阅读说明：本技术 一种抗癫痫药物的关键中间体及其制备方法 (Key intermediate of antiepileptic drug and preparation method thereof ) 是由 蔡强 殷超 商俊兵 兰柳琴 于 2021-08-31 设计创作，主要内容包括：本发明公开了一种抗癫痫药物的关键中间体及其制备方法,该方法用于合成抗癫痫药物的关键中间体(R)-4-丙基二氢呋喃-2(3H)-酮的方法,具有以下益处：采用手性制备的方法,避免了手性色谱柱制备、手性拆分剂拆分,大大提高了工艺总收率。中间体3的结构大大提高了不对称氢化的选择性,ee值可达到99%以上。避免了过柱的纯化方法,操作过程简单,更适宜工业化生产。(The invention discloses a key intermediate of an antiepileptic drug and a preparation method thereof, and the method is used for synthesizing the key intermediate (R) -4-propyl dihydrofuran-2 (3H) -ketone of the antiepileptic drug and has the following benefits: the chiral preparation method is adopted, so that the preparation of a chiral chromatographic column and the resolution of a chiral resolving agent are avoided, and the total yield of the process is greatly improved. The structure of the intermediate 3 greatly improves the selectivity of asymmetric hydrogenation, and the ee value can reach more than 99 percent. Avoids a purification method of column passing, has simple operation process and is more suitable for industrial production.)

1. A compound having the structure of formula 4:and R is a hydrocarbon group containing 1 to 10 carbons.

2. A process for preparing the compound of claim 1, comprising the steps of:

step a:

reacting the compound 2 with RCOONa in a solvent 1 to obtain a compound 3, wherein R is a hydrocarbon group containing 1-10 carbons;

step b:

compound 3 andreacting with a catalyst in a solvent 2 to obtain a compound 4, wherein R is a hydrocarbon group containing 1-10 carbons.

3. Method according to claim 2, characterized in that it comprises the following steps:

step a: taking a compound 2 and RCOONa as reaction raw materials, stirring and mixing in a solvent 1, heating, controlling the temperature to be 60-70 ℃, preserving the heat, reacting for 1-3 hours, cooling to room temperature, adding water and an organic solvent for extraction, washing an organic layer with water, and concentrating the organic layer under negative pressure to obtain a compound 3, wherein the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

step b: subjecting the compound 3 obtained in step a andstirring and mixing in a solvent 2, cooling to below 10 ℃, adding a catalyst, reacting completely at room temperature, dropwise adding 1N hydrochloric acid after the reaction is completed, adding an organic solvent for extraction, adding saturated sodium bicarbonate and saturated salt water, washing, concentrating and drying under negative pressure, and rectifying under negative pressure to obtain a compound 4, wherein R is selected from any one of methyl, ethyl, N-propyl, isopropyl, N-butyl and isobutyl.

4. The method according to claim 3, wherein the solvent 1 in the step a is any one of dimethylformamide, acetone and dimethyl sulfoxide, the solvent 2 in the step b is toluene or tetrahydrofuran, the catalyst is titanium tetrachloride and pyridine, and the organic solvent in the steps a and b is any one of ethyl acetate, dichloromethane and cyclohexane.

5. The method of claim 4, wherein the molar ratio of compound 2 to RCOONa in step a is 1:0.5-10, and the molar ratio of compound 3 to RCOONa in step b is 1:0.5-10The molar ratio of (A) to (B) is 1: 0.8-5.

6. The compound of claim 1 used for synthesizing key intermediate of antiepileptic drug, formula 1The use of (1).

7. A method for preparing a key intermediate of an antiepileptic drug, wherein the key intermediate of the antiepileptic drug is (R) -4-propyldihydrofuran-2 (3H) -one, the method comprising the following steps:

step 1:

reacting the compound 4 with hydrogen to obtain a compound 5, wherein R is a hydrocarbon group containing 1-10 carbons;

step 2:

reacting the compound 5 with a catalyst in dimethylformamide and water to obtain a compound 6, wherein R is a C1-10 alkyl group;

and step 3:

reacting the compound 6 with trifluoroacetic acid in a solvent 3 to obtain a compound 1, wherein R is a hydrocarbyl group containing 1-10 carbons.

