CN106748748B - Preparation method and intermediate of brivaracetam - Google Patents
Preparation method and intermediate of brivaracetam Download PDFInfo
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- CN106748748B CN106748748B CN201510756817.6A CN201510756817A CN106748748B CN 106748748 B CN106748748 B CN 106748748B CN 201510756817 A CN201510756817 A CN 201510756817A CN 106748748 B CN106748748 B CN 106748748B
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Abstract
The invention relates to a preparation method of brivaracetam and an intermediate thereof, in particular to brivaracetam prepared by using (R) -4-n-propyl-dihydrofuran-2-ketone with high optical purity as a raw material. Compared with the prior art, the synthetic method has lower requirements on production equipment, can prepare a crude product of the brivaracetam with higher chemical purity, higher optical purity and higher yield, and can greatly reduce the cost of large-scale industrial production of the brivaracetam.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of brivaracetam and an intermediate thereof.
Background
The chemical name of the Buvalacetam, namely (2S) -2- [ (4R) -2-oxo-4-n-propyl-1-pyrrolidinyl ] butanamide, is an antiepileptic drug developed by a superior-time pharmaceutical company (UCB), and is used for adjuvant therapy of partial epileptic seizure of epileptic patients over 16 years old. Based on the results of the bravaracetam phase III study, UCB has filed a new drug marketing application to the U.S. Food and Drug Administration (FDA) and a marketing approval application to the european drug administration (EMA), respectively, on 25/1/2015. According to the clinical research data of the original research company, the anticonvulsant capability of the brivaracetam is 10 times stronger than that of the first brand drug levetiracetam in the field of epilepsy drugs, and the affinity of the brivaracetam to the action target of the brivaracetam is much higher than that of the levetiracetam 2A. The brivaracetam is expected to become a new leader in the epileptic drug market as a substitute product after the levetiracetam patent is expired.
Compound patent CN1882535A of the original research company discloses a method for preparing bravaracetam, the synthetic route is as follows:
the second step reaction of the synthetic route needs to use catalytic hydrogenation, and the reaction has high requirements on synthetic equipment and is not suitable for large-scale industrial production of enterprises; and the two non-enantiomers generated after the reaction are subjected to chiral resolution by using a chiral chromatographic column, so that the production period is long, the equipment requirement is high, and the production cost is too high.
Kenda et al reported a synthetic route for the preparation of brivaracetam (Journal of Medicinal Chemistry,2004,Vol.47,No3See the preparation methods of page545 compounds 81a and page546 compounds 83 beta and 83 a), the preparation method can prepare the bravaracetam without using catalytic hydrogenation, solves the problem of high requirements on equipment in step 2 in the patent CN1882535A route, and has the following synthesis route:
in the route, a racemate of a compound (a) is obtained after the reaction in the step 1, and the subsequent reaction is carried out on the racemate to obtain the brivaracetam, however, the applicant finds that a crude product of the brivaracetam prepared by the method is a brownish black viscous liquid before passing through a silica gel column, so that the operation difficulty during recrystallization is high, the crystallization is difficult, and the crystallization time is long; and high performance liquid chromatography detection shows that the chemical purity of the brivaracetam is between 83% and 88%, and the content of related substances is high.
Disclosure of Invention
The applicant finds that the synthetic method in the prior art has the defects of high requirements on production equipment, long production period, high cost and the like, and also has the problems of difficult crystallization, low purity, high content of related substances and the like of the prepared crude product of the brivaracetam due to poor properties. In order to solve the above problems, the present invention provides a preparation method of brivaracetam, comprising the steps of:
the invention provides a method for preparing brivaracetam, which comprises the following steps:
(1) (R) -3-halomethyl-n-hexanoic acid is prepared by ring-opening reaction of (R) -4-n-propyl-dihydrofuran-2-one with a halogenating agent selected from the group consisting of trimethyliodosilane, trimethylchlorosilane/sodium iodide, trimethylchlorosilane/potassium iodide, hydrobromoic acid or hydrochloric acid,
(2) preparing (R) -3-halomethyl-n-hexanoyl chloride from (R) -3-halomethyl-n-hexanoic acid,
(3) the preparation of brivaracetam is carried out by reacting (R) -3-halomethyl-n-hexanoyl chloride with (S) -2 aminobutanamide or a salt thereof in the presence of a suitable strong base.
The starting material (R) -4-n-propyl-dihydrofuran-2-one according to the invention is essentially free of the enantiomer (S) -4-n-propyl-dihydrofuran-2-one. Typically, the (S) -4-n-propyl-dihydrofuran-2-one content of the starting (R) -4-n-propyl-dihydrofuran-2-one is less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5.5%, less than 5%, less than 4.5%, less than 4%, less than 3.5%, less than 3%, less than 2.5%, less than 2%, less than 1.5%, less than 1%, less than 0.5%, less than 0.3%, less than 0.1%.
The gas chromatography purity of the raw material (R) -4-n-propyl-dihydrofuran-2-one of the present invention is not particularly limited, and may be 70%, 80% or more, 85% or more, 88% or more, 90% or more, 92% or more, 94% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more, or 99.5% or more. As known by the technical personnel in the field, impurities in the raw materials can be brought into the subsequent reaction step to increase the impurity content of the final product, so that the higher the gas chromatographic purity of the raw material (R) -4-n-propyl-dihydrofuran-2-ketone is, the more beneficial the improvement of the chemical purity of the Buvalsartan is; generally, the purity of the gas chromatography of the bulk drug (R) -4-n-propyl-dihydrofuran-2-one is improved, i.e. the content of related substances is reduced, and the purification methods commonly used in the field, such as distillation, rectification, column chromatography, liquid phase preparation and the like, can be used.
The preparation method of the (R) -4-n-propyl-dihydrofuran-2-one bulk drug with high optical purity can be a preparation method of chiral pure compounds commonly used in the field, such as asymmetric synthesis; for example, the starting material of the present invention can be prepared according to the method described in Koch et al, J.O.C, vol.58,10(1993),2725-2737, for preparing the compound 33a (R) - β -propyl- γ -butyrolactone.
