CA1268709A - Process for the isolation and purification of podophyllotoxin - Google Patents
Process for the isolation and purification of podophyllotoxinInfo
- Publication number
- CA1268709A CA1268709A CA000491564A CA491564A CA1268709A CA 1268709 A CA1268709 A CA 1268709A CA 000491564 A CA000491564 A CA 000491564A CA 491564 A CA491564 A CA 491564A CA 1268709 A CA1268709 A CA 1268709A
- Authority
- CA
- Canada
- Prior art keywords
- solution
- podophyllotoxin
- aromatic
- complex
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to a process for ob-taining purified podophyllotoxin from a solution thereof which comprises forming a solid complex of podophyllo-toxin and an aromatic or heteroaromatic compound other than benzene and separating the solid complex from the solution.
The invention relates to a process for ob-taining purified podophyllotoxin from a solution thereof which comprises forming a solid complex of podophyllo-toxin and an aromatic or heteroaromatic compound other than benzene and separating the solid complex from the solution.
Description
PROCESS FOR THE ISOLATION AND PURIFICATION
OF PODOPHYLLOTOXIN
The invention relates to a new method for the isolation and purification of podophyllotoxin from relatively impure sources thereof, particularly plant extracts, for example resins obtained by extraction from plants of the genus podophyllum.
Podophyllotoxin is a highly biologically active substance which is particularly useful as a drug against condylomata acuminata (veneral warts) [G. Gabriel and R.N.T. Thin, Br. J. Vener. Dis., 59, 124-126 (1983)] as well as possessing cytostatic [G. von Krogh and H.I. Maibach, Dermatologica, 167, 70-77 (1983)3 and antiviral properties [T. Markkanen, M.L. Makinen, J. Miettinen, E. Maunuksela, T. Laijoki and J. Paranko, Drugs Exp. Clin. Res. 9, 1-7 (1983)].
Previously, podophyllotoxin has been isolated from the above-mentioned resins by various laborious procedures, all of which included solvent extraction, as a rule with chloroform, followed by further pro-cessing steps. According to the most authoritative newer literature [W.M. Hearon and W.S. MacGregor, Chem.
Rev., 55, 1002 (1955); J.L. Hartwell and W.E. Detty, J. Am. Chem. Soc., 246-253 (1950)] chromatographic purification was necessary in order to obtain podo-phyllotoxin. In many cases, benzene has been used in the course of the purification procedures despite the ~ ?~
acknowledged health hazards which arise. Furthermore, chromatography has previously been regarded as being absolutely essential in order to obtain podophyllotoxin in a degree of purity such that the podophyllotoxin is only slightly contaminated with the many congeners which exist in the plant material. This has resulted in pure podophyllotoxin being a rare and expensive sub-stance which is difficult to obtain in large amounts.
There has recently been a heightened demand for pure podophyllotoxin, both as a raw material for conversion to various pharmacologically active deriva-tives and in clinical treatments using podophyllotoxin itself. In both cases it is highly desirable to use as pure a product as possible.
According to one aspect, the present inven-tion provides a process for obtaining purified podo-phyllotoxin from a solution thereof which comprises forming a solid complex of podophyllotoxin and an aromatic or heteroaromatic compound other than benzene and separating the solid complex from the solution.
The process of the invention, according to one aspect, is well suited for the purification of podophyllotoxin in large ~uantities, it avoids the strongly carcinogenic solvent benzene, and it gives a very high yield of pure podophyllotoxin.
The process of the invention is based on the previously unknown ability of podophyllotoxin to form 126i~7~ ~
complexes with a large varie-ty of aromatic and hetero-aromatic, compounds, including phenol, toluene, chloro-benzene, anisole, o-, m- and p-xylenes and nitro-benzene, and basic substances such as aniline and pyridine, and homologues thereof such as naphthalene, quinoline and isoquinoline. Furthermore, it avoids the need to purify the crude resin by solvent extraction.
The present invention also provides a process for obtaining purified podophyllotoxin from a solution thereof which comprises:
(a) forming a solid complex of podophyllo-toxin and an aromatic or heteroaromatic compound, (b) separating the complex from the so-lution, (c) forming a solution comprising podo-phyllotoxin from said separated complex, (d) forming a solid complex of podophyllo-toxin from the solution of step (c) and an aromatic or heteroaromatic compound, and (e) separating the solid complex formed in step (d) from the solution, wherein the aromatic or heteroaromatic compounds used in steps (a) and (d) are different.
The precise condition for carrying out the methods of the invention are not critical and can be varied a great deal, but the general principle consists 4 _ of dissolving impure podophyllotoxin, for example podo-phyllum resin in a suitable solvent, preferably a sol-vent in which the entire resin is soluble, for example a Cl 3 lower aliphatic alcohol or a Cl 3 lower al]cyl carboxylic acid ester. To the solution is then added the complexing aromatic compound, and if required this may be followed by various amounts of water. This causes precipitation of generally well-crystalline com-plexes which may be isolated, and which after removal of the complexing agent can give about 90~ of pure podophyllotoxin in high yield. By repetition of this procedure with various complexing agents, 92 - 95~ pure podophyllotoxin can be obtained. It is often found that several of its congeners remain as persistent impurities, even after as many as 5 - 8 recrystalli-zations using various solvents and complexing agents and to achieve an even higher degree of purity a further process step (which itself forms a further aspect of the present invention) may be employed.
