阅读说明：本技术 一种制备噁拉戈利中间体的方法及其组合物 (Method for preparing oxa-goril intermediate and composition thereof ) 是由 苏虎 郭效文 梁玉坤 石凯强 杨锦涛 何康 陶安平 黄鲁宁 安建国 陈茜 顾虹 于 2018-12-25 设计创作，主要内容包括：本发明涉及一种噁拉戈利钠中间体(式IV)的制备方法,所述方法通过下面的路线制备,该方法操作简捷安全,收率良好,同时环境污染小,有很好的经济效应,适宜工业生产,<Image he="496" wi="700" file="DDA0002543547840000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中R代表C1-4取代或不取代的苄基、烯丙基。(The invention relates to a preparation method of an oxa-goril sodium intermediate (formula IV), which is prepared through the following route, has the advantages of simple and safe operation, good yield, small environmental pollution, good economic effect and suitability for industrial production,)

A process for the preparation of an oxadegril intermediate of the compound of formula IV, which comprises: carrying out ammonolysis reaction on a compound of formula I and a compound of formula II in a mixed solvent of an organic solvent and water, and then closing a ring under the catalysis of acid to prepare a compound of formula IV

Wherein R is selected from linear or branched C1-C4 substituent or benzyl.

The method according to claim 1, wherein the linear or branched C1-C4 substituent is an alkyl group or an alkenyl group; the alkyl group is preferably a methyl group, an ethyl group, an isopropyl group or a tert-butyl group; the alkenyl group is preferably an allyl group.

The production method according to claim 1 or 2, characterized in that the organic solvent is an aprotic organic solvent; preferably one or more selected from toluene, chlorobenzene, xylene, N-Dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).

The method according to any one of claims 1 to 3, wherein the organic solvent is toluene.

The method according to any one of claims 1 to 4, wherein the volume ratio of the organic solvent to water is 1: 0.001 to 2, preferably 1: 0.1 to 1.0.

The preparation method according to any one of claims 1 to 5, wherein the mass of the compound of formula I and the compound of formula II is 1: 0.66-4, preferably 1: 1.5-2.0.

The preparation method according to any one of claims 1 to 6, wherein the ratio of the mass of the compound of formula II to the volume of the mixed solvent is 1:8 to 1:20 in g/ml.

The method as claimed in any one of claims 1 to 7, wherein the ammonolysis reaction is carried out at a temperature of 80 to 150 ℃, preferably at a temperature of 100 ℃ to 120 ℃.

The preparation method according to any one of claims 1 to 8, wherein the reaction temperature for preparing the compound of formula IV by ring closure under acid catalysis is 40-150 ℃, preferably 60-120 ℃.

The process according to any one of claims 1 to 9, wherein the acid is selected from the group consisting of p-toluenesulfonic acid, methanesulfonic acid, disodium hydrogen phosphate, preferably p-toluenesulfonic acid.

The production method according to any one of claims 1 to 10, characterized in that: the mass ratio of the compound shown in the formula II to the acid is 1: 0.5-1.5.

A composition comprises a compound shown in the formula IV with the mass percent of not less than 99.5 percent and a compound shown in the formula IV-imp with the mass percent of not more than 0.5 percent

The composition of claim 12, wherein the mass percentages are determined by HP L C area normalization.