The reaction solvent of step (1) of the present invention may be one or more selected from the group consisting of dichloromethane, acetonitrile, chloroform, toluene, xylene, benzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 1, 2-dichloroethane, cyclohexane, cyclopentane, isooctane, and 1, 4-dioxane, and preferably dichloromethane, acetonitrile, or acetone is used as the solvent, the reaction is more likely to occur, the reaction time is shorter, and more preferably dichloromethane is used as the reaction solvent.
The reaction temperature of the step (1) of the invention is in the range of-10 ℃ to the boiling point temperature of the solvent, but the reaction temperature is not more than 70 ℃, such as-10 ℃ to 70 ℃,10 ℃ to 60 ℃,10 ℃ to 50 ℃,10 ℃ to 40 ℃, 5 ℃ to 70 ℃, 5 ℃ to 60 ℃, 5 ℃ to 50 ℃, 5 ℃ to 40 ℃, 5 ℃ to 30 ℃, 0 ℃ to 70 ℃, 0 ℃ to 60 ℃, 0 ℃ to 50 ℃, 0 ℃ to 40 ℃, 0 ℃ to 30 ℃, 5 ℃ to 70 ℃, 5 ℃ to 60 ℃, 5 ℃ to 50 ℃, 5 ℃ to 40 ℃,10 ℃ to 70 ℃,10 ℃ to 60 ℃,10 ℃ to 50 ℃,10 ℃ to 40 ℃, 15 ℃ to 70 ℃, and the like, 15-60 ℃, 15-50 ℃, 15-40 ℃, 20-70 ℃, 20-60 ℃, 20-50 ℃, 20-40 ℃, 20-30 ℃, 25 ℃, preferably-5-40 ℃, more preferably 0-30 ℃, most preferably 20-30 ℃.
The reactant halogenating agent in step (1) of the present invention is selected from the group consisting of iodotrimethylsilane, chlorotrimethylsilane/sodium iodide, chlorotrimethylsilane/potassium iodide, hydrobromic acid or hydrochloric acid, preferably iodotrimethylsilane, chlorotrimethylsilane/sodium iodide, chlorotrimethylsilane/potassium iodide, most preferably iodotrimethylsilane; the amount of the above-mentioned halogenating agent is not particularly limited. Since the above-mentioned reactants have good solubility, the halogenating agent which does not participate in the reaction after the reaction is completed can be easily removed, and usually, the amount of the iodotrimethylsilane, chlorotrimethylsilane, sodium iodide or potassium iodide, hydrobromic acid or hydrochloric acid is 1eq or more based on the amount of the reaction raw material (R) -4-n-propyl-dihydrofuran-2-one.
The (R) -3-halomethyl-n-hexanoic acid formed in step (1) of the present invention is a compound of formula (I) as defined in claim 1 of the present invention or a mixture comprising compounds of formula (I) and formula (II) as defined in claim 2 of the present invention.
The reaction temperature of the step (2) of the present invention is in the range of 10 ℃ to the boiling point temperature of the solvent, but the reaction temperature is not preferably more than 80 ℃, for example, 10 ℃ to 80 ℃,10 ℃ to 70 ℃,10 ℃ to 60 ℃,10 ℃ to 50 ℃,10 ℃ to 40 ℃, 15 ℃ to 80 ℃, 15 ℃ to 70 ℃, 15 ℃ to 60 ℃, 15 ℃ to 50 ℃, 15 ℃ to 40 ℃, 25 ℃ to 80 ℃, 25 ℃ to 70 ℃, 25 ℃ to 60 ℃, 25 ℃ to 50 ℃, 25 ℃ to 40 ℃, 25 ℃ to 30 ℃, preferably 15 ℃ to 40 ℃.
The chlorinating agent of step (2) of the present invention may be thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or methanesulfonyl chloride, preferably thionyl chloride or oxalyl chloride, most preferably thionyl chloride.
The chlorinating agent of step (2) of the present invention may be used as a reaction solvent at the same time, and the amount of the chlorinating agent is not particularly limited, so as to be able to convert the carboxyl group of the (R) -3-halomethyl-n-hexanoic acid of the present invention into an acid chloride, and to facilitate the post-treatment of the remaining chlorinating agent. The reaction solvent in step (2) of the present invention is selected from one or more of toluene, xylene, benzene, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1, 2-dichloroethane, diethyl ether, cyclohexane, cyclopentane, isooctane, isopentane, 1, 4-dioxane, and thionyl chloride, preferably toluene, xylene, and thionyl chloride, and most preferably toluene and thionyl chloride.
In the step (3), the reaction solvent is selected from one or more of toluene, xylene, benzene, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1, 2-dichloroethane, diethyl ether, isopropyl ether, cyclohexane, cyclopentane, isooctane, isopentane, 1, 4-dioxane and 1, 4-dioxane, preferably one of dichloromethane, chloroform, toluene or benzene, and most preferably dichloromethane; the strong base used in the step (3) is an organic strong base or an inorganic strong base, the organic strong base is sodium alkoxide or potassium alkoxide formed by alcohol of C1-C5, preferably sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, potassium n-propoxide, potassium isopropoxide, sodium n-butoxide, sodium i-butoxide, potassium n-butoxide, and potassium i-butoxide, and the inorganic strong base is a metal hydroxide, preferably sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide or barium hydroxide, and more preferably sodium hydroxide or potassium hydroxide.
The reaction temperature of the step (3) of the invention can be in the range of-20 ℃ to 20 ℃, such as-20 ℃ to 18 ℃, -20 ℃ to 16 ℃, -20 ℃ to 15 ℃, -20 ℃ to 14 ℃, -20 ℃ to 12 ℃, -20 ℃ to 10 ℃, -18 ℃ to 20 ℃, -18 ℃ to 18 ℃, -18 ℃ to 16 ℃, -18 ℃ to 15 ℃, -18 ℃ to 14 ℃, -18 ℃ to 12 ℃, -18 ℃ to 10 ℃, -16 ℃ to 20 ℃, -16 ℃ to 18 ℃, -16 ℃ to 16 ℃, -16 ℃ to 15 ℃, -16 ℃ to 14 ℃, -16 ℃ to 12 ℃, -16 ℃ to 10 ℃, -14 ℃ to 20 ℃, -, 14-18 ℃, 14-16 ℃, 14-14 ℃, 14-12 ℃, 14-10 ℃, 12-20 ℃, 12-18 ℃, 12-16 ℃, 12-14 ℃, 12-12 ℃, 12-10 ℃, 10-20 ℃, 10-18 ℃, 10-16 ℃, 10-14 ℃, 10-10 ℃, 9-20 ℃, 9-18 ℃, 9-16 ℃, 9-14 ℃, 9-12 ℃, 9-14 ℃, 9-12 ℃, and, -8 ℃ -8 ℃, 7 ℃ -7 ℃, 6 ℃ -6 ℃, 5 ℃ -5 ℃,4 ℃ -4 ℃, 3 ℃ -3 ℃,2 ℃ -2 ℃, 0 ℃, preferably-10 ℃ -10 ℃.