Thus according to the invention, in a pre-ferred embodiment thereof, which enables podophyllo-toxin of especially high purity to be obtained "absolute" purification can be performed in a very surprising and unforeseeable manner, namely by ex-traction of a solution of the impure podophyllotoxin in a water-immiscible solvent, for example chloroform, with aqueous base. This result is surprising because lZ~i~7~ ~
according to the literature, podophyllotoxin is very labile under basic conditions, being transformed into its epimer, picropodophyllin when treated with alkali [W. Borsche and J. Niemann, Liebiegs Ann. Chem. 494, 126-142 (1932)].
The following Examples illustrate the process of the invention.
A. Podophyllin (643 g) is dissolved in ethanol (1.5 1) with gentle heating. To the hot solution is added toluene (643 ml) followed by water (129 ml). The solution is cooled with ice-water and the precipitated crystalline material isolated by filtration and washed with ether (2 1). Yield: 342.8 g.
This material is a complex of podophyllo-toxin, toluene and water, and it was shown by HPLC to contain ca. 13% of related lignans.
The complex was redissolved in ethanol (1.0 1) with gentle heating, pyridine (140 ml) followed by water (470 ml) were added, and the solution was cooled with ice-weater. The precipitated crystalline material was isolated by filtration and washed with ether (250 ml). Yield: 292 g.
This material consists of a podophyllotoxin-pyridine-water complex which was shown by HPLC to contain ca. 7% of other related lignans. The material was recrystallized from ethanol (1.0 l)-water (430 ml) ~Z6~
to give 239 g of the pyridine-water complex.
B. The complex (119 g) was dissolved in chloro-form (1.2 1) which was treated wi-th: (i) 0.8 N HC1 (500 ml), (ii) 0.4 N NaOH (500 ml), (iii) 0.01 N HCl (450 ml), (iv) water (450 ml), and (v) saturated aqueous sodium chloride (500 ml).
The chloroform solution was dried over solid magnesium sulfate, the chloroform was removed, in vacuo, and the remaining sirupy material was recrystal-lized from ethyl acetate (450 ml) to give podophyllo-toxin, aq. (50 g). This material was shown by HPLC to contain <0.4~ of other lignans. A sample was subjected to drying (100C), in vacuo, to give analytically pure podophyllotoxin. Anal. Found (calc.) C 63.62 (63.76), H 5.39 (5.35). Its IR, H NMR and C NMR spectra were identical with those recorded in the literature.
A. Podophyllin (1 kg) was dissolved in ethanol (3 1) with gentle heating. As soon as the solution was homogeneous, toluene (1.0 1) and water (200 ml) were added and the mixture was cooled with ice-water. The precipitated crystalline material was filtered off, and washed with ether (1.0 1). This was subsequently re-crystallized from ethanol (2 1), toluene (650 ml) and water (130 ml). The isolated crystalline material was redissolved in ethanol (1.5 1), pyridine (210 ml) and water (630 ml) were added, and the solution was cooled with ice-water. The precipitated crys-talline complex was isolated, washed with ether (1.0 1) and dried to give 47~ g of ma-terial.
The product of 2A was dissolved in chloroform (5 1) and -treated with: (i) 0.4 N HCl (2 1), (ii) 0.2 N
NaOH (2 1), (iii) 0.03 N HCl (1.4 1) (iv) saturated aqueous sodium chloride (700 ml), and (v) dried over magnesium sulfate. The chloroform was removed, in vacuo, and the remaining sirupy material recrystallized from ethanol-water (1.4 1 - 0.9 1). This yielded podo-phyllotoxin, 2H2O (419 g, ~ 39%) which con-tained <0.6%
picropodophyllin and <0.1% of other related lignans.
Anal. Found (calc.) C 58.63 (58.67), H 5.53 (5.77). Identified by IR and HNMR spectroscopy. A
small sample was dried (100C), in _acuo, to give an analytically pure sample. Anal. C 63.75 (63.76), H
5.41 (5.35).
A. Podophyllin (500 g) was dissolved in ethanol (1.5 1) with gentle heating, toluene (0.5 1) and water 100 ml) were added, the solution was cooled, and the precipitated crystalline material was isolated by fil-tration and washed with ethanol-toluene-water (15:5:1, 200 ml). This was immediately redissolved in ethanol (1.0 1), toluene (330 ml) and water (66 ml), and the solution was cooled with ice-water. The precipitate was isolated as described above and dried to give 211 ~26~7~
g. This was redissolved in boiling methanol (500 ml) and the hc,t solution was filtered, water (368 ml) was added, and the solution was cooled with ice-water to give after filtration and drying, in vacuo, over H2SO~, and at ambient pressure at 100C, 192 g of podophyllo-toxin and other related lignans in a ratio of 9:1.
