Synthesis, split and racemization method for preparing chirality medicament levetiracetam midbody (S)-(+)-2-amido butyramide hydrochlorate

Abstract

The invention discloses a new synthesizing technique of chiral drug (S)-alpha-ethyl-2-oxo-1-pyrrolidine acetamide ( left Piracetam) intermediate (S)-(+)-2-aminobutanamide hydrochlorate, which comprises the following steps: adopting 2-brobutyrate as initial raw material; aminating; esterifying; ammonolyzing; detaching; looping; obtaining the object compound; making mixed rotary free alkaline (+-)-2-aminobutanamide; adopting half-quantum resolution method to connect chemical detaching salt to evolve salt; removing the detaching agent through alkalization; obtaining the (S)-(+)-2-aminobutanamidehydrochlorate with optical activity; using the mother liquor to make the product. The invention improves the receiving rate and saves the cost of raw material with simply technical operation and low cost, which resolves the resolved mother liquor after racemic action again to reduce the pollution of environment, therefore fitting for industrialized manufacturing.

Description

technical field

[0001] The invention relates to the technical field of preparation of chiral drug intermediates. In particular, it relates to the synthesis, resolution and racemization methods of the chiral drug levetiracetam intermediate (S)-(+)-2-aminobutyramide hydrochloride. Background technique

[0002] The preparation method of chiral drug levetiracetam has been reported in the literature, such as EP1566376, CN1015541B and CN1583721A have introduced the synthesis of the compound respectively, the main route has, the first is starting raw material with L-2-aminobutyric acid, through Esterification, ammonolysis, cyclization or first cyclization, esterification, and then ammonolysis, the target compound. Although this route has few steps, the starting material L-2-aminobutyric acid is expensive and the cost is higher. The second is to use n-propionaldehyde as the starting material to prepare the target compound through six steps of Streck reaction, hydrolysis, resoluti...

Examples

Embodiment 1

[0040] 1.1: Preparation of 2-aminobutyric acid

[0041] In a 5000ml flask, 1500ml of 28% ammonia water was added, and 500g of 2-bromobutyric acid was added dropwise at room temperature. After the dropwise addition was completed, the mixture was heated to 40° C. and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was purified with methanol to obtain 220 g of white crystalline 2-aminobutyric acid with a yield of 71% and a content of 99.45%.

[0042] 1.2: Preparation of the swirled free base (±)-2-aminobutanamide

[0043] In a 2000ml flask, add 88g (0.854mol) 2-aminobutyric acid, 600ml methanol, cool to below 0°C, add dropwise 142.6g (1.2mol) thionyl chloride, after the dropwise addition, reflux for 3 hours and concentrate under reduced pressure Remove methanol, add 400 ml of ammonia water, extract with 400 ml of dichloromethane, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure to remove the solv...

Embodiment 2

[0050] 2.1: Preparation of 2-aminobutyric acid

[0051] In a 5000ml flask, 2400ml of 28% ammonia water was added, and 800g of 2-bromobutyric acid was added dropwise at room temperature. After the addition was completed, it was heated to 40°C and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was refined with methanol to obtain 340 g of white crystal 2-aminobutyric acid with a yield of 68.9% and a content of 99.3%.

[0052] 2.2: Preparation of vortexed free base (±)-2-aminobutyramide

[0053] In a 5000ml flask, add 325g of 2-aminobutyric acid and 2200ml of methanol, cool to below 0°C, add 527g (1.2mol) of thionyl chloride dropwise, after the dropwise addition, reflux for 3 hours, concentrate under reduced pressure to remove methanol, and add 1480ml of ammonia water , extracted with 1500ml of dichloromethane, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to remove the solvent, added 244...

Embodiment 3

[0060] 3.1: Preparation of 2-aminobutyric acid

[0061] In a 5000ml flask, 2400ml of 28% ammonia water was added, and 800g of 2-bromobutyric acid was added dropwise at room temperature. After the addition was completed, it was heated to 40°C and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was refined with methanol to obtain 355 g of white crystal 2-aminobutyric acid, with a yield of 71.9% and a content of 99.0%.

