when the compound of formula IV is used as a substrate, the ester group of the compound can form an irreversible reaction with an ethyl metal reagent, so that more byproducts are generated, and the separation and the acquisition of a chiral product with high yield and high ee value are not facilitated;
Figure BDA0003869023070000072
r is any one of alkyl, alkenyl or aryl.
Preferably, the ring-opening reaction of the compound shown in the formula II and an ethyl metal reagent also comprises the addition of a cuprous compound;
preferably, the cuprous compound is at least one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide or cuprous trifluoromethanesulfonate;
preferably, the molar ratio of the cuprous compound to the compound represented by formula II is 0.1-2;
preferably, the ring-opening reaction of the compound shown in the formula II and an ethyl metal reagent also comprises the addition of Lewis acid;
preferably, the lewis acid is at least one of TMSCl or TMSOTf.
Preferably, the compound shown in the formula II and an ethyl metal reagent are subjected to ring opening reaction, wherein the ethyl metal reagent is at least one of ethyl magnesium bromide, ethyl magnesium chloride or ethyl magnesium iodide;
preferably, the molar ratio of the ethyl metal reagent to the compound represented by the formula II is 1-5;
preferably, the temperature of the ring-opening reaction is 20-60 ℃, and the solvent is at least one of dichloromethane, tetrahydrofuran, diethyl ether, toluene or xylene.
Preferably, the synthesis method further comprises:
performing decarboxylation on the compound shown in the formula III to obtain a target intermediate (R) -4-propyl-dihydrofuran-2-ketone;
Figure BDA0003869023070000081
preferably, the compound shown in the formula III is subjected to decarboxylation reaction, wherein the temperature of the decarboxylation reaction is 80-150 ℃;
the solvent of the decarboxylation reaction is at least one of toluene, N-methylpyrrolidone, N-dimethylformamide or dimethyl sulfoxide.
Preferably, the synthesis method further comprises: carrying out ester hydrolysis reaction on the compound shown in the formula I to obtain a compound shown in a formula II;
Figure BDA0003869023070000082
r is C 1-6 Alkyl radical, C 2-6 Any one of an alkenyl group or an aryl group;
preferably, R is ethyl.
Preferably, when the compound shown in the formula I is subjected to ester hydrolysis reaction, firstly, the hydrolysis is carried out under an alkali reagent, and then, the acidification is carried out under an acid reagent;
preferably, the alkali agent is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate;
preferably, the acid reagent is at least one of hydrochloric acid, sulfuric acid or nitric acid;
preferably, the temperature of the hydrolysis reaction is 20-60 ℃.
Preferably, the synthesis method further comprises:
reacting malonic diester with (R) -epichlorohydrin by taking the malonic diester as an initial raw material to obtain a compound shown in a formula I;
Figure BDA0003869023070000091
r is C 1-6 Alkyl radical, C 2-6 Any one of an alkenyl group or an aryl group;
preferably, R is ethyl.
Preferably, when the malonic diester reacts with (R) -epichlorohydrin, an organic base reagent is added;
preferably, the organic base reagent is at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide or sodium amide;
preferably, the molar ratio of the malonic diester to (R) -epichlorohydrin is 1.
The invention also provides a synthesis method of the brivaracetam, which comprises the following steps: the (R) -4-propyl-dihydrofuran-2-ketone is synthesized by adopting the synthesis method.
Compared with the prior patent and literature reports, the new synthesis method of the intermediate (R) -4-propyl-dihydrofuran-2-ketone of the Buvalsartan changes the reaction process, obviously reduces the content of impurities, improves the yield and the product purity, has simple whole reaction operation, low cost and low environmental pollution, and is suitable for industrial production.
Detailed Description
Hereinafter, the technical solution of the present invention will be described in detail by specific examples, but these examples should be explicitly proposed for illustration, but should not be construed as limiting the scope of the present invention.
