CN114989061A - Preparation method of brivaracetam - Google Patents
Preparation method of brivaracetam Download PDFInfo
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- CN114989061A CN114989061A CN202210926995.9A CN202210926995A CN114989061A CN 114989061 A CN114989061 A CN 114989061A CN 202210926995 A CN202210926995 A CN 202210926995A CN 114989061 A CN114989061 A CN 114989061A
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- 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
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- 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
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Abstract
The invention discloses a preparation method of brivaracetam, and belongs to the field of medicine synthesis. The preparation method specifically comprises the following steps: (1) dissolving the compound II in an organic solvent, adding T3P and diisopropylethylamine, and stirring for reaction; (2) stirring (S) -2-aminobutanamide or (S) -2-aminobutanamide hydrochloride, KOH, TBAB and dichloromethane for 1-2h, cooling to below 0 ℃, adding the solution prepared in the step (1), and reacting under heat preservation. Racemization does not occur in the reaction process, the obtained product of the brivaracetam has high chiral purity, separation by chiral chromatography is not needed, and the subsequent purification process is simple; the reaction process is simple, special equipment is not needed, the method is a conventional step, the reaction condition is mild, the process is stable, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and relates to a preparation method of brivaracetam.
Background
The chemical name of the Buvalsartan is (S) -2- ((R) -2-oxo-4-propyl pyrrolidine-1-yl) butanamide, and the molecular formula is C 11 H 2 ON 2 O 2 The structural formula is as follows:
the main action mechanism of the derivative is that the derivative combines with synaptic vesicle glycoprotein 2A (SV 2A) to affect synaptic function, and in addition, the derivative can affect sodium channel and gamma-aminobutyric acid A receptor (GABAA).
In the prior art, the preparation methods of the brivaracetam mainly comprise three methods. Route 1 (original research UCB route, PCT patent publication numbers WO0162726A2 and WO2005028435A 1) discloses a synthesis method of brivaracetam, which comprises the steps of firstly synthesizing brivaracetam and a (2S,4S) -diastereoisomer mixture thereof, then separating by a chiral Chromatography (MCC) to obtain brivaracetam, and simultaneously controlling the chiral purity and the isomer of 2-bit by controlling the chiral purity of a starting material (S) -2-aminobutanamide to be more than or equal to 99.0%. The preparation method comprises a palladium-carbon catalytic hydrogenation step and needs chiral column separation, and has the disadvantages of complex operation and insufficient safety and economy. The chemical equation of the above synthesis method is as follows:
route 2 (patent US8957226B 2) uses 2-hexenoic acid ethyl ester as starting material, and synthesizes the brivaracetam through 6 steps of reaction. The flammable and explosive nitromethane and Raney nickel are used in the reaction process, and the intermediate and the finished product need chiral preparation and separation, so the production cost is high, and the method is not suitable for industrial production. The chemical equation of the above synthesis method is as follows:
route 3 (document org. Process Res. Dev. 2016, 20, 1566-Busulfan 1575) uses biological enzyme as catalyst to prepare (R) -dihydro-4-propyl-2 (3H) -furanone, then prepares (R) -3- (bromomethyl) ethyl hexanoate through ring-opening and esterification reaction, and then reacts with (S) -2-aminobutanamide hydrochloride to obtain Buvalsartan. The method has the advantages of more steps, complex operation and lower yield in kilogram-level production, and related substances and isomers do not meet the quality requirements. The chemical equation of the above synthesis method is as follows:
as can be known from the prior art, the existing synthesis routes of the bravaracetam basically require separation and purification by a chromatographic column to obtain the high-purity bravaracetam, and meanwhile, the synthesis routes of the bravaracetam require steps of ring opening, carboxyl protection and the like, so that the operation is complex. Therefore, the development of the energy-saving, environment-friendly and simple-process method for preparing the brivaracetam is of great significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of brivaracetam. According to the preparation method, the compound II can be used for synthesizing the brivaracetam in one step through the activation of the propyl phosphoric anhydride (T3P) condensing agent, the operation is simple, the production time is saved, and the industrial production is easy to realize.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a preparation method of brivaracetam. In an organic solvent, under the alkaline condition, propyl phosphoric anhydride is used as a condensing agent, a compound II and (S) -2-aminobutanamide react to synthesize the brivaracetam in one step, and the reaction formula is as follows:
the (S) -2-aminobutanamide can also be (S) -2-aminobutanamide hydrochloride.
