CN112521352A - Preparation method of brivaracetam intermediate - Google Patents

Abstract

The invention provides a preparation method shown in a formula II, and a preparation method of (R) -4-propyl-dihydrofuran-2-ketone.

Description

Preparation method of brivaracetam intermediate

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and mainly relates to a preparation method of a brivaracetam intermediate shown as a formula I

Background

Brivaracetam (I) (trade name Brivaracetam), (S) -2- ((R) -2-oxo-4-propylpyrrolidin-1-yl) butanamide, a third generation antiepileptic drug developed by belgium chronopher (UCB) corporation. The European pharmaceutical administration (EMA) and the U.S. Food and Drug Administration (FDA) approved the marketing date of 2016 (1/14/2016) and 2016 (2/18/2016), respectively. The product can be used for treating partial seizure type epilepsy patients of 16 years old or above, with or without secondary systemic seizure as adjuvant treatment. (R) -4-propyl-dihydrofuran-2-one (II) is an important intermediate for synthesizing the brivaracetam.

Disclosure of Invention

The invention provides a preparation method of (R) -4-propyl-dihydrofuran-2-ketone in a formula II.

The preparation method comprises the following steps:

(1) reacting the formula (III) with R-epichlorohydrin (IV) in sodium ethoxide solution to obtain a compound of a formula (V);

(2) adding the compound of the formula (V) and a lattice reagent (VI) to obtain a compound (VII);

(3) hydrolyzing the compound shown in the formula (VII) under an acidic condition to obtain a compound shown in a formula (VIII);

(4) the compound of formula (VII) is heated to obtain formula (II).

。

Wherein the following conditions are preferred for step 1:

the reaction solvent is methanol, ethanol, tert-butanol, isopropanol, butanol, preferably ethanol;

the alkali used in the reaction is sodium ethoxide and sodium methoxide, preferably sodium ethoxide; the dosage is recommended to be 1-3 times, preferably 1-2 times of the compound IV;

the dosage of the solvent is 5 to 15 times of that of the compound III, preferably 5 to 7 times (volume to mass ratio);

the reaction temperature is 60-100 ℃, and preferably 80-100 ℃;

after the addition of the reaction mass is complete, the reaction time is from 12 to 24 hours, preferably from 20 to 24 hours.

Step 2 preferably comprises the following conditions:

the solvent used for the reaction is diethyl ether and tetrahydrofuran, preferably tetrahydrofuran;

the dosage of the solvent is 5 to 15 times of that of the compound III, preferably 5 to 7 times (volume to mass ratio);

the reaction temperature is recommended to be-35 to-10 ℃; preferably-35 to-20 DEG C

The reaction time after the compound IV is added is recommended to be 1-5 hours, and preferably 1-2 hours;

the following conditions are preferred for step 3:

the acid used in the reaction can be 50-70% concentrated sulfuric acid or concentrated hydrochloric acid, trifluoromethanesulfonic acid, an alcohol solution of hydrogen bromide, etc., and 50% concentrated sulfuric acid is preferred.

The amount of the acid is preferably 10 to 30 times, preferably 10 to 15 times (volume to mass ratio) of the compound VII;

the reaction temperature is recommended to be 100-150 ℃; preferably 140-150 DEG C

The reaction time is recommended to be 10-30 hours, preferably 10-15 hours;

step 4 preferably comprises the following conditions:

the solvent used for the reaction is preferably dichloromethane, toluene, preferably toluene;

the dosage of the solvent is 10 to 30 times of that of the compound VIII, preferably 10 to 15 times (volume to mass ratio);

the reaction temperature is recommended to be 80-120 ℃; preferably 100-120 DEG C

The reaction time is recommended to be 10-30 hours, and preferably 20-30 hours;

the invention avoids the use of chiral intermediates and heavy metal catalysts, effectively reduces the cost and is convenient for industrial production.

The reagent used in the invention is a conventional reagent, so that a heavy metal catalyst is avoided, and the environmental pollution is small.

The invention provides a new method for preparing the intermediate of the brivaracetam.

