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Method for preparing intermediate of ecteinascidin-743

A compound and protecting group technology, which is applied in the preparation field of ascidine-743 intermediate, can solve the problems of cumbersome operation, unsuitability for large-scale production, and high cost

Active Publication Date: 2015-04-29
JIANGSU HENGRUI MEDICINE CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In summary, the synthesis process of the above key intermediate I is not only costly and cumbersome, but also has potential safety hazards and is not suitable for large-scale production.

Method used

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  • Method for preparing intermediate of ecteinascidin-743
  • Method for preparing intermediate of ecteinascidin-743
  • Method for preparing intermediate of ecteinascidin-743

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0077] Embodiment 1: Preparation of compound Xa

[0078] Compound XIIIa (120g, prepared according to the literature J.Am.Chem.Soc.1997,119,12414) was dissolved in dichloromethane (240mL) and toluene (70mL), and after cooling down to 10 degrees, tribrominated Phosphorus (240g) was reacted at 20°C for 2 hours, water (240mL) was added to quench the reaction, the organic phase was dried over anhydrous sodium sulfate, and concentrated to obtain compound Xa (140g, yield 95%).

[0079] 1 H-NMR (400MHz, CDCl 3 )δ7.52-7.50 (m, 2H), 7.44-7.36 (m, 3H), 6.71 (s, 1H), 5.96 (s, 2H), 4.95 (s, 2H), 4.54 (s, 2H), 2.20 (s,3H).

Embodiment 2

[0080] Embodiment 2: preparation compound IXa

[0081] Compound XIa (24g, prepared according to the document J.Org.Chem.1982,47,2663) was dissolved in toluene (600mL), and the chiral phase transfer catalyst XIIa (4.9g, prepared according to the document J.Am.Chem.Soc. 1997,119,12414), after cooling to -20 degrees, add cesium hydroxide hydrate (68.2g) and compound Xa (29.8g), react at -20 degrees for 15 hours, add tert-butyl methyl ether (240mL) , the organic phase was dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound IXa (38 g, yield 75%, 95% ee).

[0082] 1 H-NMR (400MHz, CDCl 3 )δ7.59-7.56(m,2H),7.37-7.25(m,2H),6.76-6.74(m,2H),6.46(s,1H),5.87(s,2H),4.71-4.68(d, 1H),4.46-4.43(d,1H),4.28-4.24(m,1H),4.13-4.11(m,1H),3.30-3.25(m,1H),3.12-3.06(m,1H),2.09( s,3H), 1.42(s,9H).

Embodiment 3

[0083] Embodiment 3: preparation compound VIIIa

[0084]Dissolve compound IXa (57.5g) in tetrahydrofuran (690mL), add 0.5M citric acid aqueous solution (265mL), react at 20°C for 10 hours, add sodium bicarbonate to neutralize the reaction solution, add ethyl acetate (345mL) to extract , the organic phase was dried with anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain compound VIIIa (38.1 g, yield 88%).

[0085] 1 H-NMR (400MHz, CDCl 3 )δ7.47-7.45(m,2H),7.41-7.32(m,3H),6.56(s,1H),5.92(s,2H),4.78(s,2H),3.64-3.61(m,1H) ,3.04-2.99(m,1H),2.66-2.60(m,1H),2.19(s,3H),1.42(s,9H).

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Abstract

The invention relates to a method for preparing an intermediate of ecteinascidin-743 and particularly relates to a method for preparing an intermediate which is used for synthesizing ecteinascidin-743 and is represented by the formula I as shown in the description. The method comprises the following steps of carrying out protecting group conversion on a compound represented by the formula X as shown in the description in the presence of a chiral phase transfer catalyst to obtain a chiral intermediate represented by the formula V as shown in the description, carrying out esterification reaction on the intermediate V to obtain an intermediate represented by the formula IV as shown in the description and then carrying out intramolecular cyclization reaction and removing the protecting groups to obtain the intermediate which is used for synthesizing ecteinascidin-743 and is represented by the formula I. The method has the advantages of mild reaction conditions, simplicity in operation, low synthesis cost and the like and is suitable for mass production.

Description

technical field [0001] The invention relates to a preparation method of an ascidine-743 intermediate. Background technique [0002] Escidine-743 (ET-743) is a tetrahydroisoquinoline alkaloid with high antitumor activity isolated from the Caribbean sea squirt, and its antitumor activity is mainly through the formation of iminium ions or It is achieved by modifying DNA by alkylation similar to intermediates (Chem. Rev. 2002, 102, 1669). ET-743 has inhibitory activity against breast cancer, non-small cell lung cancer, colon cancer, kidney cancer, ovarian cancer, endometrial cancer, melanoma, osteosarcoma and prostate cancer, and is a novel anti-cancer drug that can bind to DNA. cancer drugs. Haiscidine-743 was developed by PharmMar, Spain, and was approved for marketing in the European Union in 2007 as a rare drug for the treatment of soft tissue sarcoma. It is used to treat patients with advanced soft tissue sarcoma who have failed traditional chemotherapy. [0003] The con...

Claims

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Application Information

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IPC IPC(8): C07D317/64C07D498/18
CPCC07D317/64C07D498/18Y02P20/55
Inventor 张富尧任国宝胡高强罗扬
Owner JIANGSU HENGRUI MEDICINE CO LTD
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