Preparation method of sea squirt compound and intermediate thereof

A compound and transformation technology, applied in the field of medicine, can solve the problems of many side reactions, deprotection of phenolic hydroxyl groups, poor selectivity, etc.

Active Publication Date: 2020-08-11
BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In this route, the main problem in the direct preparation of compound 24 from compound 21 is: in the process of protecting the primary hydroxyl group of compound 21, a large number of phenolic hydroxyl groups are also protected, resulting in more side reactions
[0016] CN100475822C discloses a preparation method of compound 170. In this method, due to the poor MEM protection selectivity of the phenolic hydroxyl group, the primary hydroxyl group needs to be protected by TBOMS first, and the protecting group TBMOS on the primary hydroxyl group needs to be removed later, resulting in cumbersome reaction steps. In the process of deprotection of primary hydroxyl group, it is easy to cause deprotection of phenolic hydroxyl group, resulting in many side reactions and low reaction yield.
[0017] From the above, it can be seen that there are still many problems to be solved in the preparation method of trabectedin at present, such as long preparation route, low selectivity of phenolic hydroxyl protection and deprotection in the reaction process, difficult purification, or the use of severe Toxic, expensive reagents, etc.

Method used

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  • Preparation method of sea squirt compound and intermediate thereof
  • Preparation method of sea squirt compound and intermediate thereof
  • Preparation method of sea squirt compound and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0096] The synthesis of embodiment 1 compound 2

[0097]

[0098] 6.9 g of sodium hydroxide and 250 ml of tetrahydrofuran were added to a 1000 ml three-necked flask, the temperature was lowered to below 0°C, 59.8 g of compound QT10 was added, and 21.5 g of 2-methoxyethoxymethyl chloride (MEM-Cl) was added dropwise. After the dropwise addition, keep warm at 0-10°C and stir for 4 hours, quench with saturated ammonium chloride aqueous solution, extract with dichloromethane (2×500ml) and combine the organic layers, dry over anhydrous sodium sulfate, and concentrate in vacuo. Ethyl acetate was recrystallized from n-hexane to obtain 64.2 g of white solid, yield: 91.8%, HPLC>99%.

[0099] 1 HNMR (400MHZ, CDCl 3 ):δ6.71(s,1H),06.10(m,1H),5.93(d,J=1.2Hz,1H),5.87(d,J=1.2Hz,1H),5.44(dd,J1=1.2Hz ,J2=17.2Hz,1H),5.30(dd,J1=1.2Hz,J2=10.4Hz,1H),5.27(d,J=6Hz,1H),5.18(d,J=6Hz,1H),4.26( d,J=2.4Hz,1H),4,18-4.14(m,2H),4.04(d,J=2.4Hz,1H),3.99(t,2H),3.86(m,1H),3.66(s ,3H),3.64(m,1H),3.60(t,2...

Embodiment 2

[0100] The synthesis of embodiment 2 compound 3

[0101]

[0102] Add 1.15 g of sodium hydroxide and 115 ml of tetrahydrofuran into a 500 ml three-necked flask, cool down to below 0° C., add 10.0 g of compound QT10, and dropwise add 2.41 g of bromomethyl methyl ether (MOM-Br). After the dropwise addition, keep warm at -5~5°C and stir for 2 hours, quench with saturated ammonium chloride aqueous solution, extract with dichloromethane (2×200ml), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate in vacuo, the obtained foamy The solid was recrystallized from ethyl acetate and n-hexane to obtain 9.8 g of white solid, yield: 90.3%, HPLC>99%.

[0103] 1 HNMR (400MHZ, CDCl 3 ):δ6.72(s,1H),6.16-6.07(m,1H),5.93(d,J=1.6Hz,1H),5.88(d,J=1.6Hz,1H),5.44(dd,J1= 1.6Hz, J2=17.2Hz, 1H), 5.30(dq, J1=1.2Hz, J2=10.4Hz, 1H), 5.12(s, 2H), 4.27(d, J=2.0Hz, 1H), 4,12 -4.11(m,2H),4.05(d,J=2.4Hz,1H),3.99(t,J=3.2Hz,2H),3.71(s,3H),3.68-3.63(dt,J1=3.2Hz, J2=10.8Hz, 1H), 3...

Embodiment 3

[0104] The synthesis of embodiment 3 compound 4

[0105]

[0106] Under the protection of argon, add 3.0 g of compound 2 to a 100 ml three-necked flask, add 0.241 g of bis(triphenylphosphine) palladium dichloride, 1.48 g of acetic acid and 60 ml of dichloromethane, and add 3.57 g of tri-n-N After the addition of butyltin hydrogen, keep warm at 0-5°C and stir for 1 hour, quench with saturated aqueous potassium fluoride, extract with dichloromethane (2×40ml), combine the organic layers, dry over anhydrous sodium sulfate, and concentrate in vacuo to obtain an oil. Column chromatography (n-hexane:ethyl acetate=4:1~1:1) gave 2.76 g of white foamy solid, yield: 98.5%, HPLC>98%.

[0107] 1 HNMR (400MHZ, CDCl 3 ):δ6.68(s,1H),5.89(d,J=1.2Hz,1H),5.82(d,J=1.2Hz,1H),5.44(dd,J1=1.2Hz,J2=17.2Hz,1H ), 5.30(dd, J1=1.2Hz, J2=10.4Hz, 1H), 5.61(s, 1H), 5.39(d, J=6Hz, 1H), 5.27(d, J=6Hz, 1H), 4.26( d,J=2.4Hz,1H),4,13-4.066(m,2H),3.99-3.93(m,2H),3.69(s,3H),3.68-3.65(m,3H),3.60(t, 1H), 3.40...

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Abstract

The invention provides a preparation method of a sea squirt compound and an intermediate thereof, and particularly provides a preparation method of a novel compound QT9 and a method for preparing thesea squirt compound by using the QT9. The method is high in reaction selectivity and high in yield, the obtained compound is easy to purify, the defects that a plurality of intermediates are oily substances and the reaction selectivity is poor in the prior art are overcome, and the method is particularly suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of an ascidin compound and an intermediate thereof. Background technique [0002] Ecteinascidin-743 (ET743), also known as trabectedin, is a class of active natural products with a unique structure. Semi-synthetic products of tetrahydroquinoline alkaloids extracted from In addition to blocking the differentiation of tumor cells in the G1 / G2 cycle, it can also inhibit the secretion of vascular endothelial growth factor (VEGF) and the expression of its receptors. Trabectedine was approved in the European Union in September 2007 for the treatment of soft tissue sarcomas that have failed treatment with anthracyclines and ifosfamide, or in patients who are not candidates for either drug; In combination for the treatment of platinum-sensitive ovarian cancer. [0003] Studies have shown that, in terms of anti-tumor activity, trabectedine is 1~2% high...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22C07D515/22
CPCC07D491/22C07D515/22Y02P20/55C07D487/18
Inventor 袁建栋符新亮孙占莉邢小佩惠京城丛启雷
Owner BRIGHTGENE BIO MEDICAL TECH (SUZHOU) CO LTD
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