The drying agent in step (3) of the present invention may be an alkaline drying agent or a neutral drying agent, and is selected from one or more of calcium sulfate, barium oxide, calcium chloride, magnesium perchlorate, aluminum oxide, calcium oxide, a molecular sieve, sodium sulfate, potassium carbonate and magnesium sulfate, preferably the drying agent is molecular sieve, sodium sulfate, magnesium perchlorate and calcium sulfate, and more preferably the drying agent is sodium sulfate, magnesium sulfate or a molecular sieve. And (3) adding an optional phase transfer catalyst, wherein the phase transfer catalyst is selected from one of tetrabutylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride, and is preferably tetrabutylammonium bromide and benzyltriethylammonium chloride.
The amount of the reaction reagent S-2-aminobutanamide or a salt thereof in step (3) of the present invention is 0.8eq or more, preferably 0.8 to 2eq, more preferably 1 to 2eq, most preferably 1 to 1.5eq, based on the starting material (R) -4-n-propyl-dihydrofuran-2-one; the dosage of the strong base in the step (3) is more than 1.5eq of the raw material (R) -4-n-propyl-dihydrofuran-2-one, preferably 2-10eq, 2-8eq, more preferably 3-8eq, 3-6eq, most preferably 4-5 eq; the amount of the drying agent in the step (3) is not particularly limited, and is generally the amount commonly used in the field of drying agents so as to ensure the normal operation of the reaction.
The invention also provides a compound of formula (I).
Wherein X is selected from I, Br or Cl, and is preferably I.
The invention also provides an intermediate mixture comprising compounds of formula (I) and formula (II),
wherein X is selected from I, Br or Cl, preferably I, and the compound of formula (I) accounts for more than 90%, preferably more than 95%, more preferably more than 98% of the mixture by weight.
In order to improve the properties of the prepared bravaracetam and reduce the content of related substances, the applicant of the invention intensively studied the synthetic route reported by Kenda et al and found that other impurities are most easily generated by the reaction of the step 1 format reagent and the furanone synthetic compound (a) and the reaction of the step 4 compounds (c) and (d). In view of this, the applicant firstly tries to obtain a crude product of the compound (a), then purifies the crude product and then uses the crude product in the next reaction step so as to reduce the content of related substances in the final product, but after experiments, the reduction amount of the related substances is almost equivalent to the amount of impurities removed by the purified compound (a), even if the purity of the purified compound (a) is more than 99 percent by gas chromatography, the finally prepared product of the.
Considering that the ring-closing reaction in the step 4 is a heterogeneous reaction system, and the types of the phase transfer catalyst and the reaction solvent may have an influence on the generation of substances related to the reaction, the applicant researches the types of the phase transfer catalyst, examines four phase transfer catalysts of benzyltrimethylammonium chloride, tetrabutylammonium tribromide, benzyltriphenylphosphonium chloride and tetradecyltrimethylammonium chloride, and finds that the optical purity of the product obtained by using tetrabutylammonium bromide and benzyltriethylammonium chloride is higher, and the chemical purity is still between 84% and 90%; in addition, several reaction solvents such as dichloromethane, toluene, tetrahydrofuran, 1, 2-dichloroethane, diethyl ether and cyclohexane are considered, and the chemical purity of the prepared bravaracetam is still not obviously improved.
After extensive investigation, the applicant of the present invention discovered that, by chance, when the isomer (R) -4-n-propylfuran-2-one with high optical purity is used as a reaction raw material instead of the racemic mixture in the prior art, the chemical purity of the prepared bravaracetam can be greatly improved: when the gas chromatography purity of (R) -4-n-propyl furan-2-ketone is more than 85 percent and the optical purity is more than 97 percent, the chemical purity of the prepared crude product of the Buvalsartan can reach more than 97 percent, and the optical purity can reach more than 98.5 percent.
The applicant of the present invention found that in the case of substantially the same gas chromatographic purity of the raw materials (i.e. the impurity species and the content thereof in the raw materials of either the single isomer or the racemic mixture are substantially the same), for example, the raw material gas chromatographic purity is only 70%, and the chemical purity of the synthetic route of the present invention for preparing the bravaracetam is higher than that of the prior art. The applicant speculates that one of the possible reasons for this result is that (R) -4-n-propylfuran-2-one and (S) -4-n-propylfuran-2-one, or the intermediates (R) -3-halomethyl-n-hexanoic acid and (S) -3-halomethyl-n-hexanoic acid produced from this starting material, or the intermediates (R) -3-halomethyl-n-hexanoic acid chloride and (S) -3-halomethyl-n-hexanoic acid chloride, have different reactivity and reaction tendencies in the preparation route of brivaracetam, possibly resulting in the formation of more of the relevant substances in the complex three-step organic synthesis reaction for the preparation of brivaracetam starting from a racemic mixture than from a single isomer.
In addition, the applicant also found that when (R) -4-n-propylfuran-2-one and racemate 4-n-propylfuran-2-one with basically the same gas chromatographic purity are respectively used as reaction raw materials (for example, the gas chromatographic purity is both 90%), and the impurity types and contents of the two raw materials are basically the same, the crude product of the Buvalsartan obtained according to the route of the invention is a white solid, while the crude product of the Buvalsartan obtained by the prior art method is a brownish black or brownish yellow sticky solid, which is extremely unfavorable for the recrystallization operation. The applicant initially guessed that the brown-black or brown-yellow color in crude product of bravaracetam is due to the (2S, 4S), (2R, 4S) or (2R, 4R) configuration of the optical isomer of bravaracetam, but the applicant isolated the three isomers and found all of them as white solids, which also increased the possibility that the applicant guessed that starting from a racemic mixture more impurities were produced in the complex 3-step organic synthesis reaction for preparing bravaracetam than starting from a single isomer, due to the different reactivity and reaction tendencies of the starting materials or intermediates in the preparation process, but the applicant failed to ascertain the exact reason for this result due to the complexity of the organic synthesis reaction.
