A kind of preparation method of levetiracetam key intermediate (s)-2-aminobutanamide salt

A technology of aminobutyramide salts and intermediates, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of poor product yield and purity, difficulties in the preparation of by-products, and many impurities, and achieve easy control of reactions, simple recovery, and process safety high effect

Active Publication Date: 2020-11-10
ZHUHAI UNITED LAB
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Wherein, the by-product that 2-bromobutyric acid reacts with ammonia water is difficult to prepare, and the yield is relatively low. In addition, the reaction is slow during ammonolysis, causing partial degradation, and the yield and purity of the product are relatively poor.
Chinese patent CN201010558447 reports the preparation method of (S)-2-aminobutanamide, first generates 2-bromobutanamide, regenerates racemic 2-aminobutanamide, and finally obtains the product by chiral resolution, but the method impurity many, low yield

Method used

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  • A kind of preparation method of levetiracetam key intermediate (s)-2-aminobutanamide salt
  • A kind of preparation method of levetiracetam key intermediate (s)-2-aminobutanamide salt
  • A kind of preparation method of levetiracetam key intermediate (s)-2-aminobutanamide salt

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add compound 1 (11.7g, 0.1mol) into 100mL of methanol, cool down to 0-5°C, pass ammonia gas to saturation, react at room temperature for 36h, after the reaction is complete, concentrate to dryness, add 50mL of methanol, and pass through ammonia gas for 1h , react at room temperature for 2 h, filter, concentrate to dryness, add 100 mL of methanol, dropwise add methanolic hydrochloric acid solution, dropwise, grow crystals for 1 h, filter, wash with methanol, and dry in vacuo to obtain compound 2 (12.5 g, molar yield 90.2%) ESI- MS(m / z)=103.2[M+H] + ; 1 HNMR (D 2 (2, 400MHz) δ: 1.0 (t, 3H), 1.9 (m, 2H), 4.2 (t, 1H), HPLC purity 99.9%, the proton nuclear magnetic resonance spectrum of compound 2 is as figure 1 shown.

Embodiment 2

[0037] Add compound 1 (11.7g, 0.1mol) into 100mL of ethanol, cool down to 0-5°C, pass ammonia gas to saturation, react at room temperature for 36h, after the reaction is completed, concentrate to dryness, add 50mL of ethanol, and pass through ammonia gas for 1h , react at room temperature for 2 h, filter, concentrate to dryness, add 100 mL of ethanol, dropwise add ethanol hydrochloric acid solution, dropwise, grow crystals for 1 h, filter, wash with ethanol, and dry in vacuo to obtain compound 2 (12.7 g, molar yield 91.6%) ESI- MS(m / z)=103.2[M+H] + ; 1 HNMR (D 2 (2, 400MHz) δ: 1.0 (t, 3H), 1.9 (m, 2H), 4.2 (t, 1H), the HPLC purity is 99.9%, and the proton nuclear magnetic resonance spectrum of compound 2 is as figure 2 shown.

Embodiment 3

[0039] Add compound 1 (11.7g, 0.1mol) into 100mL of isopropanol, cool down to 0-5°C, pass ammonia gas to saturation, react at room temperature for 36h, after the reaction is complete, concentrate to dryness, add 50mL of isopropanol, pass through Add ammonia gas for 1 h, react at room temperature for 2 h, filter, concentrate to dryness, add 100 mL of isopropanol, add isopropanol hydrochloride solution dropwise, dropwise, grow crystals for 1 h, filter, wash with isopropanol, and dry in vacuo to obtain compound 2 (12.9 g, molar yield 92.8%) ESI-MS (m / z) = 103.2 [M+H] + ; 1 HNMR (D 2 (2, 400MHz) δ: 1.0 (t, 3H), 1.9 (m, 2H), 4.2 (t, 1H), the HPLC purity is 99.9%, and the proton nuclear magnetic resonance spectrum of compound 2 is as image 3 shown.

[0040] By embodiment 1~3 and Figure 1 ~ Figure 3 It can be seen that the preparation method of the levetiracetam key intermediate (S)-2-aminobutyramide salt of the present invention is simple to operate, and the yield and purity a...

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Abstract

The invention discloses a preparation method of (S)-2-aminobutanamide as a key intermediate for levetiracetam, which belongs to the technical field of drug intermediate synthesis. According to the preparation method disclosed by the invention, a compound 1 undergoes ammonolysis reaction in C1-C3 alkyl alcohol, vacuum concentration is carried out until a dry state is formed after the reaction is complete, an alcoholic solvent is added, ammonia is further injected for freeing, an alcoholic solvent is added for clarification by dissolution after filtration and concentration, crystals are grown after an acidic alcoholic solvent is dripped for salification, a compound 2 is obtained by preparation and purification, wherein X is hydrochloric acid, hydrobromic acid or methanesulfonic acid. The preparation method disclosed by the invention is simple and effective, yield and purity are greatly increased, molar yield is higher than 90 percent, purity is higher than 99.5 percent, a high-quality intermediate is provided for the subsequent preparation of the levetiracetam, the preparation method does not have the step of chiral resolution, and adopts only one type of solvent, recovery is simple,three types of wastes are fewer, and the preparation method meets the requirement of industrial production.

Description

technical field [0001] The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a preparation method of (S)-2-aminobutyramide salt, a key intermediate of levetiracetam. Background technique [0002] Levetiracetam (Levetiracetam), chemical name: (S)-2-(2-oxo-1-pyrrolidine) butyramide, a second-generation acetylcholine agonist developed by Belgium UCB company, the trade name is Kaipu Lan (KEPPRA), which is mainly used for localized and secondary generalized epilepsy, was approved by the US FDA in April 2000 and was launched in the US, UK, Switzerland and other countries. Compared with most antiepileptic drugs, levetiracetam has stronger antiepileptic properties and can effectively control epileptic seizures. The drug not only has a high therapeutic index, but also has unique pharmacokinetic characteristics, rapid and safe oral absorption, and a bioavailability of 100%. Its pharmacokinetic distribution is similar to the idea...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C231/02C07C237/06
CPCC07B2200/07C07C231/02C07C231/12C07C237/06
Inventor 刘宏宇徐静乔明福许华锋窦振国
Owner ZHUHAI UNITED LAB
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