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harringtonine alkaloids, their preparation method and use

A technology of harringtonine and alkaloids, which is applied in the field of pharmaceutical compounds and their preparation, harringtonine alkaloids, and can solve problems such as long synthetic lines and difficult industrial production

Active Publication Date: 2019-10-11
NANKAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the harringtonine obtained by this method has high purity, optically pure raw materials need to be used, and the synthesis line is long, so it is not easy to be applied to industrial production

Method used

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  • harringtonine alkaloids, their preparation method and use
  • harringtonine alkaloids, their preparation method and use
  • harringtonine alkaloids, their preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0182] The preparation of embodiment 1 compound 19

[0183]

[0184] At room temperature, the BF 3 ·OEt 2 85.8μL was added dropwise to 5mL of CH 2 Cl 2 In the solution, the raw material basically disappeared after 5h. Add saturated NaHCO 3 The solution quenched the reaction, after stirring for 0.5h, the organic phase was washed with water until the aqueous phase was not alkaline, washed with saturated NaCl solution, dried, filtered, the solvent was spun off, and column chromatography (PE:EA:TEA=80:10:0.4) Finally, a white solid of compound 19 was obtained with a yield of 87%. mp.139-141℃; [α] D =-170.2° (c 1.03, CHCl 3 ,20℃); 1 H NMR (400MHz, CDCl 3 )δ6.62(s,1H),6.61(s,1H),6.07(s,1H),5.90(s,1H),5.89(s,1H),4.66(d,J=1.8Hz,1H), 3.98(s,1H),3.81(s,1H),3.67(s,3H),3.59(s,3H),3.29(ddd,J=13.8,12.6,7.8Hz,1H),3.05–2.90(m, 2H), 2.98(d, J=16.5Hz, 1H), 2.86–2.80(m, 1H), 2.75(d, J=16.5Hz, 1H), 2.63–2.54(m, 1H), 2.41(dd,J =14.4,7.8Hz,1H),2.28–2.22(m,1H),1.75–1.65(m,4H),1.55–1.3...

Embodiment 2

[0185] The preparation of embodiment 2 compound 3 and 20

[0186]

[0187] Same as Example 1, except that the reaction is carried out at a temperature ranging from -40°C to -78°C. The dr value was C2'R:C2'S=6:1, and compound 3 and compound 20 were obtained after column chromatography (PE:EA:TEA=60:10:0.3). Yield 90%.

[0188] Compound 3: Light yellow amorphous substance, the yield is 75%. [α] D =-122.6° (c 1.03, CHCl 3 ,20℃); 1 HNMR (400MHz, CDCl 3 )δ6.62(s,1H),6.53(s,1H),5.99(d,J=9.8Hz,1H),5.87(d,J=1.5Hz,1H),5.85(d,J=1.2Hz, 1H), 5.04(s, 1H), 3.77(d, J=9.8Hz, 1H), 3.67(s, 3H), 3.57(s, 3H), 3.48(s, 1H), 3.18–3.08(m, 2H ),2.92(td,J=11.0,6.8Hz,1H),2.61–2.57(m,2H),2.36(dd,J=14.0,6.8Hz,1H),2.26(d,J=16.5Hz,1H) ,2.08–1.98(m,1H),1.95–1.87(m,1H),1.88(d,J=16.5Hz,1H),1.77–1.72(m,2H),1.45–1.40(m,3H),1.32 –1.24(m,1H),1.03–0.93(m,1H),0.83(d,J=6.2Hz,3H),0.82(d,J=6.2Hz,3H)ppm; 13 C NMR (101MHz, CDCl 3 )δ 174.2, 170.6, 157.9, 146.7, 145.9, 133.4, 128.5, 112.7, 109.8, 100.9, 100.1...

Embodiment 3

[0190] The preparation of embodiment 3 compound 19 and 3

[0191]

[0192] Same as Example 1, except that Compound 19 and Compound 3 were obtained from Compound 18 at a temperature range of 0-30°C. , after column chromatography (PE:EA:TEA=80:10:0.4), compound 19 was obtained as a white solid with a yield of 60%, and compound 3 was obtained with a yield of 20%. The products obtained are in agreement with the data for the products of Examples 1 and 2, respectively.

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Abstract

The present invention relates to the field of pharmaceutical compounds and preparation methods thereof, and particularly relates to a Cephalotaxus ester alkaloid, and preparation method and use thereof. The Cephalotaxus ester alkaloid has a structure of formula (I). The present invention further provides a preparation method of the compound, comprising reacting a compound of formula (11) with a compound of formula (12) in the presence of a Lewis acid.

Description

technical field [0001] The invention relates to harringtonine alkaloids, a preparation method and application thereof, and belongs to the field of pharmaceutical compounds and preparation methods thereof. Background technique [0002] Harringtonine alkaloids such as harringtonine 1 (Harringtonine, HT), homoharringtonine 2 (Homoharringtonine, HHT), deoxyharringtonine 3 (Deoxyharringtonine, DHT) and isoharringtonine Base 4 (Isoharringtonine, IHT) is a broad-spectrum anticancer drug. Wherein homoharringtonine 2 was loaded into Chinese Pharmacopoeia in 1990, for the clinical treatment of acute non-lymphatic leukemia, and has been clinically used so far (Chinese Pharmacopoeia 1990 edition two, 1990, 588; Chinese Pharmacopoeia 2005 edition two, 2005 , 629). [0003] [0004] Formula (6) is the general formula of natural harringtonine alkaloids, and its molecular structure is composed of harringtonine core and side chain. The mother core harringtonine (5) has no physiological ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/20A61K31/55A61P35/00A61P35/02A61P33/06A61P31/10A61P31/04A61P33/14
Inventor 陈莉马国贞李卫东
Owner NANKAI UNIV
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