The applicant finds in further experimental research that in the step (3), only anhydrous sodium sulfate can be added as a drying agent, the same technical effect as that in the prior art that two drying agents must be used simultaneously can be achieved without adding a molecular sieve, and the yield, the chemical purity, the optical purity and the time required by the reaction of the crude product of the brivaracetam after the reaction is finished are not affected; in particular, step (3) of the present invention does not add a phase transfer catalyst, which has no effect on the reaction rate and the reaction completion time at all, and surprisingly, the chemical purity of the bravaracetam prepared according to the synthetic route of the present invention is rather improved without adding a phase transfer catalyst.
To illustrate the advantages of the present invention over the prior art, the applicant carried out the following comparative experiments:
comparative experiment 1 (according toJournal of Medicinal Chemistry,2004,Vol.47,No3，Process for the preparation of page546 compounds 83 beta and 83 alpha
4-n-propyl-dihydrofuran-2-one (103.04 g, 0.805 mol) (prepared according to the preparation method of compound 81a of document page 545) was charged into a reaction vessel under argon, dissolved in dichloromethane (820 ml), cooled to 0 ℃ and TMSI (51 ml) was added to the system. The reaction was stirred for 2 hours while warming to room temperature. The reaction was quenched by the addition of 1N dilute hydrochloric acid (870 ml) and Na2S2O3 (10% w/w, 300 ml). Extracting with DCM/water, drying organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain crude 3-iodomethyl n-hexanoic acid. The crude product was used directly in the next reaction. Under the argon condition, crude 3-iodomethyl n-hexanoic acid (148.48 g) is dissolved in benzene, thionyl chloride (138 g, 1.16 mol) is added, the mixture is reacted for 24 hours at room temperature, the solvent is removed by concentration under reduced pressure, and then the mixture is distilled (0.32 mmHg, Teb =85-90 ℃) to obtain 3-iodomethyl n-hexanoyl chloride (120 g). 3-iodomethyl n-hexanoyl chloride (119.5 g, 0.43 mol) was dissolved in dichloromethane (640 mL) at 0 degrees under argon, added dropwise to a suspension of molecular sieve (72g), powdered potassium hydroxide (72.8g), anhydrous sodium sulfate (72.8g), tetrabutylammonium bromide (7.0g, 0.02mol) and S-2-aminobutanamide ([ R ] 25D) +19.35 °) (66.6g, 0.65mol) in dichloromethane (1500 mL), the solution was stirred at-5 degrees for 5 hours, powdered potassium hydroxide (15.6g) was added, and stirred at-5 degrees overnight. Adding diatomite for filtration, and concentrating the filtrate under reduced pressure to obtain crude product of the brivaracetam.
10g of 4-n-propyl-dihydrofuran-2-one (purity of gas chromatography: 90.5%, optical purity: 45.8%) is dissolved in dichloromethane, the temperature is reduced to about 0 ℃, 15.6g of iodotrimethylsilane is added dropwise, the system is heated to room temperature to react after the dropwise addition, and TLC monitors whether the reaction is complete. After the reaction is completed, dilute hydrochloric acid is used for quenching reaction, DCM/water extraction is carried out, organic phase anhydrous sodium sulfate is dried and filtered, and the filtrate is decompressed and concentrated to be dry to obtain 3-iodomethyl n-hexanoic acid which is directly used for the reaction in the next step.
3-iodomethyl-n-hexanoic acid was dissolved in 20ml of toluene and 18.6g of thionyl chloride was added at room temperature. The reaction was run at room temperature and TLC monitored for completion. After the reaction is completed, the mixture is decompressed and concentrated to be dry at the temperature of 60 ℃ to obtain the 3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
7.88g of S-2-aminobutanamide ([ R ] 25D) +19.35 ℃ and 22.1g of anhydrous sodium sulfate were dispersed in 240ml of methylene chloride, and then cooled to 0 ℃ or lower, and 4.4g of powdered potassium hydroxide was added thereto to conduct a reaction for about 30 minutes. And adding 13.1g of powdered potassium hydroxide again, keeping the temperature below 0 ℃, dropwise adding a 3-iodomethyl n-hexanoyl chloride solution dissolved in 21ml of dichloromethane, and reacting at-10 ℃ for about 5 hours. Adjusting pH to 5-6 with dilute hydrochloric acid, filtering, extracting the filtrate with DCM/water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude product 14.69g of brivaracetam.
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 91%, optical purity 99%) is dissolved in dichloromethane, the temperature is reduced to about 0 ℃, 15.6g of iodotrimethylsilane is added dropwise, the system is heated to room temperature to react after the dropwise addition, and TLC monitors whether the reaction is complete. After the reaction is completed, dilute hydrochloric acid is used for quenching reaction, DCM/water extraction is carried out, organic phase anhydrous sodium sulfate is dried and filtered, and the filtrate is decompressed and concentrated to be dry to obtain 3-iodomethyl n-hexanoic acid which is directly used for the reaction in the next step.
3-iodomethyl-n-hexanoic acid was dissolved in 20ml of toluene and 18.6g of thionyl chloride was added at room temperature. The reaction was run at room temperature and TLC monitored for completion. After the reaction is completed, the mixture is decompressed and concentrated to be dry at the temperature of 60 ℃ to obtain the 3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
7.88g of S-2-aminobutanamide ([ R ] 25D) +19.35 ℃ and 22.1g of anhydrous sodium sulfate were dispersed in 240ml of methylene chloride, and then cooled to 0 ℃ or lower, and 4.4g of powdered potassium hydroxide was added thereto to conduct a reaction for about 30 minutes. And adding 13.1g of powdered potassium hydroxide again, keeping the temperature below 0 ℃, dropwise adding a 3-iodomethyl n-hexanoyl chloride solution dissolved in 21ml of dichloromethane, and reacting at-10 ℃ for about 5 hours. Adjusting pH to 5-6 with dilute hydrochloric acid, filtering, extracting the filtrate with DCM/water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain crude product of Buvalsartan 15.36 g.