8. The method for preparing key intermediates of antiepileptic drugs according to claim 7, characterized in that it comprises the following steps:

step 1: mixing the compound 4 with ethanol or glacial acetic acid, mixing with a metal ruthenium homogeneous catalyst of a diphosphine ligand, introducing hydrogen, controlling the pressure to be 0.1-10 Mpa, controlling the temperature to be 40-50 ℃ for reaction, and concentrating a solvent under negative pressure after the reaction is completed to obtain a compound 5, wherein the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

step 2: mixing the compound 5 with a catalyst, dimethylformamide and water, heating, controlling the temperature to 140-150 ℃ for complete reaction, cooling to room temperature after complete reaction, adding water and an organic solvent for extraction, washing an organic layer with saturated salt water after extraction and layering, and concentrating under reduced pressure to obtain a compound 6, wherein the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;

and step 3: mixing the compound 6 with the solvent 3 and trifluoroacetic acid, reacting completely at room temperature, concentrating the solvent under negative pressure after the reaction is completed, and rectifying under reduced pressure to obtain a colorless transparent liquid compound 1, wherein the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl; the specific synthetic route is as follows:

。

9. the method for preparing a key intermediate of an antiepileptic drug according to claim 8, wherein in step 1, the molar ratio of compound 4 to hydrogen is 1:0.5-5, the reaction pressure is 0.1-10 MPa, in step 2, the molar ratio of compound 5 to the catalyst is 1:0.3-3, and in step 3, the molar ratio of compound 6 to trifluoroacetic acid is 1: 0.1-3.

10. The method for preparing key intermediates of antiepileptic drugs according to claim 9, wherein in step 2, the catalyst is any one of lithium chloride, sodium chloride, potassium chloride and calcium oxide, the organic solvent in step 2 is any one of ethyl acetate, dichloromethane and cyclohexane, and the solvent 3 in step 3 is any one of methanol, ethanol and isopropanol.

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a key intermediate of an antiepileptic drug and a preparation method thereof.

Background

Brivaracetam (brivaracetam), with the chemical name (2S) -2- [ (4R) -2-oxo-4-propylpyrrolidin-1-yl ] butanamide, is a 3 rd generation antiepileptic drug developed by Belgium Yokoku (UCB) Co. European Medicines Administration (EMA) and U.S. Food and Drug Administration (FDA) approval for the treatment of partial seizures in adult juvenile epilepsy patients aged 16 and older, with or without adjuvant treatment of secondary generalized seizures, under the trade name Briviact, were obtained at 2016, 14, and 2016, 2, 18.

At present, the synthesis route of the brivaracetam is more, the key of the synthesis is the construction of a 4-position n-propyl chiral center, and an intermediate (R) -4-propyl dihydrofuran-2 (3H) -ketone has a structural formula:CAS number 63095-51-2, is a key intermediate for preparing the brivaracetam, and has a crucial influence on the product quality and the cost.

The synthetic route of (R) -4-propyldihydrofuran-2 (3H) -ketone mainly comprises the following steps:

1. the synthetic route of patent CN 105801530a (a synthetic method of 4-substituted chiral γ -butyrolactone) is:

the route needs to use a plurality of dangerous reagents such as borane, sodium hydrogen and the like, and the selectivity is poor when the chiral propyl is constructed, so that the route is not suitable for industrial production.

2. The synthetic route of patent CN106279074B (a compound and its preparation method and use in the synthesis of bwaitan) is:

the route adopts (R) -epichlorohydrin as a raw material, the raw material is cheap and easy to obtain, and the reaction step is short. However, the Grignard reaction needs to be carried out under the harsh condition of ultralow temperature of-30 ℃, and the intermediate (4R) -4-propyl-2-oxotetrahydrofuran-3-ethyl formate needs to be separated and purified by a column, so the operation is inconvenient and the method is not suitable for industrial production.

3. Document Org Process Res Dev, 2016, 20 (9): 1566-1575

TheThe route has the advantages that column chromatography is eliminated in the whole route, and kilogram-level amplification can be carried out. The disadvantages are that the price of the raw material dimethyl malonate is expensive, the chiral center is established by adopting an enzyme catalysis resolution method, and the diastereoisomer loss is over 50 percent.

The synthetic route of the preparation method of CN 106008411A-chiral 4-substituent dihydrofuran-2 (3H) -ketone is as follows:

the route needs to use reagents with high danger such as hydrogen peroxide, borane dimethyl sulfide and the like, and the substitution reaction of the (S) -4-benzyl-3-pentanoyl oxazolidine-2-ketone and the tert-butyl bromoacetate needs to use the low temperature condition of-70 ℃, so the route is not suitable for industrial production.

