CN113651745B - Buvaracetam intermediate, preparation method and purification method thereof - Google Patents
Buvaracetam intermediate, preparation method and purification method thereof Download PDFInfo
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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
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- C07D207/24—Oxygen or sulfur atoms
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- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- C07D453/04—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
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Abstract
The invention discloses a buvaracetam intermediate and a preparation method thereofAnd a purification method. The method for purifying the buvaracetam intermediate comprises the following steps: crystallizing a mixture of a compound shown in a formula C and a compound shown in a formula C 'in a solvent to obtain the compound shown in the formula C or the compound shown in the formula C'; the buvaracetam intermediate prepared by the method has high de value and good application prospect.
Description
Technical Field
The invention relates to a buvaracetam intermediate, a preparation method and a purification method thereof.
Background
Brivaracetam (biravavelam), trade name:is a third generation epileptic therapeutic drug designed and developed by Belgium-to-time ratio (UCB Pharm) company, is marketed in Europe and the United states in the year 2016, 1 month 14 and year 2016, 2 month 18 respectively, and is suitable for partial seizure of young and adult over 16 years oldAdjuvant therapy of patients.
The mechanism of action of brivaracetam is the same as that of levetiracetam, and it exerts an antiepileptic effect by binding to the protruding vesicle protein in the brain (SV 2A), affecting synaptic function and regulating neurotransmitter release. However, clinical test data show that the curative effect of the brivaracetam is obviously better than that of levetiracetam, and the brivaracetam has good tolerance and small adverse reaction.
Because two chiral centers exist in the structure of the buvaracetam, wherein the chiral center at the 2-position of the side chain can be directly introduced from a derivative of a natural amino acid, the construction difficulty of the chiral center is the construction of the 4-position chiral carbon of the lactam ring. At present, the synthetic route of the buvaracetam is more, and the method mainly comprises the methods of chiral chromatographic column preparation, chiral resolving agent resolution, asymmetric synthesis and the like. The chiral column chromatography preparation method has more literature reports, but has high separation and preparation cost and limited production scale, and can not meet the requirement of industrial production; in recent years, more and more asymmetric synthesis methods are reported, and the existing asymmetric synthesis methods have the defects of longer route, lower yield, need of column chromatography purification and the like although the use of chiral column chromatography is eliminated.
CN106748950a reports a process for preparing intermediate (S) -2-3-propylpyrrolidin-1-yl-butyric acid, as shown in the following formula. The patent uses R-phenethylamine as a resolving agent and isopropanol as a resolving solvent, and resolves (S) -2-3-propyl pyrrolidine-1-yl butyric acid to obtain the intermediate with high chiral purity, and then the intermediate is subjected to ammoniation and purification steps to obtain the high-purity buvaracetam.
CN111333563a also reports a process for preparing a brivaracetam intermediate, as shown in the following formula. The patent uses 1S, 2S-diphenylethylenediamine as a resolving agent to resolve (S) -2-3-propylpyrrolidin-1-yl butyric acid to obtain the intermediate with high chiral purity, and synthesizes high-purity brivaracetam by referring to a method reported by CN 106748950A.
However, the inventor repeatedly performs the examples of the two patents, and the inventor finds that the two resolution systems have no resolution and purification effects and no solid crystallization precipitation, and the patent reproducibility is to be examined.
In addition, CN107513031a reports a process for preparing a buvaracetam intermediate, as shown in the following formula. According to the method, the compound A can be directly reduced and converted into the excessive isomer B through heavy metal catalytic hydrogen under the low-temperature condition through asymmetric reduction, and then the high-chiral pure buvaracetam intermediate D can be obtained through recrystallization. However, after the experimental staff repeats the examples of the patent, it was found that the direct hydrogenation reduction did not reach the de value described in the patent, and the recrystallization system did not reach the height reported in the patent under the conditions described in the patent, and the reproducibility of the patent was examined.
In view of the problems of high cost, limited production scale, long route and the like existing in the existing preparation methods of the brivaracetam, the preparation method of the brivaracetam needs to be developed, which is simpler and more convenient and has low cost for industrial production.