10g of 4-n-propyl-dihydrofuran-2-one (purity of gas chromatography: 99.5%, optical purity: 48.9%) is dissolved in dichloromethane, the temperature is reduced to about 0 ℃, 15.6g of iodotrimethylsilane is added dropwise, the system is heated to room temperature for reaction after the dropwise addition, and TLC monitors whether the reaction is complete. After the reaction is completed, the diluted hydrochloric acid is quenched for reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain the 3-iodomethyl n-hexanoic acid (the optical purity is detected to be 48.1 percent) which is directly used for the next step of reaction.
The following procedure was the same as in comparative experiment 2 and was finally concentrated to give 15.9g of crude brivaracetam.
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 99%, optical purity 98.2%) is dissolved in dichloromethane, the temperature is reduced to about 0 ℃, 15.6g of iodotrimethylsilane is added dropwise, the system is heated to room temperature to react after the dropwise addition, and TLC monitors whether the reaction is complete. After the reaction is completed, the diluted hydrochloric acid is quenched for reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain the 3-iodomethyl n-hexanoic acid (the optical purity is detected to be 97.8 percent) which is directly used for the next step of reaction.
The following procedure was the same as comparative experiment 3, and finally concentrated to obtain 14.37g of crude product of brivaracetam.
The chemical purity of the crude product of brivaracetam prepared in comparative experiments 1-5 was determined as follows:
weighing a proper amount of the test sample, dissolving with a mobile phase, and preparing into a test sample solution of 1 mg/ml. Precisely measuring 20ul of the sample solution, injecting into a liquid chromatograph, recording the chromatogram, and calculating the content of each unknown impurity according to an area normalization method.
The instrument comprises the following steps: shimadzu LC-2010AHT high performance liquid chromatograph;
a workstation: LC-olutio;
a chromatographic column: symmetry Shield RP18, 3.5 μm, 150 × 3.0 mm;
mobile phase: acetonitrile: PH6.0 phosphate buffer (0.01M dipotassium hydrogenphosphate, PH6.0 adjusted with phosphoric acid) =14: 86;
detection wavelength: 210nm;
flow rate: 0.75ml/min;
the calculation formula is as follows:
in the formula, Ai is the sum of peak areas of (S, R) configuration, (S, S) configuration, (R, S) configuration and (R, R) configuration;
is the sum of the peak areas of all substances.
The optical purity of the crude product of brivaracetam prepared in comparative experiments 1-5 was determined as follows:
an appropriate amount of the sample was weighed, dissolved in a diluent (ethanol: methanol =50: 50) and prepared into a sample solution of 2 mg/ml. Precisely measuring 20ul of the sample solution, injecting into a liquid chromatograph, recording the chromatogram, and calculating the content of each unknown impurity according to the following formula.
The instrument comprises the following steps: shimadzu LC-20AT HPLC;
a workstation: LC-olutio;
a chromatographic column: chiralpak AD-H, 5 μm, 250 × 4.6 mm;
mobile phase: n-heptane: n-hexane =10: 90;
detection wavelength: 220nm;
flow rate: 0.8ml/min;
the calculation formula is as follows:
optical purity% = QUOTE
In the formula, Ai is the peak area of the configuration of the active ingredients (S, R) of the main medicine;
Σ a is the sum of peak areas of the (S, R) configuration, (S, S) configuration, (R, S) configuration, and (R, R) configuration.
The yield was calculated as: the amount of (S, R) configuration in the crude product of bwacetam/theoretical amount of (S, R) configuration can be generated.
Gas chromatography purity analysis method of raw material 4-n-propyl-dihydrofuran-2-ketone:
the instrument comprises the following steps: a gas chromatograph;
a chromatographic column: DB-624 (30 m 0.32mm, 1.8 μm);
carrier gas: n2
Sample inlet temperature: 150 ℃;
detector temperature: 240 ℃;
sample introduction amount: 1 mul; gas flow rate: 1.5ml/min
The split ratio is as follows: 20: 1; tail purge flow: 30ml/min
Air flow rate: 300 ml/min; hydrogen flow rate: 30 ml/min;
diluent agent: methanol
Test solution: taking a proper amount of the raw material 4-n-propyl-dihydrofuran-2-ketone, precisely weighing, dissolving and diluting the raw material with methanol to prepare a solution with the concentration of about 2.5mg/ml per 1ml, and shaking up;
precisely measuring 1ul of the test solution, injecting into a gas chromatograph, recording chromatogram, and calculating according to an area normalization method.
The chromatographic conditions used for the determination were:
the calculation formula is as follows:
the detection results of properties, chemical purity, optical purity and yield of the crude product of the brivaracetam prepared by the comparative experiments 1-5 are shown in the following table 1:
from the comparison experiment results, the chemical purity of the crude product of the brivaracetam prepared by the synthesis method in the prior art (comparison experiment 1) is 88.78%, and the content of related substances is high. The gas chromatographic purity of the raw material 4-n-propyl-dihydrofuran-2-one of comparative experiments 2 and 3 is basically the same, the comparative experiment 3 replaces the racemic mixture of 4-n-propyl-dihydrofuran-2-one in the comparative experiment 2 with optically pure (R) -4-n-propyl-dihydrofuran-2-one, and according to the synthetic method of the invention, the property of the prepared crude product of the Buvalsartan is improved from brown yellow viscous liquid to white solid, and the chemical purity and the optical purity are respectively and greatly improved to 97.5 percent and 99.6 percent (see attached figures 3 and 4). In addition, the applicant researches the influence of other impurities in the raw materials on the chemical purity of the product, namely, the product, namely, the product, namely, the product, the.
In addition, the optical purities of the intermediate 3 iodomethyl n-hexanoic acid prepared in the comparative experiments 4 and 5 are respectively 48.1% and 97.8%, the reduction range of the optical purities is basically almost the same as that of the optical purities (respectively 48.9% and 98.2%) of the raw material 4-n-propyl-dihydrofuran-2-one, but after the two-step reaction of the step (2) and the step (3), the optical purity of the product, namely, the product, of the comparative experiment 4, is reduced to 45.5 percent (see table 1), while the optical purity of the product, namely, the product, the optical purity, the product, the optical purity, the product, the optical purity, is surprisingly higher than that the optical purity of the raw material or the optical purity is higher than that the raw material of the raw material or the optical purity, the optical purity is higher than the product, the optical purity of the product, the optical purity of the product, the optical purity is 99, the applicants therefore speculate that the synthetic route using the 3 iodomethyl-n-hexanoic acid racemate mixture as an intermediate differs from the reaction processes or the reactivity of the reactants in steps (2) and (3) in the synthetic route of the present invention. The synthetic route of the invention which takes (R) -4-n-propyl-dihydrofuran-2-ketone with high optical purity as raw material unexpectedly improves the optical purity of the brivaracetam.
