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Method for preparing combretastatin

A technology of combretastatin and form, which is applied in the field of preparing combretastatin in base form or acid addition salt form, and can solve problems such as poor yield, multiple epimerization and the like

Inactive Publication Date: 2011-04-13
SANOFI AVENTIS SA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Chem. Commun. 1999, 1847-1848 describes T3P in the preparation of amide bonds; however, T3P is described as giving rise to more epimerization and the resulting yields are worse than HAPyU (see Table 3)

Method used

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  • Method for preparing combretastatin
  • Method for preparing combretastatin
  • Method for preparing combretastatin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1 (according to the present invention)

[0066] Step (i):

[0067] At a temperature of 5-10° C., sodium methoxide solution (5.66 kg, 29.34 mol) was flowed into a mixture containing toluene (91.1 liters), trimethoxybenzylphosphonium bromide (15.35 kg, 29.33 mol) and 4- Methoxy-3-nitrobenzaldehyde (5.06 kg, 27.93 mol). At the end of the reaction, 0.32 liters (5.59 mol) of acetic acid flowed in. After the medium was kept at 20°C, it was filtered. The filter cake was washed with toluene (11.1 L). The filtrate was washed several times with water (20.2 L), then concentrated under vacuum. Isopropanol (87.6 L) was then introduced, the medium was concentrated and then cooled. The suspension was then filtered at 10°C. The isolated product (6.46 kg, 52.2%) was dried under vacuum. The purity of the isolated product was of the order of 78% for (Z) and 22% for (E).

[0068] Step (ii):

[0069] At 50°C, water (80ml) was flowed into a medium comprising methano...

Embodiment 2

[0073] Embodiment 2 (according to the present invention)

[0074]In a jacketed 1.6-liter reactor, (Z)-amino compound-Z-aminostilbene HCl (Z-aminostil, HCl, 50.0 g), N-BOC-acetonate (41.8 g) and 500ml of DCM. Then 53.4 ml of triethylamine (2.7 equiv) was flowed in at 22±3°C, followed by a 50% solution of T3P in DCM (1.7 equiv). The mixture was stirred under reflux of DCM for 1 hour. The mixture was then cooled to 22±3°C and 500 ml of demineralized water was added. The mixture was separated by settling and the phases were separated. The DCM phase was washed with 500 ml of a 6 wt % (30 g) aqueous solution of sodium hydrogen phosphate and then with 500 ml of demineralized water. The DCM phase was concentrated at about 40-50° C. under reduced pressure of 360 to 150 mbar. A 3 mol / l solution of HCl in methanol (379 ml, 8 equivalents) was then flowed in, followed by 300 ml of demineralized water. The mixture was separated by settling and the phases were separated. The DCM / met...

Embodiment 3

[0076] Embodiment 3 (according to the present invention)

[0077] At 50° C., water (60 ml) was flowed into a medium containing methanol (50 ml), (Z)- and (E)-nitro compounds to be reduced (15 g, 0.043 mol) and sodium dithionite (27.2 g, 0.133mol). Once the reaction was complete, hydrochloric acid (26.2ml, 0.314mol) was added. Work up by adding water and DCM followed by sodium hydroxide to pH=7. Hydrogen chloride in methanol (18.9 ml, 0.0586 mol) was added to the DCM phase, and the solvent was then replaced with acetonitrile. Then get the broth. Benzyl alcohol (31 ml) was then added to the suspension at 50°C and kept at 65°C for 2 hours. After cooling, the medium is then filtered and washed. The isolated product was then dried under vacuum.

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Abstract

The invention relates to a method for preparing a combretastatin (A): formula (I) in the form of a base or of an addition salt with an acid, which comprises coupling, in the presence of a base and of T3P, the salt of the (Z)-amino compound of formula (II) with a doubly protected L-serine derivative of formula (III) in which PG denotes a group protecting the amine function, so as to obtain the compound of formula (Z)-(Ib): formula (IV), then deprotecting and opening the ring of (Z)-(Ib) in the presence of an acid, so as to obtain the combretastatin (A) in the form of a salt; and, optionally, adding a base, so as to obtain the combretastatin (A) in the form of a base, the salt of the (Z)-amino compound having been obtained by enrichment of the salt of the amino compound of formula (V) in (Z) isomer.

Description

technical field [0001] The present application relates to a process for the preparation of combretastatin (combretastatin) (A) in base form or acid addition salt form [0002] Background technique [0003] US 6 759 555 describes a process for the preparation of combretastatin having the formula [0004] [0005] Among them, X represents -NH 2 or one of the following two groups: [0006] [0007] PG denotes a group protecting the amino function. [0008] Bioorg. Med. Chem. 2000, 8, 2417-2425 and US 2003 / 0220404 also describe methods for the preparation of combretastatin. [0009] J. Pept. Res. 1999, 54(1), 54-65 compares acid activators for forming peptide bonds and concludes that TDBTU is the best. [0010] Bioorg.Med.Chem.2006, 14, 3231-3244 describes the preparation of combretastatin of formula (A), wherein DCC is used as acid activator to couple HOBt-H 2 O (step e, compound 10). [0011] Chem. Commun. 1999, 1847-1848 describes T3P in the preparation of amid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C213/10C07C217/84C07C231/16C07C237/08
CPCC07C217/84C07C237/04C07B2200/07C07C231/18Y02P20/55
Inventor 马克·弗雷德里克西尔维尼·卢茨乔尔·马尔帕特菲利普·马森斯蒂芬·马蒂
Owner SANOFI AVENTIS SA
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