Disclosure of Invention
The invention aims to overcome the defects of low de value or low yield of a buvaracetam intermediate in the prior art, and provides the buvaracetam intermediate, a preparation method and a purification method thereof. The buvaracetam intermediate obtained by the method has high de value and high yield.
The invention overcomes the technical problems by the following technical proposal.
The invention provides a method for purifying a compound shown as a formula C or a formula C', which comprises the following steps: crystallizing a mixture of a compound shown in a formula C and a compound shown in a formula C 'in a solvent to obtain the compound shown in the formula C or the compound shown in the formula C';
wherein R is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
The operation and conditions of crystallization may be conventional in the art for such purification methods, with the following being particularly preferred:
in the present invention, the solvent is preferably an ester solvent, a ketone solvent or C 1-4 One or more of the alcohol solvents. The ester solvent is preferably ethyl acetate. The ketone solvent is acetone. The C is 1-4 The alcohol solvent is preferably ethanol and/or isobutanol.
In the present invention, the crystallization is preferably performed by naturally cooling the hot saturated solution.
In the present invention, the volume/mass ratio of the solvent to the mixture of the compound represented by the formula C and the compound represented by the formula C' is preferably 1.4 to 3.0ml/g, for example, 1.5ml/g, 1.8ml/g or 2.0. 2.0 ml/g.
In the invention, the crystallization is preferably followed by suction filtration and drying.
In the present invention, the ratio of the compound represented by formula C to the compound represented by formula C in the mixture of the compound represented by formula C and the compound represented by formula C' is preferably 1:10 to 10:1, for example, 7:1.
In the present invention, the mixture of the compound represented by the formula C and the compound represented by the formula C' is preferably prepared by the following method: carrying out salt forming reaction of the compound B and the compound I in a solvent to obtain a mixture of the compound shown as the formula C and the compound shown as the formula C';
the salt-forming reaction may be conventional in the art of such reactions, and the present invention particularly preferably employs the following conditions and operations:
in the salification reaction, the compound B isMixing. The de% of the compound B is preferably more than or equal to 70%.
In the salt-forming reaction, the compound I is preferably quinine, quinidine or cinchonidine, such as cinchonidine.
In the salt-forming reaction, the molar ratio of the compound I to the compound B is preferably 0.5:1 to 2:1, for example 1.0:1.
In the salt forming reaction, the solvent is preferably one or more of an ether solvent, a nitrile solvent, an ester solvent, an alcohol solvent, a ketone solvent and water, and is preferably one or more of an ester solvent, an alcohol solvent and a ketone solvent.
Wherein, the ether solvent is preferably one or more of methyl tertiary butyl ether, isopropyl ether, tetrahydrofuran and 2-methyltetrahydrofuran.
Wherein, the nitrile solvent is preferably acetonitrile.
Wherein the ester solvent is preferably ethyl acetate and/or isopropyl acetate, more preferably ethyl acetate.
Wherein, the alcohol solvent is preferably methanol, ethanol, n-propanol or isobutanol.
Wherein, the ketone solvent is preferably acetone.
In the salt formation reaction, the volume to mass ratio of the solvent to the compound B is preferably 1:1 to 30:1, more preferably 2:1 to 15:1, for example 2.8:1 or 3:1.
The temperature of the salt forming reaction may be conventional in the art. The salt formation reaction is preferably carried out under reflux of the solvent used. The reaction temperature is, for example, 1 to 110℃C (e.g., 55℃C, 70℃C, 78℃C or 108 ℃) and, for example, 25 to 80 ℃.
The progress of the salt formation reaction can be monitored by methods conventional in the art (e.g., TLC), typically with compound B no longer reacting or disappearing as an endpoint of the reaction. The salt formation reaction is carried out for a period of time of, for example, 20 to 30 hours.