Drawings
FIG. 1 is a chemical purity detection map of a crude product of Buvalsartan prepared by the synthesis method of comparative experiment 1.
FIG. 2 is a chemical purity detection map of a crude product of Buvalsartan prepared by the synthesis method of comparative experiment 2.
FIG. 3 is a chemical purity detection map of a crude product of Buvalsartan prepared by the synthesis method of comparative experiment 3.
FIG. 4 is an optical purity detection spectrum of a crude product of Buvalsartan prepared by the synthesis method of comparative experiment 3.
FIG. 5 is a chart showing the chemical purity of the intermediate 3-iodomethyl-n-hexanoic acid prepared in comparative experiment 1.
FIG. 6 is an optical purity measurement chart of intermediate (R) -3-iodomethyl-n-hexanoic acid prepared in comparative experiment 3.
FIG. 7 is a gas chromatography purity test chart of the starting material (R) -4-n-propyl-dihydrofuran-2-one of comparative experiment 3.
FIG. 8 is a 1H-NMR spectrum of intermediate (R) -3-iodomethyl-n-hexanoic acid.
The invention will be further illustrated with reference to the following specific examples. However, these examples are only illustrative and are not intended to limit the scope of the present invention.
Example 1
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 85%, optical purity 95%) was dissolved in acetonitrile, the temperature was reduced to about-10 ℃, 8.4g of trimethylchlorosilane was added dropwise, 11.6g of sodium iodide was added, the addition was completed, and the reaction was monitored by TLC. After the reaction is completed, the diluted hydrochloric acid is quenched for reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain (R) -3-iodomethyl n-hexanoic acid (the optical purity is 94.6 percent) which is directly used for the next step of reaction. DeltaH(300 MHz, CDCl3): 0.9-0.95(3H, m), 1.29-1.36 (4H, m), 1.71-1.74 (1H, m), 2.37-2.49 (2H, m),3.27-3.41 (2H, m), 11.07(1H,s)。
(R) -3-iodomethyl-n-hexanoic acid was dissolved in 20ml of dichloromethane and 36.8g of phosphorus pentachloride were added at 10 ℃. The reaction was monitored by TLC at 10 ℃. After the reaction is completed, decompressing and concentrating to be dry to obtain (R) -3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
(R) -3-iodomethyl-n-hexanoyl chloride was dissolved in 64ml of toluene, added dropwise to a suspension of 7g of molecular sieve, 4.33g of calcium hydroxide, 17.1g of calcium chloride, 0.7g of tetrabutylammonium bromide and 16.1g of S-2-aminobutanamide hydrochloride (1.5eq) (optical purity 99.8%) in 150ml of toluene, the solution was stirred at-20 ℃ for 5 hours, 13g of calcium hydroxide (calcium hydroxide was added in total by 3 eq) was added, and stirred at-20 ℃ overnight. After the reaction is finished, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, extracting the filtrate by using DCM/water, drying the organic phase anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 12.8g of brivaracetam. The characteristics are as follows: white solid, chemical purity 97.14%, optical purity 95.51%, yield 89%
Example 2
10g of (R) -4-n-propyl-dihydrofuran-2-one (GC purity 90%, optical purity 98%) are dissolved in cyclohexane, the temperature is raised to 70 ℃, 7g of hydrobromic acid are added dropwise, the reaction is monitored by TLC after the addition is complete. After the reaction is completed, diluted hydrochloric acid is used for quenching reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain (R) -3-bromomethyl n-hexanoic acid (the optical purity is 97.3 percent) which is directly used for the next step of reaction.
(R) -3-bromomethyl-n-hexanoic acid was dissolved in 20ml of cyclohexane and 19.4g of oxalyl chloride were added at the boiling point of the solvent. The reaction was run at the boiling point of the solvent, monitored by TLC. After the reaction is completed, decompressing and concentrating to be dry to obtain (R) -3-bromomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
(R) -3-bromomethylhexanoyl chloride was dissolved in 64ml of tetrahydrofuran, added dropwise to a suspension of 7g of molecular sieve, 4.69g of sodium hydroxide, 15.6g of alumina, 3.3g of dodecyltrimethylammonium chloride and 15.75g of S-2-aminobutanamide tartrate (0.8eq) (optical purity 99.5%) in 150ml of tetrahydrofuran, the solution was stirred at 20 ℃ for 5 hours, 14g of sodium hydroxide (total addition of 6eq of sodium hydroxide) was added, and stirred at 20 ℃ overnight. After the reaction is finished, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, extracting the filtrate by using DCM/water, drying the organic phase anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 13.4g of brivaracetam. The characteristics are as follows: white solid, chemical purity 97.08%, optical purity 98.58%, yield 88%
Example 3
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 80%, optical purity 94%) are dissolved in acetone, the temperature is adjusted to the boiling point of the solvent, 8.4g of trimethylchlorosilane are added dropwise, 23.2g of sodium iodide are added, the addition is completed, and the reaction is monitored by TLC. After the reaction is completed, diluted hydrochloric acid is used for quenching reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain (R) -3-iodomethyl n-hexanoic acid (with optical purity of 93.41%) which is directly used for the next step of reaction.