B. The a~ove impure podophyllotoxin (5 g) was dissolved in chloroform (50 ml) and treated succes-sively with: (i) 0.4 N NaOH (50 ml), (ii) 0.02 N HCl (50 ml), (iii) water (50 ml), (iv) saturated sodium chloride (50 ml), the chloroform was removed, ln vacuo, and the remaining material was recrystallized from ethanol-water (1:1, 20 ml). This gave podophyllotoxin, aq., identified by IR spectroscopy which contained <1.4% of other lignans.
A. Podophyllin (50 g) was dissolved in ethanol (150 ml) with heating, followed by addition of chloro-benzene (50 ml) and water (10 ml). After cooling, the precipitate was isolated by filtration and washed with ether (20 ml). Yield of podophyllin-chlorobenzene-water complex: 19.5 g, which was shown to contain ca.
13% of other lignans.
The above material (5 g) was redissolved in ethanol (15 ml), phenol (5 g) and water (2 ml) were added, the solution was cooled, and the precipitated material was removed by filtration and washed with X
:lZ6~
ether (10 ml). Yield of podophyllotoxin-phenol-wa-ter complex: 4.2 g.
B. This was dissolved in ethyl acetate (20 ml) and the solution was treated with 2 N NaOH (20 ml).
The organic phase was separated and concentra-ted, in vacuo. The resulting material was recrystallized from ethanol-water (1:1, 20 ml) to give, after drying, in vacuo, over H2SO4: 3.75 g of >98.5% pure podophyllo-toxin, aq., determined by HPLC and identified by IR, 1H NMR and 1 C NMR spectroscopy, [~]D = ~ 118.5 .
The following example illustrates the results of using various combinations of complexing agents in Step A.
General procedure: Podophyllin (60 g) was dissolved by gentle heating in a suitable solvent (180 ml). In some cases a residue remained, in which case the solution was decanted off. This was followed by addition of an aromatic complexing agent (60 ml, or 60 g if a solid) followed by addition of various amounts of water. After cooling, the precipitated complex was isolated, and the procedure repeated with the same, or other solvents and complexing agents. The isolated material was eventually recrystallized, and the com-plexing agents removed, and in each case identified by IR spectroscopy and/or HPLC analysis. The results are shown in Table 1.
~L2~ s~
~a ul ~ I` O O ~ ~ ~ ~ ~r r~l N 1~ u~ ~ --I ~ ~D
Q)t~) ...... ...... ......
r 3 ~ U~ ~ o O Ln O O r~ O O O O ~ : :
o N rl J
,a c,~ ~1, ~1 r ~ ~ ~ .
O o o o o ~ ~
o Q~ ~ a) ~ Q~ a) a) Q) ~n I I I I I I . : : : : : .:
o 3 E o ,~
O ~ r~
r~ . . . ~ ~
,1 I X ~ -I 1~ ~1 0~ D O Ql .-1 0 ~:: C Q~ 1 0 S::
~ e c~ ~ E C~ ~J ~1 ~1 0 h O Q) _1~1 ~1 0 h al O ~I r~ 1 0 L~ a) S: ~ O ~ ~) ~ ~ ~ 0 0 N '~ 1 ~ 0 0 N ~ 0 0 N
r I rl N ~_) Q"a --1 X X X ~I r-l C ~-1 X X X rl ~1 ~ ~I X X X
w o ~ b I I s EO~ o E ~ ,) $ E-~ O E a. ~
~ 0 13 E~ ~ 0 o o --I e o O cn ~ W
al O U~ h O (~ E
O ~1 ,~
0 C ~
~1 ~ ~ C
I X ~ 1 ~
e ~ e ~ x x .,, o E~ O e N
,~ o In o ~1 ~::::: X::::: :C:::::
0 ~o ~ ~ vo ~o h U~ E~
C~
I I
0 0 _I CJ r~
h ~ ~ C o: : : : : . : : : : : o:
'~I O S ~1 L P. D---I
O
X h O r I ~1 ~ o ~1 ~ ~`1 r) ~`1 ~`J ~`1 ~1 ~1 ~I t~l O S O ~ ~:: o~
OF PODOPHYLLOTOXIN
The invention relates to a new method for the isolation and purification of podophyllotoxin from relatively impure sources thereof, particularly plant extracts, for example resins obtained by extraction from plants of the genus podophyllum.
Podophyllotoxin is a highly biologically active substance which is particularly useful as a drug against condylomata acuminata (veneral warts) [G. Gabriel and R.N.T. Thin, Br. J. Vener. Dis., 59, 124-126 (1983)] as well as possessing cytostatic [G. von Krogh and H.I. Maibach, Dermatologica, 167, 70-77 (1983)3 and antiviral properties [T. Markkanen, M.L. Makinen, J. Miettinen, E. Maunuksela, T. Laijoki and J. Paranko, Drugs Exp. Clin. Res. 9, 1-7 (1983)].
