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CN113717132B - Key intermediate of antiepileptic drug and preparation method thereof - Google Patents

Key intermediate of antiepileptic drug and preparation method thereof Download PDF

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CN113717132B
CN113717132B CN202111009316.3A CN202111009316A CN113717132B CN 113717132 B CN113717132 B CN 113717132B CN 202111009316 A CN202111009316 A CN 202111009316A CN 113717132 B CN113717132 B CN 113717132B
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CN113717132A (en
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蔡强
殷超
商俊兵
兰柳琴
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Rundu Pharmaceutical Wuhan Research Institute Co ltd
Zhuhai Rundu Pharmaceutical Co Ltd
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Zhuhai Rundu Pharmaceutical Co Ltd
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    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
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Abstract

The invention discloses a key intermediate of an antiepileptic drug and a preparation method thereof, and the method is used for synthesizing the key intermediate (R) -4-propyl dihydrofuran-2 (3H) -ketone of the antiepileptic drug and has the following benefits: the chiral preparation method is adopted, so that the preparation of a chiral chromatographic column and the resolution of a chiral resolving agent are avoided, and the total yield of the process is greatly improved. The structure of the intermediate 3 greatly improves the selectivity of asymmetric hydrogenation, and the ee value can reach more than 99 percent. Avoids a purification method of column passing, has simple operation process and is more suitable for industrial production.

Description

Key intermediate of antiepileptic drug and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a key intermediate of an antiepileptic drug and a preparation method thereof.
Background
Brivaracetam (brivaracetam), with the chemical name (2S) -2- [ (4R) -2-oxo-4-propylpyrrolidin-1-yl ] butanamide, is a 3 rd generation antiepileptic drug developed by belgium chronopheromone (UCB) limited. European Medicines Administration (EMA) and U.S. Food and Drug Administration (FDA) approval for the treatment of partial seizures in adult juvenile epilepsy patients aged 16 and older, with or without adjuvant treatment of secondary generalized seizures, under the trade name Briviact, were obtained at 2016, 14, and 2016, 2, 18.
At present, the synthesis route of the brivaracetam is more, the key of the synthesis is the construction of a 4-position n-propyl chiral center, and an intermediate (R) -4-propyl dihydrofuran-2 (3H) -ketone has a structural formula:
Figure 350645DEST_PATH_IMAGE001
CAS number 63095-51-2 is a key intermediate for preparing the brivaracetam, and has a crucial influence on the product quality and the cost.
The synthetic route of (R) -4-propyldihydrofuran-2 (3H) -ketone mainly comprises the following steps:
1. the synthesis route of patent CN 105801530a (a synthesis method of 4-substituted chiral γ -butyrolactone) is:
Figure 249331DEST_PATH_IMAGE002
the route needs to use a plurality of dangerous reagents such as borane, sodium hydrogen and the like, and the selectivity is poor when the chiral propyl is constructed, so that the route is not suitable for industrial production.
2. The patent CN106279074B (a compound and its preparation method and use in synthesis of brivaracetam) has the following synthetic route:
Figure 959798DEST_PATH_IMAGE003
the route adopts (R) -epichlorohydrin as a raw material, the raw material is cheap and easy to obtain, and the reaction step is short. However, the Grignard reaction needs to be carried out under the harsh condition of ultralow temperature of-30 ℃, and the intermediate (4R) -4-propyl-2-oxotetrahydrofuran-3-ethyl formate needs to be separated and purified by a column, so the operation is inconvenient and the method is not suitable for industrial production.
3. Document Org Process Res Dev, 2016, 20 (9): 1566-1575
Figure 969342DEST_PATH_IMAGE004
The advantage of this route is that column chromatography is abolished in the whole route, and kilogram scale amplification can be performed. The disadvantages are that the price of the raw material dimethyl malonate is expensive, the chiral center is established by adopting an enzyme catalysis resolution method, and the diastereoisomer loss is over 50 percent.
The synthetic route of the preparation method of CN106008411A-chiral 4-substituent dihydrofuran-2 (3H) -ketone is as follows:
Figure 816076DEST_PATH_IMAGE005
the method needs to use reagents with high danger such as hydrogen peroxide, borane dimethyl sulfide and the like, and the substitution reaction of the (S) -4-benzyl-3-pentanoyl oxazolidine-2-ketone and tert-butyl bromoacetate needs to be carried outThe low temperature condition of-70 ℃ is not suitable for industrial production.