In summary, the synthesis of (R) -4-propyldihydrofuran-2 (3H) -one includes methods such as chiral chromatographic column preparation, chiral resolving agent resolution, and asymmetric synthesis, and the chiral chromatographic column preparation and chiral resolving agent resolution have the disadvantages of high equipment requirement, complex operation, and over 50% diastereomer loss, resulting in low yield and high cost.

In view of the defects of the prior art, it is necessary to develop a synthetic method of (R) -4-propyl dihydrofuran-2 (3H) -ketone, which has simple operation process, high safety, low cost, high yield and high purity and is more suitable for industrial production.

Disclosure of Invention

The application aims to provide a compound of formula 4 and a preparation method thereof.

Another object of the present application is to provide a use of the compound of formula 4 for synthesizing (R) -4-propyldihydrofuran-2 (3H) -one, a key intermediate of antiepileptic drugs.

It is still another object of the present application to provide a method for synthesizing (R) -4-propyldihydrofuran-2 (3H) -one, a key intermediate of antiepileptic drugs.

The invention discloses a key intermediate of an antiepileptic drug and a preparation method thereof in order to solve the problems in the prior art, and the purpose of the invention can be achieved by the following measures:

a compound having the structure of formula 4:and R is a hydrocarbon group containing 1 to 10 carbons.

Further, the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

A process for preparing a compound of formula 4, said process comprising the steps of:

step a:

reacting the compound 2 with RCOONa in a solvent 1 to obtain a compound 3, wherein R is a hydrocarbon group containing 1-10 carbons;

step b:

compound 3 andreacting with a catalyst in a solvent 2 to obtain a compound 4, wherein R is a hydrocarbon group containing 1-10 carbons.

Further, the method comprises the following steps:

step a: taking a compound 2 and RCOONa as reaction raw materials, stirring and mixing in a solvent 1, heating, controlling the temperature to be 60-70 ℃, preserving the heat, reacting for 1-3 hours, cooling to room temperature, adding water and an organic solvent for extraction, washing an organic layer with water, and concentrating the organic layer under negative pressure to obtain a compound 3, wherein R is a hydrocarbon group containing 1-10 carbon atoms;

step b: subjecting the compound 3 obtained in step a andstirring and mixing in solvent 2, cooling to below 10 deg.C, adding catalyst, reacting at room temperature, dropwise adding 1N hydrochloric acid, and extracting with organic solventAdding saturated sodium bicarbonate and saturated saline solution, washing, concentrating under negative pressure, washing to remove salt and acidic substances, and rectifying under negative pressure to obtain compound 4, wherein R is C1-C10 alkyl.

Further, the solvent 1 in the step a is any one of dimethylformamide, acetone and dimethyl sulfoxide, the solvent 2 in the step b is toluene or tetrahydrofuran, the catalyst is titanium tetrachloride and pyridine, and the organic solvent in the steps a and b is any one of ethyl acetate, dichloromethane and cyclohexane.

Further, the molar ratio of the compound 2 to RCOONa in the step a is 1:0.5-10, and the molar ratio of the compound 3 to RCOONa in the step b is 1:0.5-10The molar ratio of (A) to (B) is 1: 0.8-5.

Further, the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

Compound 4 used as key intermediate for synthesizing antiepileptic drug 1。

A method for preparing a key intermediate of an antiepileptic drug, wherein the key intermediate of the antiepileptic drug is (R) -4-propyldihydrofuran-2 (3H) -one, the method comprising the following steps:

step 1:

reacting the compound 4 with hydrogen to obtain a compound 5, wherein R is a hydrocarbon group containing 1-10 carbons;

step 2:

reacting the compound 5 with a catalyst in dimethylformamide and water to obtain a compound 6, wherein R is a C1-10 alkyl group;

and step 3:

reacting the compound 6 with trifluoroacetic acid in a solvent 3 to obtain a compound 1, wherein R is a hydrocarbyl group containing 1-10 carbons.

Further, the method comprises the following steps:

step 1: mixing the compound 4 with ethanol or glacial acetic acid, mixing with a metal ruthenium homogeneous catalyst of a diphosphine ligand, introducing hydrogen, controlling the pressure to be 0.1-10 Mpa, controlling the temperature to be 40-50 ℃ for reaction, and concentrating a solvent under negative pressure after the reaction is completed to obtain a compound 5, wherein R is a hydrocarbon group containing 1-10 carbon atoms;

step 2: mixing the compound 5 with a catalyst, dimethylformamide and water, heating, controlling the temperature to 140-150 ℃ for complete reaction, cooling to room temperature after complete reaction, adding water and an organic solvent for extraction, washing an organic layer with saturated salt water after extraction and layering, and concentrating under reduced pressure to obtain a compound 6, wherein R is a hydrocarbon group containing 1-10 carbons;

and step 3: mixing the compound 6 with the solvent 3 and trifluoroacetic acid, reacting completely at room temperature, concentrating the solvent under negative pressure after the reaction is completed, and rectifying under reduced pressure to obtain a colorless transparent liquid compound 1, wherein R is a hydrocarbon group containing 1-10 carbons; the specific synthetic route is as follows:

。

further, the R group is selected from any one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

Further, in the step 1, the molar ratio of the compound 4 to hydrogen is 1:0.5-5, the reaction pressure is 0.1-10 MPa, in the step 2, the molar ratio of the compound 5 to the catalyst is 1:0.3-3, and in the step 3, the molar ratio of the compound 6 to trifluoroacetic acid is 1: 0.1-3.

Further, in the step 2, the catalyst is any one of lithium chloride, sodium chloride, potassium chloride and calcium oxide, the organic solvent in the step 2 is any one of ethyl acetate, dichloromethane and cyclohexane, and the solvent 3 in the step 3 is any one of methanol, ethanol and isopropanol.

Compared with the prior art, the method for synthesizing the key intermediate (R) -4-propyl dihydrofuran-2 (3H) -ketone of the antiepileptic drug has the following benefits:

1. the chiral preparation method is adopted, so that the preparation of a chiral chromatographic column and the resolution of a chiral resolving agent are avoided, and the total yield of the process is greatly improved.

2. The structure of the intermediate 3 greatly improves the selectivity of asymmetric hydrogenation, and the ee value can reach more than 99 percent.

3. Avoids a purification method of column passing, has simple operation process and is more suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.

Example 1

Stirring and mixing 120.5g of compound 2, 164g of sodium acetate and 260ml of dimethylformamide, heating, controlling the temperature to be 60-70 ℃, carrying out heat preservation reaction for two hours, cooling to room temperature, adding 250ml of water and 535ml of ethyl acetate, stirring until the solution is clear, layering, washing an organic layer with 250ml of water once, concentrating the organic layer under negative pressure to obtain 137g of compound 3-1, wherein the molar yield is 95.0%, and the purity is 98.6%.

Example 2

Stirring and mixing 120.5g of compound 2, 192g of sodium propionate and 220ml of dimethyl sulfoxide, heating, keeping the temperature at 60-70 ℃ for reaction for two hours, cooling to room temperature, adding 250ml of water and 365ml of dichloromethane, stirring until the solution is clear, layering, washing an organic layer with 250ml of water once, concentrating the organic layer under negative pressure to obtain 149.5g of compound 3-2, wherein the molar yield is 94.5%, and the purity is 99.1%.

Example 3

137g of compound 3-1, 150.6g of dimethyl malonate and 470ml of toluene are stirred, mixed, cooled to below 10 ℃, added with 310ml of dichloromethane solution containing 216g of titanium tetrachloride dropwise, continuously added with 79.1g of pyridine dropwise, the temperature is controlled to below 20 ℃ in the dropwise adding process, the mixture reacts at room temperature for 12 hours after the dropwise adding is finished, after the reaction is completed, 410ml of 1N hydrochloric acid is dropwise added, 760ml of ethyl acetate is added for extraction, 410ml of saturated sodium bicarbonate is washed, 410ml of saturated saline is washed, and then the mixture is concentrated and dried under negative pressure, and after the negative pressure rectification, 224.4g of compound 4-1 is obtained, the yield is 91.5%, and the purity is 99.0%.

The hydrogen and mass spectral data for compound 4-1 are as follows:

H NMR(400 MHz, CDCl3) δ4.98(s,2H),3.79(s,3H), 3.78(s,3H)，2.39(t,2H),2.10(s,3H),1.52-1.59(m,2H),0.96(t,1H); LCMS(ESI)(M+1)+=259.1

example 4

137g of compound 3-1, 304g of diethyl malonate and 460ml of tetrahydrofuran are stirred, mixed, cooled to below 10 ℃, then added with 310ml of dichloromethane solution containing 540g of titanium tetrachloride dropwise, 375g of pyridine is continuously dropwise added, the temperature is controlled to be below 20 ℃ in the dropwise adding process, the mixture reacts at room temperature for 12 hours after the dropwise adding is finished, 410ml of 1N hydrochloric acid is dropwise added after the reaction is completed, 760ml of ethyl acetate is added for extraction, 410ml of saturated sodium bicarbonate is washed, 410ml of saturated saline is washed and then dried in a negative pressure manner, 247.4g of compound 4-2 is obtained after the negative pressure rectification, the yield is 91.0%, and the purity is 99.2%.

Example 5

137g of compound 3-1, 627g of dimethyl malonate and 460ml of tetrahydrofuran are stirred, mixed, cooled to below 10 ℃, then added with 310ml of dichloromethane solution containing 540g of titanium tetrachloride dropwise, 150g of pyridine is continuously dropwise added, the temperature is controlled to be below 20 ℃ in the dropwise adding process, the reaction is carried out at room temperature for 12 hours after the dropwise adding is finished, 410ml of 1N hydrochloric acid is dropwise added after the reaction is completely finished, 760ml of ethyl acetate is added for extraction, 410ml of saturated sodium bicarbonate is washed, 410ml of saturated saline is washed and then is concentrated and dried under negative pressure, 225.6g of compound 4-1 is obtained after negative pressure rectification, the yield is 92.0%, and the purity is 99.1%.

Example 6

Replacing air with nitrogen in a hydrogenation kettle, mixing 224.4g of compound 4-1, 115g of ethanol and 0.46g of metal ruthenium homogeneous catalyst of a diphosphine ligand, introducing 2.1g of hydrogen, controlling the pressure to be 0.3-0.4 Mpa, controlling the temperature to be 40-50 ℃ for reaction, replacing the hydrogen with nitrogen after the reaction is completed, and concentrating a solvent under negative pressure to obtain 226g of compound 5-1, wherein the yield is 100%, the purity is 99.2% and the ee value is 99.0%.

Example 7

Replacing air with nitrogen in a hydrogenation kettle, mixing 224.4g of compound 4-1, 115g of glacial acetic acid and 0.23g of metal ruthenium homogeneous catalyst of a diphosphine ligand, introducing 6.3g of hydrogen, controlling the pressure to be 1.0-1.2 Mpa, controlling the temperature to be 40-50 ℃ for reaction, replacing the hydrogen with nitrogen after the reaction is completed, and concentrating a solvent under negative pressure to obtain 226g of compound 5-1, wherein the yield is 100%, the purity is 99.1% and the ee value is 99.2%.

Example 8

Mixing 226g of compound 5-1, 18.4g of lithium chloride, 480ml of DMF (dimethyl formamide) and 45ml of water, heating, controlling the temperature to 140-150 ℃ for reaction for 3 hours, cooling to room temperature after complete reaction, adding 450ml of water and 1250ml of ethyl acetate, washing an organic layer once with 450ml of saturated salt after extraction and layering, and concentrating under reduced pressure to obtain 165.4g of compound 6-1, wherein the yield is 94.2%, and the purity is 98.8%.

Example 9

Mixing 226g of compound 5-1, 110.6g of lithium chloride, 480ml of DMF (dimethyl formamide) and 45ml of water, heating, controlling the temperature to 140-150 ℃ for reaction for 3 hours, cooling to room temperature after the reaction is completed, adding 450ml of water and 1250ml of ethyl acetate, washing an organic layer once with 450ml of saturated salt after extraction and layering, and concentrating under reduced pressure to obtain 164.2g of compound 6-1, wherein the yield is 93.5% and the purity is 98.7%.

Example 10

Mixing 226g of compound 5-1, 48.7g of calcium oxide, 480ml of DMF (dimethyl formamide) and 45ml of water, heating, controlling the temperature to 140-150 ℃ for reaction for 3 hours, cooling to room temperature after complete reaction, adding 450ml of water and 1250ml of ethyl acetate, washing an organic layer once with 450ml of saturated salt after extraction and layering, and concentrating under reduced pressure to obtain 160.7g of compound 6-1, wherein the yield is 91.5%, and the purity is 97.7%.

Example 11

165.4g of compound 6-1, 425ml of methanol and 18.7g of trifluoroacetic acid are mixed and reacted at room temperature for 5 hours, after the reaction is completed, the solvent is concentrated under negative pressure, and after rectification under reduced pressure, 100.2g of colorless transparent liquid compound 1 is obtained, the yield is 95.5%, the purity is 99.5%, and the ee value is 99.2%.

Example 12

165.4g of compound 6-1, 425ml of methanol and 93.3g of trifluoroacetic acid are mixed and reacted at room temperature for 5 hours, after the reaction is completed, the solvent is concentrated under negative pressure, and after rectification under reduced pressure, 100.2g of colorless transparent liquid compound 1 is obtained, the yield is 95.5%, the purity is 99.3%, and the ee value is 99.0%.

The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.