Further, the molar ratio of the compound II to the (S) -2-aminobutanamide is 1: 1-1.2, the molar ratio of the compound II to the (S) -2-aminobutanamide hydrochloride is 1: 1-1.2.
Further, the reaction is carried out under basic conditions using a mixture of diisopropylethylamine and potassium hydroxide.
Further, the molar ratio of the compound II to the diisopropylethylamine is 1.0-1.4: 1, wherein the molar ratio of the compound II to the potassium hydroxide is 1: 3.
further, the reaction is carried out in a solvent, the solvent is an aprotic solvent, and the aprotic solvent comprises one or more of dichloromethane, tetrahydrofuran and acetonitrile.
Further, the reaction temperature is-10-0 ℃.
The invention provides a specific preparation method of brivaracetam, which comprises the following steps:
(1) dissolving the compound II in an organic solvent, adding propyl phosphoric anhydride and diisopropylethylamine, and stirring for reaction;
(2) stirring (S) -2-aminobutanamide or (S) -2-aminobutanamide hydrochloride, KOH, tetrabutylammonium bromide and dichloromethane for 1-2h, cooling to below 0 ℃, adding the solution prepared in the step (1), and reacting under heat preservation.
Further, the reaction time of the heat preservation in the step (2) is 5-7 h.
Further, the end point of the reaction is monitored in the step (2) by TLC (thin layer chromatography), wherein the TLC developing agent is dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 18-20: 1.
the invention also provides another preparation method of the brivaracetam, which comprises the following steps: in an organic solvent, taking (R) -4-propyl-dihydrofuran-2-ketone as a raw material, firstly using HBr/AcOH for ring opening to generate (R) -3- (bromomethyl) hexanoic acid, then using T3P as a condensing agent and (S) -2-aminobutanamide or (S) -2-aminobutanamide hydrochloride under an alkaline condition, and obtaining the brivaracetam through continuous reaction; the reaction equation is as follows:
further, the reaction temperature of the ring opening is 60-70 ℃.
Further, the dosage ratio of the organic solvent to the (R) -4-propyl-dihydrofuran-2-ketone is 5-10 mL: 1 g.
In some embodiments of the invention, the synthetic route is as follows:
preparation of (R) -3- (bromomethyl) hexanoic acid:
10-12g of (R) -4-propyl-dihydrofuran-2-one and 15-20mL of HBr/AcOH (33% hydrobromic acid in acetic acid) are added into a three-mouth bottle, stirring is carried out, the temperature is raised to 60-70 ℃, and the reaction is carried out for 1-2 h. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio) with a trace amount of starting material remaining.
Cooling to room temperature, slowly adding 20mL of water and 20-40mL of dichloromethane, fully stirring, separating liquid, washing the dichloromethane phase twice (20 mL multiplied by 2 or 30mL multiplied by 2) with water, drying the organic phase with anhydrous sodium sulfate, and spin-drying to obtain the (R) -3- (bromomethyl) hexanoic acid intermediate, and calculating the yield.
Preparation of brivaracetam:
adding 15-16.8g of the prepared intermediate ((R) -3- (bromomethyl) hexanoic acid) into a three-necked flask, dissolving the obtained intermediate in 30mL of dichloromethane, adding 29.6-30.7g T3P (propylphosphoric anhydride), stirring, dropwise adding 7.4-9.3g of DIPEA (N, N-diisopropylethylamine), and stirring for reaction for the next step;
and (2) adding 10-13.4g of (S) -2-aminobutanamide hydrochloride, 12-13.5g of KOH, 1g of TBAB (tetrabutylammonium bromide) and 100mL of dichloromethane into a three-necked bottle, stirring the mixture at room temperature for dissociating for 1-2 hours, cooling the mixture to below 0 ℃, dropwise adding the solution obtained in the previous step, and carrying out a heat preservation reaction for 6 hours after the dropwise addition. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio). After the reaction, the reaction mixture was filtered, and the filtrate was washed with 30mL of 2M HCl and 3X 60mL of water, respectively. And (4) decompressing and evaporating a dichloromethane phase to dryness to obtain a crude product of the brivaracetam, and calculating the yield.