In summary, the synthesis of (R) -4-propyldihydrofuran-2 (3H) -one includes methods such as chiral chromatographic column preparation, chiral resolving agent resolution, and asymmetric synthesis, and the chiral chromatographic column preparation and chiral resolving agent resolution have the disadvantages of high equipment requirement, complex operation, and over 50% diastereomer loss, resulting in low yield and high cost.
In view of the defects of the prior art, it is necessary to develop a synthetic method of (R) -4-propyl dihydrofuran-2 (3H) -ketone, which has simple operation process, high safety, low cost, high yield and high purity and is more suitable for industrial production.
Disclosure of Invention
The application aims to provide a compound of formula 4 and a preparation method thereof.
Another object of the present application is to provide a use of the compound of formula 4 for synthesizing (R) -4-propyldihydrofuran-2 (3H) -one, a key intermediate of antiepileptic drugs.
It is still another object of the present application to provide a method for synthesizing (R) -4-propyldihydrofuran-2 (3H) -one, a key intermediate of antiepileptic drugs.
The invention discloses a key intermediate of an antiepileptic drug and a preparation method thereof in order to solve the problems in the prior art, and the purpose of the invention can be achieved by the following measures:
a compound having the structure of formula 4:
Figure 416821DEST_PATH_IMAGE006
and R is a hydrocarbon group containing 1 to 10 carbons.
Further, the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
A process for preparing a compound of formula 4, said process comprising the steps of:
a, step a:
Figure 614584DEST_PATH_IMAGE007
reacting the compound 2 with RCOONa in a solvent 1 to obtain a compound 3, wherein R is a hydrocarbyl containing 1-10 carbons;
step b:
Figure 896661DEST_PATH_IMAGE008
compound 3 and
Figure 863480DEST_PATH_IMAGE009
reacting with a catalyst in a solvent 2 to obtain a compound 4, wherein R is a hydrocarbon group containing 1-10 carbons.
Further, the method comprises the following steps:
a, step a: taking a compound 2 and RCOONa as reaction raw materials, stirring and mixing in a solvent 1, heating, controlling the temperature to be 60-70 ℃, preserving the heat, reacting for 1-3 hours, cooling to room temperature, adding water and an organic solvent for extraction, washing an organic layer with water, and concentrating the organic layer under negative pressure to obtain a compound 3, wherein R is a hydrocarbon group containing 1-10 carbon atoms;
step b: subjecting the compound 3 obtained in step a and
Figure 103969DEST_PATH_IMAGE009
stirring and mixing the raw materials in a solvent 2, cooling to below 10 ℃, adding a catalyst, reacting at room temperature completely, dropwise adding 1N hydrochloric acid after reaction completely, adding an organic solvent for extraction, adding saturated sodium bicarbonate and saturated salt water, washing, and carrying out negative pressure concentration drying, wherein the saturated sodium bicarbonate and saturated salt water have the functions of washing off salts and acidic substances in the extract, and the compound 4,R is a hydrocarbon group with 1-10 carbon atoms is obtained after negative pressure rectification.
Further, the solvent 1 in the step a is any one of dimethylformamide, acetone and dimethyl sulfoxide, the solvent 2 in the step b is toluene or tetrahydrofuran, the catalyst is titanium tetrachloride and pyridine, and the organic solvent in the steps a and b is any one of ethyl acetate, dichloromethane and cyclohexane.
Further, the molar ratio of the compound 2 to RCOONa in the step a is 1Compound 3 with step b
Figure 195552DEST_PATH_IMAGE009
The molar ratio of (A) to (B) is 1.
Further, the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
Compound 4 used as key intermediate for synthesizing antiepileptic drug 1
Figure 546899DEST_PATH_IMAGE010
。
A method for preparing a key intermediate of an antiepileptic drug, wherein the key intermediate of the antiepileptic drug is (R) -4-propyldihydrofuran-2 (3H) -one, the method comprising the following steps:
step 1:
Figure 368225DEST_PATH_IMAGE011
reacting the compound 4 with hydrogen to obtain a compound 5, wherein R is a hydrocarbon group containing 1-10 carbons;
and 2, step:
Figure 514035DEST_PATH_IMAGE012
reacting the compound 5 with a catalyst in dimethylformamide and water to obtain a compound 6, wherein R is a C1-10 alkyl group;
and step 3:
Figure 217549DEST_PATH_IMAGE013
reacting the compound 6 with trifluoroacetic acid in a solvent 3 to obtain a compound 1, wherein R is a hydrocarbyl containing 1-10 carbons.