Example 1
(1) Synthesis of a compound of formula I:
adding sodium ethoxide (1.6 kg,23.5 mol) and absolute ethyl alcohol (10 kg) into a 50L reaction kettle, stirring and dissolving completely at 40 ℃, then adding diethyl malonate (1.5 kg,9.4 mol), stirring for 1h under heat preservation after the addition is finished, then adding R-epichlorohydrin (1.04kg, 11.2 mol), stirring and reacting for 6h under heat preservation after the addition is finished, detecting that the raw material diethyl malonate reacts completely by TLC (n-heptane/ethyl acetate = 2/1), then adding acetic acid (1.69 kg) for quenching, washing isopropyl acetate (5 kg multiplied by 2) with water (2.5 kg multiplied by 2) after extraction, and evaporating the isopropyl acetate to dryness to obtain a compound (1.51kg, yield of ee (enantiomeric excess percentage) > 98%) shown in formula I.
(2) Synthesis of a compound of formula ii:
adding a compound shown in a formula I (1.51kg, 8.9 mol), adding water (15 kg), heating to 40 ℃ after stirring, dropwise adding a sodium hydroxide aqueous solution (sodium hydroxide: 0.75kg, water: 7.5 kg), keeping the temperature and stirring for reacting for 3.5h after dropwise adding, detecting that the compound shown in the formula I completely reacts by TLC (n-heptane/ethyl acetate = 2/1), adding hydrochloric acid to adjust the pH to 2-3, extracting isopropyl acetate (5 kg × 2), combining organic phases, washing with water (2.5 kg × 2), and evaporating the isopropyl acetate to obtain a compound shown in a formula II (0.99kg, yield 79%), ee (enantiomeric excess percentage) > 99%;
(3) Synthesis of a compound of formula iii:
adding cuprous chloride (0.76kg, 7.7 mol) and tetrahydrofuran (10 kg) into a 50L reaction kettle, starting stirring, heating to 40 ℃, dropwise adding a 2-methyltetrahydrofuran solution (5.13L, 17.5 mol) of ethyl magnesium bromide, and after dropwise adding, keeping the temperature for reaction for 1h; then, a tetrahydrofuran solution of the compound represented by the formula II (intermediate II:0.99kg,7.0mol, tetrahydrofuran: 5 kg) was added thereto, and then, after completion of the addition, the reaction was carried out for 7h, and completion of the reaction of the compound represented by the formula II was detected by TLC (methylene chloride/methanol = 8/1); then adding saturated ammonium chloride solution (1.1 kg of ammonium chloride, 4kg of water) into the mixture to quench, extracting isopropyl acetate (5 kg multiplied by 2), combining organic phases, washing with water (2.5 kg multiplied by 2), evaporating the isopropyl acetate phase to dryness to obtain a compound shown in a formula III (0.98kg, yield;
(4) Synthesis of target intermediate (R) -4-propyl-dihydrofuran-2-one:
a 50L reaction vessel was charged with a compound represented by formula iii (0.98kg, 5.7mol) and toluene (10 kg), heated to reflux for reaction for 8h, tlc (dichloromethane/methanol = 8/1) detected that the compound represented by formula iii was completely reacted, and after the system was cooled to 20 ℃, the system was washed with a 5% aqueous sodium bicarbonate solution (5 kg × 2) and then with saturated brine (5 kg), dried over anhydrous sodium sulfate, evaporated to dryness, and distilled under reduced pressure to obtain the target intermediate (R) -4-propyl-dihydrofuran-2-one (0.63kg, yield.