Refining the brivaracetam:
adding 10-12g of crude product of the busulfacetam into a three-neck bottle, adding 60mL of methyl tert-ether, heating to 55-60 ℃ for dissolving, cooling for crystallization after dissolving, filtering, leaching a filter cake with cold methyl tert-ether, and drying by blowing at 50 ℃ to obtain refined busulfacetam, and calculating the yield.
The reaction mechanism of the invention is as follows:
the above reaction mechanism: the (R) -4-propyl-dihydrofuran-2-ketone is firstly subjected to ring opening in an HBr/AcOH solution to generate (R) -3- (bromomethyl) hexanoic acid, then T3P propyl phosphoric anhydride is used as a condensing agent, and(s) -2-aminobutanamide is subjected to acid-amine condensation reaction to generate (R) -N- ((s) -1-amino-1-oxobutane-2-yl) -3- (bromomethyl) hexanamide, and then cyclization is carried out under the action of alkali to obtain the Buvalsartan.
Compared with the prior art, the invention has the following beneficial effects:
(1) the synthesis route of the invention is simple, the compound II can synthesize the brivaracetam in one step under the alkaline condition through the activation of the T3P condensing agent, the carboxyl of the ring-opened compound does not need to be protected additionally, the operation is simple, the production time is saved, and the invention is easy for industrial production. Racemization does not occur in the reaction process, the obtained product of the brivaracetam has high chiral purity, separation by chiral chromatography is not needed, and the subsequent purification process is simple;
(2) according to the invention, by optimizing the process conditions such as reagent raw material proportion, reaction temperature and the like, the finally prepared product has high purity and low impurity generation rate, and the finally prepared finished product of the Buvalsartan reaches the level of raw material medicines (API);
(3) the preparation process adopts the starting raw materials which are easily available in the market, the synthesis process is green and environment-friendly, and the waste liquid and the organic solvent generated in the reaction system and the post-treatment are less. The reaction process is simple, the operation is simple, special equipment is not needed, the conventional steps are adopted, the reaction condition is mild, the process is stable, and the method is suitable for industrial production.
Drawings
FIG. 1 is the hydrogen nuclear magnetic resonance spectrum of refined Buvalsartan in example 1;
FIG. 2 is the NMR spectrum of the refined Buvalsartan in example 1;
FIG. 3 is a liquid phase detection spectrum of refined brivaracetam in example 1.
Detailed Description
It should be noted that the raw materials used in the present invention are all common commercial products, and the sources thereof are not particularly limited.
Example 1
Preparation of (R) -3- (bromomethyl) hexanoic acid:
10g of (R) -4-propyl-dihydrofuran-2-one and 15mL of HBr/AcOH (33% hydrobromic acid in acetic acid) are added into a 100mL three-necked flask, stirred, heated to 60-70 ℃ and reacted for 1-2 h. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio) with a trace amount of starting material remaining.
After cooling to room temperature, 20mL of water and 20mL of dichloromethane were slowly added, and the mixture was thoroughly stirred, separated, and the dichloromethane phase was washed twice with water (20 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate, dried by spinning, and weighed to give 16.2g of a bright yellow oily liquid with a yield of about 100%.