Further, the method comprises the following steps:
step 1: mixing the compound 4 with ethanol or glacial acetic acid, mixing with a ruthenium metal homogeneous catalyst of a diphosphine ligand, introducing hydrogen, controlling the pressure to be 0.1-10 Mpa, controlling the temperature to be 40-50 ℃ for reaction, and concentrating a dry solvent under negative pressure after the reaction is completed to obtain a compound 5, wherein R is a hydrocarbon group containing 1-10 carbons;
step 2: mixing the compound 5 with a catalyst, dimethylformamide and water, heating, controlling the temperature to 140-150 ℃ for complete reaction, cooling to room temperature after complete reaction, adding water and an organic solvent for extraction, washing an organic layer with saturated salt water after extraction and layering, and concentrating under reduced pressure to obtain a compound 6, wherein R is a hydrocarbon group containing 1-10 carbons;
and step 3: mixing the compound 6 with the solvent 3 and trifluoroacetic acid, reacting completely at room temperature, concentrating the solvent under negative pressure after the reaction is completed, and rectifying under reduced pressure to obtain a colorless transparent liquid compound 1, wherein R is a hydrocarbon group containing 1-10 carbons; the specific synthetic route is as follows:
Figure 841429DEST_PATH_IMAGE014
。
further, the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
Further, in the step 1, the molar ratio of the compound 4 to the hydrogen is 1.5 to 5, the reaction pressure is 0.1 to 10MPa, the molar ratio of the compound 5 to the catalyst is 1.
Further, in the step 2, the catalyst is any one of lithium chloride, sodium chloride, potassium chloride and calcium oxide, the organic solvent in the step 2 is any one of ethyl acetate, dichloromethane and cyclohexane, and the solvent 3 in the step 3 is any one of methanol, ethanol and isopropanol.
Compared with the prior art, the method for synthesizing the key intermediate (R) -4-propyl dihydrofuran-2 (3H) -ketone of the antiepileptic drug has the following benefits:
1. the chiral preparation method is adopted, so that the preparation of a chiral chromatographic column and the resolution of a chiral resolving agent are avoided, and the total yield of the process is greatly improved.
2. The structure of the intermediate 3 greatly improves the selectivity of asymmetric hydrogenation, and the ee value can reach more than 99 percent.
3. Avoids a purification method of column passing, has simple operation process and is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
Example 1
Stirring and mixing 120.5g of compound 2, 164g of sodium acetate and 260ml of dimethylformamide, heating, controlling the temperature to be 60-70 ℃, keeping the temperature for reaction for two hours, cooling to room temperature, adding 250ml of water and 535ml of ethyl acetate, stirring until the solution is clear, layering, washing an organic layer with 250ml of water once, concentrating the organic layer under negative pressure to obtain 137g of compound 3-1, wherein the molar yield is 95.0%, and the purity is 98.6%.
Figure 251681DEST_PATH_IMAGE015
Example 2
Stirring and mixing 120.5g of compound 2, 192g of sodium propionate and 220ml of dimethyl sulfoxide, heating, keeping the temperature at 60-70 ℃ for reacting for two hours, cooling to room temperature, adding 250ml of water and 365ml of dichloromethane, stirring until the solution is clear, layering, washing an organic layer with 250ml of water once, concentrating the organic layer under negative pressure to obtain 149.5g of compound 3-2, wherein the molar yield is 94.5%, and the purity is 99.1%.
Figure 568393DEST_PATH_IMAGE016
Example 3
137g of compound 3-1, 150.6g of dimethyl malonate and 470ml of toluene are stirred, mixed, cooled to below 10 ℃, added with 310ml of dichloromethane solution containing 216g of titanium tetrachloride dropwise, continuously added with 79.1g of pyridine dropwise, the temperature is controlled to below 20 ℃ in the dropwise adding process, the mixture reacts at room temperature for 12 hours after the dropwise adding is finished, after the reaction is completed, 410ml of 1N hydrochloric acid is dropwise added, 760ml of ethyl acetate is added for extraction, 410ml of saturated sodium bicarbonate is washed, 410ml of saturated saline is washed and then is concentrated and dried under negative pressure, and after the negative pressure rectification, 224.4g of compound 4-1 is obtained, the yield is 91.5%, and the purity is 99.0%.