The compound B is preferably prepared by the following method: in the presence of hydrogen and a metal catalyst, carrying out the reduction reaction of the compound A in an organic solvent as shown below to obtain the compound B;
the reduction is preferably carried out under a pressure, preferably 1-2bar.
In the reduction reaction, the metal catalyst may be a metal catalyst conventional in the art, preferably palladium carbon, platinum carbon, ruthenium carbon, rhodium carbon or Raney nickel, more preferably palladium carbon (e.g., 10% palladium carbon).
In the reduction reaction, the mass ratio of the metal catalyst to the compound is preferably 1:15 to 1:5, for example 1:10.
In the reduction reaction, the organic solvent may be one or more of an alcohol solvent (e.g., methanol, ethanol, isopropanol or propanol), a ketone solvent (e.g., acetone), a chlorohydrocarbon solvent (e.g., methylene chloride), an ether solvent (e.g., methyl t-butyl ether, isopropyl ether, tetrahydrofuran or 2-methyltetrahydrofuran), a nitrile solvent (e.g., acetonitrile), an ester solvent (e.g., ethyl acetate or isopropyl acetate) and water, which are conventional in the art, and more preferably an alcohol solvent.
The temperature of the reduction reaction may be a matter conventional in such reactions in the art, preferably-50 ℃ to 50 ℃, more preferably-10 ℃ to 20 ℃.
The progress of the reduction reaction can be monitored by methods conventional in the art (e.g., TLC), typically with compound a no longer reacting or disappearing as an endpoint of the reaction. The reduction reaction is carried out for a period of, for example, 17 to 72 hours.
The invention also provides a preparation method of the mixture of the compound shown in the formula C and the compound shown in the formula C', which comprises the following steps: carrying out salt forming reaction of the compound B and the compound I in a solvent to obtain a mixture of the compound shown as a formula C and the compound shown as a formula C';
the conditions and operation of the salt formation reaction are the same as described above.
The invention also provides a preparation method of the buvaracetam intermediate, which comprises the following steps: in a solvent, carrying out free reaction of the compound C and acid in the following formula to obtain a compound D (namely a buvaracetam intermediate);
r is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
The free reaction may be a conventional reaction in such reactions in the art, and the present invention particularly preferably employs the following conditions and operations:
in the free reaction, the solvent may be a water-ether solvent (e.g., water-methyl t-butyl ether). The volume ratio of water to ether solvent in the water-ether solvent may be 1:8 to 1:1, for example (1:4).
In the free reaction, the acid may be more acidic than compound D and may form a salt with compound I, for example, hydrochloric acid (concentrated hydrochloric acid).
In the free reaction, the molar concentration of hydrogen ions in the acid may be 0.01 to 0.1M.
The compound C is preferably prepared according to the preparation method of the compound shown as the formula C.
The work-up step after the reaction has ended may be extraction (for example, the extraction solvent is methyl tert-butyl ether) and concentration (for example, concentration under reduced pressure).
The invention also provides a compound shown in the formula C, a compound shown in the formula C ', or a mixture of the compound shown in the formula C and the compound shown in the formula C';
wherein R is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
The ratio of the compound of formula C to the compound of formula C in the mixture of the compound of formula C and the compound of formula C' is preferably 1:10 to 10:1, for example 7:1.
The mixture of the compound represented by formula C and the compound represented by formula C' is preferably used for preparing a buvaracetam intermediate.
The compound represented by formula C, the compound represented by formula C ', or the mixture of the compound represented by formula C and the compound represented by formula C' is preferably the following compound:
The mixture of the compound shown in the formula C and the compound shown in the formula C' is preferablyFor example, the ratio of C-1 to C' -1 is 7:1), and +.>(e.g., a ratio of C-2 to C' -2 of 7:1) or,(e.g., a ratio of C-3 to C' -3 of 7:1).
The invention also provides a preparation method of the mixture of the compound shown in the formula C and the compound shown in the formula C', which comprises the following steps:
carrying out salt forming reaction of the compound B and the compound I in a solvent to obtain a mixture of the compound shown as the formula C and the compound shown as the' formula;
the operation and conditions of the salt forming reaction are the same as those described above.