Preparation of brivaracetam:
adding 16.2g of intermediate ((R) -3- (bromomethyl) hexanoic acid) prepared in the step 1 into a 100mL three-necked flask, dissolving the mixture in 30mL dichloromethane, adding 29.6g T3P (propylphosphoric anhydride), stirring the mixture, dropwise adding 8.4g of DIPEA (N, N-diisopropylethylamine) into the mixture, and stirring the mixture for reaction for the next step;
adding 10g of (S) -2-aminobutanamide hydrochloride, 13.1g of KOH, 1g of TBAB (tetrabutylammonium bromide) and 100mL of dichloromethane into a 200mL three-necked bottle, stirring the mixture at room temperature for dissociating for 1 to 2 hours, cooling the mixture to below 0 ℃, dropwise adding the solution obtained in the previous step, and carrying out a heat preservation reaction for 6 hours after the dropwise addition. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio). After the reaction, the reaction mixture was filtered, and the filtrate was washed with 30mL of 2M HCl and 3X 60mL of water, respectively. The dichloromethane phase was evaporated to dryness under reduced pressure to give 13.4g of a white solid in 87.49% yield.
Refining the brivaracetam:
and adding 12g of crude product of the brivaracetam into a 100mL three-necked bottle, adding 60mL of methyl tert-ether, heating to 55-60 ℃ for dissolving, cooling for crystallization after dissolving, filtering, leaching a filter cake with cold methyl tert-ether, and drying by blowing at 50 ℃ to obtain 10.2g of brivaracetam with the yield of 85%. The HPLC detection spectrum of the obtained refined product of brivaracetam is shown in figure 3, and then the nuclear magnetic resonance hydrogen spectrum and carbon spectrum detection is shown in figures 1 and 2.
Example 2
Preparation of (R) -3- (bromomethyl) hexanoic acid:
10g of (R) -4-propyl-dihydrofuran-2-one and 15mL of HBr/AcOH (33% hydrobromic acid in acetic acid) are added into a 100mL three-necked flask, stirred, heated to 60-70 ℃ and reacted for 1-2 h. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio) with a trace amount of starting material remaining.
After cooling to room temperature, 20mL of water and 40mL of dichloromethane were slowly added, and the mixture was thoroughly stirred, the mixture was separated, the dichloromethane phase was washed twice with water (30 mL. times.2), the organic phase was dried over anhydrous sodium sulfate, and then spin-dried, and 16.8g of a bright yellow oily liquid was weighed, with a yield of about 100%.
Preparation of brivaracetam:
adding 16.8g of the intermediate prepared in the step 1 into a 100mL three-neck flask, dissolving 30mL of dichloromethane, adding 30.7g T3P (propylphosphoric anhydride), stirring, dropwise adding 7.4g of DIPEA (N, N-diisopropylethylamine), and reacting under stirring for later use;
adding 13.4g of (S) -2-aminobutanamide hydrochloride, 13.5g of KOH13.5g, 1g of TBAB (tetrabutylammonium bromide) and 100mL of dichloromethane into a 200mL three-necked bottle, stirring the mixture at room temperature for dissociating for 1 to 2 hours, cooling the mixture to below 0 ℃, dropwise adding the solution obtained in the previous step, and carrying out an insulation reaction for 6 hours after dropwise adding. The end of the reaction was monitored by TLC (developing solvent: dichloromethane/methanol =19/1, volume ratio). After the reaction was completed, the reaction mixture was filtered, and the filtrate was washed with 30mL of 2M HCl and 3X 60mL of water, respectively. The dichloromethane phase was evaporated to dryness under reduced pressure to give 12.5g of a white solid with a yield of 75.47%.
Refining the brivaracetam:
and adding 12g of crude product of the brivaracetam into a 100mL three-necked bottle, adding 60mL of methyl tert-ether, heating to 55-60 ℃ for dissolving, cooling for crystallization after dissolving, filtering, leaching a filter cake with cold methyl tert-ether, and drying by blowing at 50 ℃ to obtain 10.4g of brivaracetam with the yield of 86.8%.
Example 3
Preparation of (R) -3- (bromomethyl) hexanoic acid:
12g of (R) -4-propyl-dihydrofuran-2-one and 20mL of HBr/AcOH (33% hydrobromic acid in acetic acid) are added into a 100mL three-necked flask, stirred, heated to 60-70 ℃ and reacted for 1-2 h. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio) with a trace amount of starting material remaining.
