阅读说明：本技术 4取代-γ丁内酯的制备方法 (Preparation method of 4-substituted-gamma butyrolactone ) 是由 张翠燕 李恩民 赵国磊 于 2018-08-01 设计创作，主要内容包括：本发明属于药物化学领域,涉及式Ⅰ所示的(R)-4-丙基-二氢呋喃-2-酮的制备。<Image he="105" wi="138" file="470639DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention belongs to the field of pharmaceutical chemistry, and relates to preparation of (R) -4-propyl-dihydrofuran-2-ketone shown in a formula I.)

1. A process for the preparation of formula i, comprising the steps of:

。

2. the process according to claim 1, wherein the alcohol selected for the preparation of compound VI by monoesterification is selected from the group consisting of methanol, ethanol, isopropanol, tert-butanol, etc., preferably tert-butanol.

3. The process according to claim 1, wherein the esterification catalyst in the preparation of compound VI is Amberlyst 15, DCC, concentrated sulfuric acid, or the like, preferably Amberlyst 15.

4. The process according to claim 1, wherein the compound VII is prepared by a hydrogenation reduction reaction at room temperature and atmospheric pressure;

5. a process according to claim 1 wherein the reducing agent used in the preparation of compound viii is borane dimethylsulfide or a sodium borohydride and iodine system.

Technical Field

The invention belongs to the field of pharmaceutical chemistry, and relates to preparation of (R) -4-propyl-dihydrofuran-2-ketone shown in a formula I.

Background

Brivaracetam (Brivaracetam), with the chemical name of (2S) -2- [ (4R) -2-oxo-4-propylpyrrolidin-1-yl ] butanamide, is a third-generation antiepileptic drug developed by uclb corporation, belgium, and is very similar in chemical structure and mechanism of action to the previous-generation drug levetiracetam. The FDA has formal approval for marketing in month 2 of 2016 and has been used as an adjunctive therapeutic for the treatment of partial seizures, with or without secondary generalized seizures, in adults and juvenile epileptic patients over the age of 16. The brivaracetam is a second-generation SV2A ligand with high selectivity and high affinity, influences synaptic function by combining with central synaptobrevin 2A (SV 2A), and is used as a sodium channel inhibitor with high affinity to obviously improve anti-epileptic activity. The compound has unique antiepileptic mechanism, better pharmacokinetic property, safety and high-efficiency clinical effect, and becomes one of the most promising novel antiepileptic drugs.

In the process of preparing the bravaracetam, the compound (I) is frequently used, but the preparation method of the compound is difficult, the required reaction conditions are harsh or the solvent reagent has high risk.

Disclosure of Invention

The invention provides a preparation method of (R) -4-propyl-dihydrofuran-2-ketone shown in formula I, which is used for ensuring the qualification of related substances of a final product of the brivaracetam and realizing industrial production.

The preparation method comprises the following steps:

1. in an organic solvent, dimethyl fumarate (II) and nitropropane (III) react to obtain a compound shown as a formula (IV).

2. And (3) carrying out hydrolysis reaction on the compound of the formula (IV) to obtain the compound of the formula (V).

3. The compound of the formula (V) is subjected to mono-esterification, catalytic hydrogenation reaction and resolution respectively to obtain the compound of the formula (VII).

4. The compound of formula (VI) is reduced and acidified to lactone to obtain the compound of formula (I).

The invention has the following beneficial effects: firstly, the raw materials are cheap and easy to obtain, the cost is low, the environment is protected, and conditions are provided for industrial production; secondly, the operation is simple and convenient, the process is stable, the product purity is high, and the method is favorable 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.