The invention also provides an application of the compound C in preparing the buvaracetam.
In the application, the preparation method of the brivaracetam comprises the following steps:
step 1: in a solvent, carrying out free reaction on the compound C and acid to obtain a compound D;
step 2: carrying out condensation reaction on the compound D obtained in the step 1 to obtain the buvaracetam;
in step 1, the conditions and operation of the free reaction are as described above.
In step 2, the conditions and procedures of the condensation reaction may be those conventional in the art, for example, condensing ammonium chloride with compound D in a solvent (tetrahydrofuran) under the action of a condensing agent (HATU) and a base (DIEA) to give buvaracetam.
The invention also provides a preparation method of the brivaracetam, which comprises the following steps:
step 1: in a solvent, carrying out free reaction on the compound C and acid to obtain a compound D;
step 2: carrying out condensation reaction on the compound D obtained in the step 1 to obtain the buvaracetam;
wherein the conditions and operations in steps 1 and 2 are the same as those described above
In step 1, the compound C is preferably prepared according to the preparation method of the compound shown as the formula C.
The invention also provides a preparation method of the compound shown as the formula C '(namely the compound C'), which comprises the following steps: carrying out salt forming reaction of the compound B and the compound I 'in a solvent to obtain the compound C';
r' is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
The conditions and operations in the preparation method of the compound C' are the same as those in the preparation method of the compound C.
The invention also provides a preparation method of the compound shown as the formula D '(namely the compound D'), which comprises the following steps: in a solvent, carrying out free reaction of the compound C 'and acid to obtain a compound D';
r' is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
R ", C 1-4 The alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, more preferably methoxy.
The conditions and operation of the free reaction are the same as those in the free reaction.
The preparation method of the compound shown as the formula D ' can further comprise the preparation method of the compound shown as the formula C ', wherein the preparation method of the compound shown as the formula C ' is the same as that described above.
The invention also provides a compound shown as a formula C':
wherein R' is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
The compound shown as the formula C' is preferably the following compound:
the preparation methods of the above compounds may be optionally combined to obtain a compound represented by the formula C, C ' or C ', a compound represented by the formula D or D ' (i.e. a buvaracetam intermediate), or a synthetic route of buvaracetam (e.g. A.fwdarw.B.fwdarw.C.fwdarw.D.buvaracetam, B.fwdarw.C.fwdarw.D.buvaracetam, A.fwdarw.B.fwdarw.C.fwdarw.D, B.fwdarw.C.C.fwdarw.C.C, etc.).
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the buvaracetam intermediate obtained by the preparation method of the buvaracetam intermediate has high de value and high yield, and the reacted material can be recycled for multiple times and repeatedly split, so that the material utilization optimization is achieved.
Detailed Description
In document J.org.chem.1996,61,215-222, a carboxylic acid substrate containing a six-membered cyclic lactam structure was chemically resolved using cinchonidine. The yield of carboxylic acid substrate using cinchoni Ding Cafen hexabasic ring lactam structure was 45% and ee value was 98%. Compared with the resolution effect in the document, the method has higher resolution yield (> 65%) and higher chiral purity (> 98%) by using the quinine resolving agent.
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
de% normal phase HPLC detection method:
chromatographic column: IC-3; flow rate: 1mL/min; wavelength: 210nm; mobile phase: n-hexane: isopropanol=85: 15; isocratic elution for 30min; column temperature: 30 ℃.
Purity (reverse phase HPLC) detection method:
chromatographic column: c18; flow rate: 0.8mL/min; wavelength: 210nm; column temperature: 30 ℃; mobile phase: a-1% phosphoric acid aqueous solution, B-acetonitrile; gradient: 0 min-A90%, B10%; 20 min-A10%, B90%; 30 min-A10%, B90%; 30.1 min-A90%, B10%; 45 min-A90% and B10%.