After cooling to room temperature, 20mL of water and 40mL of dichloromethane were slowly added, and the mixture was thoroughly stirred, the mixture was separated, the dichloromethane phase was washed twice with water (30 mL. times.2), and the organic phase was dried over anhydrous sodium sulfate, spun-dried, and weighed to obtain 19.6g of a bright yellow oily liquid with a yield of about 100%.
Preparation of brivaracetam:
adding 15g of the intermediate prepared in the step 1 into a 100mL three-necked flask, dissolving 30mL of dichloromethane, adding 27.4g T3P (propylphosphoric anhydride), stirring, dropwise adding 9.3g of DIPEA (N, N-diisopropylethylamine), and stirring for reaction for the next step;
adding 11.9g of (S) -2-aminobutanamide hydrochloride, 12g of KOH, 1g of TBAB (tetrabutylammonium bromide) and 100mL of dichloromethane into a 200mL three-necked bottle, stirring the mixture at room temperature for dissociating for 1 to 2 hours, cooling the mixture to below 0 ℃, dropwise adding the solution obtained in the previous step, and carrying out an insulation reaction for 6 hours after the dropwise addition. The end of the reaction was monitored by TLC (developing solvent: dichloromethane/methanol =19/1, volume ratio). After the reaction was completed, the reaction mixture was filtered, and the filtrate was washed with 2M HCl and 3X 60mL of water, respectively. The dichloromethane phase was evaporated to dryness under reduced pressure to give 12.8g of a white solid with a yield of 84.04%.
Refining the brivaracetam:
and adding 10g of crude product of the brivaracetam into a 100mL three-necked bottle, adding 60mL of methyl tert-ether, heating to 55-60 ℃ for dissolving, cooling for crystallization after dissolving, filtering, leaching a filter cake with cold methyl tert-ether, and drying by blowing at 50 ℃ to obtain 8.61g of brivaracetam with the yield of 86.1%.
Example 4
Preparation of (R) -3- (bromomethyl) hexanoic acid:
in a 100mL three-necked flask, 10g of (R) -4-propyl-dihydrofuran-2-one and 15mL of HBr/AcOH (33% hydrobromic acid in acetic acid) are added, stirred, heated to 60-70 ℃ and reacted for 1-2 h. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio) with a trace amount of starting material remaining.
After cooling to room temperature, 20mL of water and 20mL of dichloromethane were slowly added, and the mixture was thoroughly stirred, separated, the dichloromethane phase was washed twice with water (2X 20 mL), and the organic phase was dried over anhydrous sodium sulfate, spun-dried, and weighed to give 16.5g of a bright yellow oily liquid with a yield of about 100%.
Preparation of brivaracetam:
adding 16.5g of intermediate ((R) -3- (bromomethyl) hexanoic acid) prepared in the step 1 into a 100mL three-necked flask, dissolving the mixture in 30mL dichloromethane, adding 29.6g T3P (propylphosphoric anhydride), stirring the mixture, dropwise adding 5.1g DIPEA (N, N-diisopropylethylamine) into the mixture, and stirring the mixture for reaction for the next step;
adding 10g of (S) -2-aminobutanamide hydrochloride, 13.3g of KOH, 1g of TBAB (tetrabutylammonium bromide) and 100mL of dichloromethane into a 200mL three-necked bottle, stirring the mixture at room temperature for dissociating the mixture for 1 to 2 hours, cooling the mixture to below 0 ℃, dropwise adding the solution obtained in the previous step, and carrying out a heat preservation reaction for 6 hours after the dropwise addition. TLC monitored the end of the reaction (developing solvent: dichloromethane/methanol =19/1, volume ratio). After the reaction, the reaction mixture was filtered, and the filtrate was washed with 30mL of 2M HCl and 3X 60mL of water, respectively. The dichloromethane phase was evaporated to dryness under reduced pressure to give 11.5g of a white solid with a yield of 75.08%.