(R) -3-iodomethyl-n-hexanoic acid was dissolved in 20ml of dichloromethane and 62.4g of thionyl chloride was added. The reaction was monitored by TLC at 80 ℃. After the reaction is completed, decompressing and concentrating to be dry to obtain (R) -3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
(R) -3-iodomethyl-n-hexanoyl chloride was dissolved in 64ml of toluene, added dropwise to a suspension of 7g of molecular sieve, 7.97g of sodium ethoxide, 17.1g of calcium chloride, 0.7g of tetrabutylammonium bromide and 21.48g of S-2-aminobutanamide hydrochloride (2eq) (optical purity 99.8%) in 150ml of toluene, the solution was stirred at-20 ℃ for 5 hours, 23.9g of sodium ethoxide (total addition of 6eq of sodium ethoxide) was added, and stirred at-20 ℃ overnight. After the reaction is finished, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, extracting the filtrate by using DCM/water, drying the organic phase anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 11.9g of the brivaracetam. The characteristics are as follows: white solid, chemical purity 96.12%, optical purity 95.51%, yield 88%
Example 4
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 90%, optical purity 96%) are dissolved in acetone, the temperature is reduced to about 0 ℃, 18g of iodotrimethylsilane is added dropwise, and the reaction is monitored by TLC after the addition. After the reaction is completed, diluted hydrochloric acid is used for quenching reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain (R) -3-iodomethyl n-hexanoic acid (optical purity is 95 percent) which is directly used for the next step of reaction.
(R) -3-iodomethyl-n-hexanoic acid was added to 77.9g of thionyl chloride. The reaction was monitored by TLC at 20 ℃. After the reaction is completed, decompressing and concentrating to be dry to obtain (R) -3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
The crude (R) -3-iodomethyl n-hexanoyl chloride was dissolved in 64ml of 1, 2-dioxyethane and added dropwise to a suspension of 2.19g of powdered potassium hydroxide, 19.5g of anhydrous magnesium sulfate, 1.9g of benzyltriethylammonium bromide and 7.97g of S-2-aminobutanamide (1 eq) (optical purity 99.8%) in 150ml of 1, 2-dioxyethane, the solution was stirred at-5 ℃ for 5 hours, 6.56g of powdered potassium hydroxide (potassium hydroxide was added in total by 2eq) was added and stirred at-5 ℃ overnight. After the reaction is finished, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, extracting the filtrate by using DCM/water, drying the organic phase anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 13.8g of brivaracetam. The characteristics are as follows: white solid, chemical purity 97.89%, optical purity 96.66%, yield 91%
Example 5
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 90%, optical purity 96%) are dissolved in acetone, the temperature is reduced to about 0 ℃, 13g of iodotrimethylsilane is added dropwise, and the reaction is monitored by TLC after the addition. After the reaction is completed, diluted hydrochloric acid is used for quenching reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain (R) -3-iodomethyl n-hexanoic acid (the optical purity is 95.1 percent) which is directly used for the next step of reaction.
(R) -3-iodomethyl-n-hexanoic acid was added to 77.9g of thionyl chloride. The reaction was monitored by TLC at 20 ℃. After the reaction is completed, decompressing and concentrating to be dry to obtain (R) -3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
The crude (R) -3-iodomethyl n-hexanoyl chloride was dissolved in 64ml of 1, 2-dioxyethane and added dropwise to a suspension of 3.98g of sodium ethoxide, 19.5g of anhydrous magnesium sulfate and 21.48g of S-2-aminobutanamide hydrochloride (2eq) (optical purity 99.8%) in 150ml of 1, 2-dioxyethane, the solution was stirred at-5 ℃ for 5 hours, 11.95g of sodium ethoxide (total addition of 3eq of sodium ethoxide) was added and stirred at-5 ℃ overnight. After the reaction is finished, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, extracting the filtrate by using DCM/water, drying the organic phase anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 13.7g of brivaracetam. The characteristics are as follows: white solid, chemical purity 99.06%, optical purity 96.78%, yield 92%
Example 6
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 80%, optical purity 91%) are dissolved in acetone, the temperature is adjusted to the boiling point of the solvent, 11.5g of trimethylchlorosilane are added dropwise, 17.7g of sodium iodide are added, the addition is completed, and the reaction is monitored by TLC. After the reaction is completed, diluted hydrochloric acid is used for quenching reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain (R) -3-iodomethyl n-hexanoic acid (with optical purity of 90.37%) which is directly used for the next step of reaction.
(R) -3-iodomethyl-n-hexanoic acid was dissolved in 20ml of dichloromethane and 62.4g of thionyl chloride was added. The reaction was monitored by TLC at 80 ℃. After the reaction is completed, decompressing and concentrating to be dry to obtain (R) -3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
(R) -3-iodomethyl-n-hexanoyl chloride was dissolved in 64ml of toluene, added dropwise to a suspension of 7g of molecular sieve, 8.67g of calcium hydroxide, 17.1g of calcium chloride and 8.59g of S-2-aminobutanamide hydrochloride (0.8eq) (optical purity 99.8%) in 150ml of toluene, the solution was stirred at-20 ℃ for 5 hours, 26g of calcium hydroxide (6 eq total calcium hydroxide was added) was added, and stirred at-20 ℃ overnight. After the reaction is finished, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, extracting the filtrate by using DCM/water, drying the organic phase anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 11.9g of the brivaracetam. The characteristics are as follows: white solid, chemical purity 97.88%, optical purity 91.99%, yield 89%
Example 7
10g of (R) -4-n-propyl-dihydrofuran-2-one (gas chromatography purity 85%, optical purity 95%) was dissolved in acetonitrile, the temperature was reduced to about-10 ℃, 8.4g of trimethylchlorosilane was added dropwise, 28g of sodium iodide was added, the addition was completed, and the reaction was monitored by TLC. After the reaction is completed, the diluted hydrochloric acid is quenched for reaction, DCM/water extraction is carried out, an organic phase is dried by anhydrous sodium sulfate, filtration is carried out, and the filtrate is decompressed and concentrated to be dry to obtain (R) -3-iodomethyl n-hexanoic acid (the optical purity is 94 percent) which is directly used for the next step of reaction.
(R) -3-iodomethyl-n-hexanoic acid was dissolved in 20ml of dichloromethane and 36.8g of phosphorus pentachloride were added at 10 ℃. The reaction was monitored by TLC at 10 ℃. After the reaction is completed, decompressing and concentrating to be dry to obtain (R) -3-iodomethyl n-hexanoyl chloride which is directly used for the reaction in the next step.