Detailed Description

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

Example 1:

(1) weighing 11.0 g of sodium ethoxide, dissolving in 300 mL of ethanol, and cooling the reaction system to 0^oC, slowly adding 40.3 g of malonic acid ethyl ester nitrile (III), reacting at 0 ℃ for 30 minutes, adding 30.0 g of R-epichlorohydrin (IV) into the reaction system in batches, and heating to 80 ℃ after the addition is finished^oC, stopping the reaction after 24 hours, and monitoring the completion of the R-epichlorohydrin (IV) reaction by TLC. Cooling the system to room temperature, performing reduced pressure rotary evaporation to remove ethanol, extracting the water phase with 2 × 100 mL ethyl acetate, collecting the organic phase after washing, washing with 200mL saturated sodium chloride solution, separating liquid after washing, collecting the organic phase, drying with anhydrous sodium sulfate for 2h, and performing rotary drying on the solvent to obtain yellow liquid. The crude product is obtained by using petroleum ether: ethyl acetate = 5:1 elution column, and all product (V) was collected and spin-dried to give 35.4 g of product in 88.7% yield and 92.6% purity.

(2) 30.0 g of the compound (V) and 46.4 g of cuprous iodide were dissolved inIn 150 mL of tetrahydrofuran, the temperature of the system is reduced to-30 DEG^oC, slowly dropwise adding 300 mL of 1.6mol/L ethyl magnesium bromide tetrahydrofuran solution (VI), changing the color of the system from bright blue to gray, and controlling the reaction temperature to be not more than-30 DEG^oC after 4h reaction with saturated NH₄And (3) quenching the reaction by using a Cl solution, then transferring the reaction to room temperature, adding 100 mL of water into the system, adding diatomite into the system for suction filtration, extracting and washing the filtrate by using 2X 200mL of ethyl acetate, collecting an organic phase after washing, washing and separating the organic phase by using 300 mL of saturated sodium chloride solution, drying the organic phase for 2h, and suction-filtering and spin-drying the solvent to obtain a yellow-green solution. The crude product is obtained by using petroleum ether: ethyl acetate = 10:1 elution column, and all product (VII) was collected and spin-dried to give 34.1 g of product in 91.4% yield and 93.7% purity.

(3) 30g of the compound VII are dissolved in 100 mL of 50% concentrated sulfuric acid solution and heated to 150%^oC, cooling to room temperature after 12h, stopping stirring, adding 120 mL of 30% NaOH into the system to neutralize to neutral, adding 2X 120 mL of ethyl acetate for extraction and washing, collecting an organic phase after washing, washing the organic phase with 300 mL of saturated sodium chloride solution, separating, drying the organic phase for 2h, and performing suction filtration and spin-drying on the solvent to obtain a product (VIII) which is a yellow-green solution and can be directly used for next reaction.

(4) And (3) dissolving the product (VIII) obtained in the step (3) in 150 mL of toluene, heating to 120 ℃, refluxing for 20 hours, cooling to room temperature, stopping the reaction, carrying out reduced pressure spin-drying on the solvent to obtain yellow liquid, and carrying out reduced pressure distillation on the crude product to obtain 20.8 g of a light yellow liquid product (II), wherein the yield is 82.9%, the purity is 98.9%, and the product is the final product of the intermediate (II) of the Buvalsartan.

Example 2:

(1) weighing 11.0 g of sodium ethoxide, dissolving in 300 mL of methanol, and cooling the reaction system to 0^oC, slowly adding 40.3 g of malonic acid ethyl ester nitrile (III), reacting at 0 ℃ for 30 minutes, adding 30.0 g of R-epichlorohydrin (IV) into the reaction system in batches, and heating to 65 ℃ after the addition is finished^oC, stopping the reaction after 24 hours, and monitoring the completion of the R-epichlorohydrin (IV) reaction by TLC. Cooling the system to room temperature, removing ethanol by rotary evaporation under reduced pressure, extracting the water phase with 2 × 100 ml ethyl acetate, and washingAnd then collecting an organic phase, washing the organic phase by using 200mL of saturated sodium chloride solution, separating liquid after washing, collecting the organic phase, drying the organic phase for 2 hours by using anhydrous sodium sulfate, and then spin-drying the solvent to obtain yellow liquid. The crude product is obtained by using petroleum ether: ethyl acetate = 5:1 elution column, and all product (V) was collected and spin-dried to give 30.2 g of product in 75.7% yield and 90.2% purity.