EXAMPLE 1 preparation of Compound B
To a 500mL three-necked flask, compound A (40 g) was added, methanol (200 mL) was dissolved with stirring, 10% palladium on carbon (4 g) was added, stirring was performed, hydrogen was replaced, the hydrogen pressure was 1-2bar, stirring was performed at room temperature, the reaction was performed for 72 hours, LCMS was controlled until the starting material disappeared completely and a peak of single compound B appeared, the reaction was stopped, filtration was performed, and rotary evaporation was performed at 45℃to obtain 37.58g of pale yellow solid with a yield of 93.3%, HPLC 99.1% and a de% of 75%.
EXAMPLE 2 preparation of Compound B
To a 25mL three-necked flask, compound A (1 g) was added, ethyl acetate (5 mL) was dissolved with stirring, 0.1g of 10% palladium on carbon was added, stirring was performed, hydrogen was replaced, the pressure of hydrogen was 1-2bar, the reaction was performed at room temperature with stirring, 17 hours of reaction was performed, LCMS was performed until the starting material disappeared completely and a peak of single compound D appeared, the reaction was stopped, filtration was performed, and rotary evaporation was performed at 45℃to obtain 95.9mg of pale yellow solid with a yield of 95%, HPLC 99% and a de% of 70%.
EXAMPLE 3 preparation of Compound C-1 (quinidine salt)
To a 10mL three-necked flask, 45mL of compound B (15.68 g) and ethyl acetate and quinidine (1 equivalent) are added, the temperature is raised to about 70 ℃, the mixture is dissolved, the temperature is naturally reduced to-18 ℃, stirring is carried out for 31 hours, suction filtration is carried out, 31.66g of wet product is obtained, 45mL of ethyl acetate is directly added into the wet product, the temperature is raised to 70 ℃ for dissolution, natural cooling is carried out to 10+/-5 ℃, suction filtration is carried out, 25.33g of wet product of compound C is obtained, and the wet product is dried to obtain 25g of white solid. Yield: 63.16%, purity: 98%, de% 99%.
EXAMPLE 4 preparation of Compound C-2 (quinic salt)
Adding 15mL of compound B (5 g) and ethyl acetate and quinine (1 equivalent) into a 10mL three-necked flask, heating to about 70 ℃, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, performing suction filtration to obtain 10g of wet product, directly adding 15mL of ethyl acetate into the wet product, heating to 70 ℃ for dissolution, naturally cooling to 10+/-5 ℃, performing suction filtration to obtain 7g of wet product of the compound C, and drying to obtain 6.7g of white solid. Yield: 67%, purity: 95%, de% was 96%.
EXAMPLE 5 preparation of Compound C-1 (quinidine salt)
Adding compound B (5 g), acetone (15 mL) and quinidine (1 equivalent) into a 10mL three-necked flask, heating to reflux, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, performing suction filtration to obtain 7.5g wet product, directly adding 15mL acetone into the wet product, heating to 70 ℃ for dissolution, naturally cooling to 10+/-5 ℃, performing suction filtration to obtain 7g wet product of compound C, and drying to obtain 6.7g of white solid. Yield: 67%, purity: 95%, de% was 96%.
EXAMPLE 6 preparation of Compound C-3 (cinchonidine salt)
Adding 15mL of compound B (5 g) and isobutanol and 1 equivalent of cinchonidine into a 10mL three-necked flask, heating to reflux, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, performing suction filtration to obtain 8g of wet product, directly adding 15mL of isobutanol into the wet product, heating to 110 ℃ for dissolution, naturally cooling to 10+/-5 ℃, performing suction filtration to obtain 7.3g of wet product of the compound C, and drying to obtain 7g of white solid. Yield: 70%, purity: 96% de% 98%.
EXAMPLE 7 preparation of Compound C-1 (quinidine salt)
Adding compound B (5 g), ethanol (15 mL) and quinidine (1 equivalent) into a 10mL three-necked flask, heating to reflux, dissolving, naturally cooling to-18 ℃, stirring for 20 hours, performing suction filtration to obtain 11g wet product, directly adding the wet product into 15mL ethanol, heating to 80 ℃ for dissolution, naturally cooling to 10+/-5 ℃, performing suction filtration to obtain 6.5g wet product of compound C, and drying to obtain 6.0g of white solid. Yield: 60%, purity: 96% de% 98%.