Previously, podophyllotoxin has been isolated from the above-mentioned resins by various laborious procedures, all of which included solvent extraction, as a rule with chloroform, followed by further pro-cessing steps. According to the most authoritative newer literature [W.M. Hearon and W.S. MacGregor, Chem.
Rev., 55, 1002 (1955); J.L. Hartwell and W.E. Detty, J. Am. Chem. Soc., 246-253 (1950)] chromatographic purification was necessary in order to obtain podo-phyllotoxin. In many cases, benzene has been used in the course of the purification procedures despite the ~ ?~
acknowledged health hazards which arise. Furthermore, chromatography has previously been regarded as being absolutely essential in order to obtain podophyllotoxin in a degree of purity such that the podophyllotoxin is only slightly contaminated with the many congeners which exist in the plant material. This has resulted in pure podophyllotoxin being a rare and expensive sub-stance which is difficult to obtain in large amounts.
There has recently been a heightened demand for pure podophyllotoxin, both as a raw material for conversion to various pharmacologically active deriva-tives and in clinical treatments using podophyllotoxin itself. In both cases it is highly desirable to use as pure a product as possible.
According to one aspect, the present inven-tion provides a process for obtaining purified podo-phyllotoxin from a solution thereof which comprises forming a solid complex of podophyllotoxin and an aromatic or heteroaromatic compound other than benzene and separating the solid complex from the solution.
The process of the invention, according to one aspect, is well suited for the purification of podophyllotoxin in large ~uantities, it avoids the strongly carcinogenic solvent benzene, and it gives a very high yield of pure podophyllotoxin.
The process of the invention is based on the previously unknown ability of podophyllotoxin to form 126i~7~ ~
complexes with a large varie-ty of aromatic and hetero-aromatic, compounds, including phenol, toluene, chloro-benzene, anisole, o-, m- and p-xylenes and nitro-benzene, and basic substances such as aniline and pyridine, and homologues thereof such as naphthalene, quinoline and isoquinoline. Furthermore, it avoids the need to purify the crude resin by solvent extraction.
The present invention also provides a process for obtaining purified podophyllotoxin from a solution thereof which comprises:
(a) forming a solid complex of podophyllo-toxin and an aromatic or heteroaromatic compound, (b) separating the complex from the so-lution, (c) forming a solution comprising podo-phyllotoxin from said separated complex, (d) forming a solid complex of podophyllo-toxin from the solution of step (c) and an aromatic or heteroaromatic compound, and (e) separating the solid complex formed in step (d) from the solution, wherein the aromatic or heteroaromatic compounds used in steps (a) and (d) are different.
The precise condition for carrying out the methods of the invention are not critical and can be varied a great deal, but the general principle consists 4 _ of dissolving impure podophyllotoxin, for example podo-phyllum resin in a suitable solvent, preferably a sol-vent in which the entire resin is soluble, for example a Cl 3 lower aliphatic alcohol or a Cl 3 lower al]cyl carboxylic acid ester. To the solution is then added the complexing aromatic compound, and if required this may be followed by various amounts of water. This causes precipitation of generally well-crystalline com-plexes which may be isolated, and which after removal of the complexing agent can give about 90~ of pure podophyllotoxin in high yield. By repetition of this procedure with various complexing agents, 92 - 95~ pure podophyllotoxin can be obtained. It is often found that several of its congeners remain as persistent impurities, even after as many as 5 - 8 recrystalli-zations using various solvents and complexing agents and to achieve an even higher degree of purity a further process step (which itself forms a further aspect of the present invention) may be employed.
Thus according to the invention, in a pre-ferred embodiment thereof, which enables podophyllo-toxin of especially high purity to be obtained "absolute" purification can be performed in a very surprising and unforeseeable manner, namely by ex-traction of a solution of the impure podophyllotoxin in a water-immiscible solvent, for example chloroform, with aqueous base. This result is surprising because lZ~i~7~ ~
according to the literature, podophyllotoxin is very labile under basic conditions, being transformed into its epimer, picropodophyllin when treated with alkali [W. Borsche and J. Niemann, Liebiegs Ann. Chem. 494, 126-142 (1932)].
The following Examples illustrate the process of the invention.
A. Podophyllin (643 g) is dissolved in ethanol (1.5 1) with gentle heating. To the hot solution is added toluene (643 ml) followed by water (129 ml). The solution is cooled with ice-water and the precipitated crystalline material isolated by filtration and washed with ether (2 1). Yield: 342.8 g.
This material is a complex of podophyllo-toxin, toluene and water, and it was shown by HPLC to contain ca. 13% of related lignans.
The complex was redissolved in ethanol (1.0 1) with gentle heating, pyridine (140 ml) followed by water (470 ml) were added, and the solution was cooled with ice-weater. The precipitated crystalline material was isolated by filtration and washed with ether (250 ml). Yield: 292 g.
This material consists of a podophyllotoxin-pyridine-water complex which was shown by HPLC to contain ca. 7% of other related lignans. The material was recrystallized from ethanol (1.0 l)-water (430 ml) ~Z6~
to give 239 g of the pyridine-water complex.