Refining the brivaracetam:
and adding 10g of crude product of the brivaracetam into a 100mL three-necked bottle, adding 60mL of methyl tert-butyl ether, heating to 55-60 ℃ for dissolving, cooling for crystallization after dissolving, filtering, leaching a filter cake with cold methyl tert-butyl ether, and drying by blowing at 50 ℃ to obtain 8.3g of brivaracetam with the yield of 83%.
Example 5
Preparation of (R) -3- (bromomethyl) hexanoic acid:
in a 100mL three-necked flask, 10g of (R) -4-propyl-dihydrofuran-2-one and 15mL of HBr/AcOH (33% hydrobromic acid in acetic acid) are added, stirred, heated to 60-70 ℃ and reacted for 1-2 h. The end of the reaction was monitored by TLC (developing solvent: dichloromethane: methanol =19/1, volume ratio) with a trace amount of starting material remaining.
After cooling to room temperature, 20mL of water and 20mL of dichloromethane were slowly added, and the mixture was sufficiently stirred, the organic phase was separated, washed twice with water (2X 20 mL), dried over anhydrous sodium sulfate, and then dried by spinning, and 16.3g of a bright yellow oily liquid was weighed to give an yield of about 100%.
Preparation of brivaracetam:
adding 16.3g of intermediate ((R) -3- (bromomethyl) hexanoic acid) prepared in the step 1 into a 100mL three-necked flask, dissolving the mixture in 30mL dichloromethane, adding T3P 29.6.6 g (propylphosphoric anhydride), stirring the mixture, dropwise adding 8.4g DIPEA (N, N-diisopropylethylamine) into the mixture, and stirring the mixture for reaction for the next step;
adding 8.6g of (S) -2-aminobutanamide hydrochloride, 13.1g of KOH, 1g of TBAB (tetrabutylammonium bromide) and 100mL of dichloromethane into a 200mL three-necked flask, stirring the mixture at room temperature for dissociating for 1 to 2 hours, cooling the mixture to below 0 ℃, dropwise adding the solution obtained in the previous step, and carrying out an incubation reaction for 6 hours after the dropwise addition. The end of the reaction was monitored by TLC (developing solvent: dichloromethane/methanol =19/1, volume ratio). After the reaction, the reaction mixture was filtered, and the filtrate was washed with 30mL of 2M HCl and 3X 60mL of water, respectively. The dichloromethane phase was evaporated to dryness under reduced pressure to give 12.1g of a white solid in 91.86% yield.
Refining the brivaracetam:
and adding 10g of crude product of the brivaracetam into a 100mL three-necked bottle, adding 60mL of methyl tert-ether, heating to 55-60 ℃ for dissolving, cooling for crystallization after dissolving, filtering, leaching a filter cake with cold methyl tert-ether, and drying by blowing at 50 ℃ to obtain 8.65g of brivaracetam with the yield of 86.5%.
Example 6
Preparation of (R) -3- (bromomethyl) hexanoic acid:
in a 100mL three-necked flask, 10g of (R) -4-propyl-dihydrofuran-2-one and 15mL of HBr/AcOH (33% hydrobromic acid in acetic acid) are added, stirred, heated to 60-70 ℃ and reacted for 1-2 h. TLC monitored the end of the reaction (developing solvent: dichloromethane: methanol =19/1, volume ratio) and traces of starting material remained.
After cooling to room temperature, 20mL of water and 20mL of dichloromethane were slowly added, and the mixture was thoroughly stirred, separated, and the dichloromethane phase was washed twice with water (2X 20 mL), and the organic phase was dried over anhydrous sodium sulfate, and then dried by spinning, and 16.3g of a bright yellow oily liquid was weighed, and the yield was about 100%.