The nuclear magnetic data of the intermediate (R) -4-propyl-dihydrofuran-2-one are as follows: 1 H NMR(400MHz,CDCl 3 ):δ4.43(1H,dd),3.95(1H,dd),2.53-2.65(2H,m),2.17(1H,dd),1.41-1.47(2H,m),1.38-1.47(2H,m),0.94(3H,t)。
example 2
Essentially the same as example 1, except for the synthesis of the compound of formula iii:
adding cuprous chloride (0.035kg, 0.35mol) and tetrahydrofuran (5 kg) into a 50L reaction kettle, starting stirring, heating to 40 ℃, dropwise adding a 2-methyltetrahydrofuran solution (5.13L, 17.5mol) of ethyl magnesium bromide, and after dropwise adding, keeping the temperature and reacting for 1h; then adding tetrahydrofuran solution of the compound shown in the formula II (intermediate II:0.5kg,3.5mol, tetrahydrofuran: 2.5 kg), keeping the temperature for 7h after the addition is finished, and detecting that the compound shown in the formula II completely reacts by TLC (dichloromethane/methanol = 8/1); then adding saturated ammonium chloride solution (0.6 kg of ammonium chloride, 2kg of water) into the mixture for quenching, extracting isopropyl acetate (2.5 kg multiplied by 2), combining organic phases, washing with water (2.5 kg multiplied by 2), and evaporating the isopropyl acetate phase to obtain a compound shown as a formula III (0.39kg, yield;
example 3
Essentially the same as in example 1, except for the synthesis of the compound of formula iii:
adding cuprous iodide (1.47kg, 7.7 mol) and tetrahydrofuran (10 kg) into a 50L reaction kettle, starting stirring, heating to 40 ℃, dropwise adding a 2-methyltetrahydrofuran solution (5.13L, 17.5 mol) of ethyl magnesium bromide, and after dropwise adding, keeping the temperature for reaction for 1h; then, a tetrahydrofuran solution of the compound represented by the formula II (intermediate II:0.99kg,7.0mol, tetrahydrofuran: 5 kg) was added thereto, and then, after completion of the addition, the reaction was carried out for 7h, and completion of the reaction of the compound represented by the formula II was detected by TLC (methylene chloride/methanol = 8/1); then adding saturated ammonium chloride solution (1.1 kg of ammonium chloride, 4kg of water) into the mixture for quenching, extracting isopropyl acetate (5 kg multiplied by 2), merging organic phases, washing with water (2.5 kg multiplied by 2), and evaporating the isopropyl acetate phase to obtain a compound shown as a formula III (0.79kg, yield: 66%), ee (enantiomeric excess) > 98%;
the above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (10)

1. A method for synthesizing a brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone is characterized by comprising the following steps:
carrying out ring-opening reaction on the compound shown in the formula II and an ethyl metal reagent to obtain a compound shown in a formula III;
Figure FDA0003869023060000011
2. the method for synthesizing the intermediate (R) -4-propyl-dihydrofuran-2-one of the brivaracetam as claimed in claim 1, which is characterized in that the method comprises the steps of carrying out ring opening reaction on the compound shown as the formula II and an ethyl metal reagent, and adding a cuprous compound;
preferably, the cuprous compound is at least one of cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide or cuprous trifluoromethanesulfonate;
preferably, the molar ratio of the cuprous compound to the compound represented by formula II is 0.1-2;
preferably, the ring-opening reaction of the compound shown in the formula II and an ethyl metal reagent also comprises the addition of Lewis acid;
preferably, the lewis acid is at least one of TMSCl or TMSOTf.
3. The synthesis method of the intermediate (R) -4-propyl-dihydrofuran-2-one of the brivaracetam as claimed in claim 1 or 2, characterized in that, when the compound shown as the formula II and an ethyl metal reagent are subjected to ring-opening reaction, the ethyl metal reagent is at least one of ethyl magnesium bromide, ethyl magnesium chloride or ethyl magnesium iodide;
preferably, the molar ratio of the ethyl metal reagent to the compound represented by the formula II is 1-5;
preferably, the temperature of the ring-opening reaction is 20-60 ℃, and the solvent is at least one of dichloromethane, tetrahydrofuran, diethyl ether, toluene or xylene.
4. A synthesis method of the intermediate (R) -4-propyl-dihydrofuran-2-one of the bravaracetam according to any one of the claims 1 to 3, characterized by further comprising:
performing decarboxylation reaction on the compound shown in the formula III to obtain a target intermediate (R) -4-propyl-dihydrofuran-2-ketone;
Figure FDA0003869023060000021
5. the synthesis method of the intermediate (R) -4-propyl-dihydrofuran-2-one of the brivaracetam as claimed in claim 4, characterized in that, the compound shown as the formula III is subjected to decarboxylation reaction, and the temperature of the decarboxylation reaction is 80-150 ℃;
the solvent of the decarboxylation reaction is at least one of toluene, N-methyl pyrrolidone, N-dimethylformamide or dimethyl sulfoxide.