B. The complex (119 g) was dissolved in chloro-form (1.2 1) which was treated wi-th: (i) 0.8 N HC1 (500 ml), (ii) 0.4 N NaOH (500 ml), (iii) 0.01 N HCl (450 ml), (iv) water (450 ml), and (v) saturated aqueous sodium chloride (500 ml).
The chloroform solution was dried over solid magnesium sulfate, the chloroform was removed, in vacuo, and the remaining sirupy material was recrystal-lized from ethyl acetate (450 ml) to give podophyllo-toxin, aq. (50 g). This material was shown by HPLC to contain <0.4~ of other lignans. A sample was subjected to drying (100C), in vacuo, to give analytically pure podophyllotoxin. Anal. Found (calc.) C 63.62 (63.76), H 5.39 (5.35). Its IR, H NMR and C NMR spectra were identical with those recorded in the literature.
A. Podophyllin (1 kg) was dissolved in ethanol (3 1) with gentle heating. As soon as the solution was homogeneous, toluene (1.0 1) and water (200 ml) were added and the mixture was cooled with ice-water. The precipitated crystalline material was filtered off, and washed with ether (1.0 1). This was subsequently re-crystallized from ethanol (2 1), toluene (650 ml) and water (130 ml). The isolated crystalline material was redissolved in ethanol (1.5 1), pyridine (210 ml) and water (630 ml) were added, and the solution was cooled with ice-water. The precipitated crys-talline complex was isolated, washed with ether (1.0 1) and dried to give 47~ g of ma-terial.
The product of 2A was dissolved in chloroform (5 1) and -treated with: (i) 0.4 N HCl (2 1), (ii) 0.2 N
NaOH (2 1), (iii) 0.03 N HCl (1.4 1) (iv) saturated aqueous sodium chloride (700 ml), and (v) dried over magnesium sulfate. The chloroform was removed, in vacuo, and the remaining sirupy material recrystallized from ethanol-water (1.4 1 - 0.9 1). This yielded podo-phyllotoxin, 2H2O (419 g, ~ 39%) which con-tained <0.6%
picropodophyllin and <0.1% of other related lignans.
Anal. Found (calc.) C 58.63 (58.67), H 5.53 (5.77). Identified by IR and HNMR spectroscopy. A
small sample was dried (100C), in _acuo, to give an analytically pure sample. Anal. C 63.75 (63.76), H
5.41 (5.35).
A. Podophyllin (500 g) was dissolved in ethanol (1.5 1) with gentle heating, toluene (0.5 1) and water 100 ml) were added, the solution was cooled, and the precipitated crystalline material was isolated by fil-tration and washed with ethanol-toluene-water (15:5:1, 200 ml). This was immediately redissolved in ethanol (1.0 1), toluene (330 ml) and water (66 ml), and the solution was cooled with ice-water. The precipitate was isolated as described above and dried to give 211 ~26~7~
g. This was redissolved in boiling methanol (500 ml) and the hc,t solution was filtered, water (368 ml) was added, and the solution was cooled with ice-water to give after filtration and drying, in vacuo, over H2SO~, and at ambient pressure at 100C, 192 g of podophyllo-toxin and other related lignans in a ratio of 9:1.
B. The a~ove impure podophyllotoxin (5 g) was dissolved in chloroform (50 ml) and treated succes-sively with: (i) 0.4 N NaOH (50 ml), (ii) 0.02 N HCl (50 ml), (iii) water (50 ml), (iv) saturated sodium chloride (50 ml), the chloroform was removed, ln vacuo, and the remaining material was recrystallized from ethanol-water (1:1, 20 ml). This gave podophyllotoxin, aq., identified by IR spectroscopy which contained <1.4% of other lignans.
A. Podophyllin (50 g) was dissolved in ethanol (150 ml) with heating, followed by addition of chloro-benzene (50 ml) and water (10 ml). After cooling, the precipitate was isolated by filtration and washed with ether (20 ml). Yield of podophyllin-chlorobenzene-water complex: 19.5 g, which was shown to contain ca.
13% of other lignans.
The above material (5 g) was redissolved in ethanol (15 ml), phenol (5 g) and water (2 ml) were added, the solution was cooled, and the precipitated material was removed by filtration and washed with X
:lZ6~
ether (10 ml). Yield of podophyllotoxin-phenol-wa-ter complex: 4.2 g.
B. This was dissolved in ethyl acetate (20 ml) and the solution was treated with 2 N NaOH (20 ml).
The organic phase was separated and concentra-ted, in vacuo. The resulting material was recrystallized from ethanol-water (1:1, 20 ml) to give, after drying, in vacuo, over H2SO4: 3.75 g of >98.5% pure podophyllo-toxin, aq., determined by HPLC and identified by IR, 1H NMR and 1 C NMR spectroscopy, [~]D = ~ 118.5 .
The following example illustrates the results of using various combinations of complexing agents in Step A.