Preparation of brivaracetam:
adding 16.3g of intermediate ((R) -3- (bromomethyl) hexanoic acid) prepared in the step 1 into a 100mL three-necked flask, dissolving the mixture in 30mL dichloromethane, adding 29.6g T3P (propylphosphoric anhydride), stirring the mixture, dropwise adding 8.4g of DIPEA (N, N-diisopropylethylamine) into the mixture, and stirring the mixture for reaction for the next step;
adding 10g of (S) -2-aminobutanamide hydrochloride, 8.7g of KOH, 1g of TBAB (tetrabutylammonium bromide) and 100mL of dichloromethane into a 200mL three-necked bottle, stirring the mixture at room temperature for dissociating for 1 to 2 hours, cooling the mixture to below 0 ℃, dropwise adding the solution obtained in the previous step, and carrying out a heat preservation reaction for 6 hours after the dropwise addition. The end of the reaction was monitored by TLC (developing solvent: dichloromethane/methanol =19/1, volume ratio). After the reaction, the reaction mixture was filtered, and the filtrate was washed with 30mL of 2M HCl and 3X 60mL of water, respectively. The dichloromethane phase was evaporated to dryness under reduced pressure to give 10.3g of a white solid in 67.25% yield.
Refining the brivaracetam:
and adding 10g of crude product of the brivaracetam into a 100mL three-necked bottle, adding 60mL of methyl tert-butyl ether, heating to 55-60 ℃ for dissolving, cooling for crystallization after dissolving, filtering, leaching a filter cake with cold methyl tert-butyl ether, and drying by blowing at 50 ℃ to obtain 8.5g of brivaracetam with the yield of 85%.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and do not limit the protection scope of the present invention, and those skilled in the art can make simple modifications or equivalent substitutions on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. The preparation method of the brivaracetam is characterized in that propyl phosphoric anhydride is used as a condensing agent, a compound II and (S) -2-aminobutanamide react to synthesize the brivaracetam, and the reaction equation is as follows:
the (S) -2-aminobutanamide can also be (S) -2-aminobutanamide hydrochloride.
2. The process according to claim 1, wherein the molar ratio of compound ii to (S) -2-aminobutanamide is 1: 1-1.2, the molar ratio of the compound II to the (S) -2-aminobutanamide hydrochloride is 1: 1-1.2.
3. The method according to claim 1, wherein the reaction is carried out under basic conditions using a mixture of diisopropylethylamine and potassium hydroxide.
4. The preparation method according to claim 3, wherein the molar ratio of the compound II to diisopropylethylamine is 1.0-1.4: 1, wherein the molar ratio of the compound II to the potassium hydroxide is 1: 3.
5. the preparation method according to claim 1, wherein the reaction is carried out in a solvent, the solvent is an aprotic solvent, and the aprotic solvent comprises one or more of dichloromethane, tetrahydrofuran and acetonitrile.
6. The method according to claim 1, wherein the reaction temperature is-10 to 0 ℃.
7. The method of claim 1, comprising the steps of:
(1) dissolving the compound II in an organic solvent, adding propyl phosphoric anhydride and diisopropylethylamine, and stirring for reaction;
(2) stirring (S) -2-aminobutanamide or (S) -2-aminobutanamide hydrochloride, KOH, tetrabutylammonium bromide and dichloromethane for 1-2h, cooling to below 0 ℃, adding the solution prepared in the step (1), and reacting under the condition of heat preservation.
8. A preparation method of the brivaracetam is characterized by comprising the following steps: in an organic solvent, taking (R) -4-propyl-dihydrofuran-2-ketone as a raw material, firstly using HBr/AcOH to open a ring to generate (R) -3- (bromomethyl) hexanoic acid, and then using T3P as a condensing agent and (S) -2-aminobutanamide or (S) -2-aminobutanamide hydrochloride to obtain the brivaracetam through continuous reaction under an alkaline condition, wherein the reaction equation is as follows:
9. the method of claim 8, wherein the reaction temperature for ring opening is 60-70 ℃.
10. The preparation method of bravaracetam according to claim 8, wherein the dosage ratio of the organic solvent to (R) -4-propyl-dihydrofuran-2-one is 5-10 mL: 1g of the total weight of the composition.
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