(2) 30.0 g of the compound (V) and 46.4 g of cuprous iodide were dissolved in 150 mL of diethyl ether, and the temperature of the system was lowered to-30%^oC, slowly dropwise adding 300 mL of 1.6mol/L ethyl magnesium bromide ether solution (VI), wherein the color of the system is changed from bright blue to gray, and the reaction temperature is controlled not to exceed-30 DEG^oC after 4h reaction with saturated NH₄And (3) quenching the reaction by using a Cl solution, then transferring the reaction to room temperature, adding 100 mL of water into the system, adding diatomite into the system for suction filtration, extracting and washing the filtrate by using 2X 200mL of ethyl acetate, collecting an organic phase after washing, washing and separating the organic phase by using 300 mL of saturated sodium chloride solution, drying the organic phase for 2h, and suction-filtering and spin-drying the solvent to obtain a yellow-green solution. The crude product is obtained by using petroleum ether: ethyl acetate = 10:1 elution column, and all product (VII) was collected and spin-dried to give 29.5 g of product in 79.1% yield and 92.3% purity.

(3) 30g of compound VII are dissolved in 100 mL of 50% concentrated hydrochloric acid solution and the temperature is raised to 150%^oC, cooling to room temperature after 12h, stopping stirring, adding 120 mL of 30% NaOH into the system to neutralize to neutral, adding 2X 120 mL of ethyl acetate for extraction and washing, collecting an organic phase after washing, washing the organic phase with 300 mL of saturated sodium chloride solution, separating, drying the organic phase for 2h, and performing suction filtration and spin-drying on the solvent to obtain a product (VIII) which is a yellow-green solution and can be directly used for next reaction.

The product (VIII) obtained in step 3 was dissolved in 150 mL of dichloromethane and heated to 40%^oAnd C, refluxing for 20 hours, cooling to room temperature, stopping the reaction, carrying out reduced pressure spin drying on the solvent to obtain yellow liquid, and carrying out reduced pressure distillation on the crude product to obtain 19.6 g of a light yellow liquid product (II), wherein the yield is 78.1%, the purity is 96.4%, and the product is the final product of the intermediate (II) of the Buvalsartan.

Claims (8)

1. A process for the preparation of (R) -4-propyl-dihydrofuran-2-one, characterized in that it comprises the following steps:

   1) dissolving the compounds shown in the formulas III and VI in an organic solvent, adding sodium ethoxide, and reacting at 80-100 ℃ to obtain a compound shown in the formula V;

   2) dissolving the compound shown in the formula V in an organic solvent, and reacting the compound with a compound VI under reflux to obtain a compound shown in a formula VII;

   3) dissolving the formula VII in an organic solvent, and acidifying under the action of 50% concentrated sulfuric acid under reflux to obtain a compound shown in the formula VIII;

   4) dissolving the formula VIII in an organic solvent, and decarboxylating at 110 ℃ to obtain a compound of a formula II;

   

   。
2. 2. the process according to claim 1, wherein the organic solvent used in step 1 is preferably ethanol, and the amount of the solvent is 5 to 15 times, preferably 5 to 7 times (volume to mass ratio) that of the compound II.
3. 3. The method according to claim 1, wherein the reaction temperature used in step 1 is preferably 80 to 100 ℃.
4. 4. The process according to claim 1, wherein the organic solvent used in step 2 is preferably tetrahydrofuran, and the amount of the solvent is preferably 5 to 15 times, preferably 5 to 7 times (volume to mass ratio) the amount of the compound V.
5. 5. The process according to claim 1, wherein the acid used in step 3 is preferably 50% concentrated sulfuric acid solution in an amount of 10 to 30 times, preferably 10 to 15 times (volume to mass ratio) the amount of compound VII.
6. 6. The process according to claim 1, wherein the reaction of step 4 is carried out using a solvent, preferably toluene, preferably 10 to 30 times, preferably 10 to 15 times (volume to mass ratio) the amount of compound VIII.
7. 7. The method according to claim 1, wherein the reaction temperature in step 5 is preferably 110 to 120 ℃.
8. 8. The method according to claim 1, wherein the reaction temperature in step 5 is preferably 20-30 h.