General procedure: Podophyllin (60 g) was dissolved by gentle heating in a suitable solvent (180 ml). In some cases a residue remained, in which case the solution was decanted off. This was followed by addition of an aromatic complexing agent (60 ml, or 60 g if a solid) followed by addition of various amounts of water. After cooling, the precipitated complex was isolated, and the procedure repeated with the same, or other solvents and complexing agents. The isolated material was eventually recrystallized, and the com-plexing agents removed, and in each case identified by IR spectroscopy and/or HPLC analysis. The results are shown in Table 1.
~L2~ s~
~a ul ~ I` O O ~ ~ ~ ~ ~r r~l N 1~ u~ ~ --I ~ ~D
Q)t~) ...... ...... ......
r 3 ~ U~ ~ o O Ln O O r~ O O O O ~ : :
o N rl J
,a c,~ ~1, ~1 r ~ ~ ~ .
O o o o o ~ ~
o Q~ ~ a) ~ Q~ a) a) Q) ~n I I I I I I . : : : : : .:
o 3 E o ,~
O ~ r~
r~ . . . ~ ~
,1 I X ~ -I 1~ ~1 0~ D O Ql .-1 0 ~:: C Q~ 1 0 S::
~ e c~ ~ E C~ ~J ~1 ~1 0 h O Q) _1~1 ~1 0 h al O ~I r~ 1 0 L~ a) S: ~ O ~ ~) ~ ~ ~ 0 0 N '~ 1 ~ 0 0 N ~ 0 0 N
r I rl N ~_) Q"a --1 X X X ~I r-l C ~-1 X X X rl ~1 ~ ~I X X X
w o ~ b I I s EO~ o E ~ ,) $ E-~ O E a. ~
~ 0 13 E~ ~ 0 o o --I e o O cn ~ W
al O U~ h O (~ E
O ~1 ,~
0 C ~
~1 ~ ~ C
I X ~ 1 ~
e ~ e ~ x x .,, o E~ O e N
,~ o In o ~1 ~::::: X::::: :C:::::
0 ~o ~ ~ vo ~o h U~ E~
C~
I I
0 0 _I CJ r~
h ~ ~ C o: : : : : . : : : : : o:
'~I O S ~1 L P. D---I
O
X h O r I ~1 ~ o ~1 ~ ~`1 r) ~`1 ~`J ~`1 ~1 ~1 ~I t~l O S O ~ ~:: o~
2~
~a c) t~' ~ Lr) t` ~ t` c~ ` r` t` c~ ` o O ~ e 0 = =
r N ~1 .,1 ~ X
~ o t~ ~: u~
Ql ~a ~ o a~ s u~ tlJ
,~
. ~ o SoQ 3 e = = =
o o s tL) ~ tJ I tJ o C ': I aJ
e ~ ~ e ~ O Ll ~" t a~ ~o ~~ o ~ ~
.IJ C al O ~1 ~:J) ~ O N ~ U2 O N 1 :~ ~ Ul O N
~-~ N t~ 1 ~I X X X rl ~J ~: ~1 X X X r/ ~1 ~:: ~I X X ~1 .--1 C
O E~ O e ~ ~ u $ E~ o e ~ ~ ~ $ ~ o ~ ~ u $
,, u~ ~ o ~ ~ r! ~
~1 ~ O e o ~
E~ ~ o c~
O tJ~ 1.1 O 3 E ~:
(~ o O ~ _~ o o a) ~ ~
e tl) O ~ ~: : : : : Ul: : : : : O N:
~ ~ tS~$
N
O
~ C 1~7 ~ ~e u I I
~.c ~ o o ~1 C ~) 01~ O ~ ~1 1` t~ 00 ~1 0 X ~ ~ ~ ') N ~1 ~1 ~1 ~ ~ ~ N ~') O
O S O ::~ C a~
~2~ ,,t$
a) t~ ~ u) N a~ O O 1` ~ O Ul 1` a~ CO
~ r~ N ~r ~) ~) N ~ r~) ~ ~ N
~a c) t~' ~ Lr) t` ~ t` c~ ` r` t` c~ ` o O ~ e 0 = =
r N ~1 .,1 ~ X
~ o t~ ~: u~
Ql ~a ~ o a~ s u~ tlJ
,~
. ~ o SoQ 3 e = = =
o o s tL) ~ tJ I tJ o C ': I aJ
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Claims (11)
1. A process for obtaining purified podophyllotoxin from a solution thereof which comprises forming a solid complex of podophyllotoxin and an aromatic or heteroaromatic compound other than benzene and separating the solid complex from the solution.
2. A process according to Claim 1, wherein the solid complex comprises podophyllotoxin, said aromatic or heteroaromatic compound and water.
3. A process according to Claim 1 or Claim 2, wherein the solution comprises ethanol.
4. A process according to Claim 1, wherein the complex is formed adding said aromatic or heteroaromatic compound and water to the solution of podophyllotoxin.
5. A process according to Claim 1, wherein a solution is formed by dissolving the separated complex in a solvent and the step of forming a solid complex of podophyllotoxin, an aromatic or heteroaromatic compound and separating the solid complex from the solution is repeated.