The hydrogen and mass spectral data for compound 4-1 are as follows:
H NMR(400 MHz, CDCl3) δ4.98(s,2H),3.79(s,3H), 3.78(s,3H)，2.39(t,2H),2.10(s,3H),1.52-1.59(m,2H),0.96(t,1H); LCMS(ESI)(M+1)+=259.1
Figure 431307DEST_PATH_IMAGE017
example 4
137g of compound 3-1, 304g of diethyl malonate and 460ml of tetrahydrofuran are stirred, mixed, cooled to below 10 ℃, then added with 310ml of dichloromethane solution containing 540g of titanium tetrachloride dropwise, 375g of pyridine is continuously dropwise added, the temperature is controlled to be below 20 ℃ in the dropwise adding process, the mixture reacts at room temperature for 12 hours after the dropwise adding is finished, 410ml of 1N hydrochloric acid is dropwise added after the reaction is completed, 760ml of ethyl acetate is added for extraction, 410ml of saturated sodium bicarbonate is washed, 410ml of saturated saline is washed and then dried in a negative pressure manner, 247.4g of compound 4-2 is obtained after the negative pressure rectification, the yield is 91.0%, and the purity is 99.2%.
Figure 124456DEST_PATH_IMAGE018
Example 5
137g of compound 3-1, 627g of dimethyl malonate and 460ml of tetrahydrofuran are stirred, mixed, cooled to below 10 ℃, then added with 310ml of dichloromethane solution containing 540g of titanium tetrachloride, 150g of pyridine is added, the temperature is controlled to be below 20 ℃ in the adding process, the mixture reacts at room temperature for 12 hours after the adding is finished, 410ml of 1N hydrochloric acid is added after the reaction is completed, 760ml of ethyl acetate is added for extraction, 410ml of saturated sodium bicarbonate is washed, 410ml of saturated saline is washed and then concentrated to dryness under negative pressure, 225.6g of compound 4-1 is obtained after the rectification under negative pressure, the yield is 92.0%, and the purity is 99.1%.
Example 6
Replacing air with nitrogen in a hydrogenation kettle, mixing 224.4g of compound 4-1, 115g of ethanol and 0.46g of metal ruthenium homogeneous catalyst of a diphosphine ligand, introducing 2.1g of hydrogen, controlling the pressure to be 0.3-0.4 Mpa, controlling the temperature to be 40-50 ℃ for reaction, replacing the hydrogen with nitrogen after the reaction is completed, and concentrating a solvent under negative pressure to obtain 226g of compound 5-1, wherein the yield is 100%, the purity is 99.2% and the ee value is 99.0%.
Figure 852198DEST_PATH_IMAGE019
Example 7
Replacing air with nitrogen in a hydrogenation kettle, mixing 224.4g of compound 4-1, 115g of glacial acetic acid and 0.23g of metal ruthenium homogeneous catalyst of a diphosphine ligand, introducing 6.3g of hydrogen, controlling the pressure to be 1.0-1.2 Mpa, controlling the temperature to be 40-50 ℃ for reaction, replacing the hydrogen with nitrogen after the reaction is completed, and concentrating a solvent under negative pressure to obtain 226g of compound 5-1, wherein the yield is 100%, the purity is 99.1% and the ee value is 99.2%.
Example 8
Mixing 226g of compound 5-1, 18.4g of lithium chloride, 480ml of DMF (dimethyl formamide) and 45ml of water, heating, controlling the temperature to 140-150 ℃ for reaction for 3 hours, cooling to room temperature after the reaction is completed, adding 450ml of water and 1250ml of ethyl acetate, washing an organic layer once by 450ml of saturated salt after extraction and layering, and concentrating under reduced pressure to obtain 165.4g of compound 6-1, wherein the yield is 94.2% and the purity is 98.8%.
Figure 543073DEST_PATH_IMAGE020
Example 9
226g of compound 5-1, 110.6g of lithium chloride, 480ml of DMF (dimethyl formamide) and 45ml of water are mixed, the temperature is raised, the temperature is controlled to 140-150 ℃ for reaction for 3 hours, the temperature is reduced to room temperature after the reaction is completed, 450ml of water and 1250ml of ethyl acetate are added, an organic layer is washed once by 450ml of saturated salt after extraction and delamination, and the mixture is concentrated under reduced pressure to obtain 164.2g of compound 6-1, the yield is 93.5 percent, and the purity is 98.7 percent.