6. The synthesis method of the intermediate (R) -4-propyl-dihydrofuran-2-one of the bravaracetam according to any one of the claims 1 to 5, characterized by further comprising the following steps: carrying out ester hydrolysis reaction on the compound shown in the formula I to obtain a compound shown in a formula II;
Figure FDA0003869023060000022
r is C 1-6 Alkyl radical, C 2-6 Any one of an alkenyl group or an aryl group;
preferably, R is ethyl.
7. The method for synthesizing the intermediate (R) -4-propyl-dihydrofuran-2-one of the brivaracetam as claimed in claim 6, which is characterized in that the compound shown in the formula I is hydrolyzed under an alkali reagent and then acidified under an acid reagent when the ester is hydrolyzed;
preferably, the alkaline agent is at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate or potassium carbonate;
preferably, the acid reagent is at least one of hydrochloric acid, sulfuric acid or nitric acid;
preferably, the temperature of the hydrolysis reaction is 20-60 ℃.
8. A synthesis method of the intermediate (R) -4-propyl-dihydrofuran-2-one of the bravaracetam according to any one of the claims 1 to 7, characterized by further comprising:
reacting malonic diester with (R) -epichlorohydrin by taking malonic diester as an initial raw material to obtain a compound shown in a formula I;
Figure FDA0003869023060000031
r is C 1-6 Alkyl radical, C 2-6 Any one of an alkenyl group or an aryl group;
preferably, R is ethyl.
9. The synthesis method of the intermediate (R) -4-propyl-dihydrofuran-2-one of the busulfan according to claim 8, wherein the reaction of the malonic acid diester with (R) -epichlorohydrin further comprises adding an organic base reagent;
preferably, the organic base reagent is at least one of sodium methoxide, sodium ethoxide, sodium tert-butoxide or sodium amide;
preferably, the molar ratio of the malonic diester to (R) -epichlorohydrin is 1.
10. A method for synthesizing bravaracetam is characterized by comprising the following steps: (R) -4-propyl-dihydrofuran-2-one synthesized by the synthesis method of any one of claims 1 to 9.
CN202211190213.6A 2022-09-28 2022-09-28 Synthetic method of brivaracetam intermediate (R) -4-propyl-dihydrofuran-2-ketone Pending CN115466233A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105646319A (en) * 2015-12-30 2016-06-08 佛山市隆信医药科技有限公司 Preparation method of brivaracetam
WO2016191435A1 (en) * 2015-05-25 2016-12-01 Peng Wang Processes to produce brivaracetam
CN106279074A (en) * 2015-05-25 2017-01-04 苏州鹏旭医药科技有限公司 A kind of compound and preparation method thereof and the purposes in synthesis Bu Waxitan
CN112521352A (en) * 2019-09-17 2021-03-19 北京万全德众医药生物技术有限公司 Preparation method of brivaracetam intermediate

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016191435A1 (en) * 2015-05-25 2016-12-01 Peng Wang Processes to produce brivaracetam
CN106279074A (en) * 2015-05-25 2017-01-04 苏州鹏旭医药科技有限公司 A kind of compound and preparation method thereof and the purposes in synthesis Bu Waxitan
CN105646319A (en) * 2015-12-30 2016-06-08 佛山市隆信医药科技有限公司 Preparation method of brivaracetam
CN112521352A (en) * 2019-09-17 2021-03-19 北京万全德众医药生物技术有限公司 Preparation method of brivaracetam intermediate

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* Cited by examiner, † Cited by third party
Title
AKIRA MIZUNO等: "Cyclopropane-Based Peptidomimetics Mimicking Wide-Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization", CHEM. EUR. J., vol. 23, pages 3159 - 3168 *

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