CN111892526A - A kind of new preparation method of brivaracetam - Google Patents

Abstract

The invention provides a preparation method of brivaracetam, which uses commercially available (R)-4-propyldihydro-2(3H)-ketone as a raw material and under certain conditions, synthesizes brivaracetam in four steps Tan. The preparation method of the present invention does not need to adopt a chiral preparation chromatographic column separation step, and can directly obtain brivaracetam with high optical purity. The method has high yield, simple and convenient post-processing, low production cost and is suitable for industrial production.

Description

A kind of new preparation method of brivaracetam

technical field

The present invention relates to a new preparation method of brivaracetam.

Background technique

Epilepsy, commonly known as "sheep horn wind" or "sheep epilepsy", is a kind of abnormal movement, sensation, consciousness, spirit, and autonomic function caused by abnormal paroxysmal discharge of neurons in the brain caused by various reasons. disease. The overall prevalence of epilepsy in China was 7.0%, the annual incidence was 28.8/100,000, and the prevalence of active epilepsy with seizures within 1 year was 4.6%. Brivaracetam, a racetam derivative, is a novel high-affinity synaptic vesicle protein 2A ligand, which can inhibit neuronal voltage-dependent sodium channels and play an anti-epileptic effect. Brivaracetam is a third-generation antiepileptic drug developed by Belgian UCB (UCB).

The chemical name for brivaracetam is (2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide.

its structural formula

Brivaracetam can be prepared in a variety of ways, mainly by the following two methods:

Method 1: Using racemic 4-propyl-dihydrofuran-2-one as raw material, through ring opening, acyl chloride reaction, and finally ring closure with BRT-2 to obtain a mixture of BRT and its diastereomers ( J.Med.Chem., 2004, 47 , 530).

This route finally needs to go through silica gel column separation and purification, and chiral resolution to obtain the target molecule, resulting in high production cost and poor industrial feasibility.

Method 2: Using (R)-4-propyl-dihydrofuran-2-one as a raw material, brivaracetam is prepared through the steps of ring opening, halogenation, condensation, and ring closure (WO2018152950).

This method requires the use of a non-nucleophilic strong base at a low temperature in order to obtain a product with high chiral purity by the ring-closure reaction.

Therefore, it is very necessary to find a brivaracetam synthesis route with few steps, high yield, simple post-processing, high purity and suitable for industrial production.

SUMMARY OF THE INVENTION

Aiming at the deficiencies of the prior art, the technical scheme of the present invention is to provide a new method for synthesizing brivaracetam. The preparation method of the present invention does not need to adopt a chiral preparation chromatographic column separation step, and can directly obtain brivaracetam with high optical purity. The method has high yield, simple and convenient post-processing, low production cost and is suitable for industrial production.

The invention provides a preparation method of brivaracetam, which uses commercially available (R)-4-propyldihydro-2(3H)-one (compound 1) as a raw material through ring-opening, acylation, esterification A four-step synthesis of brivaracetam (compound 5) was performed.

Synthetic route:[1]

The steps of synthesizing brivaracetam mainly include four steps. The first step is that (R)-4-propyldihydro-2(3H)-one (compound 1) undergoes a ring-opening reaction under certain conditions to generate compound 2. In the second step, compound 2 undergoes a halogenation reaction to generate compound 3, in the third step, compound 3 undergoes an esterification reaction to generate compound 4, and in the fourth step, compound 4 is ring-closed to prepare the target compound brivaracetam (compound 5).

In the first step of synthesizing brivaracetam, the ring-opening reagent is trimethyliodosilane, trimethylbromosilane, trimethylchlorosilane, hydrobromic acid, etc., preferably trimethyliodosilane.

In the second step of synthesizing brivaracetam, the chlorination reagent is phosphorus trichloride, phosphorus pentachloride, phosgene, thionyl chloride, etc., preferably thionyl chloride.

In the second step of synthesizing brivaracetam, the catalyst is N,N-dimethylformamide (DMF), N,N-dimethylaniline or pyridine, etc., preferably N,N-dimethylformamide.

In the third step of synthesizing brivaracetam, the preferred reagents are methanol, ethanol, etc., preferably methanol.