Example 10
226g of compound 5-1, 48.7g of calcium oxide, 480ml of DMF (dimethyl formamide) and 45ml of water are mixed and heated, the temperature is controlled to 140-150 ℃ for reaction for 3 hours, the temperature is reduced to room temperature after the reaction is completed, 450ml of water and 1250ml of ethyl acetate are added, an organic layer is washed once by 450ml of saturated salt after extraction and delamination, and 160.7g of compound 6-1 is obtained after decompression and concentration, wherein the yield is 91.5 percent, and the purity is 97.7 percent.
Example 11
165.4g of compound 6-1, 425ml of methanol and 18.7g of trifluoroacetic acid are mixed and reacted at room temperature for 5 hours, after the reaction is completed, the solvent is concentrated under negative pressure, and after rectification under reduced pressure, 100.2g of colorless transparent liquid compound 1 is obtained, the yield is 95.5%, the purity is 99.5%, and the ee value is 99.2%.
Figure 424442DEST_PATH_IMAGE021
Example 12
165.4g of compound 6-1, 425ml of methanol and 93.3g of trifluoroacetic acid are mixed and reacted at room temperature for 5 hours, after the reaction is completed, the solvent is concentrated under negative pressure, and after rectification under reduced pressure, 100.2g of colorless transparent liquid compound 1 is obtained, the yield is 95.5%, the purity is 99.3%, and the ee value is 99.0%.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and amendments can be made without departing from the principle of the present invention, and these modifications and amendments should also be considered as the protection scope of the present invention.

Claims (10)

1. A compound having the structure of formula 4:
Figure FDA0003984594830000011
wherein R is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
2. A process for preparing the compound of claim 1, comprising the steps of:
step a:
Figure FDA0003984594830000012
reacting the compound 2 with RCOONa in a solvent 1 to obtain a compound 3, wherein R is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;
step b:
Figure FDA0003984594830000013
compound 3 and
Figure FDA0003984594830000014
reacting with a catalyst in a solvent 2 to obtain a compound 4, wherein R is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
3. Method according to claim 2, characterized in that it comprises the following steps:
step a: taking a compound 2 and RCOONa as reaction raw materials, stirring and mixing in a solvent 1, heating, controlling the temperature to be 60-70 ℃, preserving the heat, reacting for 1-3 hours, cooling to room temperature, adding water and an organic solvent for extraction, washing an organic layer with water, and concentrating the solvent under negative pressure to obtain a compound 3;
step b: subjecting the compound 3 obtained in step a and
Figure FDA0003984594830000015
stirring and mixing the mixture in a solvent 2, cooling to below 10 ℃, adding a catalyst, reacting completely at room temperature, dropwise adding 1N hydrochloric acid after complete reaction, adding an organic solvent for extraction, adding saturated sodium bicarbonate and saturated salt water, washing under negative pressure, concentrating to dryness, and rectifying under negative pressure to obtain a compound 4.
4. The method according to claim 3, wherein the solvent 1 in the step a is any one of dimethylformamide, acetone and dimethyl sulfoxide, the solvent 2 in the step b is toluene or tetrahydrofuran, the catalyst is titanium tetrachloride and pyridine, and the organic solvent in the steps a and b is any one of ethyl acetate, dichloromethane and cyclohexane.
5. The method of claim 4, wherein step a is performed using Compound 2The molar ratio of the compound to RCOONa is 1.5-10, and the compound 3 and RCOONa in the step b are as follows
Figure FDA0003984594830000021
The molar ratio of (1).
6. The compound of claim 1 used for synthesizing key intermediate of antiepileptic drug, formula 1
Figure FDA0003984594830000022
The use of (1).
7. A method for preparing a key intermediate of an antiepileptic drug, wherein the key intermediate of the antiepileptic drug is (R) -4-propyldihydrofuran-2 (3H) -one, the method comprising the following steps:
step 1:
Figure FDA0003984594830000023
reacting the compound 4 with hydrogen to obtain a compound 5, wherein R is any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;
step 2:
Figure FDA0003984594830000024
reacting the compound 5 with a catalyst in dimethylformamide and water to obtain a compound 6, wherein R is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;
and 3, step 3:
Figure FDA0003984594830000031
compound 6 is reacted with trifluoroacetic acid in solvent 3 to provide compound 1.