(R) -3-iodomethyl-n-hexanoyl chloride was dissolved in 64ml of toluene, added dropwise to a suspension of 7g of molecular sieve, 5.47g of powdery potassium hydroxide, 17.1g of calcium chloride, 0.7g of tetrabutylammonium bromide and 29.76g of S-2-aminobutanamide mandelate (1.5eq) (optical purity 99.8%) in 150ml of toluene, the solution was stirred at 20 ℃ for 5 hours, 16.4g of powdery potassium hydroxide (total of 5eq of powdery potassium hydroxide) was added, and stirred at 20 ℃ overnight. After the reaction is finished, adjusting the pH value to 5-6 by using dilute hydrochloric acid, filtering, extracting the filtrate by using DCM/water, drying the organic phase anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain 12.7g of brivaracetam. The characteristics are as follows: white solid, chemical purity 98.9%, optical purity 96.02%, yield 90%.
Claims (21)
1. A compound of formula (I) (R) -3-halomethyl-n-hexanoic acid:
wherein X is selected from Br or Cl.
2. A mixture comprising compounds of formula (I) and formula (II),
wherein X in formula (I) and formula (II) is selected from I, Br or Cl, and the compound of formula (I) accounts for more than 90% of the total weight of the compounds of formula (I) and formula (II) in the mixture.
3. The mixture according to claim 2, wherein X is I.
4. The mixture according to claim 2, wherein the compound of formula (I) accounts for more than 95% of the total weight of the compounds of formula (I) and formula (II).
5. The mixture according to claim 2, wherein the compound of formula (I) accounts for more than 98% of the total weight of the compounds of formula (I) and formula (II).
6. Use of a compound or mixture according to any one of claims 1 to 5 for the preparation of brivaracetam.
7. A process for the preparation of bravaracetam comprising the steps of:
(1) (R) -3-halomethyl-n-hexanoic acid is prepared by ring-opening reaction of (R) -4-n-propyl-dihydrofuran-2-one with a halogenating agent selected from one of iodotrimethylsilane, chlorotrimethylsilane and sodium iodide, chlorotrimethylsilane and potassium iodide, hydrobromic acid or hydrochloric acid at a temperature ranging from-10 ℃ to the boiling point of the solvent;
(2) preparing (R) -3-halomethyl-n-hexanoyl chloride from (R) -3-halomethyl-n-hexanoic acid;
(3) reacting (R) -3-halomethyl-n-hexanoyl chloride with (S) -2 aminobutanamide or a salt thereof in the presence of a strong base, which is a sodium or potassium alkoxide or metal hydroxide formed from C1-C5 alcohols, at a temperature in the range of-20 ℃ to prepare bravaracetam.
8. The process according to claim 7, wherein the solvent of step (1) is one or more selected from the group consisting of dichloromethane, acetonitrile, chloroform, toluene, xylene, benzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, 1, 2-dichloroethane, cyclohexane, cyclopentane, isooctane, 1, 4-dioxane.
9. The process according to claim 7, characterized in that in step (2) (R) -3-halomethyl-n-hexanoic acid is reacted with a chlorinating agent selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or methanesulfonyl chloride to produce (R) -3-halomethyl-n-hexanoic acid chloride; and the reaction solvent used in the step (2) is one or more selected from toluene, xylene, benzene, dichloromethane, chloroform, dichloroethane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1, 2-dichloroethane, diethyl ether, cyclohexane, cyclopentane, isooctane, isopentane, 1, 4-dioxane and thionyl chloride; and the reaction temperature of the step (2) is in the range of 10 ℃ to the boiling point of the solvent.
10. The process according to claim 9, characterized in that the chlorinating reagent in step (2) is selected from thionyl chloride or oxalyl chloride.
11. The process according to claim 9, wherein the chlorinating agent in step (2) is thionyl chloride.
12. The method according to any one of claims 7 to 11, wherein the salt of (S) -2-aminobutanamide in step (3) is selected from one of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, lactate, succinate, maleate, fumarate, malate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, salicylate, mandelate or tartrate.
13. The process according to claim 7, wherein the C1-C5 alcohol used in step (3) forms sodium or potassium alkoxide which is sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium n-propoxide, sodium isopropoxide, potassium n-propoxide, potassium isopropoxide, sodium n-butoxide, sodium i-butoxide, potassium n-butoxide or potassium i-butoxide.
14. The process according to claim 7, wherein the metal hydroxide used in step (3) is sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide or barium hydroxide.
15. The process according to claim 7, wherein the metal hydroxide used in step (3) is sodium hydroxide or potassium hydroxide.
16. The method according to claim 12, wherein the salt of (S) -2-aminobutanamide in step (3) is selected from one of hydrochloride, mandelate or tartrate.
17. The process according to claim 12, wherein the salt of (S) -2-aminobutanamide in step (3) is hydrochloride.
18. The method according to claim 12, wherein the reaction solvent in step (3) is one or more selected from the group consisting of toluene, xylene, benzene, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, 1, 2-dichloroethane, diethyl ether, isopropyl ether, cyclohexane, cyclopentane, isooctane, isopentane, 1, 4-dioxane.
19. The method according to claim 12, wherein step (3) is further added with a drying agent selected from one or more of calcium sulfate, barium oxide, calcium chloride, magnesium perchlorate, aluminum oxide, calcium oxide, molecular sieves, sodium sulfate, potassium carbonate, and magnesium sulfate.
20. The method according to claim 18 or 19, wherein step (3) further comprises adding a phase transfer catalyst selected from one of tetrabutylammonium bromide, benzyltriethylammonium chloride, benzyltrimethylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride.
21. The process according to claim 18 or 19, characterized in that no phase transfer catalyst is added in step (3).
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| CN107216276A (en) * | 2017-06-29 | 2017-09-29 | 爱斯特（成都）生物制药股份有限公司 | A kind of new Bu Waxitan synthetic method |
| CN107604018A (en) * | 2017-10-17 | 2018-01-19 | 重庆迪维斯生物科技有限公司 | A kind of preparation method of Bu Waxitan intermediates |
| CN108918692A (en) * | 2018-04-27 | 2018-11-30 | 丽珠集团新北江制药股份有限公司 | A kind of method of separating and assaying of L-2- amino-butanamide hydrochloride and its isomers |
| CN108409557A (en) * | 2018-05-17 | 2018-08-17 | 丽珠集团新北江制药股份有限公司 | Bu Waxitan new intermediates and its synthetic method and application |
| CN110606817B (en) * | 2018-06-14 | 2023-01-24 | 广东东阳光药业有限公司 | Refining method of brivaracetam |
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