In the fourth step of synthesizing brivaracetam, the preferred reaction solvent is acetonitrile, toluene, ethyl acetate, isopropyl acetate, etc., preferably isopropyl acetate.

In the fourth step of synthesizing brivaracetam, the preferred reaction temperature is ^50-120 ℃, preferably 90 ^℃ .

In the fourth step of synthesizing brivaracetam, the preferred reaction time is 20 to 40 hours, preferably 28 hours.

In the method for synthesizing brivaracetam, the reaction progress can be monitored by conventional monitoring methods in the art (eg, TLC, HPLC or NMR), and generally the end of the reaction is the disappearance of the starting material.

The crude product of brivaracetam preferably undergoes dissolution, suction filtration, drying, and solvent removal. Described suction filtration, washing, drying, removing solvent adopts the conventional method of this kind of operation in this field, described dissolving preferably dichloromethane dissolving, described washing preferentially adopts tap water, described drying preferentially adopts anhydrous sulfuric acid Sodium or magnesium sulfate, the removal of the solvent is preferably concentrated under reduced pressure.

The crude product of Brivaracetam is preferentially beaten and recrystallized to obtain Brivaracetam. Described beating and recrystallization can adopt the conventional method of this kind of operation in this area, the solvent that described beating adopts is preferably the mixed solvent of lipid solvent and alcoholic solvent, the mixing of described lipid solvent and alcohol solvent. In the solvent, the volume ratio of the lipid solvent to the alcohol solvent is preferably 5:1 to 12:1, such as 8:1. The lipid solvent is preferably ethyl acetate; the alcohol solvent is preferably isopropanol. The solvent used in the recrystallization is preferably aprotic solvent; the aprotic solvent is preferably one or more of ethyl acetate, acetone, dichloromethane, methyl tert-butyl ether, isopropyl ether, and ether. kind.

The HPLC purity of the brivaracetam is greater than 99.70%.

The raw materials or reagents described in the present invention are commercially available unless otherwise specified.

The preparation method of the invention has few steps, is suitable for industrial production, does not need to be split by a chiral high-pressure liquid phase preparation column, has simple post-processing and high purity. The other single impurities of brivaracetam are less than 0.1%, reaching the API level, which is suitable for industrial production. The present invention is a green synthesis process.

Detailed ways

The present patent is further described below by means of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to commercial specifications.

Example 1

The preparation method of Bwaistan comprises the following process steps

(1) Compound 1 (5.0 g, 39 mmol) and 50 ml of dichloromethane were added to a single-necked flask, and the stirring was started. TMSI (6.7 mL, 46.8 mmol) was measured and dissolved in 10 mL of dichloromethane and added dropwise to the system. After the dropwise addition, the reaction was performed at room temperature for 3 hours, and the reaction stopped. Add 50 mL of 1M hydrochloric acid solution, stir for 20 minutes, transfer to a 250 mL separatory funnel, extract and separate the layers, collect the lower organic phase, and extract the aqueous phase with dichloromethane (30 mL*2). Collect the organic phase, wash with 50 mL of 10% sodium thiosulfate solution, collect the organic phase, wash the aqueous phase with dichloromethane (30 mL*1), and combine the organic phases. The organic phases were combined and dried over anhydrous Na ₂ SO ₄ for 2 hours. Suction filtration to remove anhydrous Na ₂ SO ₄ , and the filtrate was concentrated at 40°C. 9.4 g of reddish-brown oil was obtained with a yield of 94.0%.

(2) Add SOCl ₂ (9.6 mL, 0.1406 mol) and 270 mL of dichloromethane into a 500-ml single-neck bottle, turn on stirring, and drop in 3 drops of DMF. Under ice-water bath conditions, measure compound 2 (30.0 g, 0.117 mol) and dissolve it in 30 mL of dichloromethane and add it dropwise to the system. After the dropwise addition, remove the ice-water bath and react at room temperature (20-25 ^o C) for reaction 4. Hour. After the reaction was completed, it was first concentrated at 40 ^o C to remove dichloride, then the temperature was raised to 55 ^o C and concentrated to remove excess thionyl chloride to obtain 32.0 g of a brown liquid with a yield of 99.7%.

