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Intermediate product of trabectedin as well as preparation method and application thereof

A technology of racemates and tautomers, which is applied in the key intermediate of trabectedin and its preparation field for the treatment of advanced soft tissue sarcoma, can solve the problem that the influence of reaction temperature is very large, the reaction time is too long, and the reaction system changes. Miscellaneous problems, to achieve the effect of shortening the number of reaction steps, controllable reaction and stable yield

Active Publication Date: 2018-07-13
SHANGHAI HAOYUAN CHEMEXPRESS
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, the inventors have found in experiments that when Compound 6 is prepared from Compound 7 by reduction, the way of adding methanol and the reaction temperature have a great influence on the reaction: if the addition rate is slightly faster or the temperature of the reaction system is higher than 0°C , the reaction system is relatively complex, and a large amount of cyano group reduction by-products will be produced, especially in the scale-up experiment, the local thermal effect and uneven concentration will be generated when methanol is added dropwise, which makes the phenomenon of reaction system becoming more complicated; if the drop rate Slow or the temperature of the reaction system is lower than 0°C, the reduction reaction proceeds very slowly, the conversion rate is low, the reaction time is too long, and the generation of by-products of cyano group reduction can still be detected

Method used

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  • Intermediate product of trabectedin as well as preparation method and application thereof
  • Intermediate product of trabectedin as well as preparation method and application thereof
  • Intermediate product of trabectedin as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1: the preparation of compound C-1

[0043]

[0044] Dissolve compound D-1 (34g, 42.08mmol) in acetonitrile (500mL) at room temperature, add pyridine hydrogen fluoride (62.55g, 0.631mol), stir at room temperature until the reaction of raw materials monitored by TLC is complete, and the reaction solution is washed with dichloromethane (1.5L) Diluted, washed successively with saturated sodium bicarbonate solution (500mL), saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, concentrated, crude product flash column chromatography (ethyl acetate:petroleum ether=1:4), Concentration gave colorless oily compound C-1 (28g, yield: 96%, 1 H-NMR (400MHz, CDCl 3 ): δ6.59-6.58(s,1H),6.20(s,1H),6.18-6.10(m,1H),5.88-5.81(m,1H),5.80(s,1H),5.66(s,1H ),5.60-4.99(m,6H),4.81-4.52(m,7H),4.23(m,3H),3.88-3.80(m,2H),3.50-3.48(m,2H),3.49(s,3H ),3.45(s,3H),3.41-3.28(m,1H),3.08-2.95(m,1H),2.22(s,3H),2.11(s,3H),1.30-1.27(m,3H)) .

Embodiment 2

[0045] Embodiment 2: the preparation of compound B-1

[0046]

[0047] Compound C-1 (28g, 40.36mmol) was dissolved in dichloromethane (600mL) at room temperature, and Dess-Martin oxidant (51.35g, 121.08mmol) was added, stirred at room temperature for 0.5 hours, and the reaction of raw materials was monitored by TLC. The reaction solution was diluted with ether (600mL), filtered, and the filtrate was washed successively with saturated sodium bicarbonate solution (150mL) and saturated brine (150mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a colorless oily compound B-1 ( 26.52g, yield: 95%, 1 H-NMR (400MHz, CDCl 3 ): δ9.03(d,0.5H),8.84(d,0.5H),6.69-6.66(s,1H),6.23(d,1H),6.08-5.90(m,1H),5.88(s,1H ),6.01-5.82(m,1H),5.78(s,1H),5.75-5.56(d,1H),5.45-4.50(m,10H),4.46-4.00(m,6H),3.71-3.73(s ,3H),3.42-3.40(s,3H),3.18-3.06(m,1H),2.62-2.52(m,1H),2.22(s,3H),2.02(s,3H),1.21-1.18(m ,3H)).

Embodiment 3

[0048] Embodiment 3: the preparation of compound A-1

[0049]

[0050] Compound B-1 (26g, 37.58mmol) was added to a three-necked flask at room temperature, argon was replaced, and trifluoroacetic acid / dichloromethane (1.7L, v / v=1 / 200, wherein trifluoroacetic acid was 112.74 mmol), stirred at room temperature until the TLC monitoring reaction was complete; the reaction solution was diluted with dichloromethane (3L), and washed successively with saturated sodium bicarbonate solution (1L), saturated sodium chloride (1L), dried over anhydrous sodium sulfate, Suction filtration, concentration, column chromatography (EA / PE=1 / 5) separation, concentration to obtain off-white solid compound A-1 (23.12g, yield: 95%, 1 H-NMR (400MHz, CDCl 3 ): δ9.63-9.57(d,1H),6.76(s,1H),6.30-6.08(m,1H),6.10-5.10(m,9H)4.89-3.86(m,9H),3.82(s, 3H),3.69-3.60(m,1H),3.28-3.12(m,2H),2.77(dd,J=17.7,8.1Hz,1H),2.08(s,3H),1.52(s,3H),1.24 (t,3H)).

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Abstract

The invention relates to a key intermediate product compound A for preparing trabectedin and a method for preparing the compound A by using a compound D. According to the method disclosed by the invention, three-step reaction can be continuously operated, and individual separation and purification are not needed, and therefore, an operation is simple and convenient. The invention also relates to amethod for preparing a compound E through reduction of the compound A and application of the intermediate product. The method has the advantages of controllability, simpleness and convenience in operation and stable yield. The formula (1) is shown in the description.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to the preparation of a key intermediate of trabectedin, a drug for treating advanced soft tissue sarcoma, as well as its preparation method and application. Background technique [0002] Trabectedin (Trabectedin, trade name Yondelis), developed by Johnson & Johnson Pharmaceuticals, is a natural product isolated from marine organisms mangrove sea squirt (Ecteinascidia turbinata), but its content is extremely low, only 10 -6 ~10 -7 %w / w. Trabectidine was listed as a rare drug for soft tissue sarcoma by the European Union in 2001, becoming the first modern marine drug. In 2004, it was listed as a rare drug for soft tissue sarcoma by the US Food and Drug Administration (FDA). In the same year, it was designated as an orphan drug for the treatment of acute lymphoblastic leukemia, soft tissue sarcoma and ovarian cancer in Europe and the United States. In addition to blocking the differe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08
CPCC07D471/08
Inventor 周后佳岳庆磊周治国高强郑保富
Owner SHANGHAI HAOYUAN CHEMEXPRESS
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