| 第 51 卷第 4 期 |  | Vol. 51 No. 4 | | 2021 年 8 月 | Aug 2021 |
|
所屬欄目：醫藥及中間體
利伐沙班的合成工藝改進(jìn)及其對映異構體雜質(zhì)的制備 |
| 吳世剛，湯 燕，韓愛(ài)華，黃 勇，黃 凱*
（宿州億帆藥業(yè)有限公司，安徽 宿州 234000） |
| 摘 要：改進(jìn)了利伐沙班（1）的合成工藝。以4-（4-氨基苯基）-3-嗎啉酮（2）為起始原料、與R-環(huán)氧氯丙烷（7）加成，再與N，N'-羰基二咪唑環(huán)合、與鄰苯二甲酰亞胺鉀（8）取代，然后在水合肼中水解，最后與5-氯噻吩-2-甲酰氯（9）經(jīng)�；磻频美ド嘲喑善�，總收率達46.1%，產(chǎn)品純度大于99.8%，最大單雜小于0.1%。為了控制1 的質(zhì)量，建立1 原料藥的質(zhì)量標準，根據改進(jìn)的工藝合成路線(xiàn)，將產(chǎn)品的e.e值提高到99%以上，制備了對映異構體雜質(zhì)（有關(guān)物質(zhì)A），并經(jīng)MS和NMR確認結構。 |
| 關(guān)鍵詞：利伐沙班；對映異構體；有關(guān)物質(zhì) |
| 中圖分類(lèi)號：R97 文獻標識碼：A 文章編號：1009-9212（2021）04-0020-04 |
|
| Improved Synthetic Process for Rivaroxaban and Its Related Substances |
| WU Shi-gang, TANG Yan, HAN Ai-hua, HUANG Yong, HUANG Kai*
(Suzhou Yifan Pharmaceutial Co.,Ltd., Suzhou 234000, China) |
| Abstract：The synthetic process for Rivaroxaban (1) was improved. 4-(4-aminophenyl)-3-morpholinone (2) was used as the starting material and reacted with R-epichlorohydrin(7) followed by addition, cyclization reaction with N,N'-carbonyldiimidazole; substitution with potassium phthalimide(8); then hydrolyzed in hydrazine hydrate, and finally with 5-chlorothiophene-2-carboxylic acid chloride(9). The final product of rivaroxaban was prepared by acylation reaction with a total yield of 46.1%. A purity of more than 99.8% with the maximum single impurity of less than 0.1% was obtained. In order to control the quality of 1 and establish the quality standard of 1 API, the e.e value of the product was increased to more than 99% according to this improved synthetic process while the enantiomeric impurity (related substance A) was prepared. The enantiomeric impurity was also confirmed by MS and NMR. |
| Key words：rivaroxaban; enantiomers; related substance |
|
基金項目：安徽省科技重大專(zhuān)項（812116803026）
|
作者簡(jiǎn)介：吳世剛（1986—），男，湖南邵陽(yáng)人，執業(yè)藥師，碩士，主要從事原料藥的研發(fā)和產(chǎn)業(yè)化生產(chǎn)。
|
收稿日期：2021-08-26
|
|