(3) Compound 3 (30.0 g, 0.109 mol) was added dropwise to 150 mL of methanol solution in an ice-water bath, the dropwise addition was completed, the ice-water bath was removed, and the reaction was carried out at room temperature for 2 hours. After the reaction, concentrate to remove methanol, extract with 150 mL of water and 150 mL of dichloromethane, collect the organic phase, extract the aqueous phase with dichloromethane (100 mL*2), dry over anhydrous Na ₂ SO ₄ for 2 hours, filter with suction, remove _Na2SO4 , the organic phase was concentrated to give 26.5 g, 95.0% yield _.

(4) S-2-aminobutanamide hydrochloride (4.0 g, 29.2 mmol) was added to 40 mL of isopropyl acetate, stirred, and potassium carbonate (8.1 g, 58.5 mmol) was added, heated under reflux for 8 hours, and added dropwise. A solution of compound 4 (5 g, 19.5 mmol) in isopropyl acetate was refluxed for 28 hours. After the reaction, filter with suction, dilute 5 times, add acetic acid (1.8 mL, 5.9 mmol) dropwise at 60 °C for 2 hours, adjust the pH to about 7 with saturated sodium bicarbonate solution, separate the liquids, and concentrate to obtain crude BRT. The crude product was crystallized from ethyl acetate and methyl tert-butyl ether, filtered, and dried to obtain 2.6 g of compound with a yield of 63.4%, HPLC purity greater than 99.70%, and ee value greater than 20:1.

Example 2

(1) Compound 1 (5.0 g, 39 mmol) and 50 ml of dichloromethane were added to a single-necked flask, and the stirring was started. Zinc chloride (2.6 g, 29.5 mmol) was added in batches, TMSBr (10.3 mL, 78 mmol) was measured and dissolved in 10 mL of dichloromethane and added dropwise to the system. After the dropwise addition, the reaction was carried out at room temperature for 28 hours, and the reaction stopped. Add 50 mL of 1M hydrochloric acid solution, stir for 20 minutes, transfer to a 250 mL separatory funnel, extract and separate the layers, collect the lower organic phase, and extract the aqueous phase with dichloromethane (30 mL*2). Collect the organic phase, wash with 50 mL of 10% sodium thiosulfate solution, collect the organic phase, wash the aqueous phase with dichloromethane (30 mL*1), and combine the organic phases. The organic phases were combined and dried over anhydrous Na ₂ SO ₄ for 2 hours. Suction filtration to remove anhydrous Na ₂ SO ₄ , and the filtrate was concentrated at 40°C. 6.8 g of reddish-brown oil was obtained with a yield of 89.0%.

(2) Add SOCl ₂ (9.6 mL, 0.1406 mol) and 270 mL of toluene into a 500 mL single-neck bottle, turn on stirring, and drop 3 drops of DMF. Under ice-water bath conditions, compound 6 (30.0 g, 0.153 mol) was measured and dissolved in 30 mL of toluene and added dropwise to the system. After the dropwise addition, the ice-water bath was removed, and the reaction was carried out at room temperature (20-25 ^o C) for 4 hours. . After the reaction was completed, it was concentrated by evaporation at 70 ^o C and -0.1 MPa, and the toluene was removed to obtain 31.4 g of a brown liquid with a yield of 95.7%.

(3) Under ice-water bath conditions, compound 7 (30.0 g, 0.140 mol) was added dropwise to 150 mL of ethanol solution. After the dropwise addition was completed, the ice-water bath was removed, and the reaction was carried out at room temperature for 2 hours. After the reaction, concentrate to remove ethanol, extract with 150 mL of water and 150 mL of dichloromethane, collect the organic phase, extract the aqueous phase with dichloromethane (100 mL*2), dry over anhydrous Na ₂ SO ₄ for 2 hours, filter with suction, remove _Na2SO4 , the organic phase was concentrated to give 29.8 g, 94.8% yield _.