EXAMPLE 8 preparation of Compound D
In a 50mL three-necked flask, 14g of the above-mentioned compound C-3 (cinchonidine salt) was charged, 5mL of water and 20mL of methyl tert-butyl ether were added, pH was adjusted to 1-2 with concentrated hydrochloric acid, the mixture was allowed to stand still for delamination, an organic phase was separated, and after extraction of an aqueous phase with 20mL of methyl tert-butyl ether, the organic phases were combined and concentrated under reduced pressure to give 5.12g of compound D as a white solid, yield 65.1%, purity 99%, de% 98.01% and retention time 8.725min (which was consistent with the peak-off time of the standard compound D).
Claims (19)
1. A method for purifying a compound of formula C or formula C', comprising the steps of: crystallizing a mixture of a compound shown in a formula C and a compound shown in a formula C 'in a solvent to obtain the compound shown in the formula C or the compound shown in the formula C';
wherein R is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
the solvent is esters solvent, ketones solvent and C 1-4 One or more of the alcohol solvents.
2. The method of purifying a compound of formula C or formula C' according to claim 1, wherein the method of purification satisfies one or more of the following conditions:
(1) The ester solvent is ethyl acetate;
(2) The ketone solvent is acetone;
(3) The C is 1-4 The alcohol solvent is ethanol and/or isobutanol;
(4) The crystallization mode adopts a mode of naturally cooling the hot saturated solution for crystallization;
(5) The volume-mass ratio of the solvent to the mixture of the compound shown in the formula C and the compound shown in the formula C' is 1.4-3.0ml/g;
(6) The ratio of the compound shown in the formula C to the compound shown in the formula C in the mixture of the compound shown in the formula C and the compound shown in the formula C' is 1:10-10:1;
(7) The mixture of the compound shown in the formula C and the compound shown in the formula C' is prepared by the following method: carrying out salt forming reaction of the compound B and the compound I in a solvent to obtain a mixture of the compound shown as the formula C and the compound shown as the formula C';
3. the method of purifying a compound of formula C or formula C' according to claim 2, wherein the purification method satisfies 1 or 2 conditions:
(1) The volume-mass ratio of the solvent to the mixture of the compound shown in the formula C and the compound shown in the formula C' is 1.5ml/g, 1.8ml/g or 2.0ml/g;
(2) The ratio of the compound shown in the formula C to the compound shown in the formula C in the mixture of the compound shown in the formula C and the compound shown in the formula C' is 7:1.
4. The method of purifying a compound of formula C or formula C' according to claim 2, wherein the purification method satisfies one or more of the following conditions:
(1) In the salification reaction, the de percent of the compound B is more than or equal to 70 percent;
(2) In the salifying reaction, the compound I is quinine, quinidine or cinchonidine;
(3) In the salification reaction, the molar ratio of the compound I to the compound B is 0.5:1-2:1;
(4) In the salification reaction, the solvent is an ether solventNitrile solvent, ester solvent, C 1-4 One or more of an alcohol solvent, a ketone solvent, and water;
(5) In the salification reaction, the volume-mass ratio of the solvent to the compound B is 1:1-30:1;
(6) The temperature of the reaction is 1-110 ℃;
(7) The compound B is prepared by the following method: in the presence of hydrogen and a metal catalyst, carrying out the reduction reaction of the compound A in an organic solvent as shown below to obtain the compound B;
5. the method of purifying a compound of formula C or formula C' according to claim 4, wherein the method of purifying satisfies one or more of the following conditions:
(1) In the salifying reaction, the compound I is cinchonidine;
(2) In the salification reaction, the molar ratio of the compound I to the compound B is 1.0:1;
(3) In the salification reaction, the solvent is one or more of an ester solvent, an alcohol solvent and a ketone solvent;
(4) In the salification reaction, the volume-mass ratio of the solvent to the compound B is 2:1-15:1;
(5) The reaction temperature is 25-80 ℃.
