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Amrubicin hydrochloride intermediate compound I

A technology of amrubicin hydrochloride and amrubicin, which is applied in the field of medicine, can solve the problems of low conversion rate and long production cycle, and achieve the effects of high conversion rate, reduced splitting, and mild use conditions

Inactive Publication Date: 2020-09-11
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] For the current important intermediate of amrubicin (R)-(-)-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid methyl ester (Z- 3) The racemate existing in the preparation process needs to be obtained by chiral resolution, causing the problems of longer production cycle and low conversion rate; the present invention provides a new compound as shown in I; and provides a method using the compound by hand The important intermediate of amrubicin (R)-(-)-2-amino-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthoic acid methyl ester (Z- 3) synthetic route; this synthetic route is easy and simple to operate, and reaction condition is gentle, and production cycle is shorter, and yield is higher, is more suitable for industrialized production

Method used

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  • Amrubicin hydrochloride intermediate compound I
  • Amrubicin hydrochloride intermediate compound I
  • Amrubicin hydrochloride intermediate compound I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Under argon protection, at room temperature, add I-1 (10.31g, 0.050mol), (R)-tert-butylsulfinamide (9.70g, 0.080mol) and tetrabutyl titanate (28.93g, 0.085mol) In dry tetrahydrofuran (200mL), react at 40-45°C for 3 hours. After the reaction is detected, pour the reaction solution into saturated aqueous sodium carbonate solution (200mL), extract with dichloromethane (150mL×2), and place it on a pad of silicon Filter through alginate, dry the filtrate with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain I-2, with a molar yield of 94.9%, a purity of 99.74% by HPLC, and an optical purity of 99.98% by HPLC.

Embodiment 2

[0085] Under argon protection, at room temperature, I-1 (10.31g, 0.050mol), (R)-tert-butylsulfinamide (6.67g, 0.055mol) and tetrabutyl titanate (28.93g, 0.085mol) were added In dry chloroform (220mL), react at 40-45°C for 3 hours. After the reaction is detected, pour the reaction solution into saturated aqueous sodium carbonate solution (200mL), extract with chloroform (150mL×2), and pad with diatomaceous earth After filtration, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2, with a molar yield of 92.6%, a purity of 99.60% by HPLC, and an optical purity of 99.98% by HPLC.

Embodiment 3

[0087]Under argon protection, at room temperature, add I-1 (10.31g, 0.050mol), (R)-tert-butylsulfinamide (6.06g, 0.050mol) and tetrabutyl titanate (28.93g, 0.085mol) In dry tetrahydrofuran (200mL), react at 40-45°C for 3 hours. After the completion of the reaction, pour the reaction solution into saturated aqueous sodium carbonate solution (200mL), extract with dichloromethane (150mL×2), pad silicon After filtration with alginate, the filtrate was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain I-2. The molar yield was 91.2%. The purity by HPLC was 99.58%, and the optical purity by HPLC was 99.97%.

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to an amrubicin hydrochloride intermediate compound and a preparation method thereof. A novel intermediate is provided, and is used for synthesizing the amrubicin hydrochloride important intermediate. The preparation method solves the problem of low yield caused by chiral resolution of the amrubicin intermediate inthe prior art, and the new intermediate compound synthesized through chirality has the advantages of high product yield, simple operation, substantial reduction of the production cost, and suitableness for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to an amrubicin hydrochloride intermediate compound and a preparation method thereof. Background technique [0002] Amrubicin hydrochloride (amrubicin hydrochloride), the chemical name is (+)-(7S,9S)-9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pyranpental Glycosyl)oxy]-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-tetracenedione hydrochloride, its chemical structure is as follows: [0003] [0004] Amrubicin hydrochloride is a novel anthracycline anti-cancer drug developed by Sumiotmo Co., Ltd., which is characterized by the 9-position amino group and sugar structure, and is chemically fully synthesized. It was registered in Japan in 2002 and Launched (trade name: Calsed). It is clinically used for the treatment of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). As an anthracycline drug, its mechanism of action is slightly different from that of doxor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/50C07C227/02C07C227/18C07C255/47C07C253/30C07C313/06C07H15/252C07H1/00
CPCC07C229/50C07C227/02C07C227/18C07C253/30C07C313/06C07H15/252C07H1/00C07B2200/07C07C2602/10C07C255/47
Inventor 张乃华吴空
Owner LUNAN PHARMA GROUP CORPORATION
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