(4) S-2-aminobutanamide hydrochloride (4.7 g, 33.6 mmol) was added to 40 mL of isopropyl acetate, stirred, and potassium carbonate (9.3 g, 67.2 mmol) was added, heated under reflux for 8 hours, and added dropwise. A solution of compound 8 (5 g, 22.4 mmol) in isopropyl acetate was refluxed for 28 hours. After the reaction, suction filtration, dilute 5 times, add acetic acid (0.96 mL, 16.8 mmol) dropwise at 60 ^o C for 1.5 hours, adjust pH to about 7 with saturated sodium bicarbonate solution, separate liquids, and concentrate to obtain crude BRT. The crude product was crystallized from ethyl acetate and methyl tert-butyl ether, filtered, and dried to obtain 3.2 g of compound with a yield of 68.0%, HPLC purity greater than 99.75%, and ee value greater than 20:1.

¹ H NMR (400MHz, CDCl ₃ ): 0.83-0.91 (m, 6H), 1.26-1.34 (m, 2H), 1.31-1.45 (m, 2H), 1.67-1.72 (m, 1H), 2.59 (dd, 1H, J _A =16.8 Hz, J _B = 8.4 Hz), 3.03 (dd, 1H, J _A =9.6 Hz, J _B = 7.2 Hz), 3.49 (dd, 1H, J _A =9.6 Hz, J _B = 8.4 Hz), 4.45 (dd,1H, J _A =8.4 Hz, J _B = 7.2 Hz), 5.30(s, br, 1H), 6.20 (s, br, 1H).

Claims (10)

1. A preparation method of the brivaracetam is characterized by comprising the following steps: the preparation method is prepared by the following synthetic route: the first step is that (R) -4-propyldihydro-2 (3H) -ketone (compound 1) generates ring-opening reaction under certain conditions to generate compound 2, the second step generates halogenation reaction to generate compound 3, the third step generates esterification reaction to generate compound 4, and the fourth step generates compound 4 to close ring to prepare target compound, namely, the compound 5

。

2. The process according to claim 1, wherein in the first step of the synthesis of brivaracetam, the ring-opening reagent is selected from the group consisting of iodotrimethylsilane, bromotrimethylsilane, chlorotrimethylsilane, hydrobromic acid, and the like, preferably iodotrimethylsilane.

3. The process according to claim 1, wherein in the second step of the synthesis of bravaracetam, the chlorinating agent is phosphorus trichloride, phosphorus pentachloride, phosgene, thionyl chloride or the like, preferably thionyl chloride.

4. The process according to claim 1, wherein in the second step of the synthesis of bravaracetam the catalyst is N, N-Dimethylformamide (DMF), N-dimethylaniline or pyridine or the like, preferably N, N-dimethylformamide.

5. The process according to claim 1, wherein in the third step of the synthesis of bravaracetam, the reaction solvent is lower alcohol such as methanol, ethanol and the like, preferably methanol.

6. The process according to claim 1, wherein in the fourth step of the synthesis of bravaracetam the reaction solvent is acetonitrile, toluene, ethyl acetate or isopropyl acetate, preferably isopropyl acetate.

7. The process according to claim 1, wherein the reaction temperature in the fourth step of the synthesis of the bravaracetam is 50 to 120%^oC, preferably 90^oC。

8. The process according to claim 1, wherein in the fourth step of the synthesis of bravaracetam, the preferred reaction time is 20 to 40 hours, preferably 28 hours.

9. The crude product of the brivaracetam is subjected to pulping and recrystallization preferentially to obtain the brivaracetam; the pulping and recrystallization can adopt a conventional method operated in the field, the solvent adopted for pulping is preferably a mixed solvent of an ester solvent and an alcohol solvent, and the volume ratio of the ester solvent to the alcohol solvent in the mixed solvent of the ester solvent and the alcohol solvent is preferably 5: 1-12: 1, such as 8: 1; the ester solvent is preferably ethyl acetate; the alcohol solvent is preferably isopropanol.

10. The solvent used for recrystallization is preferably an aprotic solvent; the aprotic solvent is preferably one or more of ethyl acetate, acetone, dichloromethane, methyl tert-butyl ether, isopropyl ether and diethyl ether.