Title:
PREPARATION METHOD FOR APREPITANT INTERMEDIATE IMPURITY
Document Type and Number:
WIPO Patent Application WO/2021/103327
Kind Code:
A1
Abstract:
The present invention relates to a preparation method for an aprepitant intermediate impurity. The preparation method comprises the following reaction steps: (A) carrying out a Grignard reaction on a raw material 1 and a Grignard reagent 4-fluorophenylmagnesium halide; (B) carrying out a reduction reaction on a reaction product obtained in step (A) and a reducing agent to obtain a compound 4; (C) carrying out a debenzylation reaction on the obtained compound 4 and a deprotection reagent to obtain a crude product 5; (D) reacting the obtained crude product 5 with a protective reagent in the presence of a solvent and an alkali to obtain a compound 6; and (E) carrying out a deprotection reaction on the obtained compound 6 and an acid or alkali in the presence of a solvent, and carrying out separation and purification to obtain a refined product 5. According to the method, the compound 4 is obtained by means of the reduction reaction, and then undergoes the debenzylation reaction to synthesize the compound 5, so the compound 5 can be successfully synthesized, and the yield and purity of the crude product 5 are greatly improved. Furthermore, the crude product 5 reacts with the protective reagent and is purified to obtain the compound 6, and the compound 6 is subjected to the deprotection reaction, and then is separated by means of conventional column chromatography to obtain the high-purity compound 5.
Inventors:
LI SUYONG (CN)
MENG FAMING (CN)
WEN JINTAO (CN)
GUO JUN (CN)
MAO BO (CN)
LI YANXIONG (CN)
XU LIANG (CN)
MENG FAMING (CN)
WEN JINTAO (CN)
GUO JUN (CN)
MAO BO (CN)
LI YANXIONG (CN)
XU LIANG (CN)
Application Number:
PCT/CN2020/076463
Publication Date:
June 03, 2021
Filing Date:
February 24, 2020
Export Citation:
Assignee:
ENANTIOTECH CORPORATION LTD (CN)
GUANGXI ENANTIOTECH PHARMACEUTICAL CO LTD (CN)
GUANGXI ENANTIOTECH PHARMACEUTICAL CO LTD (CN)
International Classes:
C07C213/00; C07C217/10
Other References:
KAREL M.J.BRANDS: "Efficient Synthesis of NK1 Receptor Antagonist Aprepitant Using a Crystallization -Induced Diastereoselective Transformation", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 125, no. 8, 30 January 2003 (2003-01-30), XP002742845, ISSN: 1520-5126
WAN WEI-LI; HE YUN; GUAN MEI; LI XIAO-LONG; CHENG XU; WU YONG: "Synthesis of the major isomers of Aprepitant and Fosaprepitant", CHINESE CHEMICAL LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 24, no. 12, 18 September 2013 (2013-09-18), AMSTERDAM, NL, pages 1118 - 1122, XP028786548, ISSN: 1001-8417, DOI: 10.1016/j.cclet.2013.07.017
WAN WEI-LI; HE YUN; GUAN MEI; LI XIAO-LONG; CHENG XU; WU YONG: "Synthesis of the major isomers of Aprepitant and Fosaprepitant", CHINESE CHEMICAL LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 24, no. 12, 18 September 2013 (2013-09-18), AMSTERDAM, NL, pages 1118 - 1122, XP028786548, ISSN: 1001-8417, DOI: 10.1016/j.cclet.2013.07.017
Attorney, Agent or Firm:
ADVANCE CHINA IP LAW OFFICE (CN)
Download PDF: