Optically pure alpha-ketoacyl harringtonine and preparing and purifying method thereof

A ketoacyl harringtonine and optical technology, applied in the direction of organic chemistry, can solve the problems of complex operation, no reported yield, difficulty of harringtonine, etc.

Inactive Publication Date: 2009-11-25
NANKAI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition to low concentrations of harringtonine in natural plants, it is also mixed with many congeners with very similar structures, so it is very difficult to separate high-purity harringtonine from natural products
[0009] The α-ketoacyl harringtonine used in the above synthesis process has not been purified, and the Reformatsky reaction is directly carried out, which brings difficulties to the purification of subsequent products
Although there are two literatures reporting the purification method of α-ketoacyl harringtonine (Science Bulletin, 1976, 178; Acta Pharmaceutica Sinica, 1981, 16, 821), the former carried out recrystallization but did not report the yield after crystallization , the latter needs to be separated by an alumina column, the operation is complicated and the yield is low

Method used

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  • Optically pure alpha-ketoacyl harringtonine and preparing and purifying method thereof
  • Optically pure alpha-ketoacyl harringtonine and preparing and purifying method thereof
  • Optically pure alpha-ketoacyl harringtonine and preparing and purifying method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Preparation and purification of α-ketoacyl harringtonine (general operation)

[0025] To a solution of compound (III) in dichloromethane (2 mmol, 1.0 M), 1 drop of DMF was added. Under an ice-water bath, dropwise add oxalyl chloride (2.6mmol, 1.0M) in CH 2 Cl 2 solution, remove the ice bath after the dropwise addition, the reaction stops gassing after 1.5h, continue the reaction for 1h, spin off the solvent, add benzene and spin off excess oxalyl chloride, repeat again, the residue is dissolved in 1mL of dichloromethane, drop Add harringtonine 5 (0.315 g, 1.0 mmol) and pyridine (0.22 ml, 2.6 mmol) in 2 Cl 2 solution (cooled in an ice-water bath). After the dropwise addition, the ice bath was removed. After 30 min, TLC tracked and the raw materials disappeared. Add 5 mL of water to quench the reaction, separate the layers, extract the aqueous phase three times with ether, combine the organic phases, and successively wash with 10% Na 2 CO 3 The solution w...

Embodiment 2

[0027] Example 2 Preparation of α-ketoacyl harringtonine 7

[0028]

[0029] With the method of Example 1, the difference is that compound 15 is obtained with 20mmol compound 14, and then reacted with 10mmol harringtonine 5 to obtain the colorless crystal of the title compound 7 (structure as figure 1 shown). Yield 86%, mp.98~100℃; [α] D =-125.4° (c=1.0, CHCl 3 , 20℃); IR(KBr)v 2961, 2876, 1749, 1654, 937cm -1 ; 1 H NMR (400MHz, CDCl 3 )δ6.56(s, 1H, ArH), 6.54(s, 1H, ArH), 5.86(d, 1H, ArCHCH, J=9.2Hz), 5.82(s, 2H, OCH 2 O), 5.09(s, 1H, vinyl H), 3.81(d, 1H, ArCHCH, J=9.2Hz), 3.68(s, 3H, OCH 3), 3.19 (td, 1H, CH 2 , J=11.6, 7.6Hz), 3.04 (m, 1H, CH 2 ), 2.91 (m, 1H, CH 2 ), 2.57 (m, 2H, CH 2 ), 2.33 (m, 2H, CH 2 ), 2.22 (m, 1H, CH 2 ), 2.02 (dt, 1H, CH 2 , J=12.0, 9.6Hz), 1.88 (m, 1H, CH 2 ), 1.72 (m, 2H, CH 2 ), 1.41 (septet, 1H, (CH 3 ) 2 CH, J=6.8Hz), 1.24(m, 2H, CH 2 ), 0.80(d, 6H, (CH 3 ) 2 CH, J = 6.8Hz) ppm; 13 C NMR (100MHz, CDCl 3 )δ 194.1, 160....

Embodiment 3

[0030] Preparation of Example 3α-ketoacyl harringtonine 8

[0031]

[0032] The same method as in Example 1, except that 10 mmol of compound 16 was used to obtain compound 17, and then reacted with 5 mmol of harringtonine 5 to obtain colorless crystals of the title compound 8. The yield is 50%, mp.128~130℃; [α] D =-128.7° (c1.0, CHCl 3 , 20℃); IR(KBr)v 2958, 1728, 1654, 1478, 1369, 1223, 1042, 932cm -1 ; 1 H NMR (300MHz, CDCl 3 )δ6.58(s, 1H, ArH), 6.57(s, 1H, ArH), 5.88(d, 1H, ArCHCH, J=9.3Hz), 5.86(s, 1H, OCH 2 O), 5.84(s, 1H, OCH 2 O), 5.10(s, 1H, vinyl H), 3.83(d, 1H, ArCHCH, J=9.3Hz), 3.71(s, 3H, OCH 3 ), 3.20 (ddd, 1H, CH 2 , J=14.1, 12.0, 7.8Hz), 3.08 (m, 1H, CH 2 ), 2.92 (td, 1H, CH 2 , J=11.7, 7.2Hz), 2.59 (m, 2H, CH 2 ), 2.37 (dd, 1H, CH 2 , J=14.4, 6.9Hz), 2.26 (dd, 1H, CH 2 , J=16.8, 6.6Hz), 2.11 (dd, 1H, CH 2 , J=16.8, 6.9Hz), 2.04 (dt, 1H, CH 2 , J=13.2, 9.6Hz), 1.88(m, 2H, CH 2 , (CH 3 ) 2 CH), 1.75(m, 2H, CH 2 ), 0.80(d, 3H, (CH 3 ) 2 CH, ...

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Abstract

The present invention relates to an optically pure alpha- ketoacyl harringtonine and a preparing and purifying method thereof. In the temperature of -80 DEG C to 50 DEG C, the alpha-ketoacyl chlorine which is prepared through reacting alpha-ketonic acid and oxalyl chloride reacts with the cephalotaxine in an inert organic solvent while the organic base is used as an acid-binding agent for obtaining the oily product represented by the formula (I). The purifying steps are as follows: dissolving the oily product with the inert organic solvent, adding the saturated NaHSO3 solution, mixing and separating the liquid; after washing the water phase with the organic solvent, adjusting the pH of the water phase with saturated NaHSO3 solution to 7-8, extracting with the organic solvent; washing the organic phase with the buffering solution with pH of 6.8 and the saturated saline solution, drying and filtering the organic phase, removing the solvent for obtaining the pale-yellow solid; and then recrystallizing with the organic dissolvent for obtaining the white solid or colorless crystal. The optically pure alpha- ketoacyl harringtonine is a key intermediate for synthesizing the medicine of harringtonine alkaloid, which is widely applied for anti-tumor (malignant tumor and benign tumor), antiparasitic, antifungal and antibacterial chemotherapy. The synthesizing method is suitable for purifying and preparing the large amount of optically pure compound represented by the structural formula of (I).

Description

technical field [0001] The present invention relates to optically pure α-ketoacyl harringtonine and its preparation and purification method. Background technique [0002] In 1970, Paudler and Powell et al. (Tetrahedron Lett. 1970, 47, 815; Tetrahedron 1972, 28, 1995) isolated and identified four harringtonines from the genus Herringophytum, namely harringtonine 1 ( Harringtonine, HT), homoharringtonine 2 (Homoharringtonine, HHT), deoxyharringtonine 3 (Deoxyharringtonine, DHT) and isoharringtonine 4 (Isoharringtonine, IHT), and found to have significant anti- tumor activity. 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] Natural harringtonine is composed of harringtonine core and ester group side chain. Its parent nucleus cephal...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/20
Inventor 陈莉李卫东
Owner NANKAI UNIV
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