8. The method for preparing key intermediates of antiepileptic drugs according to claim 7, characterized in that it comprises the following steps:
step 1: mixing the compound 4 with ethanol or glacial acetic acid, mixing with a ruthenium metal homogeneous catalyst of a diphosphine ligand, introducing hydrogen, controlling the pressure to be 0.1-10 Mpa, controlling the temperature to be 40-50 ℃ for reaction, and concentrating a solvent under negative pressure after the reaction is completed to obtain a compound 5;
step 2: mixing the compound 5 with a catalyst, dimethylformamide and water, heating, controlling the temperature to 140-150 ℃ for complete reaction, cooling to room temperature after complete reaction, adding water and an organic solvent for extraction, washing an organic layer with saturated salt water after extraction and layering, and concentrating under reduced pressure to obtain a compound 6;
and 3, step 3: and mixing the compound 6 with the solvent 3 and trifluoroacetic acid, reacting completely at room temperature, concentrating the solvent under negative pressure after the reaction is completed, and rectifying under reduced pressure to obtain a colorless transparent liquid compound 1.
9. The method for preparing key intermediates of antiepileptic drugs according to claim 8, characterized in that in step 1, the molar ratio of compound 4 to hydrogen is 1.5-5, the reaction pressure is 0.1-10 Mpa, in step 2, the molar ratio of compound 5 to catalyst is 1.
10. The method for preparing key intermediate of antiepileptic drug according to claim 9, wherein in step 2, the catalyst is any one of lithium chloride, sodium chloride, potassium chloride and calcium oxide, the organic solvent in step 2 is any one of ethyl acetate, dichloromethane and cyclohexane, and the solvent 3 in step 3 is any one of methanol, ethanol and isopropanol.
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CN114751849B (en) * 2022-04-24 2024-03-22 四川奥邦古得药业有限公司 Preparation method of brivaracetam and intermediate compound

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005350426A (en) * 2004-06-14 2005-12-22 Mitsubishi Rayon Co Ltd METHOD FOR PRODUCING alpha-METHYLENE-beta-METHYL-gamma-BUTYROLACTONE
CN105801530A (en) * 2016-04-13 2016-07-27 成都拿盛科技有限公司 Synthetic method of 4-substituted chiral gamma-butyrolactone
CN108264495A (en) * 2017-01-03 2018-07-10 重庆康施恩生物科技有限公司 Bu Waxitan chiral intermediates and preparation method thereof
CN108503609A (en) * 2017-02-24 2018-09-07 北京艾百诺医药股份有限公司 A method of preparing optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one
CN109553595A (en) * 2017-09-27 2019-04-02 上虞京新药业有限公司 A kind of Preparation Method And Their Intermediate of chiral gamma-butyrolactone
CN110357839A (en) * 2019-08-29 2019-10-22 重庆经致制药技术开发有限公司 The preparation method of Bu Waxitan chiral intermediate
WO2020168510A1 (en) * 2019-02-21 2020-08-27 上海博璞诺科技发展有限公司 Method for preparing chiral butyrolactone

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005350426A (en) * 2004-06-14 2005-12-22 Mitsubishi Rayon Co Ltd METHOD FOR PRODUCING alpha-METHYLENE-beta-METHYL-gamma-BUTYROLACTONE
CN105801530A (en) * 2016-04-13 2016-07-27 成都拿盛科技有限公司 Synthetic method of 4-substituted chiral gamma-butyrolactone
CN108264495A (en) * 2017-01-03 2018-07-10 重庆康施恩生物科技有限公司 Bu Waxitan chiral intermediates and preparation method thereof
CN108503609A (en) * 2017-02-24 2018-09-07 北京艾百诺医药股份有限公司 A method of preparing optically pure (R) -4- n-propyls-dihydrofuran -2 (3H) -one
CN109553595A (en) * 2017-09-27 2019-04-02 上虞京新药业有限公司 A kind of Preparation Method And Their Intermediate of chiral gamma-butyrolactone
WO2020168510A1 (en) * 2019-02-21 2020-08-27 上海博璞诺科技发展有限公司 Method for preparing chiral butyrolactone
CN110357839A (en) * 2019-08-29 2019-10-22 重庆经致制药技术开发有限公司 The preparation method of Bu Waxitan chiral intermediate

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