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Preparation method and intermediate of trabectedin

A technology of compound and hydroxyl protecting group, applied in the field of chemistry, can solve the problems of high cost, harsh reaction conditions, long route, etc., achieve the effect of large industrial application value and simplified synthesis

Active Publication Date: 2017-12-29
ZHEJIANG HISUN PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by this invention is that the preparation of trabectedin in the prior art, especially the key intermediate Ⅹa-1 preparation of trabectedin, has a long route, low yield, high cost, harsh reaction conditions, and difficult operation. Complicated and other defects

Method used

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  • Preparation method and intermediate of trabectedin
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  • Preparation method and intermediate of trabectedin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Embodiment 1: preparation compound IIa-1

[0098]

[0099] Add Safracin B (51g) into the reaction flask at room temperature, add dichloromethane (100ml) to dissolve, add dropwise phenylisothiocyanate (76g), stir for 24h, concentrate to remove dichloromethane, and obtain a brown oil 150g. (No purification and next step reaction)

[0100] 1H NMR (400MHZ, DMSO) δ: 9.94(s, 1H), 8.66(s, 1H), 7.46-7.40(m, 3H), 7.36(t, J=8Hz, 3H), 7.15(t, J=7.6Hz ,1H),6.20(s,1H),4.47(s,1H),4.36(t,J=7.2Hz,1H),3.99-3.63(m,5H),3.52(s,1H),3.33(s, 3H), 2.99(d, J=2.8Hz, 1H), 2.96-2.73(m, 4H), 2.16(s, 3H), 1.98(s, 3H), 1.84(s, 3H), 1.59(m, 1H ), 1.15(d, J=6.1Hz, 2H), 0.46(d, J=2.8Hz, 3H).MS: m / z(675), Found: 658(M-H 2 O+H)

Embodiment 2

[0101] Embodiment 2: preparation compound IIIa-1

[0102]

[0103] Add tetrahydrofuran (250ml) and acetic acid (56ml) to the oil obtained in Example 1, cool down to -10°C, add dropwise an aqueous solution of sodium cyanide (12g sodium cyanide, 100ml water) with stirring, and react for 0.5h . Add saturated sodium carbonate to adjust the pH to 10, add ethyl acetate (200ml), separate the layers, wash the organic layer twice with saturated brine, dry the organic layer with anhydrous sodium sulfate, filter with suction, concentrate to obtain an oily substance, column chromatography (petroleum Ether: ethyl acetate = 4:1, 3:1, 2:1, 1:1) to obtain 54.9 g of a yellow solid with a yield of 85%.

[0104] 1 H NMR (400MHZ, DMSO) δ: 9.87(s, 1H), 8.55(s, 1H), 7.45-7.43(m, 3H), 7.36-7.32(m, 2H), 7.15-7.05(m, 2H), 6.22 (s,1H),4.88(d,J=5.2Hz 1H),4.42(m,1H),4.39(m,1H),4.28(m,1H),4.13(s,1H),3.90(d,J =2.4Hz,1H),3.89(s,3H),3.87(m,1H),3.53(m,4H),3.11-2.96(m,3H),2.85-2.55(m,3H),2.11(s, 3H), 2...

Embodiment 3

[0105] Embodiment 3: preparation compound IVa-1

[0106]

[0107] Take compound Ⅲa-1 (25g), add 70ml of methanol, cool down to 0°C in an ice bath, add trimethylchlorosilane (25ml) dropwise, after the addition is complete, keep the reaction for 3h, filter the filter cake with dichloromethane (20ml×2 ) was washed and dried to obtain 13.8 g of a yellow solid with a yield of 92%.

[0108] 1 H NMR (400MHz, DMSO) δ9.35(s,1H),7.53(s,3H),6.52(s,1H),5.06(s,1H),4.53(s,2H),4.14(d,J= 14.6Hz,3H),3.97(s,4H),3.64(s,3H),3.28(s,1H),3.19–2.84(m,5H),2.20(s,3H),1.85(s,3H), 1.74 (dt, J=23.8, 11.9Hz, 1H). MS: m / z (514), Found: 479 (M-Cl)

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Abstract

The invention provides a novel preparation method for trabectedin. According to the method, safracin B is used as a starting raw material and undergoes a series of reactions to synthesize trabectedin. The raw material used in the method is easily available; the method is few in synthesis steps; a highly toxic organotin reagent is not used in the method, so the method is safe and low in cost; and the method has good industrial application value.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to a preparation method of trabectedin and a synthetic intermediate thereof. Background technique [0002] Trabectedin, also known as Ecteinascidin 743, Ecteinascidin 743, ET-743, is a tetrahydroisoquinoline derivative with high anti-tumor activity isolated from the Caribbean sea squirt in 1969, and it was listed in Europe in 2007 It is used for the treatment of ovarian cancer and soft tissue sarcoma. In October 2015, it was listed in the United States as an orphan drug for the treatment of ovarian cancer. It is the first marine-derived anti-tumor drug. [0003] The preparation method of trabectedin mainly contains following several kinds at present: [0004] 1. Biological extraction: the highest yield of trabectedin is 0.0001% (ACS Chem. Biol. 2011, 6, 1244), which is not conducive to the mass production of trabectedin. [0005] 2, total synthesis: the synthetic route of total synthesis ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/18C07D491/22C07D497/22
CPCC07D471/18C07D491/22C07D497/22Y02P20/55
Inventor 张福利徐上虎王冠林塘焕俞旭峰朱津津沈创曾宪国柴健吴忠伟杨志清
Owner ZHEJIANG HISUN PHARMA CO LTD
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