6. The method of purifying a compound of formula C or formula C' according to claim 5, wherein the method of purifying satisfies one or more of the following conditions:
(1) In the salification reaction, the ester solvent is ethyl acetate;
(2) In the salification reaction, the alcohol solvent is methanol, ethanol, n-propanol or isobutanol;
(3) The ketone solvent is acetone;
(4) In the salification reaction, the volume-mass ratio of the solvent to the compound B is 2.8:1 or 3:1.
7. The method of purifying a compound of formula C or formula C' according to any one of claims 4 to 6, wherein the purification method satisfies one or more of the following conditions:
(1) In the reduction reaction, the metal catalyst is palladium carbon, platinum carbon, ruthenium carbon, rhodium carbon or Raney nickel;
(2) In the reduction reaction, the mass ratio of the metal catalyst to the compound is 1:15-1:5;
(3) In the reduction reaction, the organic solvent is one or more of alcohol solvents, ketone solvents, chlorinated hydrocarbon solvents, ether solvents, nitrile solvents, ester solvents and water;
(4) The temperature of the reduction reaction is-50 ℃ to 50 ℃.
8. The method of purifying a compound of formula C or formula C' according to claim 7, wherein the method of purifying satisfies one or more of the following conditions:
(1) In the reduction reaction, the metal catalyst is palladium carbon;
(2) In the reduction reaction, the mass ratio of the metal catalyst to the compound is 1:10;
(3) In the reduction reaction, the organic solvent is an alcohol solvent or an ester solvent;
(4) The temperature of the reduction reaction is-10 ℃ to 20 ℃.
9. The method for purifying a compound of formula C or formula C' according to claim 7, wherein the organic solvent is methanol or ethyl acetate.
10. A process for the preparation of a buvaracetam intermediate, characterized in that it comprises the steps of: in a solvent, carrying out free reaction on the compound C and acid to obtain a compound D;
r is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy.
11. The process for the preparation of a buvaracetam intermediate according to claim 10, characterized in that said process for the preparation of a buvaracetam intermediate fulfils one or more of the following conditions:
(1) In the free reaction, the solvent is a water-ether solvent;
(2) In the free reaction, the acid is inorganic acid;
(3) In the free reaction, the molar concentration of hydrogen ions in the acid is 0.01-0.1M;
12. The process for the preparation of a buvaracetam intermediate according to claim 11, characterized in that said process for the preparation of a buvaracetam intermediate fulfils one or more of the following conditions:
(1) In the free reaction, the solvent is water-methyl tertiary butyl ether;
(2) The volume ratio of water to the ether solvent in the water-ether solvent is 1:8-1:1;
(3) In the free reaction, the acid is hydrochloric acid;
(4) The compound C is prepared according to the purification method of the compound shown as a formula C or a formula C' as shown in any one of claims 1-9.
13. The process for preparing a buvaracetam intermediate according to claim 12, wherein in said free reaction, the volume ratio of water to ether solvent in said water-ether solvent is 1:4.
14. A process for preparing a mixture of a compound of formula C and a compound of formula C comprising the steps of: carrying out salt forming reaction of the compound B and the compound I in a solvent to obtain a mixture of the compound shown as a formula C and the compound shown as a formula C';
r is H, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy;
the conditions and operations of the salification reaction are as defined in any one of claims 2 to 6.
15. A process for the preparation of brivaracetam comprising the steps of:
step 1: in a solvent, carrying out free reaction on the compound C and acid to obtain a compound D;
step 2: carrying out condensation reaction on the compound D obtained in the step 1 to obtain the buvaracetam;
in step 1, the compound C is obtained according to the purification method of the compound shown as a formula C or a formula C' according to any one of claims 1 to 9; the conditions and operation of the free reaction are as defined in any one of claims 10 to 13.
19. A mixture of a compound of formula C and a compound of formula C' as claimed in claim 18,
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