[0062] 3.2: Preparation of vortexed free base (±)-2-aminobutyramide

[0063] In a 5000ml flask, add 350g 2-aminobutyric acid and 2300ml methanol, cool to below 0°C, add 549g thionyl chloride dropwise, after the dropwise addition, reflux for 3 hours, concentrate under reduced pressure to remove methanol, add 1540ml concentrated ammonia water, use 1540ml Extract with dichloromethane, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure to remove solvent, add 2540ml of anhydrous methano...

technical field

[0001] The invention relates to the technical field of preparation of chiral drug intermediates. In particular, it relates to the synthesis, resolution and racemization methods of the chiral drug levetiracetam intermediate (S)-(+)-2-aminobutyramide hydrochloride. Background technique

[0002] The preparation method of chiral drug levetiracetam has been reported in the literature, such as EP1566376, CN1015541B and CN1583721A have introduced the synthesis of the compound respectively, the main route has, the first is starting raw material with L-2-aminobutyric acid, through Esterification, ammonolysis, cyclization or first cyclization, esterification, and then ammonolysis, the target compound. Although this route has few steps, the starting material L-2-aminobutyric acid is expensive and the cost is higher. The second is to use n-propionaldehyde as the starting material to prepare the target compound through six steps of Streck reaction, hydrolysis, resoluti...

Examples

Embodiment 1

[0040] 1.1: Preparation of 2-aminobutyric acid

[0041] In a 5000ml flask, 1500ml of 28% ammonia water was added, and 500g of 2-bromobutyric acid was added dropwise at room temperature. After the dropwise addition was completed, the mixture was heated to 40° C. and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was purified with methanol to obtain 220 g of white crystalline 2-aminobutyric acid with a yield of 71% and a content of 99.45%.

[0042] 1.2: Preparation of the swirled free base (±)-2-aminobutanamide

[0043] In a 2000ml flask, add 88g (0.854mol) 2-aminobutyric acid, 600ml methanol, cool to below 0°C, add dropwise 142.6g (1.2mol) thionyl chloride, after the dropwise addition, reflux for 3 hours and concentrate under reduced pressure Remove methanol, add 400 ml of ammonia water, extract with 400 ml of dichloromethane, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure to remove the solv...

Embodiment 2

[0050] 2.1: Preparation of 2-aminobutyric acid

[0051] In a 5000ml flask, 2400ml of 28% ammonia water was added, and 800g of 2-bromobutyric acid was added dropwise at room temperature. After the addition was completed, it was heated to 40°C and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was refined with methanol to obtain 340 g of white crystal 2-aminobutyric acid with a yield of 68.9% and a content of 99.3%.

[0052] 2.2: Preparation of vortexed free base (±)-2-aminobutyramide

[0053] In a 5000ml flask, add 325g of 2-aminobutyric acid and 2200ml of methanol, cool to below 0°C, add 527g (1.2mol) of thionyl chloride dropwise, after the dropwise addition, reflux for 3 hours, concentrate under reduced pressure to remove methanol, and add 1480ml of ammonia water , extracted with 1500ml of dichloromethane, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to remove the solvent, added 244...

Embodiment 3

[0060] 3.1: Preparation of 2-aminobutyric acid

[0061] In a 5000ml flask, 2400ml of 28% ammonia water was added, and 800g of 2-bromobutyric acid was added dropwise at room temperature. After the addition was completed, it was heated to 40°C and reacted for 12 hours. It was concentrated to dryness under reduced pressure, and the residual solid was refined with methanol to obtain 355 g of white crystal 2-aminobutyric acid, with a yield of 71.9% and a content of 99.0%.

[0062] 3.2: Preparation of vortexed free base (±)-2-aminobutyramide

[0063] In a 5000ml flask, add 350g 2-aminobutyric acid and 2300ml methanol, cool to below 0°C, add 549g thionyl chloride dropwise, after the dropwise addition, reflux for 3 hours, concentrate under reduced pressure to remove methanol, add 1540ml concentrated ammonia water, use 1540ml Extract with dichloromethane, dry over anhydrous magnesium sulfate, filter, concentrate under reduced pressure to remove solvent, add 2540ml of anhydrous methano...

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