6. A process according to Claim 5, wherein different aromatic or heteroaromatic compounds are used in at least two successive stages.
7. The process of Claims 5 and 6, wherein the solid complex is treated with water before separation from the solution.
8. A process for obtaining purified podophyllotoxin from a solution thereof which comprises (a) forming a solid complex of podophyllotoxin and an aromatic or heteroaromatic compound and optionally water, (b) separating the complex from the solution, (c) forming a solution comprising podophyllotoxin from said separated complex, (d) forming a solid complex of podophyllotoxin from the solution of step (c) and an aromatic or heteroaromatic compound, and (e) separating the solid complex formed in step (d) from the solution, wherein the aromatic or heteroaromatic compounds used in steps (a) and (d) are different.
9. A process according to Claim 1, 5 or 8, wherein the aromatic or heteroaromatic compounds used are selected from toluene, o-xylene, m-xylene, p-xylene, anisole, chlorobenzene, pyridine, phenol, nitrobenzene, quinoline, isoquinoline, furfuryl alcohol and naphthalene.
10. A process according to Claim 1, 5 or 8, in which the resulting product is subjected to a further purification step comprising contacting a solution thereof in a water-immiscible solvent with an aqueous base.
11. The process of Claim 8, wherein the solid complex is treated with water before separation from the solution.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848424269A GB8424269D0 (en) | 1984-09-26 | 1984-09-26 | Isolation and purification of podophyllotoxin |
| GB8424269 | 1984-09-26 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000591830A Division CA1276110C (en) | 1984-09-26 | 1989-02-22 | Process for the isolation and purification of podophyllotoxin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1268709A true CA1268709A (en) | 1990-05-08 |
Family
ID=10567263
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000491564A Expired - Lifetime CA1268709A (en) | 1984-09-26 | 1985-09-25 | Process for the isolation and purification of podophyllotoxin |
| CA000591830A Expired - Lifetime CA1276110C (en) | 1984-09-26 | 1989-02-22 | Process for the isolation and purification of podophyllotoxin |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000591830A Expired - Lifetime CA1276110C (en) | 1984-09-26 | 1989-02-22 | Process for the isolation and purification of podophyllotoxin |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4680399A (en) |
| EP (1) | EP0197219B1 (en) |
| AT (1) | ATE48427T1 (en) |
| CA (2) | CA1268709A (en) |
| DE (2) | DE3574595D1 (en) |
| DK (1) | DK169385B1 (en) |
| ES (2) | ES8702395A1 (en) |
| FI (1) | FI84557C (en) |
| GB (1) | GB8424269D0 (en) |
| IS (1) | IS3039A7 (en) |
| NO (1) | NO164658C (en) |
| PL (1) | PL147999B1 (en) |
| PT (1) | PT81190B (en) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE68186T1 (en) * | 1984-12-28 | 1991-10-15 | Conpharm Ab | USE OF PODOPHYLLOTOXIN AND ITS DERIVATIVES. |
| US5057616A (en) * | 1989-09-29 | 1991-10-15 | Oclassen Pharmaceuticals, Inc. | Podophyllotoxin purification process |
| US5315016A (en) * | 1992-10-13 | 1994-05-24 | Nycomed Dak A/S | Process for preparing pure podophyllotoxin |
| US5589106A (en) * | 1995-02-14 | 1996-12-31 | Nalco Chemical Company | Carbon steel corrosion inhibitors |
| US6068861A (en) | 1998-06-01 | 2000-05-30 | Albemarle Corporation | Concentrated aqueous bromine solutions and their preparation |
| US6652889B2 (en) * | 1998-06-01 | 2003-11-25 | Albemarle Corporation | Concentrated aqueous bromine solutions and their preparation and use |
| US8414932B2 (en) | 1998-06-01 | 2013-04-09 | Albemarie Corporation | Active bromine containing biocidal compositions and their preparation |
| US6511682B1 (en) | 1998-06-01 | 2003-01-28 | Albemarle Corporation | Concentrated aqueous bromine solutions and their preparation |
| US7087251B2 (en) | 1998-06-01 | 2006-08-08 | Albemarle Corporation | Control of biofilm |
| US6299909B1 (en) | 1998-06-01 | 2001-10-09 | Albemarle Corporation | Concentrated aqueous bromine solutions and their preparation |
| US8293795B1 (en) | 1998-06-01 | 2012-10-23 | Albemarle Corporation | Preparation of concentrated aqueous bromine solutions and biocidal applications thereof |
| US6348219B1 (en) | 1998-06-01 | 2002-02-19 | Albemarle Corporation | Processes for preparing concentrated aqueous liquid biocidal compositions |
| US6352725B1 (en) | 1998-06-01 | 2002-03-05 | Albemarle Corporation | Continuous processes for preparing concentrated aqueous liquid biocidal composition |
| US6506418B1 (en) | 1999-09-24 | 2003-01-14 | Albemarle Corporation | Concentrated aqueous bromine solutions and their preparation |
| US6375991B1 (en) | 2000-09-08 | 2002-04-23 | Albemarle Corporation | Production of concentrated biocidal solutions |
| US6986910B2 (en) | 2001-06-28 | 2006-01-17 | Albemarle Corporation | Microbiological control in poultry processing |
| WO2003011033A1 (en) * | 2001-06-28 | 2003-02-13 | Solution Biosciences, Inc. | Microbiological control in animal processing |
| US6908636B2 (en) | 2001-06-28 | 2005-06-21 | Albermarle Corporation | Microbiological control in poultry processing |
| US7901276B2 (en) * | 2003-06-24 | 2011-03-08 | Albemarle Corporation | Microbiocidal control in the processing of meat-producing four-legged animals |
| CN100577013C (en) * | 2004-09-07 | 2010-01-06 | 雅宝公司 | Concentrated aqueous bromine solutions and preparation thereof |
| BRPI0419266A (en) * | 2004-12-23 | 2007-12-18 | Albemarle Corp | method of processing a four-legged animal in a slaughterhouse for consumption as meat and / or meat products, wherein said method comprises applying a biocidal solution |
| PE20070918A1 (en) | 2005-12-01 | 2007-10-06 | Albemarle Corp | MICROBIOCIDE CONTROL IN THE PROCESSING OF QUADRUPED MEAT-PRODUCING ANIMALS |
| US20090130017A1 (en) * | 2007-11-19 | 2009-05-21 | Searete Llc | Targeted short-lived drug delivery |
| CN104098583B (en) * | 2013-04-09 | 2018-02-02 | 中国医学科学院药物研究所 | Podophyllotoxin crystalline substance X-type material and preparation method and its pharmaceutical composition and purposes |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2984674A (en) * | 1958-06-02 | 1961-05-16 | Sandoz Ag | Amides of podophyllic acid and picropodophyllic acid |
| US4122092A (en) * | 1977-08-25 | 1978-10-24 | University Of Rochester | Total synthesis of (±)-picropodophyllone and (±)-4'-demethylpicropodophyllone |
-
1984
- 1984-09-26 GB GB848424269A patent/GB8424269D0/en active Pending
-
1985
- 1985-09-09 US US06/773,929 patent/US4680399A/en not_active Expired - Lifetime
- 1985-09-10 IS IS3039A patent/IS3039A7/en unknown
- 1985-09-24 AT AT85306787T patent/ATE48427T1/en not_active IP Right Cessation
- 1985-09-24 DE DE8585306787T patent/DE3574595D1/en not_active Expired - Fee Related
- 1985-09-24 NO NO853743A patent/NO164658C/en not_active IP Right Cessation
- 1985-09-24 EP EP85306787A patent/EP0197219B1/en not_active Expired
- 1985-09-24 DE DE8888120946T patent/DE3583043D1/en not_active Expired - Fee Related
- 1985-09-24 ES ES547248A patent/ES8702395A1/en not_active Expired
- 1985-09-25 DK DK434085A patent/DK169385B1/en not_active IP Right Cessation
- 1985-09-25 FI FI853690A patent/FI84557C/en not_active IP Right Cessation
- 1985-09-25 CA CA000491564A patent/CA1268709A/en not_active Expired - Lifetime
- 1985-09-25 PT PT81190A patent/PT81190B/en not_active IP Right Cessation
- 1985-09-26 PL PL1985255527A patent/PL147999B1/en unknown
-
1986
- 1986-05-16 ES ES555039A patent/ES8900110A1/en not_active Expired
-
1989
- 1989-02-22 CA CA000591830A patent/CA1276110C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| EP0197219B1 (en) | 1989-12-06 |
| ES547248A0 (en) | 1987-01-01 |
| FI84557B (en) | 1991-09-13 |
| PT81190B (en) | 1987-09-30 |
| CA1276110C (en) | 1990-11-13 |
| DK169385B1 (en) | 1994-10-17 |
| PL147999B1 (en) | 1989-09-30 |
| PT81190A (en) | 1985-10-01 |
| DE3583043D1 (en) | 1991-07-04 |
| NO853743L (en) | 1986-04-01 |
| DE3574595D1 (en) | 1990-01-11 |
| ATE48427T1 (en) | 1989-12-15 |
| IS3039A7 (en) | 1986-01-21 |
| DK434085A (en) | 1986-03-27 |
| FI84557C (en) | 1991-12-27 |
| EP0197219A1 (en) | 1986-10-15 |
| ES8900110A1 (en) | 1988-12-16 |
| FI853690A0 (en) | 1985-09-25 |
| US4680399A (en) | 1987-07-14 |
| DK434085D0 (en) | 1985-09-25 |
| PL255527A1 (en) | 1986-07-15 |
| ES8702395A1 (en) | 1987-01-01 |
| FI853690L (en) | 1986-03-27 |
| NO164658C (en) | 1990-10-31 |
| GB8424269D0 (en) | 1984-10-31 |
| ES555039A0 (en) | 1988-12-16 |
| NO164658B (en) | 1990-07-23 |
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